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    WASHINGTON — President Trump on Thursday pledged to send $200 prescription drug coupons to 33 million Medicare beneficiaries “in the coming weeks,” a political ploy to curry favor with seniors who view drug prices as a priority.Trump’s promise comes less than six weeks before Election Day, and represents the latest step in his administration’s (and his campaign’s) efforts to amass health care talking points, even if levitra price australia their actions do little to save Americans money.The administration is getting its authority to ship the coupons from a Medicare demonstration program, a White House spokesman told STAT in a statement. The nearly $7 billion required to send the coupons, he said, would come from savings from Trump’s “most favored nations” drug pricing proposal. That regulation has also not yet been implemented levitra price australia — meaning the Trump administration is effectively pledging to spend $6.6 billion in savings that do not currently exist. The cards, he said, would be “actual discount cards for prescription drug copays.”advertisement Trump also bragged about a new regulation allowing states and pharmacies to import prescription drugs from Canada. While the administration did publish a Food and Drug Administration regulation on importation Thursday, states would still need to apply to participate and then would have to set up new programs to actually begin importing drugs.Health secretary Alex Azar also sent a letter levitra price australia to congressional leadership formally “certifying” that importation can be done safely and that it would save the U.S.

    Money. That’s a major step in levitra price australia green-lighting widespread drug importation. Current law requires that importation can only happen if the secretary formally certifies it first. Azar is the first Department of Health and Human Services secretary in history to levitra price australia formally certify that importation is safe.advertisement Trump’s remarks came during a careening North Carolina speech address on Trump’s “America First Health Care Plan,” which he had pledged to unveil for months.During the event, Trump attacked Democrats and his election opponent, Joe Biden, and insisted that he’d done more to reform U.S. Health care than any past administration.

    (The health care law championed and signed by former president Barack Obama helped reduce the rate of Americans without insurance from 16% of the levitra price australia population in 2010 to 9% in 2016, and made other sweeping changes to the delivery of health care in the U.S.)It is unclear whether Trump’s promises on $200 credits for prescription drug coupons will come to fruition. Under the Constitution, it is Congress, not the White House, that is empowered to spend taxpayer money, and it is unclear where the roughly $6.6 billion for the program would come from. The idea has never been formally proposed or sketched out by health officials, though the New York Times reported this week that levitra price australia Trump officials had tried to convince the pharmaceutical industry to pay for similar cards worth $100. The drug industry refused.A spokesperson for PhRMA, the drug industry trade group, said that “one-time savings cards will neither provide lasting help, nor advance the fundamental reforms necessary to help seniors better afford their medicines.” Trump’s remarks followed a similarly puzzling press briefing orchestrated by two top administration health advisers. During a Thursday afternoon call with reporters, the administration teased a “historic” health care plan likely to kickstart “the most consequential health care reform in American history.”The actual policies they levitra price australia announced, however, are simple, superficial, and non-binding executive orders.

    Neither will improve the quality of Americans’ health care or lower its cost.The first, Azar said, is a declaration. €œIt is the policy of the United States that people who suffer from pre-existing conditions will be protected” from discrimination levitra price australia by health insurers. He acknowledged the order was redundant. It mirrors protections enshrined levitra price australia in the Affordable Care Act, the landmark health law that the Trump administration has asked a federal court to invalidate. The second order, Azar said, was a directive that he work with Congress to ban “surprise” out-of-network medical bills by Jan.

    1. If Congress remains gridlocked on the issue then, he added, Trump would direct him to pursue other actions or regulations.“I don’t have details for you at this point on that,” he said.Throughout a 30-minute press call, Azar and Seema Verma, the administrator of the Centers for Medicare and Medicaid Services, struggled to provide any further detail. But they continually cast the actions as historic, the latest in a series of Trump administration attempts to play up health care actions in the final run-up to Election Day. On Sept. 13, Trump rolled out a series of actions on drug pricing that will be all but impossible to implement by Nov.

    3, including a controversial plan to cap Medicare’s drug payment levels based on prices that pharmaceutical companies charge in other countries.The actions were widely viewed as motivated by election politics, not policy — Trump has sparred with drug manufacturers for years, but his administration has struggled to enact its own agenda on drug pricing thanks to a federal court setback, a series of internal conflicts, and steadfast industry opposition. Trump’s health care electioneering has even extended to his government’s widely criticized Covid-19 response. Often, Trump’s misstatements have taken a markedly political tone and generated controversy regarding the role of high-ranking government scientists. In particular, Stephen Hahn, the commissioner of the Food and Drug Administration, was criticized in August for dramatically overstating the impact of blood plasma from recovered Covid-19 patients as a coronavirus treatment.The two executive actions fall dramatically short of the “full and complete” health care plan” Trump promised in July. During Thursday’s press call, both Azar and Verma officials struggled to provide detail or cast the actions as a comprehensive plan.

    Azar was, at times, candid in acknowledging that the executive orders carried little force. The surprise billing order, he said, would require private-sector players like hospitals and insurance companies negotiate among themselves.“All the relevant players — hospitals, doctors, insurance companies — had better get their act together and get legislation passed through Congress that protects patients against surprise medical bills from anybody. Hospitals or doctors, doesn’t matter,” he said. €œThose special interest groups need to sort it out and figure out how that would work.”The protections for patients with pre-existing conditions have been in force since 2014, and are among the most popular elements of the Affordable Care Act. The administration’s announcement on the stated protections is likely empty rhetoric.

    Many legal experts believe it is unlikely that the White House could enact similar protections without help from Congress. The announcement comes in the face of intense criticism surrounding the Trump administration’s support for a lawsuit that would overturn the ACA in its entirety. The Supreme Court’s decision in the case this term could ultimately end the ACA’s expansion of state Medicaid programs, its protections for patients with pre-existing conditions, and, ironically, the very federal program that has allowed the Trump administration to attempt such drastic action to regulate lower drug prices.Azar and Verma also attempted to cast past health care actions, including a measure on hospital price transparency, as part of Trump’s new plan, perhaps in recognition of Trump’s precarious Election Day position on most health care issues.Trump trails his Democratic challenger, Joe Biden, on most health care issues, according to polls. Americans disapprove of the administration’s chaotic Covid-19 response by wide margins. And one recent Kaiser Family Foundation survey found a majority of voters trust Biden over Trump on protecting patients with pre-existing conditions, ensuring access to insurance, and protecting the Affordable Care Act, though Trump held a slight advantage on plans to tackle high drug prices..

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    Special edition cover of the classic song “We Are Family’ will be accompanied by a worldwide viral video starring celebrities, frontline health heroes, leaders and members of the public singing together in a show of solidarity and support for addressing present and http://www.amisdepasteur.fr/canadian-levitra-online/ future global stacking cialis and levitra public health needs, including COVID-19. Launching today, the #WeAreFamily video campaign will invite people worldwide to star in the music video, recording videos of themselves with their close family and friends singing the song and then sharing this on their social media channels. Part of the proceeds stacking cialis and levitra from the new song, being released 9 Nov, will be donated to the WHO Foundation to support the response to COVID-19 and promotion and protection of health for people around the world. A special edition cover of Sister Sledge’s timeless hit We Are Family will be released in a new and inspiring call for global solidarity to respond to the COVID-19 pandemic and to generate proceeds to address the most pressing global health challenges of our time.

    The initiative is being launched by The World We Want, the global social impact enterprise, and Kim Sledge, part of the legendary multi-Gold and Platinum recording music group, in benefit of the WHO Foundation, and supported by the World Health Organization (WHO).This new initiative, being launched ahead of United Nations Day on 24 October, will also be accompanied by a unique video and social media campaign, and sound a bold and hopeful call for solidarity, unity, and collaboration to promote and protect the health and wellbeing for every person on the planet. A call for stacking cialis and levitra solidarity The inspiration to release a special edition of the classic track came in March 2020 as communities around the world were left reeling from the impact of COVID-19.Kim Sledge said. €œFrom the doctors and nurses on the front lines, to the paramedics and police, from the midwives and scientists to the carers for the vulnerable, the We Are Family initiative will salute each and every one with a feeling of unity, strength and solidarity in response to the unprecedented challenges the world faces as a result of the coronavirus outbreak.”“There are many people who motivated me to embark on this new initiative in support of making We Are Family come to life, and who are very dedicated to finding ways to conquer this crisis. They include my close family friend stacking cialis and levitra Lou Weisbach, my Mercy Seat Ministry brothers and sisters, and all of the global health workers, scientists, the essential labourers, care givers and emergency personnel around the world who have been working day and night during the pandemic in support of others,” added Kim, a vocalist, philanthropist, novelist, songwriter, producer and Minister.Using music’s universal power in bringing the world together, the #WeAreFamily campaign is focused on raising awareness on, and much needed resources for, addressing global public health needs, from emergency preparedness, outbreak response, and stronger health systems to promoting mental health and preventing non-communicable diseases.Natasha Mudhar, founder of The World We Want and the driving force behind the #WeAreFamily campaign, said.

    €œWe Are Family is one of the most instantly recognizable anthems in the world. The song carries such an inspiring message of unity and solidarity. We are certain that the We Are Family song and video initiative is being stacking cialis and levitra launched at the right time. It is a rallying cry for togetherness, for the strength of our global family.

    We are all together during these times.”Special edition version song to support health effortsThe special edition of the classic We Are Family song will be released online for download on 9 November 2020 in conjunction with the opening of the World Health Assembly, at which Kim Sledge is stacking cialis and levitra also scheduled to perform the song alongside choral singers from New York to Tonga. A portion of the song’s proceeds will be donated to the WHO Foundation to support the delivery of life-saving health services.Dr Tedros Adhanom Ghebreyesus, the Director-General of the World Health Organization, said. €œWe Are Family is more than a song. It is a call to action for stacking cialis and levitra collaboration and kindness, and a reminder of the strength of family and the importance of coming together to help others in times of need.”Dr Tedros added.

    €œNow more than ever, communities and individuals all over the world need to heed this message and come together, as a global family, to support each other through this COVID-19 challenge, and to remember that our health and wellbeing is our most precious gift. I am grateful to Kim Sledge and the World We Want for sharing this masterpiece and message of stacking cialis and levitra hope with us all. It is only through national unity and global solidarity that we will overcome COVID-19 and ensure people all over the world attain the highest level of health and well-being."Join the We Are Family video campaignIn support of the song’s release, a call is being launched today (19 October) for people worldwide to submit videos of themselves singing We Are Family for inclusion in a unique and inspiring compilation video for release on 7 December 2020. This video will honour the incredible work of the frontline workforces risking their lives around to save ours, and all those around the world who have been affected by the pandemic.To submit sing-along videos to the Special Edition Cover Version of the We Are Family song, the key steps are.

    Record yourself singing We Are Family either alone, stacking cialis and levitra or with friends and family, whilst observing physical distancing guidelines. Share the video on your favourite social media channel, with the hashtag #WeAreFamily #COVID19 #HealthforAll and tag @WHO, @The_WorldWeWant and @thewhof. Upload your video to https://unitystrong.com stacking cialis and levitra. If you want your video to be considered for inclusion in the global We Are Family video, you will need to share your video by Monday, 30 November 2020.

    Video clips will be selected based on age, geographical diversity, and appropriate physical distancing if the video includes groups of people beyond immediate family members and correct handwashing if singing along to the song while washing hands. More details including Terms stacking cialis and levitra &. Conditions can be found here www.unitystrong.com. For further information, please contact The World We Want stacking cialis and levitra.

    WAFmedia@theworldwewant.globalThe World Health Organization has appointed two distinguished leaders to co-chair an Independent Commission on sexual abuse and exploitation during the response to the tenth Ebola Virus Disease epidemic in the provinces of North Kivu and Ituri, the Democratic Republic of the Congo. The commission will be co-chaired by Her Excellency Aïchatou Mindaoudou, former minister of foreign affairs and of social development of Niger, who has held senior United Nations posts in Côte d’Ivoire and in Darfur. She will be joined by co-chair Julienne Lusenge of the Democratic Republic of the stacking cialis and levitra Congo, an internationally recognized human rights activist and advocate for survivors of sexual violence in conflict. The role of the Independent Commission will be to swiftly establish the facts, identify and support survivors, ensure that any ongoing abuse has stopped, and hold perpetrators to account.

    It will comprise up to seven members, including the co-chairs, with expertise stacking cialis and levitra in sexual exploitation and abuse, emergency response, and investigations. The co-chairs will choose the other members of the Commission, which will be supported by a Secretariat based at WHO. To support the Independent Commission’s work, the Director-General has decided to use an open process to hire an independent and external organization with experience in conducting similar inquiries. The tenth epidemic of Ebola Virus Disease in the provinces of North Kivu and Ituri – the world’s second largest Ebola outbreak on record – was declared over on 25 June 2020, after persisting for nearly two years in stacking cialis and levitra an active conflict zone, and causing 2,300 deaths.

    WHO has a zero tolerance policy with regard to sexual exploitation and abuse. We reiterate our strong commitment to preventing and protecting against sexual exploitation and abuse in all our operations around the world..

    Special edition cover of the classic song “We Are Family’ will be accompanied by a worldwide viral video starring celebrities, frontline health heroes, leaders and members of the public singing together in a show of levitra price australia solidarity and support for addressing present and future global public health needs, including COVID-19. Launching today, the #WeAreFamily video campaign will invite people worldwide to star in the music video, recording videos of themselves with their close family and friends singing the song and then sharing this on their social media channels. Part levitra price australia of the proceeds from the new song, being released 9 Nov, will be donated to the WHO Foundation to support the response to COVID-19 and promotion and protection of health for people around the world.

    A special edition cover of Sister Sledge’s timeless hit We Are Family will be released in a new and inspiring call for global solidarity to respond to the COVID-19 pandemic and to generate proceeds to address the most pressing global health challenges of our time. The initiative is being launched by The World We Want, the global social impact enterprise, and Kim Sledge, part of the legendary multi-Gold and Platinum recording music group, in benefit of the WHO Foundation, and supported by the World Health Organization (WHO).This new initiative, being launched ahead of United Nations Day on 24 October, will also be accompanied by a unique video and social media campaign, and sound a bold and hopeful call for solidarity, unity, and collaboration to promote and protect the health and wellbeing for every person on the planet. A call for solidarity levitra price australia The inspiration to release a special edition of the classic track came in March 2020 as communities around the world were left reeling from the impact of COVID-19.Kim Sledge said.

    €œFrom the doctors and nurses on the front lines, to the paramedics and police, from the midwives and scientists to the carers for the vulnerable, the We Are Family initiative will salute each and every one with a feeling of unity, strength and solidarity in response to the unprecedented challenges the world faces as a result of the coronavirus outbreak.”“There are many people who motivated me to embark on this new initiative in support of making We Are Family come to life, and who are very dedicated to finding ways to conquer this crisis. They include my close family friend Lou Weisbach, my Mercy Seat Ministry brothers and sisters, and all of the global health workers, scientists, the essential labourers, care givers and emergency personnel around the world who have been working day and night during the pandemic in support of others,” added Kim, a vocalist, philanthropist, novelist, songwriter, producer and Minister.Using music’s universal power in bringing the world together, the #WeAreFamily campaign is focused on raising awareness on, and much needed resources for, addressing global public health needs, from emergency preparedness, outbreak response, and stronger health systems to promoting mental health and preventing non-communicable diseases.Natasha Mudhar, founder of The World We Want and the driving force behind the #WeAreFamily campaign, said levitra price australia. €œWe Are Family is one of the most instantly recognizable anthems in the world.

    The song carries such an inspiring message of unity and solidarity. We are certain that the We Are Family song and video initiative is being launched at levitra price australia the right time. It is a rallying cry for togetherness, for the strength of our global family.

    We are all together during these times.”Special edition version song to support health effortsThe special edition of the classic We Are Family song will be released online for download on 9 November 2020 in conjunction with the opening of the levitra price australia World Health Assembly, at which Kim Sledge is also scheduled to perform the song alongside choral singers from New York to Tonga. A portion of the song’s proceeds will be donated to the WHO Foundation to support the delivery of life-saving health services.Dr Tedros Adhanom Ghebreyesus, the Director-General of the World Health Organization, said. €œWe Are Family is more than a song.

    It is a call to action for collaboration and kindness, and levitra price australia a reminder of the strength of family and the importance of coming together to help others in times of need.”Dr Tedros added. €œNow more than ever, communities and individuals all over the world need to heed this message and come together, as a global family, to support each other through this COVID-19 challenge, and to remember that our health and wellbeing is our most precious gift. I am grateful to Kim Sledge and the World We Want for sharing this masterpiece and message of hope with us all levitra price australia.

    It is only through national unity and global solidarity that we will overcome COVID-19 and ensure people all over the world attain the highest level of health and well-being."Join the We Are Family video campaignIn support of the song’s release, a call is being launched today (19 October) for people worldwide to submit videos of themselves singing We Are Family for inclusion in a unique and inspiring compilation video for release on 7 December 2020. This video will honour the incredible work of the frontline workforces risking their lives around to save ours, and all those around the world who have been affected by the pandemic.To submit sing-along videos to the Special Edition Cover Version of the We Are Family song, the key steps are. Record yourself singing We Are Family levitra price australia either alone, or with friends and family, whilst observing physical distancing guidelines.

    Share the video on your favourite social media channel, with the hashtag #WeAreFamily #COVID19 #HealthforAll and tag @WHO, @The_WorldWeWant and @thewhof. Upload your video levitra price australia to https://unitystrong.com. If you want your video to be considered for inclusion in the global We Are Family video, you will need to share your video by Monday, 30 November 2020.

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    For further information, please contact levitra price australia The World We Want. WAFmedia@theworldwewant.globalThe World Health Organization has appointed two distinguished leaders to co-chair an Independent Commission on sexual abuse and exploitation during the response to the tenth Ebola Virus Disease epidemic in the provinces of North Kivu and Ituri, the Democratic Republic of the Congo. The commission will be co-chaired by Her Excellency Aïchatou Mindaoudou, former minister of foreign affairs and of social development of Niger, who has held senior United Nations posts in Côte d’Ivoire and in Darfur.

    She will be levitra price australia joined by co-chair Julienne Lusenge of the Democratic Republic of the Congo, an internationally recognized human rights activist and advocate for survivors of sexual violence in conflict. The role of the Independent Commission will be to swiftly establish the facts, identify and support survivors, ensure that any ongoing abuse has stopped, and hold perpetrators to account. It will comprise up to seven members, including the co-chairs, with expertise in sexual exploitation and abuse, emergency response, and levitra price australia investigations.

    The co-chairs will choose the other members of the Commission, which will be supported by a Secretariat based at WHO. To support the Independent Commission’s work, the Director-General has decided to use an open process to hire an independent and external organization with experience in conducting similar inquiries. The tenth epidemic of Ebola Virus Disease in the provinces of North Kivu and Ituri – the world’s second largest Ebola outbreak on record – was declared over on levitra price australia 25 June 2020, after persisting for nearly two years in an active conflict zone, and causing 2,300 deaths.

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    Many unaware they are sick On average, one in four men suffer from the condition, compared with one in five women, according to WHO data. In addition, two in five people are not aware that they even have levitra sale hypertension. €œWhen it comes to COVID-19 and hypertension, the 122 countries that have reported tells us that in over 50 per cent of the countries their health care services is disrupted fully or partially…In addition, we see a high number of fatalities”, Dr. Mikkelsen told journalists in Geneva.

    Noting that global figures have yet to be calculated, she added that for those countries where data was available, “we see in the range of 50, 60 per cent levitra sale of the people that are severely ill and die in hospitals from COVID have hypertension, diabetes”, and other non-communicable diseases. Pandemic resurgence Highlighting how the pandemic has made a resurgence in many countries across all continents after the easing of restrictions, and the additional health threat posed by the impending influenza season in the global north, the WHO official appealed to governments everywhere to address hypertension urgently. She also cited growing evidence that poor and salty diets along with rising inactivity, have contributed to worsening hypertension rates globally. To coincide with World Hypertension Day on 16 October, Dr Mikkelsen unveiled a series of recommendations and products developed by the WHO to promote action on hypertension “during and beyond the levitra sale pandemic”.

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    Kluge said the tightening up of restrictions by governments is “absolutely necessary” as the disease continues to surge, with “exponential increases” in cases and deaths. €œThe evolving epidemiological situation in Europe levitra sale raises great concern. Daily numbers of cases are up, hospital admissions are up, COVID-19 is now the fifth leading cause of death and the bar of 1,000 deaths per day has now been reached,” he reported. Cases reach record highs Dr.

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    The doubling time in hospital admissions is still two to three times longer,” he said, adding “in the meantime, the virus has not changed. It has not become more nor less dangerous.” Potential worsening a reality Dr. Kluge explained that one reason for the higher case rates is increased COVID-19 levitra sale testing, including among younger people. This population also partly accounts for the decreased mortality rates.

    “These figures say that the epidemiological curve rebound is so far higher, but the slope is lower and less fatal for now. But it has levitra sale the realistic potential to worsen drastically if the disease spreads back into older age cohorts after more indoor social contacts across generations,” he warned. Looking ahead, Dr. Kluge admitted that projections are “not optimistic”.

    Reliable epidemiological models indicate that prolonged relaxing of policies levitra sale could result in mortality levels four to five times higher than in April, with results visible by January 2021. He stressed the importance of maintaining simple measures already in place, as the modelling shows how wearing masks, coupled with strict control of social gathering, may save up to 281,000 lives across the region by February. This assumes a 95 per cent rate for mask use, up from the current rate, which is less than 60 per cent. Restrictions ‘absolutely necessary’ “Under proportionately more stringent scenarios, the model is reliably much more optimistic, still with slightly higher levels of morbidity and mortality than in the first wave, but with a lower slope – as if we should rather expect a higher and levitra sale longer swell instead of a sharp peak, giving us more reaction time,” said Dr.

    Kluge. “These projections do nothing but confirm what we always said. The pandemic levitra sale won’t reverse its course on its own, but we will.” The WHO bureau chief underlined the importance of targeted national responses to contain COVID-19 spread. €œMeasures are tightening up in many countries in Europe, and this is good because they are absolutely necessary,” he said.

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    The Solidarity Therapeutics Trial, overseen by the World Health Organization (WHO), shows that medications Remdesivir, hydroxychloroquine, levitra price australia lopinavir/ritonavir and interferon, repurposed to treat new coronavirus infections, “appeared to have little or no effect on 28-day mortality or the in-hospital course of COVID-19 among hospitalized patients”, WHO levitra generico usa said in a statement on Friday. The study, which began in March and spans more than 30 countries, looked at the effects of these treatments on overall mortality, initiation of ventilation, and duration of hospital stay in hospitalized individuals. Other uses of the drugs, for example in treatment of patients in the community or for prevention, would have to be examined using different trials, the WHO explained.

    Associated blood pressure risks In a related announcement, the UN health agency said that COVID-19 had levitra price australia also highlighted the increased vulnerability of people with high blood pressure to the coronavirus. The warning is based on data from more than 120 countries showing significant COVID-related disruption to treatment for people suffering from chronic health conditions, with findings showing these patients make up 50 to 60 per cent of all deaths from COVID. Dr.

    Bente Mikkelsen, Director of WHO’s Department of Noncommunicable Diseases, said that levitra price australia more than 1.13 billion people around the world suffer from hypertension. Of this number, 745,800,000 live in low and middle-income countries and 80 per cent of these nations have fewer than 50 per cent of people on treatment. Many unaware they are sick On average, one in four men suffer from the condition, compared with one in five women, according to WHO data.

    In addition, two in five people are not aware levitra price australia that they even have hypertension. €œWhen it comes to COVID-19 and hypertension, the 122 countries that have reported tells us that in over 50 per cent of the countries their health care services is disrupted fully or partially…In addition, we see a high number of fatalities”, Dr. Mikkelsen told journalists in Geneva.

    Noting that global figures have yet to be calculated, she added levitra price australia that for those countries where data was available, “we see in the range of 50, 60 per cent of the people that are severely ill and die in hospitals from COVID have hypertension, diabetes”, and other non-communicable diseases. Pandemic resurgence Highlighting how the pandemic has made a resurgence in many countries across all continents after the easing of restrictions, and the additional health threat posed by the impending influenza season in the global north, the WHO official appealed to governments everywhere to address hypertension urgently. She also cited growing evidence that poor and salty diets along with rising inactivity, have contributed to worsening hypertension rates globally.

    To coincide levitra price australia with World Hypertension Day on 16 October, Dr Mikkelsen unveiled a series of recommendations and products developed by the WHO to promote action on hypertension “during and beyond the pandemic”. By doing so, health authorities can help people to keep their blood pressure under control and prevent stroke, heart attack, and kidney damage, the WHO believes. The new protocols are based on successful patient blood pressure management in 18 countries involving more three million people.

    Today, only 20 per cent of the world’s nations are on track to reduce hypertension by 25 per cent by 2025, a global levitra price australia target set by the World Health Assembly in 2013, according to the UN health agency.Dr. Hans Henri P. Kluge said the tightening up of restrictions by governments is “absolutely necessary” as the disease continues to surge, with “exponential increases” in cases and deaths.

    €œThe evolving epidemiological situation in levitra price australia Europe raises great concern. Daily numbers of cases are up, hospital admissions are up, COVID-19 is now the fifth leading cause of death and the bar of 1,000 deaths per day has now been reached,” he reported. Cases reach record highs Dr you could check here.

    Kluge said overall, Europe has recorded more than seven million cases of COVID-19, with the jump from six million taking levitra price australia just 10 days. This past weekend, daily case totals surpassed 120,000 for the first time, and on both Saturday and Sunday, reaching new records. However, he stressed that the region has not returned to the early days of the pandemic.

    €œAlthough we record two to three times more levitra price australia cases per day compared to the April peak, we still observe five times fewer deaths. The doubling time in hospital admissions is still two to three times longer,” he said, adding “in the meantime, the virus has not changed. It has not become more nor less dangerous.” Potential worsening a reality Dr.

    Kluge explained that one reason levitra price australia for the higher case rates is increased COVID-19 testing, including among younger people. This population also partly accounts for the decreased mortality rates. “These figures say that the epidemiological curve rebound is so far higher, but the slope is lower and less fatal for now.

    But it has the realistic potential to worsen drastically if the disease spreads back into older age cohorts after more indoor social contacts across generations,” he levitra price australia warned. Looking ahead, Dr. Kluge admitted that projections are “not optimistic”.

    Reliable epidemiological models indicate that prolonged relaxing of policies levitra price australia could result in mortality levels four to five times higher than in April, with results visible by January 2021. He stressed the importance of maintaining simple measures already in place, as the modelling shows how wearing masks, coupled with strict control of social gathering, may save up to 281,000 lives across the region by February. This assumes a 95 per cent rate for mask use, up from the current rate, which is less than 60 per cent.

    Restrictions ‘absolutely necessary’ “Under proportionately more stringent scenarios, the model is reliably much more optimistic, still with slightly higher levels of morbidity and mortality than in the first wave, but with a lower slope – as if we should rather expect a higher and longer swell instead of a sharp peak, levitra price australia giving us more reaction time,” said Dr. Kluge. “These projections do nothing but confirm what we always said.

    The pandemic won’t reverse its course on its own, but levitra price australia we will.” The WHO bureau chief underlined the importance of targeted national responses to contain COVID-19 spread. €œMeasures are tightening up in many countries in Europe, and this is good because they are absolutely necessary,” he said. €œThey are appropriate and necessary responses to what the data is telling us.

    Transmission and sources of contamination occur in homes and indoor public places, and within communities poorly complying with self-protection measures.”.

    Levitra price comparison

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    In 1835 French philosopher Auguste go to website Comte asserted that nobody would ever know what the levitra price comparison stars were made of. €œWe understand the possibility of determining their shapes, their distances, their sizes and their movements,” he wrote, “whereas we would never know how to study by any means their chemical composition, or their mineralogical structure, and, even more so, the nature of any organized beings that might live on their surface.” Comte would be stunned by the discoveries made since then. Today we know that the universe is far bigger and stranger than anyone suspected. Not only does it extend beyond the Milky Way to untold numbers of other galaxies—this would come as a surprise to astronomers of the 19th levitra price comparison and early 20th century to whom our galaxy was “the universe”—but it is expanding faster every day. Now we can confidently trace cosmic history back 13.8 billion years to a moment only a billionth of a second after the big bang.

    Astronomers have pinned down our universe's expansion rate, the mean density of its main constituents, and other key numbers to a precision of 1 or 2 percent. They have levitra price comparison also worked out new laws of physics governing space—general relativity and quantum mechanics—that turn out to be much more outlandish than the classical laws people understood before. These laws in turn predicted cosmic oddities such as black holes, neutron stars and gravitational waves. The story of how we gained this knowledge is full of accidental discoveries, stunning surprises and dogged scientists pursuing goals others thought unreachable. Our first hint of the true nature of stars came in 1860, when Gustav Kirchhoff recognized that the dark lines in the spectrum of light coming from the sun were caused by different levitra price comparison elements absorbing specific wavelengths.

    Astronomers analyzed similar features in the light of other bright stars and discovered that they were made of the same materials found on Earth—not of some mysterious “fifth essence” as the ancients had believed. But it took longer to understand what fuel made the stars shine. Lord Kelvin (William Thomson) calculated that if stars derived their power just from gravity, slowly deflating as their radiation leaked out, then the sun's age was 20 million to 40 million years—far less time than Charles Darwin or the geologists of levitra price comparison the time inferred had elapsed on Earth. In his last paper on the subject, in 1908, Kelvin inserted an escape clause stating that he would stick by his estimate “unless there were some other energy source laid up in the storehouse of creation.” That source, it turned out, is nuclear fusion—the process by which atomic nuclei join to create a larger nucleus and release energy. In 1925 astrophysicist Cecilia Payne-Gaposchkin used the light spectra of stars to calculate their chemical abundances and found that, unlike Earth, they were made mainly of hydrogen and helium.

    She revealed her conclusions in what astronomer Otto Struve described as levitra price comparison “the most brilliant Ph.D. Thesis ever written in astronomy.” A decade later physicist Hans Bethe showed that the fusion of hydrogen nuclei into helium was the main power source in ordinary stars. What is the source of the sun's power?. The answer—fusion—came in levitra price comparison 1938. Credit.

    SOHO (ESA and NASA) At the same time stars were becoming less mysterious, so, too, was the nature of fuzzy “nebulae” becoming clearer. In a “great debate” held before levitra price comparison the National Academy of Sciences in Washington, D.C., on April 26, 1920, Harlow Shapley maintained that our Milky Way was preeminent and that all the nebulae were part of it. In contrast, Heber Curtis argued that some of the fuzzy objects in the sky were separate galaxies—“island universes”—fully the equal of our Milky Way. The conflict was settled not that night but just a few years later, in 1924, when Edwin Hubble measured the distances to many nebulae and proved they were beyond the reaches of the Milky Way. His evidence came from Cepheids, variable stars in the nebulae that reveal their true brightness, levitra price comparison and thus their distance, by their pulsation period—a relation discovered by Henrietta Swan Leavitt.

    Soon after Hubble realized that the universe was bigger than many had thought, he found that it was still growing. In 1929 he discovered that spectral features in the starlight from distant galaxies appeared redder—that is, they had longer wavelengths—than the same features in nearby stars. If this effect was interpreted as a Doppler shift—the natural spreading of waves as they recede—it would imply that other galaxies were levitra price comparison moving away from one another and from us. Indeed, the farther away they were, the faster their recession seemed to be. This was the first clue that our cosmos was not static but was expanding all the time.

    The universe also appeared to levitra price comparison contain much that we could not see. In 1933 Fritz Zwicky estimated the mass of all the stars in the Coma cluster of galaxies and found that they make up only about 1 percent of the mass necessary to keep the cluster from flying apart. The discrepancy was dubbed “the missing mass problem,” but many scientists at the time doubted Zwicky's suggestion that hidden matter might be to blame. The question remained levitra price comparison divisive until the 1970s, when work by Vera Rubin and W. Kent Ford (observing stars) and by Morton Roberts and Robert Whitehurst (making radio observations) showed that the outer parts of galactic disks would also fly apart unless they were subject to a stronger gravitational pull than stars and gas alone could provide.

    Finally, most astronomers were compelled to accept that some kind of “dark matter” must be present. €œWe have peered into a new world,” Rubin wrote, “and have seen that it is more mysterious and more complex than we had imagined.” Scientists now believe that dark matter outnumbers visible matter by about a factor levitra price comparison of five, yet we are hardly closer than we were in the 1930s to figuring out what it is. Gravity, the force that revealed all that dark matter, has proved to be nearly as baffling. A pivotal moment came in 1915 when Albert Einstein published his general theory of relativity, which transcended Isaac Newton's mechanics and revealed that gravity is actually the deformation of the fabric of space and time. This new levitra price comparison theory was slow to take hold.

    Even after it was shown to be correct by observations of a 1919 solar eclipse, many dismissed the theory as an interesting quirk—after all, Newton's laws were still good enough for calculating most things. €œThe discoveries, while very important, did not, however, affect anything on this earth,” astronomer W.J.S. Lockyer told the New York Times levitra price comparison after the eclipse. For almost half a century after it was proposed, general relativity was sidelined from the mainstream of physics. Then, beginning in the 1960s, astronomers started discovering new and extreme phenomena that only Einstein's ideas could explain.

    One example lurks in the Crab Nebula, one of the best-known objects in the levitra price comparison sky, which is composed of the expanding debris from a supernova witnessed by Chinese astronomers in a.d. 1054. Since it appeared, the nebula has kept on shining blue and bright—but how?. Its light source was a longtime puzzle, but the levitra price comparison answer came in 1968, when the dim star at its center was revealed to be anything but normal. It was actually an ultracompact neutron star, heavier than the sun but only a few miles in radius and spinning at 30 revolutions per second.

    €œThis was a totally unexpected, totally new kind of object behaving in a way that astronomers had never expected, never dreamt of,” said Jocelyn Bell Burnell, one of the discoverers of the phenomenon. The star's excessive spin sends levitra price comparison out a wind of fast electrons that generate the blue light. The gravitational force at the surface of such an incredibly dense object falls way outside of Newton's purview—a rocket would need to be fired at half the speed of light to escape its pull. Here the relativistic effects predicted by Einstein must be taken into account. Thousands of such spinning neutron stars—called pulsars—have been discovered levitra price comparison.

    All are believed to be remnants of the cores of stars that exploded as supernovae, offering an ideal laboratory for studying the laws of nature under extreme conditions. The most exotic result of Einstein's theory was the concept of black holes—objects that have collapsed so far that not even light can escape their gravitational pull. For decades these were only conjecture, and Einstein wrote in 1939 that they “do not levitra price comparison exist in physical reality.” But in 1963 astronomers discovered quasars. Mysterious, hyperluminous beacons in the centers of some galaxies. More than a decade passed before a consensus emerged that this intense brightness was generated by gas swirling into huge black holes lurking in the galaxies' cores.

    It was the strongest evidence yet that these bizarre predictions of general levitra price comparison relativity actually exist. When did the universe begin?. Did it even have a beginning?. Astronomers had long debated these questions when, in the middle of the 20th levitra price comparison century, two competing theories proposed very different answers. The “hot big bang” model said the cosmos began extremely small, hot and dense and then cooled and spread out over time.

    The “steady state” hypothesis held that the universe had essentially existed in the same form forever. The contest was settled by a levitra price comparison serendipitous discovery. In 1965 radio astronomers Arno Penzias and Robert Wilson were trying to calibrate a new antenna at Bell Labs in New Jersey. They had a problem. No matter what they did to levitra price comparison reduce background interference, they measured a consistent level of noise in every direction.

    They even evicted a family of pigeons that had been nesting in the antenna in the hope that they were the source of the problem. But the signal persisted. They had discovered that intergalactic levitra price comparison space is not completely cold. Instead it is warmed to nearly three kelvins (just above absolute zero) by weak microwaves. Penzias and Wilson had accidentally uncovered the “afterglow of creation”—the cooled and diluted relic of an era when everything in the universe was squeezed until it was hot and dense.

    The finding tipped the levitra price comparison balance firmly in favor of the big bang picture of cosmology. According to the model, during the earliest, hottest epochs of time, the universe was opaque, rather like the inside of a star, and light was repeatedly scattered by electrons. When the temperature fell to 3,000 kelvins, however, the electrons slowed down enough to be captured by protons and created neutral atoms. Thereafter light levitra price comparison could travel freely. The Bell Labs signal was this ancient light, first released about 300,000 years after the birth of the universe and still pervading the cosmos—what we call the cosmic microwave background.

    It took a while for the magnitude of the discovery to sink in for the scientists who made it. €œWe were very pleased to have a possible explanation [for the antenna noise], but I don't think either of us really took the cosmology very seriously at first,” levitra price comparison Wilson says. €œWalter Sullivan wrote a first-page article in the New York Times about it, and I began to think at that point that, you know, maybe I better start taking this cosmology seriously.” Measurements of this radiation have since enabled scientists to understand how galaxies emerged. Precise observations of the microwaves reveal that they are not completely uniform over the sky. Some patches are slightly levitra price comparison hotter, others slightly cooler.

    The amplitude of these fluctuations is only one part in 100,000, but they are the seeds of today's cosmic structure. Any region of the expanding universe that started off slightly denser than average expanded less because it was subjected to extra gravity. Its growth lagged further and further, the contrast levitra price comparison between its density and that of its surroundings becoming greater and greater. Eventually these clumps were dense enough that gas was pulled in and compressed into stars, forming galaxies. The crucial point is this.

    Computer models that simulate this process are fed the initial fluctuations measured in levitra price comparison the cosmic microwave background, which represent the universe when it was 300,000 years old. The output after 13.8 billion years of virtual time have elapsed is a cosmos where galaxies resemble those we see, clustered as they are in the actual universe. This is a real can you buy levitra triumph. We understand, at least in outline, 99.998 percent of cosmic history. It is not only levitra price comparison the big cosmic picture that we have come to understand.

    A series of discoveries has also revealed the history of the elemental building blocks that make up stars, planets and even our own bodies. Starting in the 1950s, progress in atomic physics led to accurate modeling of stars' surface layers. Simultaneously, detailed knowledge of the nuclei not just of hydrogen and helium atoms but also of the rest of the elements levitra price comparison allowed scientists to calculate which nuclear reactions dominate at different stages in a star's life. Astronomers came to understand how nuclear fusion creates an onion-skin structure in massive stars as atoms successively fuse to build heavier and heavier elements, ending with iron in the innermost, hottest layer. Inside the Crab Nebula is a neutron star.

    Classical physics fails, and relativity applies levitra price comparison. Credit. NASA, ESA and Hubble Heritage Team (STSCI and AURA) Astronomers also learned how stars die when they exhaust their hydrogen fuel and blow off their outer gaseous layers. Lighter stars then settle down levitra price comparison to a quiet demise as dense, dim objects called white dwarfs, but heavier stars shed more of their mass, either in winds during their lives or in an explosive death via supernova. This expelled mass turns out to be crucial to our own existence.

    It mixes into the interstellar medium and recondenses into new stars orbited by planets such as Earth. The concept was conceived by Fred Hoyle, levitra price comparison who developed it during the 1950s along with two other British astronomers, Margaret Burbidge and Geoffrey Burbidge, and American nuclear physicist William Fowler. In their classic 1957 paper in Reviews of Modern Physics (known by the initials of its authors as BBFH), they analyzed the networks of the nuclear reactions involved and discovered how most atoms in the periodic table came to exist. They calculated why oxygen and carbon, for instance, are common, whereas gold and uranium are rare. Our galaxy, it levitra price comparison turns out, is a huge ecological system where gas is being recycled through successive generations of stars.

    Each of us contains atoms forged in dozens of different stars spread across the Milky Way that lived and died more than 4.5 billion years ago. Scientists long assumed this process was seeding planets—and possibly even life—around stars other than our own sun. But we did not know for sure whether planets existed outside our solar system until the 1990s, when astronomers developed levitra price comparison clever methods for identifying worlds that are too dim for us to see directly. One technique looks for tiny periodic changes in a star's movement caused by the gravitational pull of a planet orbiting it. In 1995 Michel Mayor and Didier Queloz used this strategy to detect 51 Pegasi b, the first known exoplanet orbiting a sunlike star.

    The technique can reveal a planet's mass, the length of levitra price comparison its “year” and the shape of its orbit. So far more than 800 exoplanets have been found this way. A second technique works better for smaller planets. A star dims slightly when a planet transits in levitra price comparison front of it. An Earth-like planet passing a sunlike star can cause a dimming of about one part in 10,000 once per orbit.

    The Kepler spacecraft launched in 2009 found more than 2,000 planets this way, many no bigger than Earth. A big levitra price comparison surprise to come from astronomers' success in planet hunting was the variety of different planets out there—many much larger and closer to their stars than the bodies in our solar system—suggesting that our cosmic neighborhood may be somewhat special. By this point scientists understood where almost all the elements that form planets, stars and galaxies originated. The final piece in this puzzle, however, arrived very recently and from a seemingly unrelated inquiry. General relativity had predicted a phenomenon called gravitational waves—ripples in spacetime produced by the movement of massive objects levitra price comparison.

    Despite decades of searching for them, however, no waves were seen—until September 2015. That was when the Laser Interferometer Gravitational-wave Observatory (LIGO) detected the first evidence of gravitational waves in the form of a “chirp”—a minute shaking of spacetime that speeds up and then dies away. In this case, it was caused by two black holes in a binary system that had started out orbiting each other but gradually spiraled together and eventually converged levitra price comparison into a single massive hole. The crash occurred more than a billion light-years away. LIGO's detectors consist of mirrors four kilometers apart whose separation is measured by laser beams that reflect light back and forth between them.

    A passing gravitational wave causes the space between the two mirrors to jitter by levitra price comparison an amount millions of times as small as the diameter of a single atom—LIGO is indeed an amazing feat of precision engineering and perseverance. Since that first find, more than a dozen similar events have been detected, opening up a new field that probes the dynamics of space itself. One event was of special astrophysical interest because it signaled the merger of two pulsars. Unlike black hole mergers, this kind levitra price comparison of collision, a splat between two ultradense stars, yields a pulse of optical light, x-rays and gamma rays. The discovery filled a gap in the classic work of BBFH.

    The authors had explained the genesis of many of the elements in space but were flummoxed by the forging of gold. In the 1970s levitra price comparison David N. Schramm and his colleagues had speculated that the exotic nuclear processes involved in hypothetical mergers of pulsar stars might do the job—a theory that has since been validated. Despite the incredible progress in astronomy over the past 175 years, we have perhaps more questions now than we did back then. Take dark levitra price comparison matter.

    I am on record as having said more than 20 years ago that we would know dark matter's nature long before today. Although that prediction has proved wrong, I have not given up hope. Dark energy, levitra price comparison however, is a different story. Dark energy entered the picture in 1998, when researchers measuring the distances and speeds of supernovae found that the expansion of the universe was actually accelerating. Gravitational attraction pulling galaxies toward one another seemed to be overwhelmed by a mysterious new force latent in empty space that pushes galaxies apart—a force that came to be known as dark energy.

    The mystery of dark energy has lingered—we still do not know what causes it or why it has the particular strength it does—and we probably will not understand it until we have a model for the graininess of space on a scale a billion billion times smaller than an atomic levitra price comparison nucleus. Theorists working on string theory or loop quantum gravity are tackling this challenge, but the phenomenon seems so far from being accessible by any experiment that I am not expecting answers anytime soon. The upside, however, is that a theory that could account for the energy in the vacuum of space might also yield insights into the very beginning of our universe, when everything was so compressed and dense that quantum fluctuations could shake the entire cosmos. Which brings us to another major question facing us now levitra price comparison. How did it all begin?.

    What exactly set off the big bang that started our universe?. Did space undergo a period of extremely rapid early expansion called inflation, levitra price comparison as many theorists believe?. And there is something else. Some models, such as eternal inflation, suggest that “our” big bang could be just one island of spacetime in a vast archipelago—one big bang among many. If this hypothesis is true, different big bangs may cool down differently, leading to unique laws of physics in each case—a levitra price comparison “multiverse” rather than a universe.

    Some physicists hate the multiverse concept because it means that we will never have neat explanations for the fundamental numbers that govern our physical laws, which may in this grander perspective be just environmental accidents. But our preferences are irrelevant to nature. About 10 years ago I was on a panel at Stanford University where we were asked by someone levitra price comparison in the audience how much we would bet on the multiverse concept. I said that on a scale of betting my goldfish, my dog or my life, I was nearly at the dog level. Andrei Linde, who had spent 25 years promoting eternal inflation, said he would almost bet his life.

    Later, on being told this, physicist Steven Weinberg levitra price comparison said he would happily bet my dog and Linde's life. Linde, my dog and I will all be dead before the question is settled. But none of this should be dismissed as metaphysics. It is levitra price comparison speculative science—exciting science. And it may be true.

    And what will happen to this universe—or multiverse—of ours?. Long-range forecasts are seldom reliable, but the best and most conservative bet is that we have almost an eternity levitra price comparison ahead with an ever colder and ever emptier cosmos. Galaxies will accelerate away and disappear. All that will be left from our vantage point will be the remnants of the Milky Way, Andromeda and smaller neighbors. Protons may levitra price comparison decay, dark matter particles may be annihilated, there may be occasional flashes when black holes evaporate—and then silence.

    This possible future is based on the assumption that the dark energy stays constant. If it decays, however, there could be a “big crunch” with the universe contracting in on itself. Or if dark energy strengthens, there would be a “big rip” when galaxies, stars and even atoms are torn levitra price comparison apart. Other questions closer to home tantalize us. Could there be life on any of these new planets we are discovering?.

    Here levitra price comparison we are still in the realm of speculation. But unless the origin of life on Earth involved a rare fluke, I expect evidence of a biosphere on an exoplanet within 20 years. I will not hold my breath for the discovery of aliens, but I think the search for extraterrestrial intelligence is a worthwhile gamble. Success in the search would carry the momentous message that concepts levitra price comparison of logic and physics are not limited to the hardware in human skulls. Until now, progress in cosmology and astrophysics has owed 95 percent to advancing instruments and technology and less than 5 percent to armchair theory.

    I expect that balance to persist. What Hubble wrote in the 1930s remains a good maxim today. €œNot until the empirical resources are exhausted, need we pass on to the dreamy realms of speculation.” There have been many particularly exhilarating eras in the past 175 years—the 1920s and 1930s, when we realized the universe was not limited to the Milky Way, and the 1960s and 1970s, when we discovered objects that defy classical physics, such as neutron stars and quasars, and clues about the beginning of time from the cosmic microwave background. Since then, the pace of advancement has crescendoed rather than slackened. When the history of science gets written, this amazing progress will be acclaimed as one of its greatest triumphs—up there with plate tectonics, the genome and the Standard Model of particle physics.

    In 1835 French philosopher Auguste Comte asserted that nobody would ever know what the stars were made levitra price australia of. €œWe understand the possibility of determining their shapes, their distances, their sizes and their movements,” he wrote, “whereas we would never know how to study by any means their chemical composition, or their mineralogical structure, and, even more so, the nature of any organized beings that might live on their surface.” Comte would be stunned by the discoveries made since then. Today we know that the universe is far bigger and stranger than anyone suspected. Not only does it extend beyond the Milky Way to untold numbers of other galaxies—this would come as a surprise to astronomers of the 19th and early 20th century to whom our galaxy was levitra price australia “the universe”—but it is expanding faster every day.

    Now we can confidently trace cosmic history back 13.8 billion years to a moment only a billionth of a second after the big bang. Astronomers have pinned down our universe's expansion rate, the mean density of its main constituents, and other key numbers to a precision of 1 or 2 percent. They have also worked out new laws of levitra price australia physics governing space—general relativity and quantum mechanics—that turn out to be much more outlandish than the classical laws people understood before. These laws in turn predicted cosmic oddities such as black holes, neutron stars and gravitational waves.

    The story of how we gained this knowledge is full of accidental discoveries, stunning surprises and dogged scientists pursuing goals others thought unreachable. Our first hint of the true nature of stars came in 1860, when Gustav Kirchhoff recognized that the dark lines in the spectrum of light coming from the sun were caused by different levitra price australia elements absorbing specific wavelengths. Astronomers analyzed similar features in the light of other bright stars and discovered that they were made of the same materials found on Earth—not of some mysterious “fifth essence” as the ancients had believed. But it took longer to understand what fuel made the stars shine.

    Lord Kelvin (William Thomson) calculated that if stars derived their power just from gravity, slowly deflating as their radiation leaked out, then the sun's age was 20 million to 40 million years—far less time than Charles Darwin or the geologists of the time levitra price australia inferred had elapsed on Earth. In his last paper on the subject, in 1908, Kelvin inserted an escape clause stating that he would stick by his estimate “unless there were some other energy source laid up in the storehouse of creation.” That source, it turned out, is nuclear fusion—the process by which atomic nuclei join to create a larger nucleus and release energy. In 1925 astrophysicist Cecilia Payne-Gaposchkin used the light spectra of stars to calculate their chemical abundances and found that, unlike Earth, they were made mainly of hydrogen and helium. She revealed her conclusions in what astronomer levitra price australia Otto Struve described as “the most brilliant Ph.D.

    Thesis ever written in astronomy.” A decade later physicist Hans Bethe showed that the fusion of hydrogen nuclei into helium was the main power source in ordinary stars. What is the source of the sun's power?. The answer—fusion—came in 1938 levitra price australia. Credit.

    SOHO (ESA and NASA) At the same time stars were becoming less mysterious, so, too, was the nature of fuzzy “nebulae” becoming clearer. In a “great debate” held before the National Academy of Sciences in Washington, D.C., on April 26, 1920, Harlow Shapley maintained that our levitra price australia Milky Way was preeminent and that all the nebulae were part of it. In contrast, Heber Curtis argued that some of the fuzzy objects in the sky were separate galaxies—“island universes”—fully the equal of our Milky Way. The conflict was settled not that night but just a few years later, in 1924, when Edwin Hubble measured the distances to many nebulae and proved they were beyond the reaches of the Milky Way.

    His evidence came from Cepheids, variable stars in the nebulae that reveal their true brightness, and thus levitra price australia their distance, by their pulsation period—a relation discovered by Henrietta Swan Leavitt. Soon after Hubble realized that the universe was bigger than many had thought, he found that it was still growing. In 1929 he discovered that spectral features in the starlight from distant galaxies appeared redder—that is, they had longer wavelengths—than the same features in nearby stars. If this effect levitra price australia was interpreted as a Doppler shift—the natural spreading of waves as they recede—it would imply that other galaxies were moving away from one another and from us.

    Indeed, the farther away they were, the faster their recession seemed to be. This was the first clue that our cosmos was not static but was expanding all the time. The universe also appeared to contain much that levitra price australia we could not see. In 1933 Fritz Zwicky estimated the mass of all the stars in the Coma cluster of galaxies and found that they make up only about 1 percent of the mass necessary to keep the cluster from flying apart.

    The discrepancy was dubbed “the missing mass problem,” but many scientists at the time doubted Zwicky's suggestion that hidden matter might be to blame. The question levitra price australia remained divisive until the 1970s, when work by Vera Rubin and W. Kent Ford (observing stars) and by Morton Roberts and Robert Whitehurst (making radio observations) showed that the outer parts of galactic disks would also fly apart unless they were subject to a stronger gravitational pull than stars and gas alone could provide. Finally, most astronomers were compelled to accept that some kind of “dark matter” must be present.

    €œWe have peered into a new world,” Rubin wrote, “and have seen that it is more mysterious and more complex than we had imagined.” Scientists now believe that dark matter outnumbers visible matter by about a factor of five, yet we are hardly closer than we were in the 1930s to figuring out what levitra price australia it is. Gravity, the force that revealed all that dark matter, has proved to be nearly as baffling. A pivotal moment came in 1915 when Albert Einstein published his general theory of relativity, which transcended Isaac Newton's mechanics and revealed that gravity is actually the deformation of the fabric of space and time. This new theory was slow to levitra price australia take hold.

    Even after it was shown to be correct by observations of a 1919 solar eclipse, many dismissed the theory as an interesting quirk—after all, Newton's laws were still good enough for calculating most things. €œThe discoveries, while very important, did not, however, affect anything on this earth,” astronomer W.J.S. Lockyer told the New levitra price australia York Times after the eclipse. For almost half a century after it was proposed, general relativity was sidelined from the mainstream of physics.

    Then, beginning in the 1960s, astronomers started discovering new and extreme phenomena that only Einstein's ideas could explain. One example lurks in levitra price australia the Crab Nebula, one of the best-known objects in the sky, which is composed of the expanding debris from a supernova witnessed by Chinese astronomers in a.d. 1054. Since it appeared, the nebula has kept on shining blue and bright—but how?.

    Its light source was a longtime puzzle, but the answer came in 1968, when the dim star at its center was revealed to be anything but normal levitra price australia. It was actually an ultracompact neutron star, heavier than the sun but only a few miles in radius and spinning at 30 revolutions per second. €œThis was a totally unexpected, totally new kind of object behaving in a way that astronomers had never expected, never dreamt of,” said Jocelyn Bell Burnell, one of the discoverers of the phenomenon. The star's excessive spin sends out a wind of fast electrons that generate the blue levitra price australia light.

    The gravitational force at the surface of such an incredibly dense object falls way outside of Newton's purview—a rocket would need to be fired at half the speed of light to escape its pull. Here the relativistic effects predicted by Einstein must be taken into account. Thousands of such spinning neutron levitra price australia stars—called pulsars—have been discovered. All are believed to be remnants of the cores of stars that exploded as supernovae, offering an ideal laboratory for studying the laws of nature under extreme conditions.

    The most exotic result of Einstein's theory was the concept of black holes—objects that have collapsed so far that not even light can escape their gravitational pull. For decades levitra price australia these were only conjecture, and Einstein wrote in 1939 that they “do not exist in physical reality.” But in 1963 astronomers discovered quasars. Mysterious, hyperluminous beacons in the centers of some galaxies. More than a decade passed before a consensus emerged that this intense brightness was generated by gas swirling into huge black holes lurking in the galaxies' cores.

    It was the strongest evidence yet that these bizarre predictions of general levitra price australia relativity actually exist. When did the universe begin?. Did it even have a beginning?. Astronomers had long debated these questions when, in the middle of the 20th century, two competing theories proposed very levitra price australia different answers.

    The “hot big bang” model said the cosmos began extremely small, hot and dense and then cooled and spread out over time. The “steady state” hypothesis held that the universe had essentially existed in the same form forever. The contest levitra price australia was settled by a serendipitous discovery. In 1965 radio astronomers Arno Penzias and Robert Wilson were trying to calibrate a new antenna at Bell Labs in New Jersey.

    They had a problem. No matter what they did to reduce background interference, they measured a consistent level of noise in every direction levitra price australia. They even evicted a family of pigeons that had been nesting in the antenna in the hope that they were the source of the problem. But the signal persisted.

    They had discovered that levitra price australia intergalactic space is not completely cold. Instead it is warmed to nearly three kelvins (just above absolute zero) by weak microwaves. Penzias and Wilson had accidentally uncovered the “afterglow of creation”—the cooled and diluted relic of an era when everything in the universe was squeezed until it was hot and dense. The finding levitra price australia tipped the balance firmly in favor of the big bang picture of cosmology.

    According to the model, during the earliest, hottest epochs of time, the universe was opaque, rather like the inside of a star, and light was repeatedly scattered by electrons. When the temperature fell to 3,000 kelvins, however, the electrons slowed down enough to be captured by protons and created neutral atoms. Thereafter light could levitra price australia travel freely. The Bell Labs signal was this ancient light, first released about 300,000 years after the birth of the universe and still pervading the cosmos—what we call the cosmic microwave background.

    It took a while for the magnitude of the discovery to sink in for the scientists who made it. €œWe were very pleased to have a possible explanation levitra price australia [for the antenna noise], but I don't think either of us really took the cosmology very seriously at first,” Wilson says. €œWalter Sullivan wrote a first-page article in the New York Times about it, and I began to think at that point that, you know, maybe I better start taking this cosmology seriously.” Measurements of this radiation have since enabled scientists to understand how galaxies emerged. Precise observations of the microwaves reveal that they are not completely uniform over the sky.

    Some patches are slightly hotter, levitra price australia others slightly cooler. The amplitude of these fluctuations is only one part in 100,000, but they are the seeds of today's cosmic structure. Any region of the expanding universe that started off slightly denser than average expanded less because it was subjected to extra gravity. Its growth lagged further levitra price australia and further, the contrast between its density and that of its surroundings becoming greater and greater.

    Eventually these clumps were dense enough that gas was pulled in and compressed into stars, forming galaxies. The crucial point is this. Computer models that simulate this process are fed the initial fluctuations measured in the cosmic microwave background, which represent the universe when it was 300,000 levitra price australia years old. The output after 13.8 billion years of virtual time have elapsed is a cosmos where galaxies resemble those we see, clustered as they are in the actual universe.

    This is a real triumph. We understand, at least in outline, 99.998 percent of cosmic history. It is not only levitra price australia the big cosmic picture that we have come to understand. A series of discoveries has also revealed the history of the elemental building blocks that make up stars, planets and even our own bodies.

    Starting in the 1950s, progress in atomic physics led to accurate modeling of stars' surface layers. Simultaneously, detailed knowledge of the nuclei not just of hydrogen levitra price australia and helium atoms but also of the rest of the elements allowed scientists to calculate which nuclear reactions dominate at different stages in a star's life. Astronomers came to understand how nuclear fusion creates an onion-skin structure in massive stars as atoms successively fuse to build heavier and heavier elements, ending with iron in the innermost, hottest layer. Inside the Crab Nebula is a neutron star.

    Classical physics levitra price australia fails, and relativity applies. Credit. NASA, ESA and Hubble Heritage Team (STSCI and AURA) Astronomers also learned how stars die when they exhaust their hydrogen fuel and blow off their outer gaseous layers. Lighter stars then settle down to a quiet demise as dense, dim objects called white dwarfs, but heavier stars shed more of their mass, either levitra price australia in winds during their lives or in an explosive death via supernova.

    This expelled mass turns out to be crucial to our own existence. It mixes into the interstellar medium and recondenses into new stars orbited by planets such as Earth. The concept was conceived by Fred Hoyle, who developed it during the 1950s along with two other British astronomers, Margaret Burbidge and Geoffrey Burbidge, and American nuclear physicist William levitra price australia Fowler. In their classic 1957 paper in Reviews of Modern Physics (known by the initials of its authors as BBFH), they analyzed the networks of the nuclear reactions involved and discovered how most atoms in the periodic table came to exist.

    They calculated why oxygen and carbon, for instance, are common, whereas gold and uranium are rare. Our galaxy, it turns out, is a levitra price australia huge ecological system where gas is being recycled through successive generations of stars. Each of us contains atoms forged in dozens of different stars spread across the Milky Way that lived and died more than 4.5 billion years ago. Scientists long assumed this process was seeding planets—and possibly even life—around stars other than our own sun.

    But we did not know for sure whether planets existed outside our solar system until the 1990s, when astronomers developed clever methods for identifying levitra price australia worlds that are too dim for us to see directly. One technique looks for tiny periodic changes in a star's movement caused by the gravitational pull of a planet orbiting it. In 1995 Michel Mayor and Didier Queloz used this strategy to detect 51 Pegasi b, the first known exoplanet orbiting a sunlike star. The technique can reveal a planet's mass, levitra price australia the length of its “year” and the shape of its orbit.

    So far more than 800 exoplanets have been found this way. A second technique works better for smaller planets. A star dims slightly levitra price australia when a planet transits in front of it. An Earth-like planet passing a sunlike star can cause a dimming of about one part in 10,000 once per orbit.

    The Kepler spacecraft launched in 2009 found more than 2,000 planets this way, many no bigger than Earth. A big surprise to come from astronomers' success in planet hunting was the variety of levitra price australia different planets out there—many much larger and closer to their stars than the bodies in our solar system—suggesting that our cosmic neighborhood may be somewhat special. By this point scientists understood where almost all the elements that form planets, stars and galaxies originated. The final piece in this puzzle, however, arrived very recently and from a seemingly unrelated inquiry.

    General relativity had predicted a phenomenon called gravitational waves—ripples levitra price australia in spacetime produced by the movement of massive objects. Despite decades of searching for them, however, no waves were seen—until September 2015. That was when the Laser Interferometer Gravitational-wave Observatory (LIGO) detected the first evidence of gravitational waves in the form of a “chirp”—a minute shaking of spacetime that speeds up and then dies away. In this levitra price australia case, it was caused by two black holes in a binary system that had started out orbiting each other but gradually spiraled together and eventually converged into a single massive hole.

    The crash occurred more than a billion light-years away. LIGO's detectors consist of mirrors four kilometers apart whose separation is measured by laser beams that reflect light back and forth between them. A passing gravitational wave causes the space between the two mirrors to jitter by an amount millions of times as small as the diameter of a single levitra price australia atom—LIGO is indeed an amazing feat of precision engineering and perseverance. Since that first find, more than a dozen similar events have been detected, opening up a new field that probes the dynamics of space itself.

    One event was of special astrophysical interest because it signaled the merger of two pulsars. Unlike black hole mergers, this kind of collision, a splat between two ultradense stars, yields levitra price australia a pulse of optical light, x-rays and gamma rays. The discovery filled a gap in the classic work of BBFH. The authors had explained the genesis of many of the elements in space but were flummoxed by the forging of gold.

    In the levitra price australia 1970s David N. Schramm and his colleagues had speculated that the exotic nuclear processes involved in hypothetical mergers of pulsar stars might do the job—a theory that has since been validated. Despite the incredible progress in astronomy over the past 175 years, we have perhaps more questions now than we did back then. Take dark levitra price australia matter.

    I am on record as having said more than 20 years ago that we would know dark matter's nature long before today. Although that prediction has proved wrong, I have not given up hope. Dark energy, however, is a levitra price australia different story. Dark energy entered the picture in 1998, when researchers measuring the distances and speeds of supernovae found that the expansion of the universe was actually accelerating.

    Gravitational attraction pulling galaxies toward one another seemed to be overwhelmed by a mysterious new force latent in empty space that pushes galaxies apart—a force that came to be known as dark energy. The mystery of dark energy has lingered—we still do not know what causes it or why it has the particular strength it does—and we probably will not understand it until we have a model for the graininess of space on a scale a billion billion times smaller than levitra price australia an atomic nucleus. Theorists working on string theory or loop quantum gravity are tackling this challenge, but the phenomenon seems so far from being accessible by any experiment that I am not expecting answers anytime soon. The upside, however, is that a theory that could account for the energy in the vacuum of space might also yield insights into the very beginning of our universe, when everything was so compressed and dense that quantum fluctuations could shake the entire cosmos.

    Which brings us to another major question facing levitra price australia us now. How did it all begin?. What exactly set off the big bang that started our universe?. Did space undergo a period of extremely rapid early expansion levitra price australia called inflation, as many theorists believe?.

    And there is something else. Some models, such as eternal inflation, suggest that “our” big bang could be just one island of spacetime in a vast archipelago—one big bang among many. If this hypothesis is true, different big bangs may cool down differently, leading to unique laws of physics levitra price australia in each case—a “multiverse” rather than a universe. Some physicists hate the multiverse concept because it means that we will never have neat explanations for the fundamental numbers that govern our physical laws, which may in this grander perspective be just environmental accidents.

    But our preferences are irrelevant to nature. About 10 years ago I was on a panel at Stanford University where we were asked by someone in the levitra price australia audience how much we would bet on the multiverse concept. I said that on a scale of betting my goldfish, my dog or my life, I was nearly at the dog level. Andrei Linde, who had spent 25 years promoting eternal inflation, said he would almost bet his life.

    Later, on being told this, physicist Steven Weinberg said he would happily bet my levitra price australia dog and Linde's life. Linde, my dog and I will all be dead before the question is settled. But none of this should be dismissed as metaphysics. It is speculative science—exciting levitra price australia science.

    And it may be true. And what will happen to this universe—or multiverse—of ours?. Long-range forecasts are seldom reliable, but the best and most conservative bet is that we have almost an eternity ahead with an ever levitra price australia colder and ever emptier cosmos. Galaxies will accelerate away and disappear.

    All that will be left from our vantage point will be the remnants of the Milky Way, Andromeda and smaller neighbors. Protons may decay, dark matter levitra price australia particles may be annihilated, there may be occasional flashes when black holes evaporate—and then silence. This possible future is based on the assumption that the dark energy stays constant. If it decays, however, there could be a “big crunch” with the universe contracting in on itself.

    Or if dark energy strengthens, there levitra price australia would be a “big rip” when galaxies, stars and even atoms are torn apart. Other questions closer to home tantalize us. Could there be life on any of these new planets we are discovering?. Here we are levitra price australia still in the realm of speculation.

    But unless the origin of life on Earth involved a rare fluke, I expect evidence of a biosphere on an exoplanet within 20 years. I will not hold my breath for the discovery of aliens, but I think the search for extraterrestrial intelligence is a worthwhile gamble. Success in the search would carry the momentous message that concepts of logic and physics are not limited to the hardware in human skulls. Until now, progress in cosmology and astrophysics has owed 95 percent to advancing instruments and technology and less than 5 percent to armchair theory.

    I expect that balance to persist. What Hubble wrote in the 1930s remains a good maxim today. €œNot until the empirical resources are exhausted, need we pass on to the dreamy realms of speculation.” There have been many particularly exhilarating eras in the past 175 years—the 1920s and 1930s, when we realized the universe was not limited to the Milky Way, and the 1960s and 1970s, when we discovered objects that defy classical physics, such as neutron stars and quasars, and clues about the beginning of time from the cosmic microwave background. Since then, the pace of advancement has crescendoed rather than slackened.

    When the history of science gets written, this amazing progress will be acclaimed as one of its greatest triumphs—up there with plate tectonics, the genome and the Standard Model of particle physics.

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    IntroductionIn recent years, many studies have been published on new diagnostic possibilities how long does it take levitra 20mg to work 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 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 how long does it take levitra 20mg to work 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 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 and similar how long does it take levitra 20mg to work 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 how long does it take levitra 20mg to work 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, how long does it take levitra 20mg to work 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 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 how long does it take levitra 20mg to work from the paediatric to the adult team requires optimal communication 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 how long does it take levitra 20mg to work 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 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 how long does it take levitra 20mg to work by Burke 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 how long does it take levitra 20mg to work 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 were excluded, as were articles that were not open access or retrievable through institutional how long does it take levitra 20mg to work 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, revised into a how long does it take levitra 20mg to work 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 genetic associations how long does it take levitra 20mg to work 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 how long does it take levitra 20mg to work 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 how long does it take levitra 20mg to work situation now occurring with increasing frequency is a discrepancy between the genotypic 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 how long does it take levitra 20mg to work on legal restrictions and/or ethical considerations, the X and Y chromosomes are 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 how long does it take levitra 20mg to work 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 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 how long does it take levitra 20mg to work of this technique.

    The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information genetic testing can how long does it take levitra 20mg to work 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 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 how long does it take levitra 20mg to work 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 by some, is legal in Belgium and how long does it take levitra 20mg to work 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 how long does it take levitra 20mg to work 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 experience, parents how long does it take levitra 20mg to work 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 how long does it take levitra 20mg to work 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 how long does it take levitra 20mg to work 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 how long does it take levitra 20mg to work 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 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 levitra price australia clear that services and institutions still differ in the composition of levitra prospecto 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 levitra price australia 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 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 levitra price australia 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 levitra price australia 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 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 levitra price australia 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 healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the prenatal levitra price australia to the postnatal team and from the paediatric to the adult team requires optimal communication 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 levitra price australia centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for 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 levitra price australia 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 levitra price australia to be written in 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 were excluded, as were levitra price australia 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, revised into levitra price australia 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 levitra price australia 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 out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex levitra price australia 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 levitra price australia genotypic 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 levitra price australia Y chromosomes are 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 levitra price australia 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 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 levitra price australia technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of information genetic testing can and levitra price australia 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 given the limited time span levitra price australia 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 levitra price australia 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 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 levitra price australia 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 experience, parents appreciate having already spoken to some members of the DSD team during pregnancy levitra price australia 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 levitra price australia with parents should be carefully chosen,22 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 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 levitra price australia 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 levitra price australia 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 Our site 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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    NCHS Data prescription free levitra Brief Discover More No. 286, September 2017PDF Versionpdf icon (374 KB)Anjel Vahratian, Ph.D.Key findingsData from the National Health Interview Survey, 2015Among those aged 40–59, perimenopausal women (56.0%) were more likely than postmenopausal (40.5%) and premenopausal (32.5%) women to sleep less than 7 hours, on average, in a 24-hour period.Postmenopausal women aged 40–59 were more likely than premenopausal women aged 40–59 to have trouble falling asleep (27.1% compared with 16.8%, respectively), and staying asleep (35.9% compared with 23.7%), four times or more in the past week.Postmenopausal women aged 40–59 (55.1%) were more likely than premenopausal women aged 40–59 (47.0%) to not wake up feeling well rested 4 days or more in the past week.Sleep duration and quality are important contributors to health and wellness. Insufficient sleep is associated with an increased risk for chronic conditions prescription free levitra such as cardiovascular disease (1) and diabetes (2).

    Women may be particularly vulnerable to sleep problems during times of reproductive hormonal change, such as after the menopausal transition. Menopause is “the prescription free levitra permanent cessation of menstruation that occurs after the loss of ovarian activity” (3). This data brief describes sleep duration and sleep quality among nonpregnant women aged 40–59 by menopausal status.

    The age range selected for this analysis reflects the focus on midlife sleep health. In this analysis, 74.2% of women are premenopausal, 3.7% are perimenopausal, prescription free levitra and 22.1% are postmenopausal. Keywords.

    Insufficient sleep, menopause, National Health Interview Survey Perimenopausal women were more likely than premenopausal and postmenopausal women to sleep less than 7 prescription free levitra hours, on average, in a 24-hour period.More than one in three nonpregnant women aged 40–59 slept less than 7 hours, on average, in a 24-hour period (35.1%) (Figure 1). Perimenopausal women were most likely to sleep less than 7 hours, on average, in a 24-hour period (56.0%), compared with 32.5% of premenopausal and 40.5% of postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to sleep less than 7 hours, on average, in a 24-hour period.

    Figure 1 prescription free levitra. Percentage of nonpregnant women aged 40–59 who slept less than 7 hours, on average, in a 24-hour period, by menopausal status. United States, 2015image prescription free levitra icon1Significant quadratic trend by menopausal status (p <.

    0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago or less prescription free levitra.

    Women were premenopausal if they still had a menstrual cycle. Access data prescription free levitra table for Figure 1pdf icon.SOURCE. NCHS, National Health Interview Survey, 2015.

    The percentage of women aged 40–59 who had trouble falling asleep four times or more in the past week varied by menopausal status.Nearly one in five nonpregnant women aged 40–59 had trouble falling asleep four times or more in the past prescription free levitra week (19.4%) (Figure 2). The percentage of women in this age group who had trouble falling asleep four times or more in the past week increased from 16.8% among premenopausal women to 24.7% among perimenopausal and 27.1% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to have trouble falling asleep four times or more in the past week.

    Figure 2 prescription free levitra. Percentage of nonpregnant women aged 40–59 who had trouble falling asleep four times or more in the past week, by menopausal status. United States, prescription free levitra 2015image icon1Significant linear trend by menopausal status (p <.

    0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last prescription free levitra menstrual cycle was 1 year ago or less.

    Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 2pdf icon.SOURCE prescription free levitra. NCHS, National Health Interview Survey, 2015.

    The percentage of women aged 40–59 who had trouble staying asleep four times or more in the past week varied by menopausal status.More than one in four nonpregnant women aged 40–59 prescription free levitra had trouble staying asleep four times or more in the past week (26.7%) (Figure 3). The percentage of women aged 40–59 who had trouble staying asleep four times or more in the past week increased from 23.7% among premenopausal, to 30.8% among perimenopausal, and to 35.9% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to have trouble staying asleep four times or more in the past week.

    Figure 3 prescription free levitra. Percentage of nonpregnant women aged 40–59 who had trouble staying asleep four times or more in the past week, by menopausal status. United States, 2015image prescription free levitra icon1Significant linear trend by menopausal status (p <.

    0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual prescription free levitra cycle was 1 year ago or less.

    Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 3pdf prescription free levitra icon.SOURCE. NCHS, National Health Interview Survey, 2015.

    The percentage of women aged 40–59 who did not wake up feeling well rested 4 days or more in the past week varied by menopausal status.Nearly one in two nonpregnant women aged 40–59 did not wake up feeling well rested 4 days or more in the past week (48.9%) (Figure 4). The percentage of women in this age group who did not wake up feeling well rested 4 days or more in the past prescription free levitra week increased from 47.0% among premenopausal women to 49.9% among perimenopausal and 55.1% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to not wake up feeling well rested 4 days or more in the past week.

    Figure 4 prescription free levitra. Percentage of nonpregnant women aged 40–59 who did not wake up feeling well rested 4 days or more in the past week, by menopausal status. United States, 2015image icon1Significant linear trend by menopausal status (p <.

    0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago or less.

    Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 4pdf icon.SOURCE. NCHS, National Health Interview Survey, 2015.

    SummaryThis report describes sleep duration and sleep quality among U.S. Nonpregnant women aged 40–59 by menopausal status. Perimenopausal women were most likely to sleep less than 7 hours, on average, in a 24-hour period compared with premenopausal and postmenopausal women.

    In contrast, postmenopausal women were most likely to have poor-quality sleep. A greater percentage of postmenopausal women had frequent trouble falling asleep, staying asleep, and not waking well rested compared with premenopausal women. The percentage of perimenopausal women with poor-quality sleep was between the percentages for the other two groups in all three categories.

    Sleep duration changes with advancing age (4), but sleep duration and quality are also influenced by concurrent changes in women’s reproductive hormone levels (5). Because sleep is critical for optimal health and well-being (6), the findings in this report highlight areas for further research and targeted health promotion. DefinitionsMenopausal status.

    A three-level categorical variable was created from a series of questions that asked women. 1) “How old were you when your periods or menstrual cycles started?. €.

    2) “Do you still have periods or menstrual cycles?. €. 3) “When did you have your last period or menstrual cycle?.

    €. And 4) “Have you ever had both ovaries removed, either as part of a hysterectomy or as one or more separate surgeries?. € Women were postmenopausal if they a) had gone without a menstrual cycle for more than 1 year or b) were in surgical menopause after the removal of their ovaries.

    Women were perimenopausal if they a) no longer had a menstrual cycle and b) their last menstrual cycle was 1 year ago or less. Premenopausal women still had a menstrual cycle.Not waking feeling well rested. Determined by respondents who answered 3 days or less on the questionnaire item asking, “In the past week, on how many days did you wake up feeling well rested?.

    €Short sleep duration. Determined by respondents who answered 6 hours or less on the questionnaire item asking, “On average, how many hours of sleep do you get in a 24-hour period?. €Trouble falling asleep.

    Determined by respondents who answered four times or more on the questionnaire item asking, “In the past week, how many times did you have trouble falling asleep?. €Trouble staying asleep. Determined by respondents who answered four times or more on the questionnaire item asking, “In the past week, how many times did you have trouble staying asleep?.

    € Data source and methodsData from the 2015 National Health Interview Survey (NHIS) were used for this analysis. NHIS is a multipurpose health survey conducted continuously throughout the year by the National Center for Health Statistics. Interviews are conducted in person in respondents’ homes, but follow-ups to complete interviews may be conducted over the telephone.

    Data for this analysis came from the Sample Adult core and cancer supplement sections of the 2015 NHIS. For more information about NHIS, including the questionnaire, visit the NHIS website.All analyses used weights to produce national estimates. Estimates on sleep duration and quality in this report are nationally representative of the civilian, noninstitutionalized nonpregnant female population aged 40–59 living in households across the United States.

    The sample design is described in more detail elsewhere (7). Point estimates and their estimated variances were calculated using SUDAAN software (8) to account for the complex sample design of NHIS. Linear and quadratic trend tests of the estimated proportions across menopausal status were tested in SUDAAN via PROC DESCRIPT using the POLY option.

    Differences between percentages were evaluated using two-sided significance tests at the 0.05 level. About the authorAnjel Vahratian is with the National Center for Health Statistics, Division of Health Interview Statistics. The author gratefully acknowledges the assistance of Lindsey Black in the preparation of this report.

    ReferencesFord ES. Habitual sleep duration and predicted 10-year cardiovascular risk using the pooled cohort risk equations among US adults. J Am Heart Assoc 3(6):e001454.

    2014.Ford ES, Wheaton AG, Chapman DP, Li C, Perry GS, Croft JB. Associations between self-reported sleep duration and sleeping disorder with concentrations of fasting and 2-h glucose, insulin, and glycosylated hemoglobin among adults without diagnosed diabetes. J Diabetes 6(4):338–50.

    2014.American College of Obstetrics and Gynecology. ACOG Practice Bulletin No. 141.

    Management of menopausal symptoms. Obstet Gynecol 123(1):202–16. 2014.Black LI, Nugent CN, Adams PF.

    Tables of adult health behaviors, sleep. National Health Interview Survey, 2011–2014pdf icon. 2016.Santoro N.

    Perimenopause. From research to practice. J Women’s Health (Larchmt) 25(4):332–9.

    2016.Watson NF, Badr MS, Belenky G, Bliwise DL, Buxton OM, Buysse D, et al. Recommended amount of sleep for a healthy adult. A joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society.

    J Clin Sleep Med 11(6):591–2. 2015.Parsons VL, Moriarity C, Jonas K, et al. Design and estimation for the National Health Interview Survey, 2006–2015.

    National Center for Health Statistics. Vital Health Stat 2(165). 2014.RTI International.

    SUDAAN (Release 11.0.0) [computer software]. 2012. Suggested citationVahratian A.

    Sleep duration and quality among women aged 40–59, by menopausal status. NCHS data brief, no 286. Hyattsville, MD.

    National Center for Health Statistics. 2017.Copyright informationAll material appearing in this report is in the public domain and may be reproduced or copied without permission. Citation as to source, however, is appreciated.National Center for Health StatisticsCharles J.

    Rothwell, M.S., M.B.A., DirectorJennifer H. Madans, Ph.D., Associate Director for ScienceDivision of Health Interview StatisticsMarcie L. Cynamon, DirectorStephen J.

    Blumberg, Ph.D., Associate Director for Science.

    NCHS Data levitra price australia Brief No http://www.amisdepasteur.fr/levitra-uk-buy/. 286, September 2017PDF Versionpdf icon (374 KB)Anjel Vahratian, Ph.D.Key findingsData from the National Health Interview Survey, 2015Among those aged 40–59, perimenopausal women (56.0%) were more likely than postmenopausal (40.5%) and premenopausal (32.5%) women to sleep less than 7 hours, on average, in a 24-hour period.Postmenopausal women aged 40–59 were more likely than premenopausal women aged 40–59 to have trouble falling asleep (27.1% compared with 16.8%, respectively), and staying asleep (35.9% compared with 23.7%), four times or more in the past week.Postmenopausal women aged 40–59 (55.1%) were more likely than premenopausal women aged 40–59 (47.0%) to not wake up feeling well rested 4 days or more in the past week.Sleep duration and quality are important contributors to health and wellness. Insufficient sleep levitra price australia is associated with an increased risk for chronic conditions such as cardiovascular disease (1) and diabetes (2).

    Women may be particularly vulnerable to sleep problems during times of reproductive hormonal change, such as after the menopausal transition. Menopause is “the permanent cessation of menstruation that occurs levitra price australia after the loss of ovarian activity” (3). This data brief describes sleep duration and sleep quality among nonpregnant women aged 40–59 by menopausal status.

    The age range selected for this analysis reflects the focus on midlife sleep health. In this analysis, 74.2% of levitra price australia women are premenopausal, 3.7% are perimenopausal, and 22.1% are postmenopausal. Keywords.

    Insufficient sleep, menopause, National Health Interview Survey Perimenopausal women were more likely than premenopausal and postmenopausal women to sleep less than 7 hours, on average, in a 24-hour period.More than one in three nonpregnant women aged 40–59 slept less than 7 hours, on average, in a 24-hour period levitra price australia (35.1%) (Figure 1). Perimenopausal women were most likely to sleep less than 7 hours, on average, in a 24-hour period (56.0%), compared with 32.5% of premenopausal and 40.5% of postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to sleep less than 7 hours, on average, in a 24-hour period.

    Figure 1 levitra price australia. Percentage of nonpregnant women aged 40–59 who slept less than 7 hours, on average, in a 24-hour period, by menopausal status. United States, 2015image icon1Significant levitra price australia quadratic trend by menopausal status (p <.

    0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago or less levitra price australia.

    Women were premenopausal if they still had a menstrual cycle. Access data levitra price australia table for Figure 1pdf icon.SOURCE. NCHS, National Health Interview Survey, 2015.

    The percentage of women aged 40–59 who had trouble falling asleep four times or more in the past week varied by menopausal status.Nearly one in five nonpregnant women aged 40–59 had trouble levitra price australia falling asleep four times or more in the past week (19.4%) (Figure 2). The percentage of women in this age group who had trouble falling asleep four times or more in the past week increased from 16.8% among premenopausal women to 24.7% among perimenopausal and 27.1% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to have trouble falling asleep four times or more in the past week.

    Figure 2 levitra price australia. Percentage of nonpregnant women aged 40–59 who had trouble falling asleep four times or more in the past week, by menopausal status. United States, 2015image icon1Significant levitra price australia linear trend by menopausal status (p <.

    0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were levitra price australia perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago or less.

    Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 2pdf levitra price australia icon.SOURCE. NCHS, National Health Interview Survey, 2015.

    The percentage of women aged 40–59 who had trouble staying asleep four times or more in the past week varied by menopausal status.More than one in four nonpregnant women aged 40–59 levitra price australia had trouble staying asleep four times or more in the past week (26.7%) (Figure 3). The percentage of women aged 40–59 who had trouble staying asleep four times or more in the past week increased from 23.7% among premenopausal, to 30.8% among perimenopausal, and to 35.9% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to have trouble staying asleep four times or more in the past week.

    Figure 3 levitra price australia. Percentage of nonpregnant women aged 40–59 who had trouble staying asleep four times or more in the past week, by menopausal status. United States, 2015image icon1Significant linear trend by menopausal status levitra price australia (p <.

    0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was levitra price australia 1 year ago or less.

    Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 3pdf levitra price australia icon.SOURCE. NCHS, National Health Interview Survey, 2015.

    The percentage of women aged 40–59 who did not wake up feeling well rested 4 days or more in the past week varied by menopausal status.Nearly one in two nonpregnant women aged 40–59 did not wake up feeling well rested 4 days or more in the past week (48.9%) (Figure 4). The percentage of women in this age group who did not wake up feeling well rested 4 days or more in the past week increased from 47.0% among premenopausal women to levitra price australia 49.9% among perimenopausal and 55.1% among postmenopausal women. Postmenopausal women were significantly more likely than premenopausal women to not wake up feeling well rested 4 days or more in the past week.

    Figure 4 levitra price australia. Percentage of nonpregnant women aged 40–59 who did not wake up feeling well rested 4 days or more in the past week, by menopausal status. United States, 2015image icon1Significant linear trend by menopausal status (p <.

    0.05).NOTES. Women were postmenopausal if they had gone without a menstrual cycle for more than 1 year or were in surgical menopause after the removal of their ovaries. Women were perimenopausal if they no longer had a menstrual cycle and their last menstrual cycle was 1 year ago or less.

    Women were premenopausal if they still had a menstrual cycle. Access data table for Figure 4pdf icon.SOURCE. NCHS, National Health Interview Survey, 2015.

    SummaryThis report describes sleep duration and sleep quality among U.S. Nonpregnant women aged 40–59 by menopausal status. Perimenopausal women were most likely to sleep less than 7 hours, on average, in a 24-hour period compared with premenopausal and postmenopausal women.

    In contrast, postmenopausal women were most likely to have poor-quality sleep. A greater percentage of postmenopausal women had frequent trouble falling asleep, staying asleep, and not waking well rested compared with premenopausal women. The percentage of perimenopausal women with poor-quality sleep was between the percentages for the other two groups in all three categories.

    Sleep duration changes with advancing age (4), but sleep duration and quality are also influenced by concurrent changes in women’s reproductive hormone levels (5). Because sleep is critical for optimal health and well-being (6), the findings in this report highlight areas for further research and targeted health promotion. DefinitionsMenopausal status.

    A three-level categorical variable was created from a series of questions that asked women. 1) “How old were you when your periods or menstrual cycles started?. €.

    2) “Do you still have periods or menstrual cycles?. €. 3) “When did you have your last period or menstrual cycle?.

    €. And 4) “Have you ever had both ovaries removed, either as part of a hysterectomy or as one or more separate surgeries?. € Women were postmenopausal if they a) had gone without a menstrual cycle for more than 1 year or b) were in surgical menopause after the removal of their ovaries.

    Women were perimenopausal if they a) no longer had a menstrual cycle and b) their last menstrual cycle was 1 year ago or less. Premenopausal women still had a menstrual cycle.Not waking feeling well rested. Determined by respondents who answered 3 days or less on the questionnaire item asking, “In the past week, on how many days did you wake up feeling well rested?.

    €Short sleep duration. Determined by respondents who answered 6 hours or less on the questionnaire item asking, “On average, how many hours of sleep do you get in a 24-hour period?. €Trouble falling asleep.

    Determined by respondents who answered four times or more on the questionnaire item asking, “In the past week, how many times did you have trouble falling asleep?. €Trouble staying asleep. Determined by respondents who answered four times or more on the questionnaire item asking, “In the past week, how many times did you have trouble staying asleep?.

    € Data source and methodsData from the 2015 National Health Interview Survey (NHIS) were used for this analysis. NHIS is a multipurpose health survey conducted continuously throughout the year by the National Center for Health Statistics. Interviews are conducted in person in respondents’ homes, but follow-ups to complete interviews may be conducted over the telephone.

    Data for this analysis came from the Sample Adult core and cancer supplement sections of the 2015 NHIS. For more information about NHIS, including the questionnaire, visit the NHIS website.All analyses used weights to produce national estimates. Estimates on sleep duration and quality in this report are nationally representative of the civilian, noninstitutionalized nonpregnant female population aged 40–59 living in households across the United States.

    The sample design is described in more detail elsewhere (7). Point estimates and their estimated variances were calculated using SUDAAN software (8) to account for the complex sample design of NHIS. Linear and quadratic trend tests of the estimated proportions across menopausal status were tested in SUDAAN via PROC DESCRIPT using the POLY option.

    Differences between percentages were evaluated using two-sided significance tests at the 0.05 level. About the authorAnjel Vahratian is with the National Center for Health Statistics, Division of Health Interview Statistics. The author gratefully acknowledges the assistance of Lindsey Black in the preparation of this report.

    ReferencesFord ES. Habitual sleep duration and predicted 10-year cardiovascular risk using the pooled cohort risk equations among US adults. J Am Heart Assoc 3(6):e001454.

    2014.Ford ES, Wheaton AG, Chapman DP, Li C, Perry GS, Croft JB. Associations between self-reported sleep duration and sleeping disorder with concentrations of fasting and 2-h glucose, insulin, and glycosylated hemoglobin among adults without diagnosed diabetes. J Diabetes 6(4):338–50.

    2014.American College of Obstetrics and Gynecology. ACOG Practice Bulletin No. 141.

    Management of menopausal symptoms. Obstet Gynecol 123(1):202–16. 2014.Black LI, Nugent CN, Adams PF.

    Tables of adult health behaviors, sleep. National Health Interview Survey, 2011–2014pdf icon. 2016.Santoro N.

    Perimenopause. From research to practice. J Women’s Health (Larchmt) 25(4):332–9.

    2016.Watson NF, Badr MS, Belenky G, Bliwise DL, Buxton OM, Buysse D, et al. Recommended amount of sleep for a healthy adult. A joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society.

    J Clin Sleep Med 11(6):591–2. 2015.Parsons VL, Moriarity C, Jonas K, et al. Design and estimation for the National Health Interview Survey, 2006–2015.

    National Center for Health Statistics. Vital Health Stat 2(165). 2014.RTI International.

    SUDAAN (Release 11.0.0) [computer software]. 2012. Suggested citationVahratian A.

    Sleep duration and quality among women aged 40–59, by menopausal status. NCHS data brief, no 286. Hyattsville, MD.

    National Center for Health Statistics. 2017.Copyright informationAll material appearing in this report is in the public domain and may be reproduced or copied without permission. Citation as to source, however, is appreciated.National Center for Health StatisticsCharles J.

    Rothwell, M.S., M.B.A., DirectorJennifer H. Madans, Ph.D., Associate Director for ScienceDivision of Health Interview StatisticsMarcie L. Cynamon, DirectorStephen J.

    Blumberg, Ph.D., Associate Director for Science.

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