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    €‹15 full-time equivalent specialist counsellors will be deployed across rural NSW to help prevent suicide, with the first two counsellors starting in the Eurobodalla and Snowy Mountains regions.NSW Mental Health Minister Bronnie amoxil pills online Taylor said the relatively high rates of suicide in rural areas are devastating families and communities, and the $6.75 million investment will add another layer of help.“Many factors can contribute to suicide, from domestic violence, to relationship issues or unemployment, to stress and hardship,” Mrs Taylor said. €œThese specialist mental health counsellors are there on the ground to support people thinking of suicide or impacted by suicide, and I encourage communities across the state to lean on them for support.”Director Mental Health Drug and Alcohol for Southern NSW Local Health District Damien Eggleton said he wants more people to ask for help when they need it. €œOur rural communities have proven amoxil pills online beyond a doubt they’re resilient and fearless when faced with adversity, whether that be geographic isolation, searing drought or the impact of the current pandemic – but they don’t need to go it alone,” Mr Eggleton said.

    €œThe support provided by these counsellors will complement the peer work and drought support provided by our Farm Gate Counsellors and Drought Counsellors.”Rural counsellor Samara Byrne said she wants young people to know there are people you can turn to when feeling overwhelmed with life or feeling like a burden on others. €œWe are here for amoxil pills online you and here to listen if you are feeling distressed, anxious or a burden to loved ones. The service is easily accessible through the Mental Health Line.

    Just ask for the Rural Counsellor.”“Having moved from Sydney in 2016 to our beautiful farm in SNSW, I am so pleased to be able to do what I am most passionate about, supporting people’s wellbeing in Rural Australia and building on the amoxil pills online natural local community resilience”.Minister Taylor urges people in the bush to get help by contacting these rural counsellors. €œSupport is available, all you need to do is pick up the phone and make an appointment by calling the NSW Mental Health Line on 1800 011 511.”The 15 rural counselling positions are part of the Towards Zero Suicides. A $87 million investment over three years in new amoxil pills online suicide prevention initiatives.

    A NSW Premier’s Priority, this is a whole-of-government commitment to transforming the way we identify and support anyone impacted by suicide.If you, or someone you know, is thinking about suicide or experiencing a personal crisis or distress, please seek help immediately in a life-threatening situation by calling 000 or seek support though one of these services:Lifeline 13 11 14Suicide Call Back Service 1300 659 467NSW Mental Health Line 1800 011 511Minister for Mental Health Bronnie Taylor and Minister for Police and Emergency Services David Elliott today announced the expansion of the Police Ambulance and Clinical Early Response (PACER) pilot program.“This ground breaking collaboration embeds mental health experts with first responders to support them to appropriately recognise, assess, and respond to mental health emergencies live at the scene,” Mrs Taylor said. €œThe pilot program has had incredible results with significant reductions amoxil pills online in emergency department presentations, police and ambulance time on scene. €œThis approach has enormous potential to change lives, with the community getting more appropriate care at the time when they need it most.” Mr Elliott welcomed the support for the police officers who are deeply committed to serving and protecting the people of NSW “During the pilot program, police time-on-scene was reduced by an average of 45 minutes, not only supporting first responders to appropriately recognise and respond to psychiatric incidents in the community, but also freeing up officers to serve thecommunity in other areas,” Mr Elliott said.

    €œThe presence and availability of a PACER clinician in a police station increases the knowledge and understanding of mental health issues amongst officers This initiative is crucial, amoxil pills online now more than ever, following the devastating ‘Black Summer’ bushfires and the COVID-19 pandemic, which have affected us all.” NSW Police Force Deputy Commissioner, Malcolm Lanyon APM, said the PACER model has been a success at the trial site in St George Police Area Command. €œDuring the trial we saw a significant reduction in time taken for police to respond to these matters. It translated to a better outcome for both our officers and the individuals amoxil pills online in need of assistance,” Mr Lanyon said.

    The PACER program will expand to Campbelltown, Nepean, Northern Beaches, Sutherland Shire, Blacktown, Eastern Beaches, Kuring-gai, Metro Combined consisting of Kings Cross/Surry Hills/City of Sydney, South Sydney and Bankstown Police Area Commands with recruitment underway for the specialist mental health clinicians from July 2020. This investment is part amoxil pills online of the $73 million suite of mental health measures recently announced by the NSW Government. This includes 216 new mental health staff, additional funding for the NSW Mental Health Line, extra support for Telehealth, funding for extra therapeutic programs to aid recovery in mental health units and a $6 million investment in Lifeline to expand their invaluable service..

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    As soon as vaccines are licensed for use, the world will need as many syringes as doses of vaccine, buy amoxil online with free samples said UNICEF on Monday.To begin preparations, this year, UNICEF will stockpile 520 million syringes in its warehouses, part of a larger plan to have a billion syringes ready for use through 2021, to guarantee initial supply and help ensure that syringes arrive before vaccines are distributed.During 2021, assuming there are enough doses of COVID-19 vaccines, UNICEF expects to deliver around a billion syringes to support COVID-19 vaccination efforts on top of the 620 million syringes the agency will purchase for other vaccination programmes, against other diseases such as measles, typhoid and more.Historic undertaking“Vaccinating the world against COVID-19 will be one of the largest mass undertakings in human history, and we will need to how to order amoxil online move as quickly as the vaccines can be produced,” said Henrietta Fore, UNICEF Executive Director.“In order to move fast later, we must move fast now. By the end of the year, we will already have over half a buy amoxil online with free samples billion syringes pre-positioned where they can be deployed quickly and cost effectively. That’s enough syringes to wrap around the world one and a buy amoxil online with free samples half times.” In line with the longstanding collaboration between the two partners, the global vaccine alliance Gavi, will reimburse UNICEF for the cost of syringes and safety boxes, which will then be used for the COVID-19 Vaccine Global Access Facility (COVAX Facility) and for other Gavi-funded immunization programmes, if needed‘Safety boxes’ for disposalBesides syringes, UNICEF is also buying 5 million safety boxes so that used syringes and needles can be disposed in a safe manner by personnel at health facilities, reducing the risk of needle stick injuries and blood borne diseases.Every safety box carries 100 syringes. Accordingly, UNICEF said it was “bundling” the syringes with safety boxes to ensure enough safety boxes are available to go along buy amoxil online with free samples with the syringes.Injection equipment such as syringes and safety boxes have a shelf life of five years, the agency notes. Lead-times for such equipment are also long as these items are bulky and buy amoxil online with free samples need to be transported by sea freight.

    Vaccines, which are heat sensitive, buy amoxil online with free samples are normally transported more quickly by air.As the key procurement coordinator for Gavi, UNICEF is already the largest single vaccine buyer in the world, procuring more than 2 billion doses of vaccines annually for routine immunization and outbreak response on behalf of nearly 100 countries. Every year,UNICEF provides vaccines for almost half of the world’s children and procures and supplies around 600-800 million syringes buy amoxil online with free samples for regular immunization programmes.Huge increaseCOVID-19 vaccines will likely treble or quadruple that number, depending on the number that are ultimately produced and secured by UNICEF.“Over two decades, Gavi has helped an additional 822 million children from the world’s most vulnerable countries access critical, life-saving vaccines”, said Seth Berkley, CEO of Gavi. €œThis would not have been possible without our partnership with UNICEF, and it is this same collaboration that will be essential to Gavi’s work with the COVAX Facility.”To make sure that vaccines are transported and stored at the right temperature, UNICEF, along with the World Health Organization (WHO), is also mapping out existing cold chain equipment and storage capacity – in the buy amoxil online with free samples private as well as public sector – and preparing necessary guidance for countries to receive vaccines.“We are doing everything we can to deliver these essential supplies efficiently, effectively and at the right temperature, as we already do so well all over the world,” Ms. Fore said.Even prior to the COVID-19 pandemic, with support from Gavi and in partnership with WHO, UNICEF has been upgrading the existing cold chain equipment across health facilities in countries to ensure that vaccines remain safe and effective throughout their journey.Fridges boost health servicesSince 2017, over 40,000 cold-chain fridges, including solar fridges, have been installed across health facilities, mostly in Africa, said the agency.And in many countries, UNICEF is promoting solar technologies to help countries maintain supply chains.In South Sudan, the least electrified country in the world, where temperatures frequently exceed 40 degrees Celsius, more than 700 health facilities have been equipped by UNICEF with solar power fridges - around 50 per cent of all facilities nationwide..

    As soon as vaccines are licensed for use, the world will need as many syringes as doses of vaccine, said UNICEF on Monday.To begin preparations, this year, UNICEF will stockpile 520 million syringes in its warehouses, part of a larger plan to have a billion syringes ready for use through 2021, to guarantee initial supply and help ensure that syringes arrive before vaccines are distributed.During 2021, assuming there are enough doses of COVID-19 vaccines, UNICEF expects to deliver around a billion syringes to support COVID-19 vaccination efforts on top of the 620 million syringes the agency will amoxil pills online purchase for other vaccination programmes, against other diseases such as measles, typhoid and more.Historic undertaking“Vaccinating the world against COVID-19 will be one of the largest mass undertakings in human history, and More hints we will need to move as quickly as the vaccines can be produced,” said Henrietta Fore, UNICEF Executive Director.“In order to move fast later, we must move fast now. By the end amoxil pills online of the year, we will already have over half a billion syringes pre-positioned where they can be deployed quickly and cost effectively. That’s enough syringes to wrap around the world one and a half times.” In line with the longstanding collaboration between the two partners, the global vaccine alliance Gavi, will reimburse UNICEF for the cost of syringes and safety boxes, which will amoxil pills online then be used for the COVID-19 Vaccine Global Access Facility (COVAX Facility) and for other Gavi-funded immunization programmes, if needed‘Safety boxes’ for disposalBesides syringes, UNICEF is also buying 5 million safety boxes so that used syringes and needles can be disposed in a safe manner by personnel at health facilities, reducing the risk of needle stick injuries and blood borne diseases.Every safety box carries 100 syringes. Accordingly, UNICEF said amoxil pills online it was “bundling” the syringes with safety boxes to ensure enough safety boxes are available to go along with the syringes.Injection equipment such as syringes and safety boxes have a shelf life of five years, the agency notes. Lead-times for his response such equipment are also long amoxil pills online as these items are bulky and need to be transported by sea freight.

    Vaccines, which are heat sensitive, are normally transported more quickly by air.As the key procurement coordinator for Gavi, UNICEF is already the largest single vaccine buyer in the world, procuring amoxil pills online more than 2 billion doses of vaccines annually for routine immunization and outbreak response on behalf of nearly 100 countries. Every year,UNICEF provides vaccines for almost half of the world’s children and procures and supplies around 600-800 million syringes for regular immunization programmes.Huge increaseCOVID-19 vaccines will likely treble or quadruple that number, depending on the number that are ultimately produced and secured by UNICEF.“Over two decades, Gavi has helped amoxil pills online an additional 822 million children from the world’s most vulnerable countries access critical, life-saving vaccines”, said Seth Berkley, CEO of Gavi. €œThis would not have been possible without our partnership with UNICEF, and it is this same collaboration that will be essential to Gavi’s work with the COVAX Facility.”To make sure that vaccines are transported and stored at the right temperature, UNICEF, along with the World Health Organization (WHO), is also mapping out existing cold chain equipment and storage capacity – in the private as well as public sector – and preparing necessary guidance for countries to receive vaccines.“We are doing everything we can to deliver amoxil pills online these essential supplies efficiently, effectively and at the right temperature, as we already do so well all over the world,” Ms. Fore said.Even prior to the COVID-19 pandemic, with support from Gavi and in partnership with WHO, UNICEF has been upgrading the existing cold chain equipment across health facilities in countries to ensure that vaccines remain safe and effective throughout their journey.Fridges boost health servicesSince 2017, over 40,000 cold-chain fridges, including solar fridges, have been installed across health facilities, mostly in Africa, said the agency.And in many countries, UNICEF is promoting solar technologies to help countries maintain supply chains.In South Sudan, the least electrified country in the world, where temperatures frequently exceed 40 degrees Celsius, more than 700 health facilities have been equipped by UNICEF with solar power fridges - around 50 per cent of all facilities nationwide..

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    New research buy real amoxil online shows that high levels of microplastics (MPs) are released from infant-feeding bottles (IFBs) during formula preparation can you buy amoxil over counter. The research also indicates a strong relationship between heat and MP release, such that warmer liquids (formula or water used to sterilise bottles) result in far greater release of MPs.In response, the researchers involved -- from AMBER, the SFI Research Centre for Advanced Materials and Bioengineering Research, TrinityHaus and the Schools of Engineering and Chemistry at Trinity College Dublin -- have developed a set of recommendations for infant formula preparation when using plastic IFBs that minimise MP release.Led by Dr Jing Jing Wang, Professor John Boland and Professor Liwen Xiao at Trinity, the team analysed the potential for release of MPs from polypropylene infant-feeding bottles (PP-IFBs) during formula preparation by following international guidelines. They also estimated the exposure of 12-month-old infants to MPs in 48 countries buy real amoxil online and regions and have just published their findings in the high-profile journal Nature Food.Key findings PP-IFBs can release up to 16 million MPs and trillions of smaller nanoplastics per litre. Sterilisation and exposure to high temperature water significantly increase microplastic release from 0.6 million to 55 million particles/l when temperature increases from 25 to 95 °C Other polypropylene plastic-ware products (kettles, lunchboxes) release similar levels of MPs The team undertook a global survey and estimated the exposure of 12-month-old infants to microplastics in 48 regions.

    Following current buy real amoxil online guidelines1 for infant-feeding bottle sterilisation and feeding formula preparation the average daily exposure level for infants is in excess of 1 million MPs. Oceania, North America and Europe have the highest levels of potential exposure, at 2,100,000, 2,280,000, and 2,610,000 particles/day, respectively The level of microplastics released from PP-IFBs can be significantly reduced by following modified sterilisation and formula preparation proceduresRecommended sterilisation and formula preparation procedures Sterilising infant feeding bottles Sterilise the bottle following WHO recommended guidelines and allow to cool Prepare sterilised water by boiling in a non-plastic kettle/cooker (e.g. Glass or stainless steel) Rinse the sterilised bottle using room temperature sterilised water at least 3 timesPreparing infant formula Prepare hot water using a non-plastic kettle/cooker Prepare infant formula in a non-plastic container using at least buy real amoxil online 70oC water. Cool to room temperature and transfer prepared formula into a high-quality plastic infant feeding bottleStandard Precautions Do not reheat prepared formula in plastic containers and avoid microwave ovens Do not vigorously shake the formula in the bottle at any time Do not use sonication to clean plastic infant feeding bottles advertisement Studying microplastics through a project of scale There is growing evidence to suggest that micro2 and nano plastics are released into our food and water sources through the chemical and physical degradation of larger plastic items.

    Some studies have demonstrated the potential transfer of micro and nano plastics buy real amoxil online from oceans to humans via the food chain3 but little is known about the direct release of microplastics (MPs) from plastic products through everyday use.Polypropylene (PP) is one of the most commonly produced plastics in the world for food preparation and storage. It is used to make everyday items such as lunch boxes, kettles and infant-feeding bottles (IFBs). Despite its widespread use the capacity of PP to release microplastics was not appreciated until now.Measuring buy real amoxil online Polypropylene microplastic release (PP-MPs) from infant feeding bottles (IFB)Drawing on international guidelines for infant formula preparation (cleaning, sterilising, and mixing techniques), the team developed a protocol4 to quantify the PP-MPs released from 10 representative infant-feeding bottles that account for 68.8% of the global infant-feeding bottle market. advertisement When the role of temperature on the release of PP-MPs was analysed a clear trend emerged.

    The higher the temperature buy real amoxil online of liquid inside the bottle, the more microplastics released.Under a standardised protocol, after sterilisation and exposure to water at 70?. C, the PP-IFBs released up to 16.2 million PP-MP per litre. When the water buy real amoxil online temperature was increased to 95?. C, as much as 55 million PP-MP per litre were released, while when the PP-IFB's were exposed to water at 25?.

    C -- well under international guidelines for sterilisation or formula preparation -- 600,000 PP-MP per litre were generated.Estimating the exposure of 12-month-old infants to MPs from PP-IFBsGiven the widespread buy real amoxil online use of PP-IFBs and the quantity of MPs released through normal daily use, the team realised the potential exposure of infants to MPs is a worldwide issue. The team estimated the exposure of 12-month-old infants to MPs in 48 countries and regions by using MP release rates from PP-IFBs, the market share of each PP-IFB, the infant daily milk-intake volume, and breastfeeding rates.The team found that the overall average daily consumption of PP-MPs by infants per capita was 1,580,000 particles.Oceania, North America and Europe were found to have the highest levels of potential exposure corresponding to 2,100,000, 2,280,000, and 2,610,000 particles/day, respectively.Mitigating exposureGiven the global preference for PP-IBFs it is important to mitigate against unintended generation of micro and nanoplastics in infant formula. Based on buy real amoxil online their findings the team devised and tested a series of recommendations for the preparation of baby formula that will help minimise the production of MPs.They note though, that given the prevalence of plastic products in daily food storage and food preparation, and the fact that every PP product tested in the study (infant bottles, kettles, lunch boxes and noodle cups) released similar levels of MPs, there is an urgent need for technological solutions.As Professor John Boland, AMBER, CRANN, and Trinity's School of Chemistry explains:"When we saw these results in the lab we recognised immediately the potential impact they might have. The last thing we want is to unduly alarm parents, particularly when we don't have sufficient information on the potential consequences of microplastics on infant health."We are calling on policy makers, however, to reassess the current guidelines for formula preparation when using plastic infant feeding bottles.

    Crucially, we have found that it is possible to mitigate the risk of ingesting microplastics by changing practices around sterilisation and formula preparation."Professor Liwen Xiao at TrinityHaus and Trinity's School of Engineering said:"Previous research has predominantly focused on human exposure to micro and nanoplastics via transfer from ocean and soils into the food chain driven by the degradation of plastics in the environment."Our study indicates that daily use of plastic products is an important source buy real amoxil online of microplastic release, meaning that the routes of exposure are much closer to us than previously thought. We need to urgently assess the potential risks of microplastics to human health. Understanding their fate and transport through the body following ingestion buy real amoxil online is an important focus of future research. Determining the potential consequences of microplastics on our health is critical for the management of microplastic pollution."Lead authors, Dr Dunzhu Li and Dr Yunhong Shi, researchers at CRANN and Trinity's School of Engineering, said:"We have to accept that plastics are pervasive in modern life, and that they release micro and nano plastics through everyday use.

    We don't yet know the risks to human health of these tiny plastic particles, but we can develop behavioural and technological solutions and buy real amoxil online strategies to mitigate against their exposure."Dr Jing Jing Wang, Microplastics Group at AMBER and CRANN, said. "While this research points to the role of plastic products as a direct source of microplastic the removal of microplastics from the environment and our water supplies remains a key future challenge."Our team will investigate specific mechanisms of micro and nano plastic release during food preparation in a host of different contexts. We want to develop appropriate technologies that will prevent plastics degrading and effective filtration technologies that will remove micro and nanoplastics from our environment for large scale buy real amoxil online water treatment and local distribution and use."This work has been undertaken by the Microplastics Group led by Dr Jing Jing Wang at AMBER and CRANN, with internal collaboration from TrinityHaus and Trinity's School of Engineering and School of Chemistry. This research was supported by Enterprise Ireland, Science Foundation Ireland, a School of Engineering Scholarship at Trinity, and the China Scholarship Council.Strategies meant to motivate people in the workplace may have unintended consequences -- depending on who's in charge.

    Recent research from Michigan State University and Ohio State University shows that empowerment initiatives aren't necessarily the answer for business leaders hoping to motivate their employees."People tend to think of empowerment in uniformly positive ways," said Nicholas Hays, study buy real amoxil online co-author and associate professor of management in MSU's Eli Broad College of Business. "After all, humans crave independence and control so giving it to them at work should be a good thing. However, as people feel increasingly autonomous, they can also become unmoored from others' needs, expectations and social norms."Hays explained that, in recent decades, companies have increasingly implemented various forms of empowerment initiatives that assume empowered leaders will translate into empowered workers.The paper -- published in Journal of Applied Psychology -- found that, when properly implemented, empowerment initiatives can buy real amoxil online lead to heightened motivation, productivity and creativity. However, whether these initiatives are effective at all levels of the organization depends on the management style of the person implementing them.Hays -- along with Broad College of Business colleague, Russell E.

    Johnson, MSU Foundation Professor of management, and Hun Whee Lee, assistant professor of management at Ohio buy real amoxil online State University and lead author of the study -- found that superiors who value being respected will respond to empowerment initiatives by, in turn, empowering their workers. But, superiors who value being in charge will, somewhat ironically, respond to empowerment initiatives by closely controlling, dominating and managing their employees.The researchers conducted three separate studies measuring outcomes of empowerment initiatives that considered personality trait data and leader behavior."We found that leaders who really care about being respected by their subordinates tend to react to empowerment initiatives by 'paying it forward' with certain behaviors. This could include buy real amoxil online things like allowing subordinates to set their own goals or decide how to accomplish tasks," Lee said. "In contrast, leaders who prefer to be in control and tell others what to do tend to react to these initiatives by doubling down on their desire for control.

    This is when we see things like micromanaging or setting specific goals for subordinates."If an employee is uncomfortable with a superior's leadership style, the researchers say it may be beneficial to have a candid conversation between worker and boss."Many leaders are receptive to feedback and want to provide employees what they need to buy real amoxil online succeed at work," Hays said. "If that doesn't work, looking for different groups to join -- either within an organization and with a different supervisor or even by changing organizations altogether -- is sometimes the best option."And in the unprecedented workplace environment of 2020, Hays also offered insight into what he believes the paper's findings may indicate for employees in real time."To the extent that leaders prioritize dominance and being in charge, they may go out of their way to micromanage employees by, for example, monitoring their online status and requesting frequent check-ins," Hays said. "I wouldn't necessarily characterize this as abusing an empowerment buy real amoxil online initiative, but certainly could rub employees the wrong way." Story Source. Materials provided by Michigan State University.

    Original written by Caroline Brooks and Zach Richardson buy real amoxil online. Note. Content may be edited for style and length.Artificial light abnormally increases mosquito biting behavior at night in a species that typically prefers to bite people during the day, according to research from the University of Notre Dame that was published in The American Journal of Tropical Medicine and Hygiene.Increased biting by Aedes aegypti mosquitoes, which normally fly and bite in the early morning and during the afternoon, highlights the concern that increasing levels of light pollution could impact transmission of diseases such as dengue fever, yellow fever, chikungunya and Zika."This is potentially a very valid problem that shouldn't be overlooked," said Giles Duffield, associate professor in the Department of Biological Sciences, who is also affiliated with the Eck Institute for Global Health and the Neuroscience and Behavior Program. Unlike other species that may emerge from the forest to feed on humans and animals, Aedes aegypti evolved with humans and prefers to feed on them."They live and breed in buy real amoxil online the vicinity of houses, so the chances of Aedes aegypti being exposed to light pollution are very likely," he added.To conduct the experiment, the study's first author, Samuel S.

    C. Rund, a staff scientist in the Department of Biological Sciences, allowed mosquitoes in cages to bite his arms under controlled conditions, including during the day, at night buy real amoxil online or at night while exposed to artificial light. The female mosquitoes -- the only ones that bite -- were twice as likely to bite, or blood-feed, at night when they were exposed to artificial light. Twenty-nine percent of the mosquitoes in the control group, which had no light, fed at night, while 59 percent of the mosquitoes exposed to artificial light blood-fed.The findings will help epidemiologists better understand the true risk of disease transmission by this buy real amoxil online species.

    The discovery could also lead to more recommendations for bed net use. Usually mosquito bed nets are used at night to ward off bites from a different genus of mosquitoes, Anopheles, but because Aedes aegypti were shown to be stimulated by artificial light, mosquito nets could also be used in areas with a likelihood of disease transmission even with limited Anopheles activity."The impact of this research could be huge, and it probably has been buy real amoxil online overlooked," Duffield said. "Epidemiologists may want to take light pollution into account when predicting infection rates."Duffield and his collaborators plan to experiment with additional variables of artificial light to further study Aedes aegypti biting activity. These variables include the duration of light, its intensity and color, and the timing of the biting -- whether early at buy real amoxil online night or later.

    The team is also interested in the molecular genetic pathways that might be involved with biting activity, after noticing that not every mosquito in the population under study was interested in biting at night even with artificial light."So, we think there is a genetic component within the Aedes aegypti species," Duffield said. Story Source buy real amoxil online. Materials provided by University of Notre Dame. Original written by Deanna McCool buy real amoxil online.

    Note. Content may be edited for style and length.Manajit Hayer-Hartl, head of the buy real amoxil online research group "Chaperonin-assisted Protein Folding," has a long-standing interest in the central enzyme of photosynthesis called Rubisco. Her team has already reported on many of the interacting partners of Rubisco that are required for the folding and assembly of this highly abundant protein. In the buy real amoxil online current study, they have elucidated how Rubisco activase works.

    As the name indicates, this enzyme is critical for repairing Rubisco once it has lost its activity. The study was published in Cell.The enzyme Rubisco catalyzes the assimilation of CO2 from the atmosphere into organic buy real amoxil online matter. This is the central step in photosynthesis that generates sugar molecules for the production of essentially all biomass. Despite its pivotal role, Rubisco works relatively slowly and is easily inhibited buy real amoxil online by sugar products.

    By improving the function of Rubisco Hayer-Hartl hopes to be able to boost the process of photosynthesis. The goal is to address the growing global demand for food and reduce the current greenhouse gas-induced climate change.The enzyme Rubisco activase, Rca, is present in plants, algae and buy real amoxil online certain cyanobacteria. Rca is a ring-shaped complex of six subunits with a central pore. How exactly Rca interacts buy real amoxil online with the inhibited Rubisco and releases the bound sugar from the active site pocket of Rubisco, restoring its CO2 fixing activity, was unclear until now.

    With the help of biochemistry, crystallography and cryo-electron microscopy, Hayer-Hartl &. Colleagues have buy real amoxil online now succeeded in deciphering the molecular mechanism of a cyanobacterial Rca.They discovered that the Rca grabs the N-terminal tail of Rubisco and by pulling and pushing actions, using the energy of ATP, opens the active site pocket. This results in the release of the inhibitory sugar molecule. In cyanobacteria Rubisco is packaged into specialized micro-compartments called carboxysomes, in which a high concentration of CO2 is generated to facilitate the function of Rubisco.In an earlier study, Hayer-Hartl showed how Rubisco is recruited into carboxysomes via interactions with the SSUL buy real amoxil online domains of the scaffolding protein CcmM.

    Interestingly, the researchers now found that Rca is recruited into carboxysomes using a very similar trick. The Rca hexamer also contains SSUL domains that dock buy real amoxil online onto Rubisco during carboxysome formation. This makes sure that enough Rca is present inside carboxysomes to perform its essential repair function. Thus, Rca not only buy real amoxil online functions in Rubisco activation but also mediates its own recruitment into carboxysomes.Manajit Hayer-Hartl concludes.

    "Rca is absolutely required for Rubisco to function optimally. Deciphering its mechanism and dual buy real amoxil online function in cyanobacteria will further help us to make photosynthesis more effective in the future. Hopefully, this will get us closer to our ultimate goal, to increase agricultural productivity." Story Source. Materials provided buy real amoxil online by Max-Planck-Gesellschaft.

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    New research shows that high levels of microplastics (MPs) are released from my blog infant-feeding amoxil pills online bottles (IFBs) during formula preparation. The research also indicates a strong relationship between heat and MP release, such that warmer liquids (formula or water used to sterilise bottles) result in far greater release of MPs.In response, the researchers involved -- from AMBER, the SFI Research Centre for Advanced Materials and Bioengineering Research, TrinityHaus and the Schools of Engineering and Chemistry at Trinity College Dublin -- have developed a set of recommendations for infant formula preparation when using plastic IFBs that minimise MP release.Led by Dr Jing Jing Wang, Professor John Boland and Professor Liwen Xiao at Trinity, the team analysed the potential for release of MPs from polypropylene infant-feeding bottles (PP-IFBs) during formula preparation by following international guidelines. They also estimated the exposure of 12-month-old infants to MPs in 48 countries and regions and have just published their findings in the high-profile journal Nature Food.Key amoxil pills online findings PP-IFBs can release up to 16 million MPs and trillions of smaller nanoplastics per litre.

    Sterilisation and exposure to high temperature water significantly increase microplastic release from 0.6 million to 55 million particles/l when temperature increases from 25 to 95 °C Other polypropylene plastic-ware products (kettles, lunchboxes) release similar levels of MPs The team undertook a global survey and estimated the exposure of 12-month-old infants to microplastics in 48 regions. Following current guidelines1 for infant-feeding amoxil pills online bottle sterilisation and feeding formula preparation the average daily exposure level for infants is in excess of 1 million MPs. Oceania, North America and Europe have the highest levels of potential exposure, at 2,100,000, 2,280,000, and 2,610,000 particles/day, respectively The level of microplastics released from PP-IFBs can be significantly reduced by following modified sterilisation and formula preparation proceduresRecommended sterilisation and formula preparation procedures Sterilising infant feeding bottles Sterilise the bottle following WHO recommended guidelines and allow to cool Prepare sterilised water by boiling in a non-plastic kettle/cooker (e.g.

    Glass or stainless steel) Rinse the sterilised bottle using room temperature sterilised water at least 3 timesPreparing infant amoxil pills online formula Prepare hot water using a non-plastic kettle/cooker Prepare infant formula in a non-plastic container using at least 70oC water. Cool to room temperature and transfer prepared formula into a high-quality plastic infant feeding bottleStandard Precautions Do not reheat prepared formula in plastic containers and avoid microwave ovens Do not vigorously shake the formula in the bottle at any time Do not use sonication to clean plastic infant feeding bottles advertisement Studying microplastics through a project of scale There is growing evidence to suggest that micro2 and nano plastics are released into our food and water sources through the chemical and physical degradation of larger plastic items. Some studies have demonstrated the potential transfer of micro and nano plastics from oceans to humans via the food amoxil pills online chain3 but little is known about the direct release of microplastics (MPs) from plastic products through everyday use.Polypropylene (PP) is one of the most commonly produced plastics in the world for food preparation and storage.

    It is used to make everyday items such as lunch boxes, kettles and infant-feeding bottles (IFBs). Despite its widespread use the capacity of PP to release microplastics was not appreciated until now.Measuring Polypropylene microplastic release (PP-MPs) from infant feeding bottles (IFB)Drawing on international guidelines for infant formula preparation (cleaning, sterilising, and mixing techniques), the team developed a protocol4 to quantify the PP-MPs released from 10 representative infant-feeding bottles that amoxil pills online account for 68.8% of the global infant-feeding bottle market. advertisement When the role of temperature on the release of PP-MPs was analysed a clear trend emerged.

    The higher the temperature of liquid inside the bottle, the more microplastics released.Under a standardised protocol, after amoxil pills online sterilisation and exposure to water at 70?. C, the PP-IFBs released up to 16.2 million PP-MP per litre. When the amoxil pills online water temperature was increased to 95?.

    C, as much as 55 million PP-MP per litre were released, while when the PP-IFB's were exposed to water at 25?. C -- well under international guidelines amoxil pills online for sterilisation or formula preparation -- 600,000 PP-MP per litre were generated.Estimating the exposure of 12-month-old infants to MPs from PP-IFBsGiven the widespread use of PP-IFBs and the quantity of MPs released through normal daily use, the team realised the potential exposure of infants to MPs is a worldwide issue. The team estimated the exposure of 12-month-old infants to MPs in 48 countries and regions by using MP release rates from PP-IFBs, the market share of each PP-IFB, the infant daily milk-intake volume, and breastfeeding rates.The team found that the overall average daily consumption of PP-MPs by infants per capita was 1,580,000 particles.Oceania, North America and Europe were found to have the highest levels of potential exposure corresponding to 2,100,000, 2,280,000, and 2,610,000 particles/day, respectively.Mitigating exposureGiven the global preference for PP-IBFs it is important to mitigate against unintended generation of micro and nanoplastics in infant formula.

    Based on their findings the team devised and tested a series of recommendations for the preparation of baby formula that will help minimise the production of MPs.They note though, that given the prevalence of plastic products in daily food storage and food preparation, and the fact that every PP product tested in the study (infant bottles, kettles, lunch boxes and noodle cups) released similar levels of MPs, there is an urgent need for technological solutions.As Professor John Boland, AMBER, CRANN, and amoxil pills online Trinity's School of Chemistry explains:"When we saw these results in the lab we recognised immediately the potential impact they might have. The last thing we want is to unduly alarm parents, particularly when we don't have sufficient information on the potential consequences of microplastics on infant health."We are calling on policy makers, however, to reassess the current guidelines for formula preparation when using plastic infant feeding bottles. Crucially, we have found that it is possible to mitigate the risk of ingesting microplastics amoxil pills online by changing practices around sterilisation and formula preparation."Professor Liwen Xiao at TrinityHaus and Trinity's School of Engineering said:"Previous research has predominantly focused on human exposure to micro and nanoplastics via transfer from ocean and soils into the food chain driven by the degradation of plastics in the environment."Our study indicates that daily use of plastic products is an important source of microplastic release, meaning that the routes of exposure are much closer to us than previously thought.

    We need to urgently assess the potential risks of microplastics to human health. Understanding their fate and transport through the body following ingestion is an important amoxil pills online focus of future research. Determining the potential consequences of microplastics on our health is critical for the management of microplastic pollution."Lead authors, Dr Dunzhu Li and Dr Yunhong Shi, researchers at CRANN and Trinity's School of Engineering, said:"We have to accept that plastics are pervasive in modern life, and that they release micro and nano plastics through everyday use.

    We don't yet know the risks to human health of these tiny plastic particles, but we can develop amoxil pills online behavioural and technological solutions and strategies to mitigate against their exposure."Dr Jing Jing Wang, Microplastics Group at AMBER and CRANN, said. "While this research points to the role of plastic products as a direct source of microplastic the removal of microplastics from the environment and our water supplies remains a key future challenge."Our team will investigate specific mechanisms of micro and nano plastic release during food preparation in a host of different contexts. We want to develop appropriate technologies that will prevent plastics degrading and effective filtration technologies that will remove micro and nanoplastics from our environment for large scale water treatment and local distribution and use."This work has been undertaken by the Microplastics Group led by Dr amoxil pills online Jing Jing Wang at AMBER and CRANN, with internal collaboration from TrinityHaus and Trinity's School of Engineering and School of Chemistry.

    This research was supported by Enterprise Ireland, Science Foundation Ireland, a School of Engineering Scholarship at Trinity, and the China Scholarship Council.Strategies meant to motivate people in the workplace may have unintended consequences -- depending on who's in charge. Recent research from Michigan amoxil pills online State University and Ohio State University shows that empowerment initiatives aren't necessarily the answer for business leaders hoping to motivate their employees."People tend to think of empowerment in uniformly positive ways," said Nicholas Hays, study co-author and associate professor of management in MSU's Eli Broad College of Business. "After all, humans crave independence and control so giving it to them at work should be a good thing.

    However, as people amoxil pills online feel increasingly autonomous, they can also become unmoored from others' needs, expectations and social norms."Hays explained that, in recent decades, companies have increasingly implemented various forms of empowerment initiatives that assume empowered leaders will translate into empowered workers.The paper -- published in Journal of Applied Psychology -- found that, when properly implemented, empowerment initiatives can lead to heightened motivation, productivity and creativity. However, whether these initiatives are effective at all levels of the organization depends on the management style of the person implementing them.Hays -- along with Broad College of Business colleague, Russell E. Johnson, MSU Foundation Professor of management, and amoxil pills online Hun Whee Lee, assistant professor of management at Ohio State University and lead author of the study -- found that superiors who value being respected will respond to empowerment initiatives by, in turn, empowering their workers.

    But, superiors who value being in charge will, somewhat ironically, respond to empowerment initiatives by closely controlling, dominating and managing their employees.The researchers conducted three separate studies measuring outcomes of empowerment initiatives that considered personality trait data and leader behavior."We found that leaders who really care about being respected by their subordinates tend to react to empowerment initiatives by 'paying it forward' with certain behaviors. This could include things like allowing subordinates to set their own goals or amoxil pills online decide how to accomplish tasks," Lee said. "In contrast, leaders who prefer to be in control and tell others what to do tend to react to these initiatives by doubling down on their desire for control.

    This is when we see things like micromanaging or setting specific goals for subordinates."If an employee is uncomfortable with a superior's leadership style, the researchers say it may be beneficial to have a candid conversation between worker and boss."Many leaders are receptive to feedback and want amoxil pills online to provide employees what they need to succeed at work," Hays said. "If that doesn't work, looking for different groups to join -- either within an organization and with a different supervisor or even by changing organizations altogether -- is sometimes the best option."And in the unprecedented workplace environment of 2020, Hays also offered insight into what he believes the paper's findings may indicate for employees in real time."To the extent that leaders prioritize dominance and being in charge, they may go out of their way to micromanage employees by, for example, monitoring their online status and requesting frequent check-ins," Hays said. "I wouldn't necessarily characterize this as abusing an amoxil pills online empowerment initiative, but certainly could rub employees the wrong way." Story Source.

    Materials provided by Michigan State University. Original written amoxil pills online by Caroline Brooks and Zach Richardson. Note.

    Content may be edited for style and length.Artificial light abnormally increases mosquito biting behavior at night in a species that typically prefers to bite people during the day, according to research from the University of Notre Dame that was published in The American Journal of Tropical Medicine and Hygiene.Increased biting by Aedes aegypti mosquitoes, which normally fly and bite in the early morning and during the afternoon, highlights the concern that increasing levels of light pollution could impact transmission of diseases such as dengue fever, yellow fever, chikungunya and Zika."This is potentially a very valid problem that shouldn't be overlooked," said Giles Duffield, associate professor in the Department of Biological Sciences, who is also affiliated with the Eck Institute for Global Health and the Neuroscience and Behavior Program. Unlike other species that may emerge from the forest to feed on humans and animals, Aedes aegypti evolved with humans and prefers to feed on them."They live and breed in the amoxil pills online vicinity of houses, so the chances of Aedes aegypti being exposed to light pollution are very likely," he added.To conduct the experiment, the study's first author, Samuel S. C.

    Rund, a amoxil pills online staff scientist in the Department of Biological Sciences, allowed mosquitoes in cages to bite his arms under controlled conditions, including during the day, at night or at night while exposed to artificial light. The female mosquitoes -- the only ones that bite -- were twice as likely to bite, or blood-feed, at night when they were exposed to artificial light. Twenty-nine percent of the mosquitoes in the control group, which had no light, fed at night, while 59 percent of the mosquitoes exposed to artificial light blood-fed.The findings will help epidemiologists better understand the true risk of disease amoxil pills online transmission by this species.

    The discovery could also lead to more recommendations for bed net use. Usually mosquito bed nets are used at night to ward off amoxil pills online bites from a different genus of mosquitoes, Anopheles, but because Aedes aegypti were shown to be stimulated by artificial light, mosquito nets could also be used in areas with a likelihood of disease transmission even with limited Anopheles activity."The impact of this research could be huge, and it probably has been overlooked," Duffield said. "Epidemiologists may want to take light pollution into account when predicting infection rates."Duffield and his collaborators plan to experiment with additional variables of artificial light to further study Aedes aegypti biting activity.

    These variables include the duration amoxil pills online of light, its intensity and color, and the timing of the biting -- whether early at night or later. The team is also interested in the molecular genetic pathways that might be involved with biting activity, after noticing that not every mosquito in the population under study was interested in biting at night even with artificial light."So, we think there is a genetic component within the Aedes aegypti species," Duffield said. Story Source amoxil pills online.

    Materials provided by University of Notre Dame. Original written by amoxil pills online Deanna McCool. Note.

    Content may be edited for style and length.Manajit Hayer-Hartl, head of the research group "Chaperonin-assisted Protein Folding," has a amoxil pills online long-standing interest in the central enzyme of photosynthesis called Rubisco. Her team has already reported on many of the interacting partners of Rubisco that are required for the folding and assembly of this highly abundant protein. In the current study, they amoxil pills online have elucidated how Rubisco activase works.

    As the name indicates, this enzyme is critical for repairing Rubisco once it has lost its activity. The study was published in Cell.The enzyme Rubisco catalyzes the assimilation of CO2 amoxil pills online from the atmosphere into organic matter. This is the central step in photosynthesis that generates sugar molecules for the production of essentially all biomass.

    Despite its pivotal role, amoxil pills online Rubisco works relatively slowly and is easily inhibited by sugar products. By improving the function of Rubisco Hayer-Hartl hopes to be able to boost the process of photosynthesis. The goal is to address the growing global amoxil pills online demand for food and reduce the current greenhouse gas-induced climate change.The enzyme Rubisco activase, Rca, is present in plants, algae and certain cyanobacteria.

    Rca is a ring-shaped complex of six subunits with a central pore. How exactly Rca interacts with the inhibited Rubisco and releases the amoxil pills online bound sugar from the active site pocket of Rubisco, restoring its CO2 fixing activity, was unclear until now. With the help of biochemistry, crystallography and cryo-electron microscopy, Hayer-Hartl &.

    Colleagues have now succeeded in deciphering the molecular mechanism of a cyanobacterial Rca.They discovered that the Rca grabs the N-terminal tail of Rubisco and amoxil pills online by pulling and pushing actions, using the energy of ATP, opens the active site pocket. This results in the release of the inhibitory sugar molecule. In cyanobacteria Rubisco is packaged into specialized micro-compartments called carboxysomes, in which a high concentration of CO2 is generated to facilitate the function of Rubisco.In an earlier study, Hayer-Hartl showed how Rubisco is recruited into carboxysomes via interactions with the SSUL domains amoxil pills online of the scaffolding protein CcmM.

    Interestingly, the researchers now found that Rca is recruited into carboxysomes using a very similar trick. The Rca hexamer also contains SSUL domains that amoxil pills online dock onto Rubisco during carboxysome formation. This makes sure that enough Rca is present inside carboxysomes to perform its essential repair function.

    Thus, Rca not only functions in Rubisco activation but also mediates its own amoxil pills online recruitment into carboxysomes.Manajit Hayer-Hartl concludes. "Rca is absolutely required for Rubisco to function optimally. Deciphering its mechanism and dual function in cyanobacteria will further help us to make photosynthesis more effective in the amoxil pills online future.

    Hopefully, this will get us closer to our ultimate goal, to increase agricultural productivity." Story Source. Materials provided amoxil pills online by Max-Planck-Gesellschaft. Note.

    Content may be edited for style and length..

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    The wildfire season is off to a roaring start can amoxil treat tooth infection http://www.amisdepasteur.fr/amoxil-pill-price/. The hot summer is worsening drought and drying out vegetation—an unfortunately ideal environment for wildfires to rage. But that’s just one can amoxil treat tooth infection consequence of global warming. It’s also leading to flooding, torrential rainstorms and heat-related deaths.

    In fact, the climate crisis has led to a widespread public health crisis. And as an ear, nose and can amoxil treat tooth infection throat physician, I see the effects more and more often. I vividly remember a patient who came in late for her appointment during a July heat wave. When I walked in, she said, “I’m so sorry I’m late, I was up all night walking my grandbaby around the train station.” Without air conditioning at home, the child was sweating through her clothes in the heat of the night, putting her at risk for dehydration.

    July 2019 can amoxil treat tooth infection was the hottest July on record. September 2019 was the hottest on record. January 2020 was the hottest on record. May 2020 can amoxil treat tooth infection was the hottest on record.

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    Intergovernmental Panel on Climate Change special report pointed out that the world has already warmed about one degree can amoxil treat tooth infection Celsius from pre-industrial levels. It stressed the urgency to act to limit warming to 1.5 degrees, and that a two-degree increase will lead to unprecedented extreme heat, water scarcity and food shortages around the globe. Heat affects every part of our body. It can lead to heat exhaustion, heat stroke, anxiety, impaired cognitive function and even premature death from heart can amoxil treat tooth infection and lung disease.

    Across the country, the health concerns of the climate crisis are increasingly being recognized, pushing thousands of medical providers—doctors, nurses, pharmacists, therapists, medical students—to become advocates for change. In my own practice, I explain to patients how the climate crisis affects their health. For example, can amoxil treat tooth infection apart from contributing to global warming, rising carbon dioxide levels increase the amount of pollen that plants produce as a consequence of higher rates of photosynthesis. This rise in pollen levels can lead to worsening allergy symptoms.

    Another example is fine particulate matter (known as PM2.5) associated with air pollution, much of it linked to the burning of fossil fuels that help drive the warming. When we breathe in these particles, they travel down the airway and settle in the tiny air sacs called alveoli of the can amoxil treat tooth infection lungs, causing inflammation and potentially worsening asthma symptoms. The explanations are simple, but the health risks are widespread and complex. Ground-level ozone pollution, which is worse in hotter weather, can also harm people with asthma and other respiratory diseases.

    And that harm falls can amoxil treat tooth infection disproportionately on the poor. Wealthier people living in North America have a per capita carbon footprint that is 25 percent higher than those of lower-income residents, with some affluent suburbs producing emissions 15 times higher than nearby neighborhoods. These carbon emissions contribute to global warming, and the can amoxil treat tooth infection subsequent health consequences are felt far beyond the neighborhood that produces them. Older adults, children, low-income communities and communities of color are less resilient on average to the health impacts of climate change.

    The climate crisis is thus leading to a disproportionate public health crisis—and worse, it is a threat multiplier. At a time when many Americans are economically challenged, continued heat waves and the higher energy bills they trigger threaten access to water and energy security can amoxil treat tooth infection. The economic benefits of a low-carbon economy are clear. Estimates suggest that without climate investments, the United States will face economic damage from climate change equivalent to 1–3 percent of GDP per year by 2100.

    The majority of Americans think global warming is happening can amoxil treat tooth infection. The climate crisis has unfairly been labeled as political, when in fact, people recognize that something needs to be done about it. Even for those who are seemingly unaffected, there is increasing global recognition that the safeguards of living in a protected community and affording expert medical care will eventually fail if global warming continues unchecked. Unfortunately, there will be no vaccine in six months can amoxil treat tooth infection or a year for the climate crisis.

    The only treatment is collective climate action in the present. Climate action is required of our elected leaders, and we must mandate it of ourselves. It can be as simple as can amoxil treat tooth infection educating family and friends, while making sustainable shopping and traveling choices. It includes eating less meat, unplugging electronics and raising a voice against the fossil fuel industry.

    With a rise in demand for absentee ballots for the election this November, it is crucial to request mail-in ballots can amoxil treat tooth infection right away to make sure our voices are heard. The United States is the second largest emitter of greenhouse gases, and we must vote for green policy. Legislative action and policy change work, as evidenced by the Clean Air Act and its subsequent amendments, which are projected to save 230,000 lives in 2020. The climate crisis is a public health issue, and we must start healing the planet in order to heal each other can amoxil treat tooth infection.

    Fighting against the climate crisis is one of the most patriotic things we can do right now. It will protect our health and the health of our neighbors across the country and the globe, and will allow all of us to live on this planet, the only home we have.The items below are highlights from the free newsletter, “Smart, useful, science stuff about COVID-19.” To receive newsletter issues daily in your inbox, sign up here. Please consider a monthly contribution can amoxil treat tooth infection to support this newsletter. Women’s immune response to SARS-CoV-2 is stronger than men’s immune response to the virus, according to a study published 8/26/20 in Nature and covered the same day by Apoorva Mandavilli at The New York Times.

    The finding could explain why men “are twice as likely to become severely sick and to die [from COVID-19] as women of the same age,” Mandavilli writes. The study also suggests that older men might need multiple shots of a coronavirus vaccine compared perhaps with young women, who might need just one shot, according can amoxil treat tooth infection to an immunologist quoted in the story. He's at the Heinrich Pette Institute and the University Medical Center Hamburg-Eppendorf in Germany. The study leader, a Yale University immunologist, is quoted in the story as saying, “Women who are older — even very old, like 90 years — the women are still making pretty good, decent immune response” to SARS-CoV-2.

    The U.S can amoxil treat tooth infection. Food and Drug Administration (FDA) on 8/26/20 gave emergency-use authorization to Abbott Laboratories' $5, portable nasal-swab SARS-CoV-2 test that returns results in 15 minutes, reports Sheila Kaplan at The New York Times (8/26/20). The test detects viral fragments called antigens. Such tests miss more infections can amoxil treat tooth infection than widely used, slower tests that rely on a technology called polymerase chain reaction (PCR).

    But the speed of antigen tests, three others of which previously received FDA emergency-use approval, could prove useful in relieving test backlogs. Abbott says can amoxil treat tooth infection its new antigen test will become available in September, the story states. Autopsies of 11 people who died of COVID-19 revealed that their spleens and lymph nodes lacked sites called germinal centers where B cells (immune cells) gather to “mature and refine their antibody response to the virus,” writes Jon Cohen at Science (8/25/20). The researchers compared tissue from the people who died of COVID-19 with tissue from 6 people who died of other causes, the story states.

    The finding, which confirms an earlier study’s findings in a smaller group, could provide can amoxil treat tooth infection insights into the progression of severe cases of COVID-19, the story states. The studies “establish a profound lack of [antibody] responses in the deceased population of COVID-19 patients,” says a Huazhong University of Science and Technology (HUST) researcher who co-authored the smaller study and is quoted in the story. The missing germinal centers in severe COVID-19 patients could be linked to the biochemical “cytokine storms” that often occur in the dangerous, second phase of the disease, the HUST researcher is quoted as saying. Meanwhile, a MGH, MIT and Harvard immunologist who is a co-author of the newer study, published earlier this month in can amoxil treat tooth infection the journal Cell, says it won’t be difficult to stop SARS-CoV-2 with a vaccine.

    He is quoted as saying, “This is a piece of cake.” The United States, UK, Japan, and the European Union nations all have pre-ordered in bulk doses of vaccines under development to protect against SARS-CoV-2, reports Ewen Callaway at Nature (8/24/20). Some of these candidate vaccines could be approved in late 2020 or early 2021 at the earliest, the story states. But only "1 billion doses will be available by the fourth quarter of 2021,” according to a life-sciences market analytics firm, the story states can amoxil treat tooth infection. A different organization estimates 2 billion to 4 billion doses will be available by the end of 2021, the story states.

    A chart near the top of the piece illustrates pre-order details by vaccine manufacturer, nation and number of doses. Meanwhile, an international effort to secure vaccine doses for people living in a total of 92 low- and middle-income, as well as some wealthier countries, is can amoxil treat tooth infection “far short of raising the roughly $18 billion that it estimates” will be needed to meet its target number of doses, Callaway reports. Lower in the piece, a chart illustrates pre-orders made by several countries and regions worldwide. Callaway writes that “patents and intellectual property are not what’s standing in the way of fair distribution of COVID-19 vaccines…rather, equitable access and affordable prices require collaboration between governments and vaccine makers,” according to the head of the International AIDS Vaccine Initiative in New York can amoxil treat tooth infection City, which reportedly is co-developing a COVID-19 vaccine.

    In an 8/22/20 essay for The Washington Post, Elizabeth Svoboda writes that many people in the U.S. Have become desensitized to the risks of SARS-CoV-2, which has led to some behavioral backsliding, especially in crowded places. €œThis habituation stems from a can amoxil treat tooth infection principle well-known in psychological therapy,” Svoboda writes. €œThe more we’re exposed to a given threat, the less intimidating it seems.” Some researchers recommend a return to stricter distancing, outdoor masking and stay-at-home orders, the essay suggests.

    But we also need authorities to “supply in-your-face reminders of those mandates, especially visual cues, so people won’t draw their own erroneous conclusions about what’s safe,” she writes. In any case, we should cultivate an awareness of the diminishing effectiveness of our “snap judgments about COVID-19’s can amoxil treat tooth infection dangers,” and make more careful decisions, a la Nobel laureate Daniel Kahneman's “slow thinking,” she advises. Ventilation discussions in public-health circles predate the current pandemic. Infection control theories born of the U.S.

    Experience with the Spanish flu pandemic of 1918-1919 inspired engineers of the early 20th century to design steam-heating systems for buildings that could be effective in cold weather even with apartment windows open, reports Patrick can amoxil treat tooth infection Sisson for Bloomberg CityLab. That’s right. Steam-heat radiators were designed to be used with the open windows, allowing fresh air to gush in, which “health officials thought (correctly)…would ward off airborne diseases,” Sisson writes. The piece draws from a 1992 book “The can amoxil treat tooth infection Lost Art of Steam Heating,” by heating-systems researcher Dan Holohan.

    Radiators were designed, according to Holohan the story states, in response to a New York City Board of Health order that windows should remain open for ventilation in the winter. €œAnybody who’s thrown their windows open in January, when their apartment is stifling, can amoxil treat tooth infection is in an odd way, replicating what engineers hoped would happen a century ago,” Sisson writes (8/5/20). You might enjoy. €œJerry Seinfeld.

    So You Think New York Is ‘Dead’ (It’s not.)” (8/24/20).In four days of speeches can amoxil treat tooth infection lasting more than eight hours at the Republican National Convention, climate change was never mentioned as a threat to the country. That silence stands apart from the climate alarm bells that have been sounding since Donald Trump accepted his first nomination for president four years ago. Thousands of Americans have been killed in natural disasters such as hurricanes and wildfires during Trump’s first term in office. Each of those four years has been among the world’s hottest can amoxil treat tooth infection on record.

    Leaders of other nations have taken action as the United States ignores the issue. Even Wall Street has begun to take notice of how climate change could affect economic growth. None of that was apparent can amoxil treat tooth infection during the convention. Instead, Republican speakers insisted that the real concern was the climate ideas presented by Democrats.

    Many experts say that if climate change is left unanswered, it could cost trillions of dollars to the U.S. Economy. Republicans said the real costs would come from Democratic plans to restrain the use of fossil fuels. €œBiden has promised to abolish the production of American oil, coal, shale and natural gas—laying waste to the economies of Pennsylvania, Ohio, Texas, North Dakota, Oklahoma, Colorado and New Mexico,” Trump said.

    €œMillions of jobs will be lost, and energy prices will soar.” (Biden’s plan does not call for a fracking ban). Those sentiments play well with Trump’s core supporters, but they’re askew from what most voters believe, including younger Republicans, according to polls. They don’t reflect the events that many Americans are either experiencing or seeing online. Uncontrolled wildfires in California and the strongest hurricane to hit Louisiana in 160 years.

    Even as an unrelinquishing pandemic has killed more than 180,000 people in the United States and kept millions of children across the country from returning to school, climate change remains on the minds of voters, polls show. Here are five climate themes that have advanced since Trump accepted his first nomination in 2016. Natural disasters More than 3,000 Americans have died in natural catastrophes during the past four years. Most of them were victims of Hurricane Maria in 2017.

    The massive Category 5 storm killed an estimated 2,975 people in Puerto Rico and forced thousands to flee the U.S. Territory. The devastation continues to have ripple effects three years later. Tens of thousands of people still live under leaky blue tarps.

    The island’s power supply, never reliable to begin with, has become far worse, and some parts of Puerto Rico were without power for a year. That was the same year that Hurricane Harvey dumped 60 inches of rain on parts of Houston, becoming the wettest cyclone on record. Tens of thousands of homes were damaged, and about 70 people were killed. Harvey caused more than $100 billion in damage, making it one of the costliest disasters to strike the United States.

    Record wildfires have also burned across the West. The 2018 Camp Fire in California was the deadliest. It killed 85 people and destroyed more than 10,000 homes. It was fueled by drought, an outcome of climate change.

    This week, California continued to battle the second- and third-largest wildfires in state history. Officials have connected the fires to climate change. €œAll but three of the Top 20 Largest #Wildfires have occurred since 2000, with 10 of these large and damaging wildfires occurring in the last decade,” the California Department of Forestry and Fire Protection tweeted yesterday. €œAs fire weather continues to become more extreme, California is adjusting to fight these larger and more destructive wildfires.” Heat The Trump years have been some of the hottest since record-keeping began after the Civil War, according to NASA.

    After a record-warm July, this year may break the all-time annual heat record set in 2016. That’s a likely outcome, said Gavin Schmidt, director of the NASA Goddard Institute for Space Studies. That’s notable because four years ago, the record warmth was fueled by El Niño, a band of warm water covering the tropical Pacific Ocean. That influence is absent this year, Schmidt said, and long-term trends point to rising heat.

    €œWe know that the trend is moving up. On average, every decade is warmer than the last,” he said. €œThe changes we’re seeing now are so far outside what would be possible in an un-globally-warmed world.” Public opinion Polling shows that voter concern about climate change has been growing for years and that it has not diminished as a result of the coronavirus pandemic. Concern among some voters has spiked during Trump’s tenure.

    Before the virus, polling showed climate change was the second-most important issue for Democratic primary voters, behind only health care. Now, responding to the virus and restoring the economy top the list. But the public still wants the federal government to address climate change, recent polling shows. More Americans than ever—about 25%—view climate change as “extremely personally important,” according to a poll released last week by Stanford University, Resources for the Future and ReconMR.

    That number is twice as large as it was in 2006, said the poll, which surveyed 1,000 adults between May and August. It also found that 82% of respondents want the federal government to act on climate change. And three-quarters of those surveyed said they had personally experienced the effects of global warming. €œThe COVID-19 pandemic has offered a unique opportunity to learn how people feel about climate change when faced with a global crisis,” said Ray Kopp, vice president of research and policy engagement at Resources for the Future.

    €œThe claim that we can’t do anything about climate change without crashing the economy, or that we need to focus only on the pandemic and not do anything on climate right now, simply doesn’t resonate with Americans,” he said. The U.S. (and everyone else) Since Trump pledged to withdraw from the Paris climate agreement in 2017, world leaders have pressed him to rejoin and to take the issue seriously. Among them are German Chancellor Angela Merkel and French President Emmanuel Macron.

    Last year, Trump said Prince Charles spent 90 minutes talking to him about climate change, trying to convince him to take stronger action and to once again make the United States a world leader. In response, Trump said he wanted “good climate,” but his administration has continued to roll back environmental safeguards meant to reduce emissions. In December, Macron said other governments, including China, Russia and the European Union, would lead the world in reducing emissions. The yearslong process of withdrawing from the Paris Agreement won’t be done until November.

    Yesterday, Biden tweeted that if he wins the election, he would rejoin the pact on the first day of his presidency. Climate hits Wall Street This week, it was announced that Exxon Mobil Corp. Would be dropped from the Dow Jones Industrial Average stock index. It’s a significant departure, as Exxon was the longest-tenured company on the Dow, having been listed for almost a century.

    It’s also a reflection of how oil companies have taken a financial hit amid growing concerns about climate change and as a result of declining consumption due to the pandemic. At the same time, some solar and wind companies have grown bigger than their fossil fuel competitors. The same factors that have weakened fossil fuel companies, including more aggressive climate targets, helped drive clean energy technologies. On Wall Street, business interests are increasingly warning the Federal Reserve and other regulators that climate change could pose a significant risk to the economy.

    Earlier this year, 40 investment firms and organizations that handle more than $1 trillion in assets urged Fed Chairman Jerome Powell to take action. They warned him that climate “threats have the potential to compound in ways we don’t yet understand, with disastrous impacts the likes of which we haven’t seen before.” Reprinted from Climatewire with permission from E&E News. E&E provides daily coverage of essential energy and environmental news at www.eenews.net..

    The wildfire season is off amoxil pills online to a roaring start. The hot summer is worsening drought and drying out vegetation—an unfortunately ideal environment for wildfires to rage. But that’s just one amoxil pills online consequence of global warming.

    It’s also leading to flooding, torrential rainstorms and heat-related deaths. In fact, the climate crisis has led to a widespread public health crisis. And as an ear, nose and throat physician, I see amoxil pills online the effects more and more often.

    I vividly remember a patient who came in late for her appointment during a July heat wave. When I walked in, she said, “I’m so sorry I’m late, I was up all night walking my grandbaby around the train station.” Without air conditioning at home, the child was sweating through her clothes in the heat of the night, putting her at risk for dehydration. July 2019 was the hottest July on amoxil pills online record.

    September 2019 was the hottest on record. January 2020 was the hottest on record. May 2020 amoxil pills online was the hottest on record.

    This is not a coincidence. It is a pattern. Carbon dioxide, an important greenhouse gas amoxil pills online contributing to global warming, has increased by 9 percent since 2005 and by 31 percent since 1950.

    A U.N. Intergovernmental Panel on Climate Change special report pointed out that the world has already warmed about one degree Celsius amoxil pills online from pre-industrial levels. It stressed the urgency to act to limit warming to 1.5 degrees, and that a two-degree increase will lead to unprecedented extreme heat, water scarcity and food shortages around the globe.

    Heat affects every part of our body. It can lead to heat exhaustion, heat amoxil pills online stroke, anxiety, impaired cognitive function and even premature death from heart and lung disease. Across the country, the health concerns of the climate crisis are increasingly being recognized, pushing thousands of medical providers—doctors, nurses, pharmacists, therapists, medical students—to become advocates for change.

    In my own practice, I explain to patients how the climate crisis affects their health. For example, apart from contributing to global warming, rising carbon dioxide levels increase the amount of pollen amoxil pills online that plants produce as a consequence of higher rates of photosynthesis. This rise in pollen levels can lead to worsening allergy symptoms.

    Another example is fine particulate matter (known as PM2.5) associated with air pollution, much of it linked to the burning of fossil fuels that help drive the warming. When we breathe in these particles, they travel down the airway and settle in amoxil pills online the tiny air sacs called alveoli of the lungs, causing inflammation and potentially worsening asthma symptoms. The explanations are simple, but the health risks are widespread and complex.

    Ground-level ozone pollution, which is worse in hotter weather, can also harm people with asthma and other respiratory diseases. And that harm falls disproportionately on amoxil pills online the poor. Wealthier people living in North America have a per capita carbon footprint that is 25 percent higher than those of lower-income residents, with some affluent suburbs producing emissions 15 times higher than nearby neighborhoods.

    These carbon emissions contribute to global warming, and the subsequent amoxil pills online health consequences are felt far beyond the neighborhood that produces them. Older adults, children, low-income communities and communities of color are less resilient on average to the health impacts of climate change. The climate crisis is thus leading to a disproportionate public health crisis—and worse, it is a threat multiplier.

    At a time when many Americans are economically challenged, continued heat waves and the higher energy amoxil pills online bills they trigger threaten access to water and energy security. The economic benefits of a low-carbon economy are clear. Estimates suggest that without climate investments, the United States will face economic damage from climate change equivalent to 1–3 percent of GDP per year by 2100.

    The majority amoxil pills online of Americans think global warming is happening. The climate crisis has unfairly been labeled as political, when in fact, people recognize that something needs to be done about it. Even for those who are seemingly unaffected, there is increasing global recognition that the safeguards of living in a protected community and affording expert medical care will eventually fail if global warming continues unchecked.

    Unfortunately, there amoxil pills online will be no vaccine in six months or a year for the climate crisis. The only treatment is collective climate action in the present. Climate action is required of our elected leaders, and we must mandate it of ourselves.

    It can be as simple as educating family and friends, while amoxil pills online making sustainable shopping and traveling choices. It includes eating less meat, unplugging electronics and raising a voice against the fossil fuel industry. With a rise in demand for absentee ballots for the election this November, it is crucial to request mail-in ballots right away to make sure our voices amoxil pills online are heard.

    The United States is the second largest emitter of greenhouse gases, and we must vote for green policy. Legislative action and policy change work, as evidenced by the Clean Air Act and its subsequent amendments, which are projected to save 230,000 lives in 2020. The climate crisis is a public health issue, and we must start healing amoxil pills online the planet in order to heal each other.

    Fighting against the climate crisis is one of the most patriotic things we can do right now. It will protect our health and the health of our neighbors across the country and the globe, and will allow all of us to live on this planet, the only home we have.The items below are highlights from the free newsletter, “Smart, useful, science stuff about COVID-19.” To receive newsletter issues daily in your inbox, sign up here. Please consider amoxil pills online a monthly contribution to support this newsletter.

    Women’s immune response to SARS-CoV-2 is stronger than men’s immune response to the virus, according to a study published 8/26/20 in Nature and covered the same day by Apoorva Mandavilli at The New York Times. The finding could explain why men “are twice as likely to become severely sick and to die [from COVID-19] as women of the same age,” Mandavilli writes. The study also suggests that older men might need multiple shots of a coronavirus vaccine compared perhaps amoxil pills online with young women, who might need just one shot, according to an immunologist quoted in the story.

    He's at the Heinrich Pette Institute and the University Medical Center Hamburg-Eppendorf in Germany. The study leader, a Yale University immunologist, is quoted in the story as saying, “Women who are older — even very old, like 90 years — the women are still making pretty good, decent immune response” to SARS-CoV-2. The U.S amoxil pills online.

    Food and Drug Administration (FDA) on 8/26/20 gave emergency-use authorization to Abbott Laboratories' $5, portable nasal-swab SARS-CoV-2 test that returns results in 15 minutes, reports Sheila Kaplan at The New York Times (8/26/20). The test detects viral fragments called antigens. Such tests miss more infections than widely used, slower tests that rely on a amoxil pills online technology called polymerase chain reaction (PCR).

    But the speed of antigen tests, three others of which previously received FDA emergency-use approval, could prove useful in relieving test backlogs. Abbott says its new amoxil pills online antigen test will become available in September, the story states. Autopsies of 11 people who died of COVID-19 revealed that their spleens and lymph nodes lacked sites called germinal centers where B cells (immune cells) gather to “mature and refine their antibody response to the virus,” writes Jon Cohen at Science (8/25/20).

    The researchers compared tissue from the people who died of COVID-19 with tissue from 6 people who died of other causes, the story states. The finding, which confirms an amoxil pills online earlier study’s findings in a smaller group, could provide insights into the progression of severe cases of COVID-19, the story states. The studies “establish a profound lack of [antibody] responses in the deceased population of COVID-19 patients,” says a Huazhong University of Science and Technology (HUST) researcher who co-authored the smaller study and is quoted in the story.

    The missing germinal centers in severe COVID-19 patients could be linked to the biochemical “cytokine storms” that often occur in the dangerous, second phase of the disease, the HUST researcher is quoted as saying. Meanwhile, a MGH, MIT and Harvard immunologist who is a co-author of the newer study, published earlier this amoxil pills online month in the journal Cell, says it won’t be difficult to stop SARS-CoV-2 with a vaccine. He is quoted as saying, “This is a piece of cake.” The United States, UK, Japan, and the European Union nations all have pre-ordered in bulk doses of vaccines under development to protect against SARS-CoV-2, reports Ewen Callaway at Nature (8/24/20).

    Some of these candidate vaccines could be approved in late 2020 or early 2021 at the earliest, the story states. But only "1 amoxil pills online billion doses will be available by the fourth quarter of 2021,” according to a life-sciences market analytics firm, the story states. A different organization estimates 2 billion to 4 billion doses will be available by the end of 2021, the story states.

    A chart near the top of the piece illustrates pre-order details by vaccine manufacturer, nation and number of doses. Meanwhile, an international effort to secure vaccine doses for people living in a total of amoxil pills online 92 low- and middle-income, as well as some wealthier countries, is “far short of raising the roughly $18 billion that it estimates” will be needed to meet its target number of doses, Callaway reports. Lower in the piece, a chart illustrates pre-orders made by several countries and regions worldwide.

    Callaway writes that “patents and intellectual property are not what’s standing in the way of fair distribution of COVID-19 vaccines…rather, equitable access and affordable prices require collaboration between governments and amoxil pills online vaccine makers,” according to the head of the International AIDS Vaccine Initiative in New York City, which reportedly is co-developing a COVID-19 vaccine. In an 8/22/20 essay for The Washington Post, Elizabeth Svoboda writes that many people in the U.S. Have become desensitized to the risks of SARS-CoV-2, which has led to some behavioral backsliding, especially in crowded places.

    €œThis habituation stems from a amoxil pills online principle well-known in psychological therapy,” Svoboda writes. €œThe more we’re exposed to a given threat, the less intimidating it seems.” Some researchers recommend a return to stricter distancing, outdoor masking and stay-at-home orders, the essay suggests. But we also need authorities to “supply in-your-face reminders of those mandates, especially visual cues, so people won’t draw their own erroneous conclusions about what’s safe,” she writes.

    In any amoxil pills online case, we should cultivate an awareness of the diminishing effectiveness of our “snap judgments about COVID-19’s dangers,” and make more careful decisions, a la Nobel laureate Daniel Kahneman's “slow thinking,” she advises. Ventilation discussions in public-health circles predate the current pandemic. Infection control theories born of the U.S.

    Experience with the Spanish flu pandemic of 1918-1919 inspired engineers of the early 20th century to design steam-heating systems for buildings that could be effective in cold weather even with apartment windows amoxil pills online open, reports Patrick Sisson for Bloomberg CityLab. That’s right. Steam-heat radiators were designed to be used with the open windows, allowing fresh air to gush in, which “health officials thought (correctly)…would ward off airborne diseases,” Sisson writes.

    The piece draws from amoxil pills online a 1992 book “The Lost Art of Steam Heating,” by heating-systems researcher Dan Holohan. Radiators were designed, according to Holohan the story states, in response to a New York City Board of Health order that windows should remain open for ventilation in the winter. €œAnybody who’s thrown their windows open in January, when their amoxil pills online apartment is stifling, is in an odd way, replicating what engineers hoped would happen a century ago,” Sisson writes (8/5/20).

    You might enjoy. €œJerry Seinfeld. So You amoxil pills online Think New York Is ‘Dead’ (It’s not.)” (8/24/20).In four days of speeches lasting more than eight hours at the Republican National Convention, climate change was never mentioned as a threat to the country.

    That silence stands apart from the climate alarm bells that have been sounding since Donald Trump accepted his first nomination for president four years ago. Thousands of Americans have been killed in natural disasters such as hurricanes and wildfires during Trump’s first term in office. Each of those four years has amoxil pills online been among the world’s hottest on record.

    Leaders of other nations have taken action as the United States ignores the issue. Even Wall Street has begun to take notice of how climate change could affect economic growth. None of that was apparent during the convention amoxil pills online.

    Instead, Republican speakers insisted that the real concern was the climate ideas presented by Democrats. Many experts say that if climate change is left unanswered, it could cost trillions of dollars to the U.S. Economy.

    Republicans said the real costs would come from Democratic plans to restrain the use of fossil fuels. €œBiden has promised to abolish the production of American oil, coal, shale and natural gas—laying waste to the economies of Pennsylvania, Ohio, Texas, North Dakota, Oklahoma, Colorado and New Mexico,” Trump said. €œMillions of jobs will be lost, and energy prices will soar.” (Biden’s plan does not call for a fracking ban).

    Those sentiments play well with Trump’s core supporters, but they’re askew from what most voters believe, including younger Republicans, according to polls. They don’t reflect the events that many Americans are either experiencing or seeing online. Uncontrolled wildfires in California and the strongest hurricane to hit Louisiana in 160 years.

    Even as an unrelinquishing pandemic has killed more than 180,000 people in the United States and kept millions of children across the country from returning to school, climate change remains on the minds of voters, polls show. Here are five climate themes that have advanced since Trump accepted his first nomination in 2016. Natural disasters More than 3,000 Americans have died in natural catastrophes during the past four years.

    Most of them were victims of Hurricane Maria in 2017. The massive Category 5 storm killed an estimated 2,975 people in Puerto Rico and forced thousands to flee the U.S. Territory.

    The devastation continues to have ripple effects three years later. Tens of thousands of people still live under leaky blue tarps. The island’s power supply, never reliable to begin with, has become far worse, and some parts of Puerto Rico were without power for a year.

    That was the same year that Hurricane Harvey dumped 60 inches of rain on parts of Houston, becoming the wettest cyclone on record. Tens of thousands of homes were damaged, and about 70 people were killed. Harvey caused more than $100 billion in damage, making it one of the costliest disasters to strike the United States.

    Record wildfires have also burned across the West. The 2018 Camp Fire in California was the deadliest. It killed 85 people and destroyed more than 10,000 homes.

    It was fueled by drought, an outcome of climate change. This week, California continued to battle the second- and third-largest wildfires in state history. Officials have connected the fires to climate change.

    €œAll but three of the Top 20 Largest #Wildfires have occurred since 2000, with 10 of these large and damaging wildfires occurring in the last decade,” the California Department of Forestry and Fire Protection tweeted yesterday. €œAs fire weather continues to become more extreme, California is adjusting to fight these larger and more destructive wildfires.” Heat The Trump years have been some of the hottest since record-keeping began after the Civil War, according to NASA. After a record-warm July, this year may break the all-time annual heat record set in 2016.

    That’s a likely outcome, said Gavin Schmidt, director of the NASA Goddard Institute for Space Studies. That’s notable because four years ago, the record warmth was fueled by El Niño, a band of warm water covering the tropical Pacific Ocean. That influence is absent this year, Schmidt said, and long-term trends point to rising heat.

    €œWe know that the trend is moving up. On average, every decade is warmer than the last,” he said. €œThe changes we’re seeing now are so far outside what would be possible in an un-globally-warmed world.” Public opinion Polling shows that voter concern about climate change has been growing for years and that it has not diminished as a result of the coronavirus pandemic.

    Concern among some voters has spiked during Trump’s tenure. Before the virus, polling showed climate change was the second-most important issue for Democratic primary voters, behind only health care. Now, responding to the virus and restoring the economy top the list.

    But the public still wants the federal government to address climate change, recent polling shows. More Americans than ever—about 25%—view climate change as “extremely personally important,” according to a poll released last week by Stanford University, Resources for the Future and ReconMR. That number is twice as large as it was in 2006, said the poll, which surveyed 1,000 adults between May and August.

    It also found that 82% of respondents want the federal government to act on climate change. And three-quarters of those surveyed said they had personally experienced the effects of global warming. €œThe COVID-19 pandemic has offered a unique opportunity to learn how people feel about climate change when faced with a global crisis,” said Ray Kopp, vice president of research and policy engagement at Resources for the Future.

    €œThe claim that we can’t do anything about climate change without crashing the economy, or that we need to focus only on the pandemic and not do anything on climate right now, simply doesn’t resonate with Americans,” he said. The U.S. (and everyone else) Since Trump pledged to withdraw from the Paris climate agreement in 2017, world leaders have pressed him to rejoin and to take the issue seriously.

    Among them are German Chancellor Angela Merkel and French President Emmanuel Macron. Last year, Trump said Prince Charles spent 90 minutes talking to him about climate change, trying to convince him to take stronger action and to once again make the United States a world leader. In response, Trump said he wanted “good climate,” but his administration has continued to roll back environmental safeguards meant to reduce emissions.

    In December, Macron said other governments, including China, Russia and the European Union, would lead the world in reducing emissions. The yearslong process of withdrawing from the Paris Agreement won’t be done until November. Yesterday, Biden tweeted that if he wins the election, he would rejoin the pact on the first day of his presidency.

    Climate hits Wall Street This week, it was announced that Exxon Mobil Corp. Would be dropped from the Dow Jones Industrial Average stock index. It’s a significant departure, as Exxon was the longest-tenured company on the Dow, having been listed for almost a century.

    It’s also a reflection of how oil companies have taken a financial hit amid growing concerns about climate change and as a result of declining consumption due to the pandemic. At the same time, some solar and wind companies have grown bigger than their fossil fuel competitors. The same factors that have weakened fossil fuel companies, including more aggressive climate targets, helped drive clean energy technologies.

    On Wall Street, business interests are increasingly warning the Federal Reserve and other regulators that climate change could pose a significant risk to the economy. Earlier this year, 40 investment firms and organizations that handle more than $1 trillion in assets urged Fed Chairman Jerome Powell to take action. They warned him that climate “threats have the potential to compound in ways we don’t yet understand, with disastrous impacts the likes of which we haven’t seen before.” Reprinted from Climatewire with permission from E&E News.

    E&E provides daily coverage of essential energy and environmental news at www.eenews.net..

    Amoxil for dogs

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    How to amoxil for dogs cite this article:Singh OP. The need for routine psychiatric assessment of COVID-19 survivors. Indian J Psychiatry 2020;62:457-8COVID-19 pandemic amoxil for dogs is expected to bring a Tsunami of mental health issues. Public health emergencies may affect the well-being, safety, and security of both individuals and communities, which lead to a range of emotional reactions, unhealthy behavior, and noncompliance, with public health directives (such as home confinement and vaccination) in people who contact the disease as well as in the general population.[1] Thus far, there has been an increased emphasis on psychosocial factors such as loneliness, effect of quarantine, uncertainty, vulnerability to COVID-19 infection, economic factors, and career difficulties, which may lead to increased psychiatric morbidity.Time has now come to pay attention to the direct effect of the virus on brain and psychiatric adverse symptoms, resulting from the treatment provided.

    Viral infections are known to be associated with psychiatric amoxil for dogs disorders such as depression, bipolar disorder, obsessive–compulsive disorder (OCD), or schizophrenia. There was an increased incidence of psychiatric disorders following the Influenza Pandemic. Karl Menninger amoxil for dogs described 100 cases of influenza presenting with psychiatric sequelae, which could mainly be categorized as dementia praecox, delirium, other psychoses, and unclassified subtypes. Dementia praecox constituted the largest number among all these cases.[2] Neuroinflammation is now known as the key factor in genesis and exacerbation of psychiatric disorders, particularly depression and bipolar disorders.Emerging evidence points toward the neurotropic properties of the SARS-CoV-2 virus.

    Loss of smell and taste as an initial symptom points toward early involvement amoxil for dogs of olfactory bulb. The rapid spread to brain has been demonstrated through retrograde axonal transport.[3] The virus can enter the brain through endothelial cells lining the blood–brain barrier and also through other nerves such as the vagus nerve.[4] Cytokine storm, a serious immune reaction to the virus, can activate brain glial cells, leading to delirium, depression, bipolar disorder, and OCD.Studies examining psychiatric disorders in acute patients suffering from COVID-19 found almost 40% of such patients suffering from anxiety, depression, and posttraumatic stress disorder.[5] The data on long-term psychiatric sequelae in patients who have recovered from acute illness are limited. There are anecdotal reports of psychosis and mania occurring in patients of COVID-19 following discharge from hospital. This may be either due to the direct effect of the virus on the brain or due to the neuropsychiatric effects amoxil for dogs of drugs used to treat the infection or its complications.

    For example, behavioral toxicity of high-dose corticosteroids which are frequently used during the treatment of severe cases to prevent and manage cytokine storm.The patients with COVID-19 can present with many neuropsychiatric disorders, which may be caused by direct inflammation, central nervous system effects of cytokine storm, aberrant epigenetic modifications of stress-related genes, glial activation, or treatment emergent effects.[6] To assess and manage various neuropsychiatric complications of COVID-19, the psychiatric community at large should equip itself with appropriate assessment tools and management guidelines to effectively tackle this unprecedented wave of psychiatric ailments. References 1.Pfefferbaum B, North CS amoxil for dogs. Mental health and the COVID-19 pandemic. N Engl J Med 2020;383:510-2 amoxil for dogs.

    2.Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology amoxil for dogs in Wuhan, China. The mystery and the miracle. J Med Virol 2020;92:401-2.

    3.Fodoulian L, amoxil for dogs Tuberosa J, Rossier D, Landis BN, Carleton A, Rodriguez I. SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium. BioRxiv 2020.03.31.013268 amoxil for dogs. Doi.

    Https://doi.org/10.1101/2020.03.31.013268. 4.Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system. Adv Drug Deliv Rev 2012;64:614-28.

    5.Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections. A systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry 2020;7:611-27.

    6.Steardo L Jr., Steardo L, Verkhratsky A. Psychiatric face of COVID-19. Transl Psychiatry 2020;10:261. Correspondence Address:Om Prakash SinghAA 304, Ashabari Apartments, O/31, Baishnabghata, Patuli Township, Kolkata - 700 094, West Bengal IndiaSource of Support.

    None, Conflict of Interest. NoneDOI. 10.4103/indianjpsychiatry.indianjpsychiatry_1169_2Abstract The COVID-19 pandemic has emerged as a major stressor of a global scale, affecting all aspects of our lives, and is likely to contribute to a surge of mental ill health. Ancient Hindu scriptures, notably the Bhagavad Gita, have a wealth of insights that can help approaches to build psychological resilience for individuals at risk, those affected, as well as for caregivers.

    The path of knowledge (Jnana yoga) promotes accurate awareness of nature of the self, and can help reframe our thinking from an “I” to a “we mode,” much needed for collectively mitigating the spread of the coronavirus. The path of action (Karma yoga) teaches the art of selfless action, providing caregivers and frontline health-care providers a framework to continue efforts in the face of uncertain consequences. Finally, the path of meditation (Raja yoga) offers a multipronged approach to healthy lifestyle and mindful meditation, which may improve resilience to the illness and its severe consequences. While more work is needed to empirically examine the potential value of each of these approaches in modern psychotherapy, the principles herein may already help individuals facing and providing care for the COVID-19 pandemic.Keywords.

    Bhagavad Gita, Covid-19, YogaHow to cite this article:Keshavan MS. Building resilience in the COVID-19 era. Three paths in the Bhagavad Gita. Indian J Psychiatry 2020;62:459-61The COVID-19 crisis has changed our world in just a matter of months, thrusting us into danger, uncertainty, fear, and of course social isolation.

    At the time of this writing, over 11 million individuals have been affected worldwide (India is fourth among all countries, 674,515) and over half a million people have died. The COVID-19 pandemic has been an unprecedented global stressor, not only because of the disease burden and mortality but also because of economic upheaval. The very fabric of the society is disrupted, affecting housing, personal relationships, travel, and all aspects of lifestyle. The overwhelmed health-care system is among the most major stressors, leading to a heightened sense of vulnerability.

    No definitive treatments or vaccine is on the horizon yet. Psychiatry has to brace up to an expected mental health crisis resulting from this global stressor, not only with regard to treating neuropsychiatric consequences but also with regard to developing preventive approaches and building resilience.Thankfully, there is a wealth of wisdom to help us in our ancient scriptures such as the Bhagavad Gita[1] for building psychological resilience. The Bhagavad Gita is a dialog between the Pandava prince Arjuna and his charioteer Krishna in the epic Mahabharata, the great tale of the Bharata Dynasty, authored by Sage Vyasa (c. 4–5 B.C.E.).

    The dialog occurs in the 6th chapter of the epic and has over 700 verses. In this epic story, Arjuna, the righteous Pandava hero was faced with the dilemma of waging a war against his cousins, the Kauravas, for territory. Arjuna is confused and has no will to initiate the war. In this context, Krishna, his charioteer and spiritual mentor, counsels him.

    The key principles of this spiritual discourse in the Gita are embodied in the broad concept of yoga, which literally means “Yog” or “to unite.” Applying three tenets of yoga can greatly help developing resilience at individual, group, and societal levels. A fourth path, Bhakti yoga, is a spiritual approach in the Gita which emphasizes loving devotion toward a higher power or principle, which may or may not involve a personal god. In this editorial, I focus on three paths that have considerable relevance to modern approaches to reliance-focused psychotherapy that may be especially relevant in the COVID-19 era. Path of Knowledge The first concept in the Gita is the path of knowledge (Jnana Yoga, chapter 2).

    The fundamental goal of Jnana yoga is to liberate oneself from the limited view of the individual ego, and to develop the awareness of one's self as part of a larger, universal self. Hindu philosophers were among the earliest to ask the question of “who am I” and concluded that the self is not what it seems. The self as we all know is a collection of our physical, mental, and social attributes that we create for ourselves with input from our perceptions, and input by our families and society. Such a world view leads to a tendency to crave for the “I” and for what is mine, and not consider the “We.” As Krishna in the Bhagavad Gita points out, the person who sees oneself in others, and others in oneself, really “sees.” Such awareness, which guides action in service of self as well as others, is critically important in our goals of collectively preventing the spread of the coronavirus.

    A glaring example is the use of face masks, known to effectively slow the viral infection. Using the mask is as important to protecting oneself from the virus as well as protecting others from oneself. Nations such as the USA (and their leaders), who have given mixed messages to the public about the need to wear masks, have been showing a strikingly high number of cases as well as mortality. Unfortunately, such reluctance to wear masks (and thus model protective hygiene for the population), as in the case of the US leader, has stemmed from ego or vanity-related issues (i.e., how he would appear to other leaders!.

    ). This factor may at least partly underlie the worse COVID-19 outcome in the USA. The simple lesson here is that it is important to first flatten the ego if one wants to flatten the pandemic curve!. Path of Action The second key concept is the path of action (Karma yoga, chapter 3).

    Karma yoga is all about taking action without thinking, “what's in it for me.” As such, it seeks to mainly let go of one's ego. In the Bhagavad Gita, Arjuna is ambivalent about fighting because of the conflict regarding the outcome brought on by waging the war, i.e., having to kill some of his own kith and kin. Krishna reminds him that he should not hesitate, because it is his nature and duty (or Dharma), as a warrior, to protect the larger good, though it will have some downside consequences. The frontline health-care worker caring for severely ill patients with COVID-19 is likely to have a similar emotional reaction as Arjuna, facing a lack of adequate treatments, high likelihood of mortality and of unpredictable negative outcomes, and risk to him/herself.

    Compounding this, especially when resources such as ventilators are limited, the doctor may have to make tough decisions of whose life to save and whose not. Adding to this are personal emotions when facing with the death of patients, having to deliver bad news, and dealing with grieving relatives.[2] All these are likely to result in emotional anguish and guilt, leading to burnout and a war “neurosis.”So, what should the frontline health-care provider should do?. Krishna's counsel would be that the doctor should continue to perform his/her own dharma, but do so without desire or attachment, thereby performing action in the spirit of Karma yoga. Such action would be with detachment, without a desire for personal gain and being unperturbed by success or failure.

    Such “Nishkaama Karma” (or selfless action) may help doctors working today in the COVID outbreak to carry forward their work with compassion, and accept the results of their actions with equanimity and without guilt. Krishna points out that training one's mind to engage in selfless action is not easy but requires practice (Abhyasa). Krishna is also emphatic about the need to protect oneself, in order to be able to effectively carry out one's duties. Path of Meditation The third core concept in the Gita is the path of meditation and self-reflection (Raja yoga, or Dhyana yoga, chapter 6).

    It is considered the royal path (Raja means royal) for attaining self-realization, and often considered the 8-fold path of yoga (Ashtanga yoga) designed to discipline lifestyle, the body and mind toward realizing mindfulness and self-reflection. These techniques, which originated in India over two millennia ago, have evolved over recent decades and anticipate several approaches to contemplative psychotherapy, including dialectical behavior therapy, acceptance and commitment therapy, and mindfulness-based stress reduction.[3] These approaches are of particular relevance for stress reduction and resilience building in individuals faced by COVID-19-related emotional difficulties as well as health-care providers.[4]The majority of people affected by the COVID-19 virus recover, but about 20% have severe disease, and the mortality is around 5%. Older individuals, those with obesity and comorbid medical illnesses such as diabetes and lung disease, are particularly prone to developing severe disease. It is possible that a state of chronic low-grade inflammation which underlies each of these conditions may increase the risk of disproportionate host immune reactions (with excessive release of cytokines), characterizing severe disease in those with COVID-19.[4] With this in mind, it is important to note that exercise, some forms of meditation, anti-inflammatory and antioxidant diet (such as turmeric and melatonin), and yoga have known benefits in reducing inflammation.[5],[6],[7],[8],[9] Sleep loss also elevates inflammatory cytokines.

    Healthy sleep may reduce inflammation.[10] Clearly, a healthy lifestyle, including healthy sleep, exercise, and diet, may be protective against developing COVID-19-related severe complications. These principles of healthy living are beautifully summarized in the Bhagavad Gita.Yuktahara-viharasya yukta-cestasya karmasuYukta-svapnavabodhasya yogo bhavati duhkha-haHe who is temperate in his habits of eating, sleeping, working and recreation can mitigate all sorrows by practicing the yoga system.–Bhagavad Gita, Chapter 6, verse 17.The relevance of the Bhagavad Gita for modern psychotherapy has been widely reviewed.[11],[12] However, relatively little empirical literature exists on the effectiveness of versus spiritually integrated psychotherapy incorporating Hindu psychotherapeutic insights. Clearly, more work is needed, and COVID-19 may provide an opportunity for conducting further empirical research.[13] In the meantime, using the principles outlined here may already be of benefit in helping those in need, and may be rapidly enabled in the emerging era of telehealth and digital health.[14]Financial support and sponsorshipNil.Conflicts of interestThere are no conflicts of interest. References 1.Pandurangi AK, Shenoy S, Keshavan MS.

    Psychotherapy in the Bhagavad Gita, the Hindu scriptural text. Am J Psychiatry 2014;171:827-8. 2.Arango C. Lessons learned from the coronavirus health crisis in Madrid, Spain.

    How COVID-19 has changed our lives in the last 2 weeks [published online ahead of print, 2020 Apr 8]. Biol Psychiatry 2020;26:S0006-3223 (20) 31493-1. [doi. 10.1016/j.biopsych.

    2020.04.003]. 3.Keshavan MS, Gangadhar GN, Hinduism PA. In. Spirituality and Mental Health Across Cultures, Evidence-Based Implications for Clinical Practice.

    Oxford, England. Oxford University Press. In Press. 4.Habersaat KB, Betsch C, Danchin M, Sunstein CR, Böhm R, Falk A, et al.

    Ten considerations for effectively managing the COVID-19 transition. Nat Hum Behav 2020;4:677-87. Doi. 10.1038/s41562-020-0906-x.

    Epub 2020 Jun 24. 5.Kumar K. Building resilience to Covid-19 disease severity. J Med Res Pract 2020;9:1-7.

    6.Bushell W, Castle R, Williams MA, Brouwer KC, Tanzi RE, Chopra D, et al. Meditation and Yoga practices as potential adjunctive treatment of SARS-CoV-2 infection and COVID-19. A brief overview of key subjects [published online ahead of print, 2020 Jun 22]. J Altern Complement Med 2020;26:10.1089/acm.

    7.Gupta H, Gupta M, Bhargava S. Potential use of turmeric in COVID-19 [published online ahead of print, 2020 Jul 1]. Clin Exp Dermatol. 2020;10.1111/ced.14357.

    Doi:10.1111/ced.14357. 8.Damiot A, Pinto AJ, Turner JE, Gualano B. Immunological implications of physical inactivity among older adults during the COVID-19 pandemic [published online ahead of print, 2020 Jun 25]. Gerontology 2020:26;1-8.

    [doi. 10.1159/000509216]. 9.El-Missiry MA, El-Missiry ZM, Othman AI. Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19 [published online ahead of print, 2020 Jun 29].

    Eur J Pharmacol 2020;882:173329. 10.Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab 2010;24:775-84.

    11.Balodhi JP, Keshavan MS. Bhagavad Gita and psychotherapy. Asian J Psychiatr 2011;4:300-2. 12.Bhatia SC, Madabushi J, Kolli V, Bhatia SK, Madaan V.

    The Bhagavad Gita and contemporary psychotherapies. Indian J Psychiatry 2013;55:S315-21. 13.Keshavan MS. Pandemics and psychiatry.

    Repositioning research in context of COVID-19 [published online ahead of print, 2020 May 7]. Asian J Psychiatr 2020;51:102159. [doi. 10.1016/j.ajp.

    2020.102159]. 14.Torous J, Keshavan M. COVID-19, mobile health and serious mental illness. Schizophr Res 2020;218:36-7.

    Correspondence Address:Matcheri S KeshavanRoom 542, Massachusetts Mental Health Center, 75 Fenwood Road, Boston, MA 02115 USASource of Support. None, Conflict of Interest. NoneDOI. 10.4103/psychiatry.IndianJPsychiatry_829_20.

    How to http://www.amisdepasteur.fr/where-can-i-buy-amoxil/ cite this amoxil pills online article:Singh OP. The need for routine psychiatric assessment of COVID-19 survivors. Indian J Psychiatry 2020;62:457-8COVID-19 pandemic amoxil pills online is expected to bring a Tsunami of mental health issues.

    Public health emergencies may affect the well-being, safety, and security of both individuals and communities, which lead to a range of emotional reactions, unhealthy behavior, and noncompliance, with public health directives (such as home confinement and vaccination) in people who contact the disease as well as in the general population.[1] Thus far, there has been an increased emphasis on psychosocial factors such as loneliness, effect of quarantine, uncertainty, vulnerability to COVID-19 infection, economic factors, and career difficulties, which may lead to increased psychiatric morbidity.Time has now come to pay attention to the direct effect of the virus on brain and psychiatric adverse symptoms, resulting from the treatment provided. Viral infections are known to be associated with psychiatric disorders such as depression, bipolar disorder, obsessive–compulsive disorder (OCD), or amoxil pills online schizophrenia. There was an increased incidence of psychiatric disorders following the Influenza Pandemic.

    Karl Menninger described 100 cases of influenza presenting with psychiatric sequelae, which could mainly be categorized as dementia amoxil pills online praecox, delirium, other psychoses, and unclassified subtypes. Dementia praecox constituted the largest number among all these cases.[2] Neuroinflammation is now known as the key factor in genesis and exacerbation of psychiatric disorders, particularly depression and bipolar disorders.Emerging evidence points toward the neurotropic properties of the SARS-CoV-2 virus. Loss of smell and taste as an initial symptom points toward early involvement of olfactory bulb amoxil pills online.

    The rapid spread to brain has been demonstrated through retrograde axonal transport.[3] The virus can enter the brain through endothelial cells lining the blood–brain barrier and also through other nerves such as the vagus nerve.[4] Cytokine storm, a serious immune reaction to the virus, can activate brain glial cells, leading to delirium, depression, bipolar disorder, and OCD.Studies examining psychiatric disorders in acute patients suffering from COVID-19 found almost 40% of such patients suffering from anxiety, depression, and posttraumatic stress disorder.[5] The data on long-term psychiatric sequelae in patients who have recovered from acute illness are limited. There are anecdotal reports of psychosis and mania occurring in patients of COVID-19 following discharge from hospital. This may be either due to the direct effect of the virus on the brain or due to amoxil pills online the neuropsychiatric effects of drugs used to treat the infection or its complications.

    For example, behavioral toxicity of high-dose corticosteroids which are frequently used during the treatment of severe cases to prevent and manage cytokine storm.The patients with COVID-19 can present with many neuropsychiatric disorders, which may be caused by direct inflammation, central nervous system effects of cytokine storm, aberrant epigenetic modifications of stress-related genes, glial activation, or treatment emergent effects.[6] To assess and manage various neuropsychiatric complications of COVID-19, the psychiatric community at large should equip itself with appropriate assessment tools and management guidelines to effectively tackle this unprecedented wave of psychiatric ailments. References 1.Pfefferbaum B, North CS amoxil pills online. Mental health and the COVID-19 pandemic.

    N Engl J Med amoxil pills online 2020;383:510-2. 2.Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, China amoxil pills online.

    The mystery and the miracle. J Med Virol 2020;92:401-2. 3.Fodoulian L, Tuberosa J, Rossier D, Landis BN, amoxil pills online Carleton A, Rodriguez I.

    SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium. BioRxiv 2020.03.31.013268 amoxil pills online. Doi.

    Https://doi.org/10.1101/2020.03.31.013268. 4.Lochhead JJ, Thorne RG. Intranasal delivery of biologics to the central nervous system.

    Adv Drug Deliv Rev 2012;64:614-28. 5.Rogers JP, Chesney E, Oliver D, Pollak TA, McGuire P, Fusar-Poli P, et al. Psychiatric and neuropsychiatric presentations associated with severe coronavirus infections.

    A systematic review and meta-analysis with comparison to the COVID-19 pandemic. Lancet Psychiatry 2020;7:611-27. 6.Steardo L Jr., Steardo L, Verkhratsky A.

    Psychiatric face of COVID-19. Transl Psychiatry 2020;10:261. Correspondence Address:Om Prakash SinghAA 304, Ashabari Apartments, O/31, Baishnabghata, Patuli Township, Kolkata - 700 094, West Bengal IndiaSource of Support.

    None, Conflict of Interest. NoneDOI. 10.4103/indianjpsychiatry.indianjpsychiatry_1169_2Abstract The COVID-19 pandemic has emerged as a major stressor of a global scale, affecting all aspects of our lives, and is likely to contribute to a surge of mental ill health.

    Ancient Hindu scriptures, notably the Bhagavad Gita, have a wealth of insights that can help approaches to build psychological resilience for individuals at risk, those affected, as well as for caregivers. The path of knowledge (Jnana yoga) promotes accurate awareness of nature of the self, and can help reframe our thinking from an “I” to a “we mode,” much needed for collectively mitigating the spread of the coronavirus. The path of action (Karma yoga) teaches the art of selfless action, providing caregivers and frontline health-care providers a framework to continue efforts in the face of uncertain consequences.

    Finally, the path of meditation (Raja yoga) offers a multipronged approach to healthy lifestyle and mindful meditation, which may improve resilience to the illness and its severe consequences. While more work is needed to empirically examine the potential value of each of these approaches in modern psychotherapy, the principles herein may already help individuals facing and providing care for the COVID-19 pandemic.Keywords. Bhagavad Gita, Covid-19, YogaHow to cite this article:Keshavan MS.

    Building resilience in the COVID-19 era. Three paths in the Bhagavad Gita. Indian J Psychiatry 2020;62:459-61The COVID-19 crisis has changed our world in just a matter of months, thrusting us into danger, uncertainty, fear, and of course social isolation.

    At the time of this writing, over 11 million individuals have been affected worldwide (India is fourth among all countries, 674,515) and over half a million people have died. The COVID-19 pandemic has been an unprecedented global stressor, not only because of the disease burden and mortality but also because of economic upheaval. The very fabric of the society is disrupted, affecting housing, personal relationships, travel, and all aspects of lifestyle.

    The overwhelmed health-care system is among the most major stressors, leading to a heightened sense of vulnerability. No definitive treatments or vaccine is on the horizon yet. Psychiatry has to brace up to an expected mental health crisis resulting from this global stressor, not only with regard to treating neuropsychiatric consequences but also with regard to developing preventive approaches and building resilience.Thankfully, there is a wealth of wisdom to help us in our ancient scriptures such as the Bhagavad Gita[1] for building psychological resilience.

    The Bhagavad Gita is a dialog between the Pandava prince Arjuna and his charioteer Krishna in the epic Mahabharata, the great tale of the Bharata Dynasty, authored by Sage Vyasa (c. 4–5 B.C.E.). The dialog occurs in the 6th chapter of the epic and has over 700 verses.

    In this epic story, Arjuna, the righteous Pandava hero was faced with the dilemma of waging a war against his cousins, the Kauravas, for territory. Arjuna is confused and has no will to initiate the war. In this context, Krishna, his charioteer and spiritual mentor, counsels him.

    The key principles of this spiritual discourse in the Gita are embodied in the broad concept of yoga, which literally means “Yog” or “to unite.” Applying three tenets of yoga can greatly help developing resilience at individual, group, and societal levels. A fourth path, Bhakti yoga, is a spiritual approach in the Gita which emphasizes loving devotion toward a higher power or principle, which may or may not involve a personal god. In this editorial, I focus on three paths that have considerable relevance to modern approaches to reliance-focused psychotherapy that may be especially relevant in the COVID-19 era.

    Path of Knowledge The first concept in the Gita is the path of knowledge (Jnana Yoga, chapter 2). The fundamental goal of Jnana yoga is to liberate oneself from the limited view of the individual ego, and to develop the awareness of one's self as part of a larger, universal self. Hindu philosophers were among the earliest to ask the question of “who am I” and concluded that the self is not what it seems.

    The self as we all know is a collection of our physical, mental, and social attributes that we create for ourselves with input from our perceptions, and input by our families and society. Such a world view leads to a tendency to crave for the “I” and for what is mine, and not consider the “We.” As Krishna in the Bhagavad Gita points out, the person who sees oneself in others, and others in oneself, really “sees.” Such awareness, which guides action in service of self as well as others, is critically important in our goals of collectively preventing the spread of the coronavirus. A glaring example is the use of face masks, known to effectively slow the viral infection.

    Using the mask is as important to protecting oneself from the virus as well as protecting others from oneself. Nations such as the USA (and their leaders), who have given mixed messages to the public about the need to wear masks, have been showing a strikingly high number of cases as well as mortality. Unfortunately, such reluctance to wear masks (and thus model protective hygiene for the population), as in the case of the US leader, has stemmed from ego or vanity-related issues (i.e., how he would appear to other leaders!.

    ). This factor may at least partly underlie the worse COVID-19 outcome in the USA. The simple lesson here is that it is important to first flatten the ego if one wants to flatten the pandemic curve!.

    Path of Action The second key concept is the path of action (Karma yoga, chapter 3). Karma yoga is all about taking action without thinking, “what's in it for me.” As such, it seeks to mainly let go of one's ego. In the Bhagavad Gita, Arjuna is ambivalent about fighting because of the conflict regarding the outcome brought on by waging the war, i.e., having to kill some of his own kith and kin.

    Krishna reminds him that he should not hesitate, because it is his nature and duty (or Dharma), as a warrior, to protect the larger good, though it will have some downside consequences. The frontline health-care worker caring for severely ill patients with COVID-19 is likely to have a similar emotional reaction as Arjuna, facing a lack of adequate treatments, high likelihood of mortality and of unpredictable negative outcomes, and risk to him/herself. Compounding this, especially when resources such as ventilators are limited, the doctor may have to make tough decisions of whose life to save and whose not.

    Adding to this are personal emotions when facing with the death of patients, having to deliver bad news, and dealing with grieving relatives.[2] All these are likely to result in emotional anguish and guilt, leading to burnout and a war “neurosis.”So, what should the frontline health-care provider should do?. Krishna's counsel http://www.amisdepasteur.fr/amoxil-street-price/ would be that the doctor should continue to perform his/her own dharma, but do so without desire or attachment, thereby performing action in the spirit of Karma yoga. Such action would be with detachment, without a desire for personal gain and being unperturbed by success or failure.

    Such “Nishkaama Karma” (or selfless action) may help doctors working today in the COVID outbreak to carry forward their work with compassion, and accept the results of their actions with equanimity and without guilt. Krishna points out that training one's mind to engage in selfless action is not easy but requires practice (Abhyasa). Krishna is also emphatic about the need to protect oneself, in order to be able to effectively carry out one's duties.

    Path of Meditation The third core concept in the Gita is the path of meditation and self-reflection (Raja yoga, or Dhyana yoga, chapter 6). It is considered the royal path (Raja means royal) for attaining self-realization, and often considered the 8-fold path of yoga (Ashtanga yoga) designed to discipline lifestyle, the body and mind toward realizing mindfulness and self-reflection. These techniques, which originated in India over two millennia ago, have evolved over recent decades and anticipate several approaches to contemplative psychotherapy, including dialectical behavior therapy, acceptance and commitment therapy, and mindfulness-based stress reduction.[3] These approaches are of particular relevance for stress reduction and resilience building in individuals faced by COVID-19-related emotional difficulties as well as health-care providers.[4]The majority of people affected by the COVID-19 virus recover, but about 20% have severe disease, and the mortality is around 5%.

    Older individuals, those with obesity and comorbid medical illnesses such as diabetes and lung disease, are particularly prone to developing severe disease. It is possible that a state of chronic low-grade inflammation which underlies each of these conditions may increase the risk of disproportionate host immune reactions (with excessive release of cytokines), characterizing severe disease in those with COVID-19.[4] With this in mind, it is important to note that exercise, some forms of meditation, anti-inflammatory and antioxidant diet (such as turmeric and melatonin), and yoga have known benefits in reducing inflammation.[5],[6],[7],[8],[9] Sleep loss also elevates inflammatory cytokines. Healthy sleep may reduce inflammation.[10] Clearly, a healthy lifestyle, including healthy sleep, exercise, and diet, may be protective against developing COVID-19-related severe complications.

    These principles of healthy living are beautifully summarized in the Bhagavad Gita.Yuktahara-viharasya yukta-cestasya karmasuYukta-svapnavabodhasya yogo bhavati duhkha-haHe who is temperate in his habits of eating, sleeping, working and recreation can mitigate all sorrows by practicing the yoga system.–Bhagavad Gita, Chapter 6, verse 17.The relevance of the Bhagavad Gita for modern psychotherapy has been widely reviewed.[11],[12] However, relatively little empirical literature exists on the effectiveness of versus spiritually integrated psychotherapy incorporating Hindu psychotherapeutic insights. Clearly, more work is needed, and COVID-19 may provide an opportunity for conducting further empirical research.[13] In the meantime, using the principles outlined here may already be of benefit in helping those in need, and may be rapidly enabled in the emerging era of telehealth and digital health.[14]Financial support and sponsorshipNil.Conflicts of interestThere are no conflicts of interest. References 1.Pandurangi AK, Shenoy S, Keshavan MS.

    Psychotherapy in the Bhagavad Gita, the Hindu scriptural text. Am J Psychiatry 2014;171:827-8. 2.Arango C.

    Lessons learned from the coronavirus health crisis in Madrid, Spain. How COVID-19 has changed our lives in the last 2 weeks [published online ahead of print, 2020 Apr 8]. Biol Psychiatry 2020;26:S0006-3223 (20) 31493-1.

    3.Keshavan MS, Gangadhar GN, Hinduism PA. In. Spirituality and Mental Health Across Cultures, Evidence-Based Implications for Clinical Practice.

    Oxford, England. Oxford University Press. In Press.

    4.Habersaat KB, Betsch C, Danchin M, Sunstein CR, Böhm R, Falk A, et al. Ten considerations for effectively managing the COVID-19 transition. Nat Hum Behav 2020;4:677-87.

    Doi. 10.1038/s41562-020-0906-x. Epub 2020 Jun 24.

    5.Kumar K. Building resilience to Covid-19 disease severity. J Med Res Pract 2020;9:1-7.

    6.Bushell W, Castle R, Williams MA, Brouwer KC, Tanzi RE, Chopra D, et al. Meditation and Yoga practices as potential adjunctive treatment of SARS-CoV-2 infection and COVID-19. A brief overview of key subjects [published online ahead of print, 2020 Jun 22].

    J Altern Complement Med 2020;26:10.1089/acm. 2020.0177. [doi.

    10.1089/acm. 2020.0177]. 7.Gupta H, Gupta M, Bhargava S.

    Potential use of turmeric in COVID-19 [published online ahead of print, 2020 Jul 1]. Clin Exp Dermatol. 2020;10.1111/ced.14357.

    Doi:10.1111/ced.14357. 8.Damiot A, Pinto AJ, Turner JE, Gualano B. Immunological implications of physical inactivity among older adults during the COVID-19 pandemic [published online ahead of print, 2020 Jun 25].

    Gerontology 2020:26;1-8. [doi. 10.1159/000509216].

    9.El-Missiry MA, El-Missiry ZM, Othman AI. Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19 [published online ahead of print, 2020 Jun 29]. Eur J Pharmacol 2020;882:173329.

    10.Mullington JM, Simpson NS, Meier-Ewert HK, Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metab 2010;24:775-84.

    11.Balodhi JP, Keshavan MS. Bhagavad Gita and psychotherapy. Asian J Psychiatr 2011;4:300-2.

    12.Bhatia SC, Madabushi J, Kolli V, Bhatia SK, Madaan V. The Bhagavad Gita and contemporary psychotherapies. Indian J Psychiatry 2013;55:S315-21.

    13.Keshavan MS. Pandemics and psychiatry. Repositioning research in context of COVID-19 [published online ahead of print, 2020 May 7].

    Asian J Psychiatr 2020;51:102159. [doi. 10.1016/j.ajp.

    2020.102159]. 14.Torous J, Keshavan M. COVID-19, mobile health and serious mental illness.

    Schizophr Res 2020;218:36-7. Correspondence Address:Matcheri S KeshavanRoom 542, Massachusetts Mental Health Center, 75 Fenwood Road, Boston, MA 02115 USASource of Support. None, Conflict of Interest.

    NoneDOI. 10.4103/psychiatry.IndianJPsychiatry_829_20.

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    Follow OSHA on Twitter at @OSHA_DOL.On this page Policy objectiveThis guidance is to provide Canadians with access to information on amoxil 500g the safety and efficacy/effectiveness of products being used for the COVID-19 pandemic. These products are being imported and sold in Canada under 2 interim orders. All personal and confidential business information (CBI) will be protected prior to release.

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    For information on this authority, see the amoxil 500g guidance document Disclosure of Confidential Business Information under Paragraph 21.1(3)(c) of the Food and Drugs Act.Proactive release of drug application informationWe will proactively publish safety and efficacy information used to support interim order drug applications upon authorization. This includes clinical information in applications submitted under sections 3, 6 and 14 of the interim order.How to request clinical information in medical device applicationsWe will publish safety and effectiveness information used to support interim order medical device applications when we receive a request from the public and within the limits of our administrative capacity. Requests made for multiple applications will be processed in sequence and subject to prioritization.

    Further prioritization may be given to products that have a greater impact on the health system, such amoxil 500g as. Products that are used a lot products that have a higher public interestRequests received for information in applications under the interim order will be prioritized over requests for clinical information in non-COVID19-related drugs submissions and device applications.To request clinical information on medical device applications, use our special portal to submit an electronic request form. Be sure to identify the product name listed on the following sites.

    Publication process Publication of safety and efficacy information used to support drug interim order applications The publication of information follows the process http://www.amisdepasteur.fr/get-amoxil-prescription-online/ described in section 4 and Appendix C of the Public Release amoxil 500g of Clinical Information guidance document.In accordance with PRCI timelines, we aim to publish a final redacted and anonymized package on our clinical information portal within 120 calendar days from starting the process. The process starts automatically on the day an authorization is issued.Step 1. Notice to the company and request for proposed CBI redactions and anonymizationFollowing the authorization of a drug under the interim order, Health Canada will give the manufacturer an opportunity to take part in a process initiation meeting.

    The first 60 days of the 120-day publication process amoxil 500g is allocated for the company to review the clinical information. The company uses the Proposed Redaction Control Sheet (Appendix E, Public Release of Clinical Information (PRCI) guidance document) to propose any redaction of CBI. Proposed CBI redactions should pertain to information that meets the definition of confidential business information.

    This is defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the following 3 elements of the amoxil 500g definition. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitorsFollowing an assessment of the proposals, text within an in-scope document found to meet the above definition will be protected. Similar to Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential business information.

    Exceptions to the PRCI amoxil 500g regulations described in C.08.009.2(2)(a) and (b) of the Food and Drug Regulations or section 43.12(2)(a) and (b) of the Medical Device Regulations will be considered when applying redactions to confidential business information. Further information on the application of these exceptions can be found in the Health Canada PRCI guidance document.All personal information should be anonymized in accordance with section 6 of the Public Release of Clinical Information guidance document. The proposal package from the manufacturer should include.

    The proposed redaction control sheet the draft anonymization report annotated documentsManufacturers submit for amoxil 500g Health Canada assessment using either CanadaPost ePost Connect or a suitable secure file transfer site of the manufacturer’s choosing.Step 2. Health Canada assessment of company representationsWithin 30 days of receiving the proposal package, Health Canada will complete and return our assessment of the proposed CBI redactions and anonymization methodology. Proposed redactions that meet the definition of confidential business information will be protected.

    We will review amoxil 500g the anonymization methodology to ensure all personal information is protected while maximizing the disclosure of useful clinical information. Step 3. Revision of proposed CBI redactions and anonymizationIf proposed CBI redactions are rejected or revision is required to the anonymization methodology, in accordance with the Public Release of Clinical Information.

    Guidance document, the manufacturer will be given 15 days to make the amoxil 500g revisions and resubmit. We will send our final assessment to the manufacturer within 5 days of receiving the revised package. Step 4.

    Finalization and publicationWithin 5 days of receiving our final assessment, the manufacturer must format and submit the final redacted and anonymization clinical documents within 5 days of receiving our final amoxil 500g assessment. The final documents must comply with the Guidance Document. Preparation of Regulatory Activities using the Electronic Common Technical Document (eCTD) Format.

    These documents are to be submitted using amoxil 500g the Common Electronic Submission Gateway. We will publish the final redacted documents within 5 days of receiving the final sequence.Publication of safety and effectiveness information used to support medical device interim order applicationsThe publication of information within an interim order application will proceed through the abbreviated process described below. Our goal is to publish a final redacted and anonymized package on our clinical information portal within 120 calendar days from initiation of the process.Step 1.

    Health Canada screening of requestsAfter we receive a request for information, we will amoxil 500g retrieve the interim order application from docubridge (or other location). Information related to safety and effectiveness will be considered in-scope of publication. Other information will not be released publicly.

    Only information amoxil 500g available at the time the request is made will be considered for disclosure. Information submitted after the original request for disclosure will be considered for public release upon receipt of a subsequent request.Examples of in scope information include. Clinical testing information validation testing that supports the effectiveness of the product, including testing performed in vitro or in silico summaries or overviews on safety or efficacy pre- or post-market, including literature reviewsExamples of out of scope information include.

    Manufacturing details not related to safety or efficacy engineering and design details general documents, such as user manuals, package inserts amoxil 500g and instructions for use individual patient information, such as patient listings and case report forms, that require extensive anonymization interim clinical study data (see the PRCI guidance)Step 2a. Health Canada assessment of confidential business information To reduce administrative burden on the manufacturer, we will review in-scope records for confidential business information, as defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the following 3 elements of the definition will be protected. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitorsText in an in-scope document found to meet this definition will be redacted using a PDF redaction tool.

    Similar to Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential amoxil 500g business information. Exceptions to the PRCI regulations are outlined section 43.12(2)(a) and (b) of the Medical Device Regulations. These exceptions will be considered when applying redactions to confidential business information.

    Further information on the application of these exceptions can be found in the PRCI amoxil 500g guidance document.Step 2b. Assessing personal informationIn general, in-scope records do not contain a large volume of personal identification information. Any personal information, as defined in the Privacy Act and in accordance with PRCI guidance, information that could help to identify an individual will be protected.

    For example, this can include the names of authors and investigators as well as subject identification numbers.A large volume of indirectly identifying information is not expected in the medical device amoxil 500g records that are in-scope of publication. Consequently, limited protection of personal information is anticipated.Personal information will be redacted using a PDF redaction tool. Step 3.

    Notice to the company and request for redaction amoxil 500g proposalFollowing the review and redaction of in scope documents, we will send the manufacturer a written notice indicating our intent to publish the identified documents. A copy of the release package will be sent for the manufacturer’s review. Any further proposed redactions by the manufacturer must be received within 14 calendar days.Manufacturer are asked to use the Proposed Redaction Control Sheet (see Appendix E of the PRCI guidance document) to suggest further redactions.Step 4.

    Health Canada assessment of company representationsAny further redactions proposed by the manufacturer will be assessed in accordance with the amoxil 500g process outlined in step 2, above. Those that meet the definition of personal or confidential business information will be accepted.Step 5. PublicationIn-scope documents will be published within 120 days following receipt of the request.

    The redacted information amoxil 500g will be uploaded to the Clinical Information Portal, indexed by application number. Published documents will carry a watermark and be subject to terms of use, as described in the PRCI guidance.Mailing addressInformation Science and Openness DivisionResource Management and Operations DirectorateHealth Products and Food BranchHealth Canada Graham Spry Building 250 Lanark Ave Ottawa ON K1A 0K9 Telephone. 613-960-4687Email.

    Hc.clinicaldata-donneescliniques.sc@canada.ca Terminology and definitions Anonymization amoxil 500g. Means the process through which personal information is modified by. removing direct identifiers and any related code that would enable linkage with identifying information and ensuring that the remaining indirect identifiers no longer present a serious possibility of re-identifying an individual CBI.

    Confidential business information, as amoxil 500g meant in common law and as defined in Section 2 of the Food and Drugs Act. in respect of a person to whose business or affairs the information relates, means (subject to the regulations) business information that. Is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitors Clinical information.

    Means information in respect of a clinical trial, clinical studies or investigational testing, such as amoxil 500g. clinical overviews, clinical summaries and clinical study reports for drugs summaries and detailed information of all clinical studies and investigational testing that provided evidence of safety and effectiveness for medical devices Clinical study report. Means an "integrated" full report of an individual study of any therapeutic, prophylactic or diagnostic agent (drug or treatment) conducted in patients, in which.

    the clinical and statistical description, presentations and analyses are integrated into a single report incorporating tables and figures into the main text of the report or at the end of the text appendices contain the protocol, sample case report forms, investigator-related information, information related to the test drugs/investigational products, including active control/comparators, technical statistical documentation, related publications, patient data amoxil 500g listings and technical statistical details such as derivations, computations, analyses and computer output FDA. Food and Drugs Act FDR. Food and Drug Regulations IMDRF ToC.

    International Medical Device Regulators Forum Table amoxil 500g of Contents Medical device. Has the same meaning as insee the Medical Devices Regulations. For information on the classification of medical devices, please see the guidance documents on the.

    risk-based classification system for in vitro diagnostic devices (IVDDs) risk-based classification system for non-in vitro diagnostic devices (non-IVDDs) Non-commercial purpose.

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    Workers and employers who have questions or concerns about workplace safety can contact OSHA online or by phone at 1-800-321-6742 (OSHA). You can find additional resources and learn more about OSHA’s response to the coronavirus at www.osha.gov/coronavirus. Loren Sweatt is the Principal Deputy Assistant Secretary for the U.S amoxil pills online. Department of Labor’s Occupation Safety and Health Administration Editor’s Note. It is important to note that information and guidance about COVID-19 continually evolve as conditions change.

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    Make sure all workers understand how to stay healthy at work during flu season, including new and temporary workers. Wear a face covering. These can help limit the amoxil pills online flu's spread. Consider alternate work arrangements. If feasible, offer options such as telework or staggered shifts for workers considered high risk for seasonal flu (such as older workers, pregnant women, and those with asthma).

    Learn more about workplace safety and the flu on OSHA's amoxil pills online website. You can find additional resources and learn more about OSHA's response to the coronavirus at osha.gov/coronavirus. Workers and employers who have questions or concerns about workplace safety can contact OSHA online or by phone at 1-800-321-6742 (OSHA). Loren Sweatt is the Principal Deputy Assistant Secretary for the U.S amoxil pills online. Department of Labor's Occupational Safety and Health Administration.

    Follow OSHA on Twitter at @OSHA_DOL.On this page Policy objectiveThis guidance is to provide Canadians with access to information on the safety and efficacy/effectiveness of products being used for the COVID-19 pandemic. These products amoxil pills online are being imported and sold in Canada under 2 interim orders. All personal and confidential business information (CBI) will be protected prior to release. The disclosed information will be made publicly available for non-commercial purposes after Health Canada completes its regulatory review process, while adhering to Canada’s Privacy Act.Providing public access to this information supports Canada’s objective for transparent decision-making. Public access also provides valuable information that may help with the use or development of COVID19 drugs and medical devices.This guidance document outlines the process for publicly disclosing information in a market authorization application under the 2 interim amoxil pills online orders.

    The process includes. procedures when releasing information types of information that fall under the guidelines for CBI and that may be eligible for redaction protection of personal informationScope and application This document applies to information relied upon to issue a market authorization under the. Interim order amoxil pills online respecting the importation, sale and advertising of drugs for use in relation to COVID-19 (September 16, 2020) and interim order respecting the importation and sale of medical devices for use in relation to COVID-19(March 18, 2020)The public release of safety and efficacy/effectiveness information reviewed under the 2 interim orders is governed by common law. Information requested for release is assessed case by case to determine what is CBI. Personal information is removed before the safety and efficacy/effectiveness information is released to the public.Following Health Canada’s review of an application, safety and efficacy information will be released as follows.

    Automatically disclosed in applications submitted under the interim order for importing, selling and advertising drugs (proactive release) disclosed on request in applications submitted under the interim order for importing and selling medical devices (released upon request)Information amoxil pills online in applications that have been authorized, including those authorized and then revoked, is in scope for public release. This includes. Original application documents documents filed after market authorization is issued (filed at Health Canada’s request or to meet a condition of approval)Information in applications that are refused and were never authorized is out of scope for public release. This document does not amoxil pills online apply to clinical information submitted to support the market authorization of a medical device under the Medical Device Regulations or of a new drug submission under the Food and Drug Regulations (FDR). The exception are new drug submissions for COVID-19 indications submitted under the FDR.

    For more information on the public release of this information, see the Public Release of Clinical Information. Guidance document.Also not applicable under this document is the CBI disclosure authority under section 21.1(3)(c) of the Food and Drugs amoxil pills online Act. This section permits the Minister of Health to disclose CBI to certain persons for the purpose of protection or promotion of human health or the safety of the public. For information on this authority, see the guidance document Disclosure of Confidential Business Information under Paragraph 21.1(3)(c) of the Food and Drugs Act.Proactive release of drug application informationWe will proactively publish safety and efficacy information used to support interim order drug applications upon authorization. This includes clinical information in applications submitted under sections 3, 6 and 14 of the interim order.How to request amoxil pills online clinical information in medical device applicationsWe will publish safety and effectiveness information used to support interim order medical device applications when we receive a request from the public and within the limits of our administrative capacity.

    Requests made for multiple applications will be processed in sequence and subject to prioritization. Further prioritization may be given to products that have a greater impact on the health system, such as. Products that are used a lot products that have a higher public interestRequests received for information in applications under the interim order will be prioritized over requests for clinical information in non-COVID19-related drugs submissions and device applications.To request amoxil pills online clinical information on medical device applications, use our special portal to submit an electronic request form. Be sure to identify the product name listed on the following sites. Publication process Publication of safety and efficacy information used to support drug interim order applications The publication of information follows the process described in section 4 and Appendix C of the Public Release of Clinical Information guidance document.In accordance with PRCI timelines, we aim to publish a final redacted and anonymized package on our clinical information portal within 120 calendar days from starting the process.

    The process starts automatically amoxil pills online on the day an authorization is issued.Step 1. Notice to the company and request for proposed CBI redactions and anonymizationFollowing the authorization of a drug under the interim order, Health Canada will give the manufacturer an opportunity to take part in a process initiation meeting. The first 60 days of the 120-day publication process is allocated for the company to review the clinical information. The company uses the Proposed Redaction Control Sheet (Appendix E, Public Release of Clinical Information (PRCI) guidance document) to propose amoxil pills online any redaction of CBI. Proposed CBI redactions should pertain to information that meets the definition of confidential business information.

    This is defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the following 3 elements of the definition. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the amoxil pills online person or a material financial gain to their competitorsFollowing an assessment of the proposals, text within an in-scope document found to meet the above definition will be protected. Similar to Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential business information. Exceptions to the PRCI regulations described in C.08.009.2(2)(a) and (b) of the Food and Drug Regulations or section 43.12(2)(a) and (b) of the Medical Device Regulations will be considered when applying redactions to confidential business information. Further information on the application of these exceptions can be found in the Health Canada PRCI guidance document.All amoxil pills online personal information should be anonymized in accordance with section 6 of the Public Release of Clinical Information guidance document.

    The proposal package from the manufacturer should include. The proposed redaction control sheet the draft anonymization report annotated documentsManufacturers submit for Health Canada assessment using either CanadaPost ePost Connect or a suitable secure file transfer site of the manufacturer’s choosing.Step 2. Health Canada assessment of company representationsWithin 30 days of receiving the proposal package, Health Canada will complete and return our assessment of the proposed CBI redactions and anonymization methodology amoxil pills online. Proposed redactions that meet the definition of confidential business information will be protected. We will review the anonymization methodology to ensure all personal information is protected while maximizing the disclosure of useful clinical information.

    Step 3 amoxil pills online. Revision of proposed CBI redactions and anonymizationIf proposed CBI redactions are rejected or revision is required to the anonymization methodology, in accordance with the Public Release of Clinical Information. Guidance document, the manufacturer will be given 15 days to make the revisions and resubmit. We will send our final assessment to the manufacturer within amoxil pills online 5 days of receiving the revised package. Step 4.

    Finalization and publicationWithin 5 days of receiving our final assessment, the manufacturer must format and submit the final redacted and anonymization clinical documents within 5 days of receiving our final assessment. The final documents must comply with the Guidance amoxil pills online Document. Preparation of Regulatory Activities using the Electronic Common Technical Document (eCTD) Format. These documents are to be submitted using the Common Electronic Submission Gateway. We will publish the final redacted documents within 5 days of receiving the final sequence.Publication of safety and effectiveness information used to support medical device interim order applicationsThe publication of amoxil pills online information within an interim order application will proceed through the abbreviated process described below.

    Our goal is to publish a final redacted and anonymized package on our clinical information portal within 120 calendar days from initiation of the process.Step 1. Health Canada screening of requestsAfter we receive a request for information, we will retrieve the interim order application from docubridge (or other location). Information related amoxil pills online to safety and effectiveness will be considered in-scope of publication. Other information will not be released publicly. Only information available at the time the request is made will be considered for disclosure.

    Information submitted after the original request for disclosure will be considered for public release upon receipt of a subsequent request.Examples of in scope information amoxil pills online include. Clinical testing information validation testing that supports the effectiveness of the product, including testing performed in vitro or in silico summaries or overviews on safety or efficacy pre- or post-market, including literature reviewsExamples of out of scope information include. Manufacturing details not related to safety or efficacy engineering and design details general documents, such as user manuals, package inserts and instructions for use individual patient information, such as patient listings and case report forms, that require extensive anonymization interim clinical study data (see the PRCI guidance)Step 2a. Health Canada assessment of confidential business information To reduce administrative burden on the manufacturer, we will review in-scope records for confidential business information, as defined in Section 2 of the Food and Drugs Act, which mirrors common law in the context of confidential business information that meets each of the following 3 elements of the definition will be amoxil pills online protected. That is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available and that has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitorsText in an in-scope document found to meet this definition will be redacted using a PDF redaction tool.

    Similar to Public Release of Clinical Information policies, any information that meets the definition of “clinical information” will not be considered confidential business information. Exceptions to the amoxil pills online PRCI regulations are outlined section 43.12(2)(a) and (b) of the Medical Device Regulations. These exceptions will be considered when applying redactions to confidential business information. Further information on the application of these exceptions can be found in the PRCI guidance document.Step 2b. Assessing personal informationIn amoxil pills online general, in-scope records do not contain a large volume of personal identification information.

    Any personal information, as defined in the Privacy Act and in accordance with PRCI guidance, information that could help to identify an individual will be protected. For example, this can include the names of authors and investigators as well as subject identification numbers.A large volume of indirectly identifying information is not expected in the medical device records that are in-scope of publication. Consequently, limited protection of personal information is anticipated.Personal information will be amoxil pills online redacted using a PDF redaction tool. Step 3. Notice to the company and request for redaction proposalFollowing the review and redaction of in scope documents, we will send the manufacturer a written notice indicating our intent to publish the identified documents.

    A copy amoxil pills online of the release package will be sent for the manufacturer’s review. Any further proposed redactions by the manufacturer must be received within 14 calendar days.Manufacturer are asked to use the Proposed Redaction Control Sheet (see Appendix E of the PRCI guidance document) to suggest further redactions.Step 4. Health Canada assessment of company representationsAny further redactions proposed by the manufacturer will be assessed in accordance with the process outlined in step 2, above. Those that meet the definition of personal or confidential amoxil pills online business information will be accepted.Step 5. PublicationIn-scope documents will be published within 120 days following receipt of the request.

    The redacted information will be uploaded to the Clinical Information Portal, indexed by application number. Published documents will carry a watermark and be subject to terms of use, as described in the PRCI guidance.Mailing addressInformation Science and Openness DivisionResource Management and Operations DirectorateHealth Products and Food BranchHealth Canada Graham Spry Building 250 Lanark Ave amoxil pills online Ottawa ON K1A 0K9 Telephone. 613-960-4687Email. Hc.clinicaldata-donneescliniques.sc@canada.ca Terminology and definitions Anonymization. Means the process through which personal information is modified by amoxil pills online.

    removing direct identifiers and any related code that would enable linkage with identifying information and ensuring that the remaining indirect identifiers no longer present a serious possibility of re-identifying an individual CBI. Confidential business information, as meant in common law and as defined in Section 2 of the Food and Drugs Act. in respect of a person to whose business or affairs the information relates, means (subject amoxil pills online to the regulations) business information that. Is not publicly available in respect of which the person has taken measures that are reasonable in the circumstances to ensure that it remains not publicly available has actual or potential economic value to the person or their competitors because it is not publicly available and its disclosure would result in a material financial loss to the person or a material financial gain to their competitors Clinical information. Means information in respect of a clinical trial, clinical studies or investigational testing, such as.

    clinical overviews, clinical summaries and clinical study reports for drugs summaries and detailed information of all clinical studies and investigational testing that provided evidence of amoxil pills online safety and effectiveness for medical devices Clinical study report. Means an "integrated" full report of an individual study of any therapeutic, prophylactic or diagnostic agent (drug or treatment) conducted in patients, in which. the clinical and statistical description, presentations and analyses are integrated into a single report incorporating tables and figures into the main text of the report or at the end of the text appendices contain the protocol, sample case report forms, investigator-related information, information related to the test drugs/investigational products, including active control/comparators, technical statistical documentation, related publications, patient data listings and technical statistical details such as derivations, computations, analyses and computer output FDA. Food and Drugs Act FDR.

    Amoxil generic name

    NONE

    IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients amoxil generic name suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it my site has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability amoxil generic name of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them.

    Nonetheless, four amoxil generic name DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine amoxil generic name conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders.

    For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for amoxil generic name these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral.

    Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between the amoxil generic name specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for amoxil generic name updating the literature for a specific part of the guideline.

    Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to amoxil generic name substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

    Abstracts had to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, amoxil generic name DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that amoxil generic name were not open access or retrievable through institutional access.

    Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the amoxil generic name writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft. This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline.

    After receiving and incorporating their input, the final version was presented to the paediatric and amoxil generic name genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, amoxil generic name but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

    In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is amoxil generic name now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus.

    However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are not amoxil generic name always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line amoxil generic name sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

    After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and the limitations of this amoxil generic name technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

    And the type of information genetic testing can and amoxil generic name cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities amoxil generic name given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

    Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial amoxil generic name by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress amoxil generic name of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely.

    Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our amoxil generic name experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist.

    The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly amoxil generic name instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional amoxil generic name anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

    NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight amoxil generic name time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm.

    *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

    NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9.

    Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition.

    Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

    The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers.

    A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively. Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process.

    Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm.

    NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting.

    A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

    AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9.

    Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting.

    A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

    Conventional karyotyping can be useful. NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype.

    Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

    If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing.

    Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites. Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another.

    This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions.

    What do laboratories report?. How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity.

    It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

    In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring.

    This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise. For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium.

    We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD.

    These should be published in widely available general medical journals and online, along with a national list of DSD centres. Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved.

    A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

    This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication.

    Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline. Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital.

    The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The hop over to here majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors.

    Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

    Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

    We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk.

    Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used. €œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”.

    No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion.

    Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92. Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected.

    For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

    For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included.

    As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs. The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score.

    Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis.

    Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported. Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons.

    Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

    Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement.

    PLoS Med 6(6). E1000097. Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram.

    *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study.

    Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

    The PRISMA Statement. PLoS Med 6(6). E1000097.

    Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies.

    Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene.

    Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04.

    P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38. P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis.

    It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

    These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21.

    P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20. P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated.

    The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele.

    Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses.

    However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

    We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer.

    For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS. The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s.

    However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality.

    Thus, these should be interpreted with caution. Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants.

    However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

    This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data.

    Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit.

    In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1.

    Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes.

    The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

    Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women.

    This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours.

    Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes.

    It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all. Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk.

    Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

    Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

    IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have http://www.amisdepasteur.fr/where-can-i-buy-amoxil/ a DSD.11 14 Several projects amoxil pills online have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by amoxil pills online an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems amoxil pills online and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues.

    International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have amoxil pills online been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these amoxil pills online healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication amoxil pills online between the specialists involved.

    Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating amoxil pills online the literature for a specific part of the guideline. Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke amoxil pills online et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

    Abstracts had to be written in amoxil pills online English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports amoxil pills online were excluded, as were articles that were not open access or retrievable through institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after having obtained agreement on remaining points of discussion, amoxil pills online revised into a final draft.

    This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and amoxil pills online incorporating their input, the final version was presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried amoxil pills online out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound. In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately.

    More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic amoxil pills online sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are amoxil pills online not always included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should amoxil pills online prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

    After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the amoxil pills online ultrasound findings and the limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of amoxil pills online information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved.

    The clinical geneticist should be amoxil pills online experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy. Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when amoxil pills online the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, amoxil pills online treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

    In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, amoxil pills online MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 amoxil pills online 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was amoxil pills online recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

    NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) amoxil pills online in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

    Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

    Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

    The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively.

    Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing.

    CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

    AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

    NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

    NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype. Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

    If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites.

    Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another. This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions. What do laboratories report?.

    How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity. It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

    In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring. This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise.

    For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres.

    Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved. A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

    This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication. Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline.

    Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers.

    Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality. Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

    We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk. Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used.

    €œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”. No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion. Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92.

    Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

    For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs.

    The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score. Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis. Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported.

    Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

    Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

    Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

    Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

    Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies. Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations.

    Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38.

    P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis. It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

    These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21. P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20.

    P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated. The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele. Two more original studies were identified through our full-text evaluation.

    However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

    We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS.

    The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s. However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality. Thus, these should be interpreted with caution.

    Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants. However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

    This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data. Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene.

    In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14.

    In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes. The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

    Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women. This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations.

    Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all.

    Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk. Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

    Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

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    Acute Kidney Injury (AKI) as http://www.amisdepasteur.fr/how-much-does-amoxil-cost-per-pill/ a result of ischaemia-reperfusion injury (IRI), amoxil cost is a common cause of kidney damage especially in older individuals. In many forms of amoxil cost AKI, infiltrating pro-inflammatory macrophages are critical mediators of tubular damage. Repeated episodes of AKI can lead to, or exacerbate, chronic kidney disease (CKD), and effective therapies for treatment or prevention are lacking.

    Most research into AKI is based on in vivo rodent models of IRI, which are poor at replicating human risk amoxil cost factors (e.g. Ageing, diabetes and pre-existing CKD). As a result there has been a striking failure of promising pre-clinical targets to translate to clinical amoxil cost efficacy and there is a pressing need for alternative models to better understand AKI.The aim of the proposed study is to develop, characterize, and validate a novel in vitro model based on human kidney cells co-cultured with macrophages under conditions mimicking ischemia reperfusion, to provide new insights in the pathobiology of macrophage-tubular cell interactions in AKI.

    Interesting novel findings will be validated using an ex vivo co-culture system based on human kidney tissue slices and macrophages. This will amoxil cost also provide novel platforms for testing new therapeutics.Based in the Division of Medicine - Research Department of Renal Medicine, the student will have the opportunity to work with leading academics and clinicians. The studentship is funded by the St Peters Trust and there will be opportunity for the student to access a wide range of scientific platforms and technologies.

    Any new therapeutic outcome in our models that attenuates injury could be further developed for clinical application through existing collaborations with the amoxil cost pharmaceutical industry.Studentship DescriptionHuman proximal tubular cells in transwell co-culture with macrophages will be evaluated under conditions mimicking IRI in clinically-relevant scenarios viz. Repeated injury, diabetes amoxil cost and aging. Cellular responses will be assessed for established markers of cell injury using a range of techniques, including LNA GapmeR RNA silencing, qPCR, RNASeq, fluorescence-activated cells sorting (FACS), confocal microscopy and multiplex secretome analysis.

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