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    1 September 2020 This September we're asking you to send us your best how to buy cheap antabuse laboratory bloopers Our members work long hours and everything they do has to be 100% correct - so sometimes the slack falls out of their mouths. We got the idea how to buy cheap antabuse for this competition courtesy of Gayatri Chohan who overheard the line in the image when one of her colleagues answered the phone (and was overdue a holiday). What has come out of your mouth in the lab?. Keep how to buy cheap antabuse it family-friendly scientists!. The rules of the competition are simple:One entry per person (we will add your blooper to a randomly selected photo from our Biomedical Science Day archives - unless you want to send us your own photo)Use how to buy cheap antabuse the #IBMSCompetition or #LaboratoryLaughs hashtag on Facebook, Twitter or Instagram along with your entry or email to website@ibms.orgThe competition starts Tuesday 1st September and closes at 12pm on Friday 18th SeptemberTwo entries will be chosen for the semi-finals and presented to our members in a social media poll on the week of 21th - 25th SeptemberThe winner will be announced at the end of the month and sent some goodies when we return to our officesOnce we get some entries, we will start a Facebook gallery so that you can see the all the bloopers in one place by clicking here.27 August 2020 The IBMS outlines and assesses the principal testing options currently available for the SARS-CoV-2 virus (COVID-19).

    This statement aims to support scientists and other laboratory professionals in selecting and advising on the most appropriate testing route for patients. The information is based on known clinical need, the requirement to support the management of patients within different care settings, and the limited supply of rapid testing kits.Background ContextIn early how to buy cheap antabuse August 2020, the UK government announced two new rapid SARS-CoV-2 tests. Capable of delivering a result in 90 minutes, they are due to be made available in accredited NHS laboratories, lighthouse laboratories and care homes. However, these tests are not the silver bullets in the coronavirus response, they are only one part how to buy cheap antabuse of the armoury. The most important aspect of laboratory medicine is the diagnostic how to buy cheap antabuse testing pathway which includes the end to end process consisting of:correctly identifying those who need testingobtaining appropriate samples from the correct patientproducing results in a timely mannermaking the results available to the clinical decision makerinterpreting the results and taking the appropriate actionThe goal of all high quality medical laboratory services can be summarised as.

    Ensuring the right test, for the right patient, at the right time, and giving the ‘right’ result to inform the right response.Access to rapid testing in the UK will support individuals and communities and complement the national COVID-19 testing strategy for PCR testing across NHS and lighthouse laboratories, but will not be the solution.There is a clear need for biomedical scientists and clinical scientists to provide advice to clinical teams on the appropriate use of the range of tests currently available, including these rapid tests. All diagnostic how to buy cheap antabuse tests have limitations and it is fundamental to patient safety that all those involved in clinical decision making are aware of them.Testing Options1. Rapid testingTest definitionRapid testing is defined as an analytical test performed for a patient by a healthcare professional with a short delivery time to results (less than 4 hours).Where it is carried outRapid testing may be carried out as a point of care/near patient test.Due to the complex nature of the testing process, it is more likely that this rapid testing is carried out in a laboratory setting and supervised by Health and Care Professions Council (HCPC) registered biomedical or clinical scientists.Clinical requirement. Current priorities for rapid testing are to how to buy cheap antabuse enable the acute management of patients and clinical services where only the use of rapid testing will facilitate better patient care.Rapid testing devices are currently available to healthcare providers on a limited scale and have been unable and are unlikely to meet testing demand in this setting. It is therefore vital that rapid tests are only used where there is no other clinically acceptable alternative.As supply increases there may be a role for rapid testing in situations where a fast turnaround is beneficial such as managing an outbreak in a community setting, but only if the test is suitably validated for the how to buy cheap antabuse patient cohort being tested.InstrumentationRapid testing utilises qualitative or semi-quantitative in vitro diagnostics (IVDs), used singly or in a small series which involve non-automated procedures.

    They have been designed to give a ‘rapid’ result and can deliver SARS-CoV-2 direct viral test results from a swab sample, usually within 90-120 minutes. Where the device is sited close to the point of swab collection, a rapid result can be how to buy cheap antabuse obtained for an individual patient.AdvantagesResults may be available near to the point of patient care and may support rapid patient triage. This can assist hospitals in managing emergency departments and other acute services to support bed availability and efficient patient flow. Multiple instruments can how to buy cheap antabuse be linked so that a set of instruments can provide small scale throughput.A laboratory may not need to be on the same site as the rapid testing device, depending upon the processes involved in the testing. Conditional upon the patient cohort and testing platform being used, these devices may provide sufficient how to buy cheap antabuse result sensitivity to not require confirmation by a laboratory test.

    However, there will remain a need to repeat equivocal positive, potential false negative, and potential false positive results as deemed clinically appropriate.DisadvantagesSpeed of reporting is countered with the compromise of limited test processing capacity and is dependent upon the platform used. Capacity can be as low as 9 tests or as high as 138 test per day on a 24-hour how to buy cheap antabuse operating schedule. This is compounded by a number of systems only being able to process samples one at a time.Rapid testing devices are not enabled with automated loading and require a trained healthcare professional to operate the equipment, often with multiple interventions. A lack how to buy cheap antabuse of result interpretation, that would normally be undertaken by HCPC registered scientists before result issue, may also result in a failure to detect erroneous results.Unfortunately, the performance characteristics of these new assays cannot always be assured, resulting in some of the faster instruments requiring equivocal results to be rechecked by a different method before diagnosis can be made. This defeats the how to buy cheap antabuse point of rapid testing.

    These tests often have significantly lower testing sensitivity than laboratory-based platforms meaning they have the potential to miss weak positive patients. This is a significant risk, particularly if this test is being used to triage patients to COVID-19 and non-COVID-19 areas of how to buy cheap antabuse a hospital.The equipment directions for use must also be carefully scrutinised to ensure that the platform is only being used for the purposes that it has been validated for. Some systems are only recommended for symptomatic patients, while others have not specified, meaning a validation on its clinical performance that is relevant to the patient cohort to be tested should be undertaken by the testing centre before implemented into routine use.Results often need to be manually linked to the patient health record as these platforms do not generally allow electronic transmission of data to patient files. This may also present challenges with the how to buy cheap antabuse reporting of results to the NHS and appropriate public health bodies.The absence of economies of scale means that decentralised rapid testing can be prohibitively expensive (reports of £140 per test for reagents only), especially when compared to large scale laboratory testing (typically £20 per test for reagents). Rapid testing is the most expensive modality of testing.Rapid testing devices are currently available how to buy cheap antabuse to healthcare providers on a limited scale – this falls short of expected testing demand.

    It is therefore vital rapid tests are only used where there is a clinical requirement.Staffing requirementRapid testing is labour intensive due to the need for numerous interventions during the testing process and the need to operate multiple instruments.Rapid testing instruments should be operated by suitably trained members of staff and require the oversight of an accredited laboratory to ensure the instrument is appropriately evaluated and validated prior to use. Devices should be regularly maintained and properly calibrated by qualified scientific staff to ensure reliability and consistency of results.SummaryRapid testing is not a replacement for the laboratory based PCR test.It must only be used in the patient context that it has been approved and validated to undertakeThese tests often have a low level of sensitivityIt should be used only where it is clinically appropriate to improve patient outcomes and no equivalent laboratory alternative is availableRapid testing is the most expensive modality of testing.Rapid testing is labour intensive how to buy cheap antabuse per sample processed when compared to traditional laboratory testing.Systems and processes must be in place to ensure that results are physically linked to the patient health record – these often require manual interventions.Clinicians and laboratory professionals must work together to ensure rapid testing is managed and used appropriately for the patient and wider healthcare systems benefit.2. Medical laboratory high throughput RT-PCR testingTest definitionThis is the most widespread form of testing nationally, where swab samples how to buy cheap antabuse are processed using automated or semi-automated instruments. This is also an area where constant innovation is improving the testing pathway. For example, a study is underway to validate tests that use a saliva sample rather than a nose/throat swab.Where it is carried outPCR testing is carried out in accredited NHS laboratories, usually hospital based, or other laboratories and should be overseen by a team how to buy cheap antabuse of competent HCPC registered biomedical scientists and/or clinical scientists.Clinical requirementIt is used for testing patients, NHS staff and social care workers.

    It is typically the preferred test, due to its sensitivity (ability to detect weak positives), for patients before elective operations and invasive procedures. Symptomatic patients may require further testing as the differential diagnosis between COVID-19 and other respiratory infections how to buy cheap antabuse may not be initially clear. It can also be used how to buy cheap antabuse to manage local outbreaks, and targeted testing to prevent nosocomial infections. This is due to its suitability to large scale testing over a clinically acceptable timeframe. Results are typically delivered within 15-24 hours back to the hospital or the requesting clinician.InstrumentationSamples how to buy cheap antabuse are processed on highly automated or semi-automated platforms that are capable of undertaking a high volume of workload per day.

    Testing capacity can be further increased through 24-7 working arrangements, or further automation of the laboratory process. This can often be undertaken with minimal increases in staffing.AdvantagesResults should be available within how to buy cheap antabuse 15 hours. Results are transferred directly into the patient’s healthcare records (usually electronically) providing how to buy cheap antabuse clinicians and public health teams reliable access to all the information they need. Results are available with the complete patient record supporting safe patient care.Thousands of results can be available quickly and efficiently supporting hospitals to return to ‘business as usual’ and re-instate routine services such as cancer and surgical services that have built up backlogs of planned care, due to suspension of surgery during the height of the pandemic.Results are provided in a high quality, clinically controlled environment, by qualified and registered staff who we expect to be working to stringent international quality standards.These assays are typically very sensitive meaning they are able to detect the vast majority of ‘positive’ patients. This is especially important when testing those with a low viral load, such as asymptomatic patients and how to buy cheap antabuse those in the early stages of infection.DisadvantagesRoutine high throughput RT-PCR is provided by hospital laboratories that are undertaking a very large range of other diagnostic tests.

    Laboratories will prioritise clinically urgent patients over routine services and, in rare circumstances, this may delay some testing.There may be delays associated with transporting samples to laboratories. However, there will be no delay in reporting the result where it is electronically logged in the patient how to buy cheap antabuse record.There is a risk that the current level of laboratory testing capacity will be constricted as ‘routine workloads’ continue to return, as hospital services that have been suspended start to be reinstated.Staffing requirementLaboratories carrying out these tests are staffed by scientific and support staff. The IBMS would how to buy cheap antabuse expect that these staff consist of HCPC registered biomedical and/or clinical scientists to oversee the service. There may be a requirement for additional staff should the service be required to support 24/7 working, increased testing volumes or the requirement to make the enhanced service a permanent arrangement rather than a temporary ‘surge’ response.SummaryRoutine high throughput PCR testing is the primary resource of hospital-based testingThis testing is highly sensitive and has been validated for use in a wide range of clinical scenariosThis testing is laboratory based, often highly automated and typically operates in an accredited environmentThis form of testing provides results in a timely manner for the majority of clinical situations and is cost effectiveThe testing is undertaken by highly qualified staff and supervised by HCPC registered scientistsThis testing can often be upscaled with limited amounts of additional staffingRobust systems are in place for results to be linked with patient health recordsHigh quality, comprehensive data is available to public health officials when required. Laboratory based testing is the ‘usual’ route for healthcare professionals so there is a high level how to buy cheap antabuse of confidence in the quality of the results and testing service provided.3.

    Centralised mass testingTest definitionMass testing provides testing for screening purposes in the wider population. Swabs are collected at sampling centres from symptomatic and asymptomatic individuals.Where it is carried outSamples are processed how to buy cheap antabuse on a large scale in a laboratory setting which enables thousands of tests to be processed each day.Clinical requirementThese services are used for large scale community screening and care home resident testing. Results for these samples are expected to be reported within 24 how to buy cheap antabuse hours.InstrumentationTesting is processed on highly automated platforms that are capable of undertaking a high volume of workload. These services typically function 24-7 to support testing from a wide geographical area.AdvantagesVery large volumes of samples can be undertaken. This is through the use of highly automated processes that allow a small number of how to buy cheap antabuse large laboratories to receive samples from swabbing stations across the country, including ‘pop-up’ sites.These testing facilities only focus on screening for SARS-CoV-2 so are not impacted by the need to process other tests.Individuals showing symptoms can access a test on-line and receive their result directly to their phone or email, with an expected turnaround of 24 hours.DisadvantagesThere are potential issues with sample integrity due to variable consistency from both self-sampling and pop-up stations.Data sets need to be returned to multiple parties including the individual, the GP and public health, and it has widely been reported that these centres have experienced issues with the flow of this data, particularly during the early phase of the pandemic.The limited data sets collected from the patient also mean that insufficient data is often available to public health officials to assist in local public health initiatives (e.g.

    Workplace outbreaks).Due to the scale of the testing operations any failures in the system can cause a delay upon many thousands of sample results being available in a timely manner.These new services have been stood up rapidly and therefore may have issues with long term sustainability and business continuity.These services have often not been ‘kite marked’ by recognised laboratory medicine accreditation.Staffing requirementThese laboratories are staffed by a combination of academic, scientific and support staff. It is unclear how to buy cheap antabuse on the levels of HCPC registered biomedical scientists and/or clinical scientists that are currently involved in these services. The IBMS expect sufficient HCPC registered staff to be employed to provide adequate supervision of non-registered staff to provide how to buy cheap antabuse a safe service. These laboratories operate on a 24-7 basis and must be safely staffed to allow this intensity of test processing.SummaryCapacity to process very high volume testing for population screening purposesHave the infrastructure to provide results direct to the patient via text or emailThis testing is laboratory based and highly automatedThis form of testing typically provides results in a timely manner for the patient cohort being testedDo not collect sufficient data to provide public health bodies with all the information they needThe ability for these services to link result with patient health records is unknown and likely to be limited.ConclusionDespite the wide publicity that ‘rapid testing’ has received in the press it is only a small part of the national response to fighting COVID-19. There will need to be an integrated use of all three forms of testing outlined above.Rapid testing should only be utilised when results are clinically required quicker than can be provided by a traditional how to buy cheap antabuse laboratory-based system.

    This is due to a lack of testing capacity, limited availability of platforms and reagents, significant expense of testing and the limitations of the tests (i.e. Risk of how to buy cheap antabuse incorrect results). It is paramount for patient how to buy cheap antabuse safety that these tests are only used in the clinical scenarios approved by the manufacturer and local validation. It must not be assumed that these systems are appropriate for testing in all patient cohorts.Routine high throughput RT-PCR testing is the backbone of testing for hospital patients, NHS and social care staff. It is also useful for local how to buy cheap antabuse public health testing initiatives.

    These are high throughput, how to buy cheap antabuse high quality services that utilise tests sensitive enough for the vast majority of clinical situations. These are cost effective and adaptable operations that provide timely results. Primary and secondary healthcare professionals have high confidence in the services that they provide.Mass screening services are how to buy cheap antabuse designed solely for largescale population screening. These are large scale single test services that have the ability to provide results directly back to the patient, and receive samples from a wide geographical area. Use of these services allows the hospital laboratories to focus on immediate patient care needs for their local populations.Highlights how to buy cheap antabuse and updates Delaware exchange overviewHow hard is Delaware fighting to preserve the Affordable Care Act’s provisions?.

    Compare to other state efforts.Delaware’s exchange is a partnership between the state (Choose Health how to buy cheap antabuse Delaware) and HHS, with residents enrolling through HealthCare.gov. Delaware is responsible for plan management and consumer assistance while the federal government handles all other functions. As of early 2020, there were 22,497 people with effectuated individual market coverage through Delaware’s exchange.Two health insurance companies offered coverage in the exchange in 2017, but that dropped to just one – Highmark BCBS of Delaware – in 2018, and Highmark continues to be the only insurer offering plans in the state’s exchange in 2020.Highmark already covered more than half of Delaware’s exchange enrollees as of 2017, but nearly 12,000 people with Aetna coverage had to select new how to buy cheap antabuse plans from Highmark for 2018.Delaware received federal approval to implement a reinsurance program for 2020, and also enacted legislation to codify ACA consumer protections into state law. Highmark had already proposed a premium reduction for 2020, and the rate decrease was even more significant once the reinsurance program was approved. Highmark has proposed another how to buy cheap antabuse slight rate decrease for 2021.

    Without the how to buy cheap antabuse reinsurance program, Highmark’s proposed rate change would have been an increase from 2020.Average approved rate decrease of 1% for 2021Open enrollment for 2021 health plans runs from November 1 – December 15, 2020. Outside of that window, residents can enroll or make changes to their coverage if they experience a qualifying event.Highmark, which is the only insurer in Delaware’s marketplace, proposed an overall average rate decrease of half a percent for 2021 (across all plans, the proposed rate changes vary from a decrease of 3.6 percent to an increase of 5.3 percent). But after how to buy cheap antabuse the rate review process was complete, Delaware’s Insurance Commissioner, Trinidad Navarro, announced that Highmark’s average premiums would decrease by 1 percent for 2021.The state’s reinsurance program, which debuted in 2020, reduced Highmark’s proposed rates for 2021 by 2.5 percentage points, so without the reinsurance program, the proposed rate change would have been an increase of about 2 percent. And although the approved rate decrease is a little more significant than Highmark had initially proposed, it’s likely that rates would have increased slightly for 2021 without the reinsurance program [More details about the state’s reinsurance program are described below, including the program’s enhanced benefits in 2021.]Highmark has 21,828 members enrolled in ACA-compliant individual market plans. Highmark is discontinuing two bronze plans at the end of 2020, and introducing a total of six new plans how to buy cheap antabuse (bronze, silver, gold, and platinum) for 2021.New Delaware law caps insulin out-of-pocket at $100 per month on state-regulated health plansDelaware HB263, enacted in July 2020, caps out-of-pocket costs for insulin at $100 per month on all individual and group plans that are regulated by the state of Delaware (note that states to not regulate self-insured group plans).

    Plans are also required to include at least one insulin product in the lowest tier (ie, least expensive) of the plan’s covered drug list.The rule takes effect for plans that are issued or renewed after the end of 2020.Delaware codifies ACA consumer protections into state lawIn August how to buy cheap antabuse 2019, Delaware Governor John Carney signed SB35, codifying various ACA consumer protections into Delaware state law and joining several other states that have taken similar action over the last few years. Although the ACA remains the law of the land, Delaware’s new law ensures that if the ACA is ever repealed or changed, its consumer protections will remain in effect in Delaware.This includes provisions such as guaranteed-issue coverage (regardless of medical history), coverage for essential health benefits, a ban on lifetime and annual benefit maximums, limits on out-of-pocket costs, and rules regarding the factors that insurers can use to set premiums.Governor Carney also signed legislation that ensures adult Medicaid enrollees in Delaware will have dental coverage.Delaware’s reinsurance program took effect in 2020In June 2019, Governor Carney signed HB193 into law, paving the way for Delaware to create a reinsurance program in order to stabilize the state’s individual insurance market. The legislation called for an assessment on insurers how to buy cheap antabuse in the state, plus federal pass-through funding to cover the cost of the reinsurance program.Reinsurance programs work by paying a portion of high-cost claims, which reduces costs for insurers (in 2020, Delaware’s reinsurance program pays 75 percent of claims that are between $65,000 and $215,000. In 2021, it will pay 80 percent of claims that are between $65,000 and $335,000). Because their claims costs are lower, how to buy cheap antabuse insurers can charge lower premiums.

    This results in higher enrollment among people who have to pay full-price, and it also means that the federal government spends less on premium subsidies, as the subsidies don’t have to be as large in order to bring net premiums down to an affordable level.States can use how to buy cheap antabuse a 1332 waiver in order to request pass-through funding, which means the state (instead of the federal government) gets to keep the savings that result from the premium subsidies being smaller. The state then uses that money to fund the reinsurance program. Several states have implemented reinsurance programs over the last couple of years, and have seen improvement in their individual markets as a result.Delaware estimated that the reinsurance program would cost about $44 million in 2020, and that 80 percent of that would be covered by the federal pass-through funding, with the state generating the other 20 percent how to buy cheap antabuse via the health insurer assessment (1 percent in years when the ACA’s Health Insurance Provider Fee is assessed, and 2.75 percent in years that it isn’t). CMS determined that Delaware’s pass-through funding would amount to $21.7 million in 2020, which was less than the state had initially projected.Delaware submitted a 1332 waiver proposal to CMS in July 2019, and it was approved in mid-August. With the reinsurance program in place, Delaware projected that premiums in the individual market to be 13.7 percent lower in 2020 than they would otherwise have been, and that enrollment in the individual market would increase by as much as 2.3 percent, thanks to smaller premiums for people who don’t get premium subsidies (for those who do get subsidies, the subsidies shrink commensurately with the cost of the benchmark plan).19% rate decrease for 2020, thanks how to buy cheap antabuse in large part to reinsuranceHighmark initially proposed an average rate decrease of 5.85 percent for 2020.

    The filing, which was submitted before the state’s reinsurance legislation was enacted, noted that it did not account for the reinsurance program (including the insurer assessment that would fund the program as well as the impact of the reinsurance program itself), and that a new filing would need to be submitted if and when the reinsurance program was approved.The 1332 waiver proposal that Delaware submitted to CMS in July noted that with the reinsurance program in place, premiums were expected to be 13.7 percent lower in 2020 than they would otherwise have been, and up to 20 percent lower in future years than they would otherwise have been (the waiver proposal is for a five-year program).Ultimately, a 19 percent average rate decrease was approved for how to buy cheap antabuse Highmark’s plans, which was very much in line with the state’s initial projections (ie, the 5.9 percent decrease that Highmark had proposed, in addition to the 13.7 percent estimated decrease due to the reinsurance program).For perspective, unsubsidized premiums in Delaware are among the highest in the country in 2019. The average unsubsidized premium in Delaware is $842/month, versus $612 across all of the states that use HealthCare.gov. Enrollment grew in 2020, after declining for three years in a row23,961 people enrolled in plans through Delaware’s exchange how to buy cheap antabuse during the open enrollment period for 2020 coverage. That was an increase of about 6 percent how to buy cheap antabuse over the number of people who enrolled the year before, and came on the heels of three straight year-over-year enrollment declines.The enrollment drops in recent years were not unexpected. For 2019, two significant factors were the elimination of the individual mandate penalty after the end of 2018 and the Trump Administration’s decision to sharply reduce funding for exchange marketing and enrollment assistance, after already implementing funding cuts the year before.

    In many states, the expansion of short-term plans also played a role in declining enrollment for 2019, but Delaware regulators implemented emergency regulations that limit short-term plans to just three months in duration, eliminating the option for people to how to buy cheap antabuse use them as long-term coverage alternatives to ACA-compliant plans. There was a window, however, from early October until the end of November, when residents in Delaware were able to purchase longer short-term plans, and some may have done so in order to obtain coverage for much of 2019.The enrollment increase in 2020 also was not unexpected, as Delaware’s new reinsurance program resulted in lower premiums for people who don’t get premium subsidies, making coverage more affordable for that population.Enrollment in individual market plans through Delaware’s exchange has reached the following totals during open enrollment each year. Although enrollment in the exchange dropped about 20 percent from 2016 through how to buy cheap antabuse 2019, Delaware’s 1332 waiver proposal noted that total individual market enrollment in the state (including on-exchange and off-exchange enrollment) had dropped by 37 percent in that same time period. Off-exchange enrollees don’t get premium subsidies, but the state’s how to buy cheap antabuse new reinsurance program has made their coverage more affordable, potentially resulting in enrollment gains outside the marketplace as well. 2019 rates and plans.

    Highmark silver loaded instead of broad loadingDelaware was one of five states where the cost of cost-sharing reductions (CSR) was added to premiums for plans at all metal levels in 2018, rather than just how to buy cheap antabuse silver plan premiums. For 2019 coverage, the rate and form filing submission window in Delaware ran from May 9, 2018 to June 20, 2018.In April 2018, the Department of Insurance published an extensive guide to 2019 rate and form filing submissions, but it did not address the CSR loading issue. The Department of Insurance clarified that they were not leaving the decision entirely up to Highmark, and had been involved in numerous meetings with the insurer about 2019 coverage.Highmark, which also offers coverage in the exchanges in Pennsylvania and West Virginia, recorded their first profitable how to buy cheap antabuse year in the ACA-compliant market in 2017, after losing a billion dollars in the ACA-compliant market from 2014 through 2016.When the rates were publicized in early August, Highmark had requested a 5.7 percent average premium increase for 2019 (this was a revised filing. Their initial how to buy cheap antabuse proposed rate increase that still shows up on ratereview.healthcare.gov was 13 percent). And when the Delaware Department of Insurance published final rates later in August, the approved average rate increase for Highmark was just 3 percent.Part of the reason Highmark revised their rates was that the Delaware Insurance Department has been working on regulations to limit short-term health insurance plans to three months in duration and prohibit renewals.

    Highmark’s initial filing had included higher rates (a 1 percent load) to offset the fact that the risk pool was expected to be sicker once the federal how to buy cheap antabuse regulations were relaxed to allow much longer short-term plans. But Delaware regulators stepped in to prevent that, and the result is a more stable individual market, since healthy people won’t have the option to leave the ACA-compliant market and switch to year-long short-term plans instead.The final rate approval notice clarifies that the cost of CSR was added only to silver plan rates for 2019, as opposed to the broad load strategy that was used for 2018. And the approved rate notice also clarified that the cost of CSR was not added to premiums how to buy cheap antabuse for plans purchased outside the exchange, which means that Highmark only added the cost of CSR to on-exchange silver plans. That’s the best approach for consumers, as it allows people who don’t qualify for premium subsidies to purchase an off-exchange plan (if they want a silver plan) and not have the added how to buy cheap antabuse cost of CSR baked into their premiums. 2018 coverage.

    Aetna out, Highmark left as the only how to buy cheap antabuse insurer. 25% average rate increase included adding cost of CSR to all premiums.Highmark Blue Cross Blue Shield of Delaware had the majority of the market share in the state’s exchange in 2017, and they became the only available option as of 2018. Aetna confirmed in May 2017 that they planned to exit all four of the exchanges where they offered coverage in 2017, including Delaware, at how to buy cheap antabuse the end of the year. The Delaware how to buy cheap antabuse Department of Insurance reported that Aetna insured 11,854 people via exchange plans in 2017 (about 42 percent of the exchange enrollees), all of whom needed to pick a new plan for 2018.In response to Aetna’s market exit announcement, Trinidad Navarro, Delaware’s Insurance Commissioner, said “I would hope that our elected officials in Washington will come up with solutions to guarantee that health insurance in Delaware and elsewhere is both available and affordable. Continuing funding for Cost-Sharing Reductions is a first step in the right direction.”The Trump Administration’s lack of commitment to funding the ACA’s cost-sharing reductions (CSR) was a driving factor in the rates that insurers filed for 2018.

    Insurers in most states — including Delaware how to buy cheap antabuse — added the cost of CSR to premiums for 2018. That ended up being a prescient decision, as the Trump Administration announced in mid-October that CSR funding would end immediately.Highmark initially proposed an average rate increase of 33.6 percent, but ultimately agreed to a 25 percent average rate increase in October. Their rate filing noted that the average rate increase would have been about 16.8 percent if CSR funding had continued and if the federal government was robustly enforcing the individual mandate (the mandate was still in effect in 2018, although it’s been eliminated as of 2019 how to buy cheap antabuse. But insurers were concerned in 2017 that the Trump Administration might not adequately enforce the mandate for 2018, leading to higher premiums in many areas).The Delaware Department of Insurance confirmed that the cost of CSR how to buy cheap antabuse was added to premiums at all metal levels for 2018 (ie, a broad load). And Highmark’s rate template indicated that average rate increases for all of their plans were in a very narrow range of about 23 – 26.5 percent, with the average increase for silver plans is roughly the same as the average increase for plans at other metal levels.Ultimately, only a handful of other states opted to add the cost of CSR to plans at all metal levels.

    Colorado, Mississippi, West Virginia, and Indiana how to buy cheap antabuse. For 2019, Delaware and Colorado both switched to adding the cost of CSR only to silver plans, although Mississippi, West Virginia, and Indiana have continued to use a broad load strategy.Highmark had about 91,600 members enrolled in exchange plans across Delaware, Pennsylvania, and West Virginia in 2018 (including all of the exchange enrollees in Delaware, since Highmark is the only insurer offering exchange plans in the state. That’s down from about 350,000 exchange enrollees in those three states in earlier years of exchange how to buy cheap antabuse implementation, when the insurer was actively pursuing that market. But amid concerns about financial losses in the exchange markets, Highmark scaled back, reduced how to buy cheap antabuse network sizes, and generally became much less aggressive in their approach to exchange market share. In 2017, however, for the first time, Highmark made money on its exchange business, after losses in the prior years.

    Exchange plans make up a tiny fraction of the how to buy cheap antabuse insurer’s overall book of business, which includes 4.6 million members.2017 ratesTwo companies offered health insurance through Delaware’s exchange for 2017. Aetna and Highmark Blue Cross Blue how to buy cheap antabuse Shield of Delaware. Aetna had a PPO division and an HMO division, which were listed as separate entities for rate filings. Although Aetna exited the exchanges at the end of 2016 in most of the states where they had been participating, Delaware was one of four states where how to buy cheap antabuse continued to offer exchange plans in 2017 (although they ultimately exited all four states at the end of 2017).In Delaware, the approved average rate increases for 2017 were:Aetna Health (HMO). 23.6 percentAetna Life (PPO).

    22.8 percentHighmark BCBS how to buy cheap antabuse of Delaware. 32.5 percentA public comment how to buy cheap antabuse period on the proposed rates ran through July 15, 2016. The rates that were approved were very similar to what the carriers had requested when they originally filed rates for 2017.Initially, Delaware Insurance Commissioner Karen Weldin Stewart had approved a lower-than-requested rate for Highmark, and forwarded that on to CMS for review. But in light of the carriers opting to leave exchanges in numerous states around the country, CMS urged how to buy cheap antabuse Delaware to accept Highmark’s initial rates, and the state agreed. As a result, no carriers left the Delaware exchange at the end of 2016, while most other states saw at least some insurers exit their exchanges.Higher subsidies offset the bulk of the rate hikes for exchange enrollees who are subsidy-eligible, which accounts for the large majority of enrollees.2016 ratesA study released in December 2014 by The Commonwealth Fund showed just a 3 percent increase in average marketplace premiums for Delaware between 2014 and 2015.

    The weighted how to buy cheap antabuse analysis looked at rates across all metal tiers and in urban/suburban/rural areas of most states.But rate increases the following year, for 2016 coverage, were much more significant. On September 29, 2015, Stewart announced final rates for 2016, after vowing earlier in the year that the Insurance Department in Delaware would “vigorously examine” the 2016 rate proposals they received from the state’s two exchange insurers, hoping to find ways to reduce the final rates.Highmark Blue Cross Blue Shield of Delaware initially requested an average rate increase of just over 25 percent in the individual market, how to buy cheap antabuse although they increased their proposed rate increase to 33 percent in August. State regulators ultimately approved a 22.4 percent average rate increase for Highmark’s individual market plans, and Highmark had almost 95 percent of the individual market share in Delaware, including both on and off-exchange enrollments.Aetna proposed raising rates by an average of nearly 17 percent for 2016, which was approved by regulators.In 2014, Highmark garnered more than 90 percent of the exchange market share. For 2015, they only how to buy cheap antabuse increased their average rates by 4 percent. Highmark’s rates increased significantly for 2016, but their market share remained similar to what it had been in 2015.No discrimination against transgender enrolleesIn March 2016, Delaware became the 15th state to prohibit health insurance companies from discriminating against transgender enrollees.

    The rules apply both on and off exchange, and in the individual and group market.The bulletin issued by Insurance Commissioner Karen Weldin Stewart specifically notes that while the plan that constitutes the Essential Health Benefits benchmark plan in Delaware for 2016 did have an exclusion for “change of sex surgery” (except for correcting a congenital defect), the bulletin detailing the ban on transgender discrimination supersedes the benchmark plan design, and that insurers may not issue such a blanket exclusion.Specialty drugs costs are capped under Delaware lawDelaware how to buy cheap antabuse is one of several states that have taken steps to limit patients’ out-of-pocket costs for prescription drugs. Delaware law limits specialty drugs to how to buy cheap antabuse $150/month copays or coinsurance. The regulations apply on and off-exchange, and to employer-sponsored plans that are regulated by the state (self-insured plans are regulated by the federal government under ERISA instead).And Delaware insurance plans are not allowed to designate all drugs in a particular drug class as specialty drugs, so patients shouldn’t have a situation in which their only available drugs are specialty drugs.Delaware opted to stay with federally-run exchangeIn the months leading up to the Supreme Court’s 2015 ruling on King v. Burwell, Delaware devised a back-up plan how to buy cheap antabuse. Because Delaware uses the federally-run marketplace (the state has a partnership exchange, which is a variation of the federally-run exchange), subsidies were in jeopardy in the state.

    If the how to buy cheap antabuse King plaintiffs had prevailed, an estimated 18,000 people would have lost their subsidies in Delaware. And statewide, the entire individual market would have seen spiraling premiums over the next few years as healthy individuals dropped coverage that became unaffordable without how to buy cheap antabuse subsidies.To avoid that outcome, the state submitted a proposal for transitioning from a state-federal partnership exchange to a federally-supported state-based marketplace (Oregon, Nevada, Arkansas, Kentucky, and New Mexico use that model as of 2019, with state-run exchanges that utilize Healthcare.gov for enrollment). And on June 15, 2015, HHS issued conditional approval for Delaware’s plan (Pennsylvania and Arkansas also got conditional approval for state-run exchanges as contingency plans in case the Court had sided with King).At that point, Delaware was the only state with a Democratic governor and Democratic majority in both congressional chambers that didn’t have a state-run exchange, in large part because the state’s small population would make it financially difficult to sustain an exchange.But then on June 25, the Supreme Court ruled that subsidies are legal in every state, including those that use the federally-run marketplace, meaning that subsidies would continue to be available in Delaware regardless of whether the state runs its own exchange. Initially, it was unclear whether how to buy cheap antabuse Delaware would continue with their plan to implement a supported state-based marketplace. The state issued a press release immediately after the King verdict was announced, stating that they would continue to evaluate the possibility of transitioning the exchange, and make a decision later in the summer.But in August 2015, Delaware officials announced that they would continue to operate as a state-federal partnership exchange, noting that it would be more cost-effective than operating their own exchange.Delaware health insurance exchange linksChoose Health Delaware800-318-2596HealthCare.gov800-318-2596Health Benefit Exchange informationExchange information from the Delaware Health Care CommissionWho Serves on the Delaware Health Care Commission?.

    State Exchange how to buy cheap antabuse Profile. DelawareThe Henry how to buy cheap antabuse J. Kaiser Family Foundation overview of Delaware’s progress toward creating a state health insurance exchange.Louise Norris is an individual health insurance broker who has been writing about health insurance and health reform since 2006. She has written dozens of opinions and educational pieces about the Affordable Care how to buy cheap antabuse Act for healthinsurance.org. Her state health exchange updates are regularly cited by media who cover health reform and by other health insurance experts..

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    Sept. 24, 2020 -- Up to 70% of N95 masks certified in China do not meet U.S. Standards for effectiveness, the nonprofit patient safety organization ECRI warned this week.

    "Because of the dire situation, U.S. Hospitals bought hundreds of thousands of masks produced in China over the past 6 months, and we're finding that many aren't safe and effective against the spread of COVID-19," Marcus Schabacker, MD, ECRI president and CEO, said in a statement. ECRI quality assurance researchers tested nearly 200 N95-style masks, reflecting 15 different manufacturer models purchased by some of the largest health systems in the United States.

    They found that 60% to 70% of the imported masks – known as KN95 masks -- that had not been certified by the National Institute for Occupational Safety and Health (NIOSH), do not as effectively filter particles from the air. They are "significantly inferior" to NIOSH-certified N95s, the report says. These masks did not filter 95% of aerosol particulates, despite what their name suggests.

    "Using masks that don't meet U.S. Standards puts patients and frontline healthcare workers at risk of infection. As ECRI research shows, we strongly recommend that health care providers going forward do more due diligence before purchasing masks that aren't made or certified in America," Schabacker said.

    According to ECRI, U.S. Domestic production capacity for N95s has increased significantly, but there remain widespread limits on how many can be purchased. The organization says non-NIOSH-certified masks should only be used as a "last resort" when treating COVID-19 patients and only when NIOSH-certified N95s or other respirators offering comparable or better protection are not available.

    "KN95 masks that don't meet U.S. Regulatory standards still generally provide more respiratory protection than surgical or cloth masks and can be used in certain clinical settings," Michael Argentieri, ECRI vice president for technology and safety, said in the statement. Medscape Medical News © 2020 WebMD, LLC.

    Sept. 24, 2020 -- Up to 70% of N95 masks certified in China do not meet U.S. Standards for effectiveness, the nonprofit patient safety organization ECRI warned this week. "Because of the dire situation, U.S.

    Hospitals bought hundreds of thousands of masks produced in China over the past 6 months, and we're finding that many aren't safe and effective against the spread of COVID-19," Marcus Schabacker, MD, ECRI president and CEO, said in a statement. ECRI quality assurance researchers tested nearly 200 N95-style masks, reflecting 15 different manufacturer models purchased by some of the largest health systems in the United States. They found that 60% to 70% of the imported masks – known as KN95 masks -- that had not been certified by the National Institute for Occupational Safety and Health (NIOSH), do not as effectively filter particles from the air. They are "significantly inferior" to NIOSH-certified N95s, the report says.

    These masks did not filter 95% of aerosol particulates, despite what their name suggests. "Using masks that don't meet U.S. Standards puts patients and frontline healthcare workers at risk of infection. As ECRI research shows, we strongly recommend that health care providers going forward do more due diligence before purchasing masks that aren't made or certified in America," Schabacker said.

    According to ECRI, U.S. Domestic production capacity for N95s has increased significantly, but there remain widespread limits on how many can be purchased. The organization says non-NIOSH-certified masks should only be used as a "last resort" when treating COVID-19 patients and only when NIOSH-certified N95s or other respirators offering comparable or better protection are not available. "KN95 masks that don't meet U.S.

    Regulatory standards still generally provide more respiratory protection than surgical or cloth masks and can be used in certain clinical settings," Michael Argentieri, ECRI vice president for technology and safety, said in the statement. Medscape Medical News © 2020 WebMD, LLC. All rights reserved..

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    The items below are highlights from the free newsletter, “Smart, useful, science stuff about antabuse effects on liver COVID-19.” To receive newsletter issues daily in your inbox, sign-up here. Are you in need of a “dose of optimism” about the pandemic, at least in the U.S.?. Check out this 10/12/20 story at The New York Times by by Donald McNeil Jr., who has covered infectious diseases and epidemics for many years antabuse effects on liver. McNeil notes the 215,000 people in the U.S. Dead so far from the novel coronavirus, as well as the estimates that the figure could go as high as 400,000 before this era draws to a close.

    But here is some of the good news antabuse effects on liver that he tallies. 1) mask-wearing by the public is “widely accepted”. 2) the development of vaccines to protect against SARS-CoV-2 and of treatments for COVID-19 are proceeding at record antabuse effects on liver speed. 3) “experts are saying, with genuine confidence, that the pandemic in the United States will be over far sooner than they expected, possibly by the middle of next year”. And 4) fewer infected people die today than did earlier this year, even at nursing homes.

    About 10 percent of people antabuse effects on liver in the U.S. Have been infected with the virus so far, according to the U.S. Centers for Disease Control, the story states. €œPandemics don’t end antabuse effects on liver abruptly. They decelerate gradually,” McNeil writes.

    A 10/14/20 story by Carl Zimmer for The New York Times puts into context three late-stage (Phase 3 safety and effectiveness) COVID-19 experiments that have been paused in recent weeks due to illness among some antabuse effects on liver study participants. Pauses in vaccine studies — in this case Johnson &. Johnson’s vaccine candidate and AstraZeneca’s vaccine candidate — are “not unusual,” the story states, partly because the safety threshold is extremely high for a product that, if approved, could be given to millions or billions of people. But pauses are rare in treatment studies antabuse effects on liver — in this case Eli Lilly’s monoclonal antibody cocktail drug. Once a drug or treatment experiment (trial) is paused, a safety board determines whether the ill participant was given the new product or a placebo.

    If it was the placebo, the study can resume. If not, the antabuse effects on liver board looks deeper into the case to determine whether or not the illness is related to the drug or treatment. If a clear connection is discovered, “the trial may have to stop,” Zimmer writes. Dr. Eric Topol at Scripps Research is quoted in the piece as saying he is “still fairly optimistic” about monoclonal antibody treatments for COVID-19.

    The safety-related pauses of all three experiments are “an example of how things are supposed to work,” says Dr. Anna Durbin of Johns Hopkins Bloomberg School of Public Health in the story. The top of a story at The Washington Post features an instructive interactive that sketches “Scienceville,” a fictional place where “politicians and public health officials use every tool at their disposal to contain the coronavirus.” It basically shows how genetic analysis and tracing of viral strains found in a frequently and widely tested population could help officials control outbreaks of SARS-CoV-2. Then the 10/13/20 text story below, by Brady Dennis, Chris Mooney, Sarah Kaplan, and Harry Stevens, focuses on the details of such a “genomic epidemiology” approach and describes some real-life efforts under way, primarily in the UK, to implement the approach. The U.S.

    Has not been able to effectively use the approach, in part because genetic sequencing of viral strains “has largely been left up to states and individual researchers, rather than being part of a coordinated and well-funded national program,” the story states. The rise in SARS-CoV-2 infections in the U.S. Is now driven by “small gatherings in people’s homes,” according to officials with the U.S. Centers for Disease Control, reports Carolyn Crist for WebMD (10/14/20). People should continue to wear face masks and to practice social distancing “since most people have still not been exposed to the coronavirus worldwide," the researchers suggest, Crist writes.

    A newly developed test can detect SARS-CoV-2 in 5 minutes, reports Robert F. Service at Science (10/8/20). The test relies on CRISPR gene-editing technology, for which Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier of the Max Planck Unit for the Science of Pathogens won the Nobel Prize in Chemistry earlier this month. Doudna heads up the work that led to this new 5-minute CRISPR test for the coronavirus. By comparison, it can take a day or more to get back standard SARS-CoV-2 test results, the story states.

    Donald G. McNeil Jr. At The New York Times has written a guide to distinguishing common cold, flu, and COVID-19 symptoms (10/3/20). A major difference between having a cold and having the flu is that "Flu makes you feel as if you were hit by a truck,” McNeil quotes experts as saying. The symptom that best distinguishes COVID-19 from flu is loss of your sense of smell — strong smells don’t register, he writes.

    But many flu and COVID-19 symptoms overlap, the story states. The most common symptoms for COVID-19 are a high fever, chills, dry cough and fatigue. For flu, it’s a fever, headaches, body aches, sore throat, runny nose, stuffed sinuses, coughing and sneezing, the story states. Dr. Anthony Fauci’s three daughters do not plan to visit him for Thanksgiving to avoid potentially transmitting the new coronavirus to their parents, reports Ralph Ellis at WebMD.

    The story includes holiday traveling and visiting tips from a pulmonary critical care doctor at the University of Washington Medical Center who “believes traveling for the holidays is risky.” The tips include ensuring you have no COVID-19-like symptoms two weeks before traveling, getting tested before traveling, quarantining in a hotel for at least 48 hours before visiting with loved ones, traveling by car, and cutting down on “close contact and talking without a mask” (10/9/20). Adele Chapin has written a guide for reducing kids’ risk of catching and spreading SARS-CoV-2 at the playground. The 10/8/20 piece in The Washington Post makes the usual recommendations for mask-wearing, hand-washing, hand-sanitizer, disinfecting wipes, and distancing. It quotes a Children’s National Hospital pediatrician advises against gloves, because “people wearing them often touch their faces, which defeats the purpose.” The piece also recommends visiting playgrounds at less busy times and choosing playgrounds with more than one play structure, which makes it easier for kids to distance from one another. A story by Carl Zimmer for The New York Times beautifully describes and illustrates some of the amazing imaging work that scientists have done to study the structure of SARS-CoV-2 and how it infects our cells and multiplies (10/9/20).

    For starters, check out a mesmerizing video about a quarter of the way down-page that simulates spike proteins (complex molecules) doing a “molecular dance” on the virus membrane. The video (just one of several in this stunning piece) is part of research by a computational biophysicist at the Max Planck Institute of Biophysics and colleagues. The spikes appear to shimmy, which “increases the odds of encountering the protein on the surface of our cells it uses to attach,” the researchers suspect, Zimmer writes. You might enjoy, “A letter of recommendation in the age of Zoom,” by Matt Cheung, for McSweeney’s (10/14/20).Editor’s Note (10/16/20). This story is being republished in light of the interim results of a large international clinical trial of remdesivir by the World Health Organization.

    The trial found that the drug, which is widely used to treat COVID patients, failed to prevent deaths. An experimental drug—and one of the world’s best hopes against COVID-19—could shorten the time to recovery from coronavirus infection, according to the largest and most rigorous clinical trial of the compound. The experimental drug, called remdesivir, interferes with replication of some viruses, including the SARS-CoV-2 virus responsible for the current pandemic. On 29 April, Anthony Fauci, director of the US National Institute of Allergy and Infectious Disease (NIAID), announced that a clinical trial of more than a thousand people showed that people taking remdesivir recovered in 11 days on average, compared to 15 days for those on a placebo. €œAlthough a 31% improvement doesn’t seem like a knockout 100%, it is a very important proof of concept,” Fauci said.

    €œWhat it has proven is that a drug can block this virus.” Deaths were also lower in trial participants who received the drug, he said, but that trend was not statistically significant. The shortened recovery time, however, was significant, and was enough of a benefit that investigators decided to stop the trial early for ethical reasons, he said, to ensure that those participants who were receiving placebo could now access the drug. Fauci added that remdesivir would become a standard treatment for COVID-19. The news comes after weeks of data leaks and on a day of mixed results from clinical trials of the drug. In a trial run by the drug’s maker, Gilead Sciences of Foster City, California, more than half of 400 participants with severe COVID-19 recovered from their illness within two weeks of receiving treatment.

    But the study lacked a placebo controlled arm, making the results difficult to interpret. Another smaller trial run in China found no benefits from remdesivir when compared with a placebo. But the trial was stopped early due to the difficulty in enroling participants as the outbreak subsided in China. Nevertheless, onlookers are hopeful that the large NIAID trial provides the first glimmer of hope in a race to find a drug that works against the coronavirus, which has infected more than 3 million people worldwide. €œThere is a lot of focus on remdesivir because it’s potentially the best shot we have,” says virologist Stephen Griffin at the University of Leeds in the UK.

    Small trials The fast-flowing, conflicting information on remdesivir has left people reeling over the past weeks. In the rush to find therapies to combat COVID-19, small, clinical trials without control groups have been common. €œI’m just very annoyed by all of these non-controlled studies,” says Geoffrey Porges, an analyst for the investment bank SVB Leerink in New York City. €œIt’s reassuring that 50–60% of patients are discharged from the hospital, but this is a disease that mostly gets better anyway.” With so much uncertainty, the remdesivir-watchers were waiting anxiously for final results from the NIAID trial, which were not expected until the end of May. In lieu of a vaccine, which could still be more than a year away, effective therapies are critical to reducing deaths and limiting economic damage from the pandemic.

    Yet, despite the flood of small clinical trials, no therapy has been convincingly shown to boost survival in people with COVID-19. The NIAID results put a new sheen on remdesivir. €œIt may not be the wonder drug that everyone’s looking for, but if you can stop some patients from becoming critically ill, that’s good enough,” says Griffin. Fauci said the finding reminded him of the discovery in the 1980s that the drug AZT helped to combat HIV infection. The first randomized, controlled clinical only showed a modest improvement, he said, but researchers continued to build on that success, eventually developing highly effective therapies.

    For now, he said, remdesivir would become a standard treatment for COVID-19. Remdesivir works by gumming up an enzyme that some viruses, including SARS-CoV-2, use to replicate. In February, researchers showed that the drug reduces viral infection in human cells grown in a laboratory. Gilead began to ramp up production of remdesivir well before the NIAID results. By the end of March, the company had produced enough to treat 30,000 patients.

    By streamlining its manufacturing process and finding new sources of raw materials, Gilead announced that it hoped to produce enough remdesivir to treat more than a million people by the end of the year. That calculation was based on the assumption that people would take the drug for 10 days, but the results announced from Gilead’s trial today suggest that a 5-day course of treatment could work just as well. If so, that would effectively double the number of people who could be treated, says Porges. Many drugs needed In the long term, clinicians will likely want a bevy of anti-viral drugs—with different ways of disabling the virus—in their arsenal, says Timothy Sheahan, a virologist at the University of North Carolina in Chapel Hill, who has teamed up with Gilead researchers to study remdesivir. €œThere is always the potential for antiviral resistance,” he says.

    €œAnd to hedge against that potential, it’s good to have not only a first-line, but also a second-, third-, fourth-, fifth-line antiviral.” Researchers are furiously testing a wide range of therapies, but early results, while not yet definitive, have not been encouraging. The malaria drugs chloroquine and hydroxychloroquine, both of which also have anti-inflammatory effects, drew so much attention from physicians and the public that some countries have depleted their supplies of the drugs. Yet studies in humans have failed to show a consistent benefit, and some have highlighted the risks posed by side effects of the drugs on the heart. Early interest in a mix of two HIV drugs called lopinavir and ritonavir flagged when a clinical trial in nearly 200 people did not find any benefit of the mix for those with severe COVID-19. Another promising therapeutic hypothesis—that inhibiting the action of an immune system regulator called IL-6 could reduce the severe inflammation seen in some people with severe COVID-19—has met with mixed results thus far.

    Still, a host of other therapies are being tested in people, and many researchers are hunting for new drugs at the bench. Sheahan and his colleagues have found a compound that is active against SARS-CoV-2 and other coronaviruses, including a remdesivir-resistant variant of a coronavirus, when tested in laboratory-grown human cells. But much more testing would need to be done before the compound could be tried in people. €œWhat we’re doing now will hopefully have an impact on the current pandemic,” he says. €œBut maybe more importantly, it could position us to better respond more quickly in the future.” This article is reproduced with permission and was first published on April 29 2020.

    Read more about the coronavirus outbreak here.During a press conference in early September, President Donald Trump was asked when he thought a vaccine for COVID-19 might become available. His prediction was upbeat. €œWe’re going to have a vaccine very soon,” Trump said. €œMaybe even before a very special day—you know what day I’m talking about.” Trump was referring, of course, to the presidential election on November 3. But the odds of a vaccine materializing for public use before then appear slim.

    New drugs and vaccines ordinarily go through a lengthy review process prior to regulatory approval. Vaccines for COVID-19, however, are widely expected to be released under emergency use authorization (EUA) protocols, which allow for the sale of unapproved medical products during national health crises. On October 6 the White House agreed to new EUA guidelines that call on COVID-19 vaccine developers to monitor their phase III clinical trial subjects for at least two months for side effects and severe disease. The U.S. Food and Drug Administration, which administers EUAs, will host a widely anticipated meeting on October 22 to address standards for efficacy, safety and manufacturing of COVID-19 vaccines.

    But the FDA’s recommended two-month observation period puts a preelection vaccine approval out of reach. EUAs could, however, make the first successful COVID-19 vaccines available to frontline workers by the start of 2021, although distribution in the general U.S. Population will take longer, starting with elderly and other high-risk groups and then younger, healthier people who may not have access to them until late in the year, according to Paul Offit, a pediatrician and director of the Vaccine Education Center at Children’s Hospital of Philadelphia. The FDA has already granted hundreds of COVID-related EUAs for products such as diagnostic tests, medical devices and therapies—including for convalescent plasma and hydroxychloroquine (the latter was later revoked). €œAll the COVID-19 vaccine developers are going for an EUA first,” says Eric Topol, a cardiologist and head of the Scripps Research Translational Institute in La Jolla, Calif., who has directed numerous multinational clinical trials (although none for vaccines).

    €œIt makes no sense to wait for formal licensure.” Defining Success Obtaining an EUA hinges on how independent reviewers judge a vaccine’s performance during periodic readouts of phase III clinical trial data. The trials are each enrolling tens of thousands of people and are also double-blinded—meaning that neither the subjects nor the experimenters know which participants got a vaccine versus a placebo. They were designed to continue until the number of symptomatic infections reaches 150 in the vaccinated and control groups combined. If a vaccine halves the risk of symptomatic infections among the vaccinated group, it will meet the FDA’s minimum bar for approval. Reviewers examining the interim data readouts will be looking for better protection than that.

    Pfizer, which began a phase III trial for its vaccine on July 27, plans to conduct its first readout when the number of symptomatic cases reaches 32. The company expects that could happen this month, making it first in line for a potential EUA. Statistical thresholds are set such that if COVID case numbers in the vaccinated group are, at that point, at least five times lower than they are among vaccinated subjects, then reviewers can declare overwhelming efficacy. In that event, the company will “consult with regulatory authorities about next steps,” which could include an EUA, says a Pfizer spokesperson. In an October 16 open letter, Pfizer chairman and CEO Albert Bourla wrote that if the efficacy data are positive, the company will apply for an EUA in the U.S.

    €œsoon after the safety milestone is achieved in the third week of November.” The company’s study protocol also includes data readouts at 62, 92 and 120 cases, respectively, although the amount of protection the vaccine has to achieve at each step declines progressively until it reaches the FDA’s minimum target of 50 percent. Other companies racing to develop COVID-19 vaccines are taking a less aggressive approach. Cambridge, Mass.–based Moderna, for instance, plans for a first data readout when it reaches 53 cases among its study subjects and another at 106 cases. The company anticipates filing for an EUA in late November. Meanwhile Johnson &.

    Johnson recently paused its clinical trials after a participant got sick. This delay follows a similar pause by AstraZeneca, which has since resumed its trials outside of the U.S. What Happens Postapproval A significant issue is how vaccine developers will continue to assess safety and efficacy after an EUA. The FDA has said they should include strategies for monitoring a vaccine’s long-term performance in their EUA applications and generate the data needed to support future licensing. The agency has also stressed that companies should continue collecting placebo-controlled trial data for as long as feasible.

    Yet Pfizer representatives said in an e-mail that if an interim readout shows overwhelming efficacy, they have the option to unblind the data, vaccinate placebo recipients and then follow all the subjects in an unblinded fashion—meaning experimenters and participants would know who got the vaccine. (A Pfizer spokesperson later said the company would only unblind the study with regulatory approval.) The problem with unblinding the data is that a compromised control group “makes it harder to ascertain a vaccine’s risks and benefits and, in particular, how well it protects against severe disease—which isn’t as common as milder infections,” says Peter Gilbert, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle, who helped design clinical trials for the leading U.S. Candidates. Topol argues that with a few more weeks, developers could amass the 150 cases that might allow them to more fully assess protection from severe disease, especially in elderly and other vulnerable populations. €œThere shouldn’t be any shortcuts,” he says.

    €œWe’re talking about giving these vaccines to billions of people. You can’t risk compromising public trust.” Echoing those concerns, Patricia Whitley-Williams, an infectious disease specialist at Rutgers University’s Robert Wood Johnson Medical School, worries that doctors who mainly treat African-Americans and other people of color might be reluctant to recommend vaccines that they believe have not been adequately tested in these populations. Black Americans are hospitalized with COVID-19 at nearly three times the rate white Americans are, so with vaccination, “we need time to look at potential harms in all ethnic, age and gender groups,” she says. Still, if a vaccine’s interim review shows very high efficacy—say, 90 percent or greater—there will be “appropriate pressure to offer it to control groups immediately,” Gilbert says. These sorts of scenarios are under discussion now, he says, and what is unknown is how many control subjects will opt to be vaccinated if given the opportunity.

    Gilbert adds that more safety and efficacy data will come from so-called phase IV studies, which monitor immunized people after a vaccine has reached the market. One way to conduct these studies is for researchers to scour health data for cases of severe COVID-19 and assess vaccination histories among them. Vaccine developers are already gearing up for what is expected to be the largest immunization program in history. Larry St. Onge, president of life sciences and health care at the global shipping company DHL, says the “mRNA vaccines” developed by Pfizer and Moderna, which need to be stored at temperatures below –70 degrees Celsius, will face the greatest distribution challenges, especially in parts of the developing world where climates are harsh.

    Even as vaccine manufacturing ramps up to meet global demand, the logistics industry is building the capacity for vaccine delivery that “we don’t currently have in some countries,” St. Onge says. €œThis takes a lot of planning and forethought. But the world fully understands how important it is to get these vaccines out here so we can achieve some level of normalcy.” Read more about the coronavirus outbreak from Scientific American here. And read coverage from our international network of magazines here.In this time-lapse video, mathematicians at New York University immersed a block of blue candy in water and filmed it as it dissolved.

    The candy surface sunk unevenly as some areas melted faster than others, creating ever sharper and longer shards. Eventually the forest of candy spikes toppled as each “tree” fell.The researchers were aiming to mimic the natural processes that form stone forests—stunning rocky pinnacles of limestone—such as the famous Stone Forestin Kunming, China.The formation processes behind these “tall, slender, and sharply tipped” rock spires “remain unclear,” the scientists wrote in a paper published on September 22 in the Proceedings of the National Academy of Sciences USA. Though the geologic mechanisms are complex, the study showed that the relatively simple process of melting a solid in a liquid produced strikingly similar spikes. The scientists hope that by clarifying how stone forests might form, they can aid conservation efforts. Science in Images is a new category of articles featuring photographs and videos from all the disciplines of science.

    Click on the button below to see the full collection. Science in Images.

    The items antabuse pill price below how to buy cheap antabuse are highlights from the free newsletter, “Smart, useful, science stuff about COVID-19.” To receive newsletter issues daily in your inbox, sign-up here. Are you in need of a “dose of optimism” about the pandemic, at least in the U.S.?. Check out this 10/12/20 story at The how to buy cheap antabuse New York Times by by Donald McNeil Jr., who has covered infectious diseases and epidemics for many years. McNeil notes the 215,000 people in the U.S. Dead so far from the novel coronavirus, as well as the estimates that the figure could go as high as 400,000 before this era draws to a close.

    But here is some of the good news that how to buy cheap antabuse he tallies. 1) mask-wearing by the public is “widely accepted”. 2) the development of vaccines to protect against SARS-CoV-2 how to buy cheap antabuse and of treatments for COVID-19 are proceeding at record speed. 3) “experts are saying, with genuine confidence, that the pandemic in the United States will be over far sooner than they expected, possibly by the middle of next year”. And 4) fewer infected people die today than did earlier this year, even at nursing homes.

    About 10 percent of people in how to buy cheap antabuse the U.S. Have been infected with the virus so far, according to the U.S. Centers for Disease Control, the story states. €œPandemics don’t how to buy cheap antabuse end abruptly. They decelerate gradually,” McNeil writes.

    A 10/14/20 story by Carl Zimmer for The New York Times puts into context three late-stage (Phase 3 safety and effectiveness) COVID-19 experiments that have how to buy cheap antabuse been paused in recent weeks due to illness among some study participants. Pauses in vaccine studies — in this case Johnson &. Johnson’s vaccine candidate and AstraZeneca’s vaccine candidate — are “not unusual,” the story states, partly because the safety threshold is extremely high for a product that, if approved, could be given to millions or billions of people. But pauses are rare in treatment studies — how to buy cheap antabuse in this case Eli Lilly’s monoclonal antibody cocktail drug. Once a drug or treatment experiment (trial) is paused, a safety board determines whether the ill participant was given the new product or a placebo.

    If it was the placebo, the study can resume. If not, the board looks deeper into the case to determine whether or not the illness is related to the drug or how to buy cheap antabuse treatment. If a clear connection is discovered, “the trial may have to stop,” Zimmer writes. Dr. Eric Topol at Scripps Research is quoted in the piece as saying he is “still fairly optimistic” about monoclonal antibody treatments for COVID-19.

    The safety-related pauses of all three experiments are “an example of how things are supposed to work,” says Dr. Anna Durbin of Johns Hopkins Bloomberg School of Public Health in the story. The top of a story at The Washington Post features an instructive interactive that sketches “Scienceville,” a fictional place where “politicians and public health officials use every tool at their disposal to contain the coronavirus.” It basically shows how genetic analysis and tracing of viral strains found in a frequently and widely tested population could help officials control outbreaks of SARS-CoV-2. Then the 10/13/20 text story below, by Brady Dennis, Chris Mooney, Sarah Kaplan, and Harry Stevens, focuses on the details of such a “genomic epidemiology” approach and describes some real-life efforts under way, primarily in the UK, to implement the approach. The U.S.

    Has not been able to effectively use the approach, in part because genetic sequencing of viral strains “has largely been left up to states and individual researchers, rather than being part of a coordinated and well-funded national program,” the story states. The rise in SARS-CoV-2 infections in the U.S. Is now driven by “small gatherings in people’s homes,” according to officials with the U.S. Centers for Disease Control, reports Carolyn Crist for WebMD (10/14/20). People should continue to wear face masks and to practice social distancing “since most people have still not been exposed to the coronavirus worldwide," the researchers suggest, Crist writes.

    A newly developed test can detect SARS-CoV-2 in 5 minutes, reports Robert F. Service at Science (10/8/20). The test relies on CRISPR gene-editing technology, for which Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier of the Max Planck Unit for the Science of Pathogens won the Nobel Prize in Chemistry earlier this month. Doudna heads up the work that led to this new 5-minute CRISPR test for the coronavirus. By comparison, it can take a day or more to get back standard SARS-CoV-2 test results, the story states.

    Donald G. McNeil Jr. At The New York Times has written a guide to distinguishing common cold, flu, and COVID-19 symptoms (10/3/20). A major difference between having a cold and having the flu is that "Flu makes you feel as if you were hit by a truck,” McNeil quotes experts as saying. The symptom that best distinguishes COVID-19 from flu is loss of your sense of smell — strong smells don’t register, he writes.

    But many flu and COVID-19 symptoms overlap, the story states. The most common symptoms for COVID-19 are a high fever, chills, dry cough and fatigue. For flu, it’s a fever, headaches, body aches, sore throat, runny nose, stuffed sinuses, coughing and sneezing, the story states. Dr. Anthony Fauci’s three daughters do not plan to visit him for Thanksgiving to avoid potentially transmitting the new coronavirus to their parents, reports Ralph Ellis at WebMD.

    The story includes holiday traveling and visiting tips from a pulmonary critical care doctor at the University of Washington Medical Center who “believes traveling for the holidays is risky.” The tips include ensuring you have no COVID-19-like symptoms two weeks before traveling, getting tested before traveling, quarantining in a hotel for at least 48 hours before visiting with loved ones, traveling by car, and cutting down on “close contact and talking without a mask” (10/9/20). Adele Chapin has written a guide for reducing kids’ risk of catching and spreading SARS-CoV-2 at the playground. The 10/8/20 piece in The Washington Post makes the usual recommendations for mask-wearing, hand-washing, hand-sanitizer, disinfecting wipes, and distancing. It quotes a Children’s National Hospital pediatrician advises against gloves, because “people wearing them often touch their faces, which defeats the purpose.” The piece also recommends visiting playgrounds at less busy times and choosing playgrounds with more than one play structure, which makes it easier for kids to distance from one another. A story by Carl Zimmer for The New York Times beautifully describes and illustrates some of the amazing imaging work that scientists have done to study the structure of SARS-CoV-2 and how it infects our cells and multiplies (10/9/20).

    For starters, check out a mesmerizing video about a quarter of the way down-page that simulates spike proteins (complex molecules) doing a “molecular dance” on the virus membrane. The video (just one of several in this stunning piece) is part of research by a computational biophysicist at the Max Planck Institute of Biophysics and colleagues. The spikes appear to shimmy, which “increases the odds of encountering the protein on the surface of our cells it uses to attach,” the researchers suspect, Zimmer writes. You might enjoy, “A letter of recommendation in the age of Zoom,” by Matt Cheung, for McSweeney’s (10/14/20).Editor’s Note (10/16/20). This story is being republished in light of the interim results of a large international clinical trial of remdesivir by the World Health Organization.

    The trial found that the drug, which is widely used to treat COVID patients, failed to prevent deaths. An experimental drug—and one of the world’s best hopes against COVID-19—could shorten the time to recovery from coronavirus infection, according to the largest and most rigorous clinical trial of the compound. The experimental drug, called remdesivir, interferes with replication of some viruses, including the SARS-CoV-2 virus responsible for the current pandemic. On 29 April, Anthony Fauci, director of the US National Institute of Allergy and Infectious Disease (NIAID), announced that a clinical trial of more than a thousand people showed that people taking remdesivir recovered in 11 days on average, compared to 15 days for those on a placebo. €œAlthough a 31% improvement doesn’t seem like a knockout 100%, it is a very important proof of concept,” Fauci said.

    €œWhat it has proven is that a drug can block this virus.” Deaths were also lower in trial participants who received the drug, he said, but that trend was not statistically significant. The shortened recovery time, however, was significant, and was enough of a benefit that investigators decided to stop the trial early for ethical reasons, he said, to ensure that those participants who were receiving placebo could now access the drug. Fauci added that remdesivir would become a standard treatment for COVID-19. The news comes after weeks of data leaks and on a day of mixed results from clinical trials of the drug. In a trial run by the drug’s maker, Gilead Sciences of Foster City, California, more than half of 400 participants with severe COVID-19 recovered from their illness within two weeks of receiving treatment.

    But the study lacked a placebo controlled arm, making the results difficult to interpret. Another smaller trial run in China found no benefits from remdesivir when compared with a placebo. But the trial was stopped early due to the difficulty in enroling participants as the outbreak subsided in China. Nevertheless, onlookers are hopeful that the large NIAID trial provides the first glimmer of hope in a race to find a drug that works against the coronavirus, which has infected more than 3 million people worldwide. €œThere is a lot of focus on remdesivir because it’s potentially the best shot we have,” says virologist Stephen Griffin at the University of Leeds in the UK.

    Small trials The fast-flowing, conflicting information on remdesivir has left people reeling over the past weeks. In the rush to find therapies to combat COVID-19, small, clinical trials without control groups have been common. €œI’m just very annoyed by all of these non-controlled studies,” says Geoffrey Porges, an analyst for the investment bank SVB Leerink in New York City. €œIt’s reassuring that 50–60% of patients are discharged from the hospital, but this is a disease that mostly gets better anyway.” With so much uncertainty, the remdesivir-watchers were waiting anxiously for final results from the NIAID trial, which were not expected until the end of May. In lieu of a vaccine, which could still be more than a year away, effective therapies are critical to reducing deaths and limiting economic damage from the pandemic.

    Yet, despite the flood of small clinical trials, no therapy has been convincingly shown to boost survival in people with COVID-19. The NIAID results put a new sheen on remdesivir. €œIt may not be the wonder drug that everyone’s looking for, but if you can stop some patients from becoming critically ill, that’s good enough,” says Griffin. Fauci said antabuse drugs list the finding reminded him of the discovery in the 1980s that the drug AZT helped to combat HIV infection. The first randomized, controlled clinical only showed a modest improvement, he said, but researchers continued to build on that success, eventually developing highly effective therapies.

    For now, he said, remdesivir would become a standard treatment for COVID-19. Remdesivir works by gumming up an enzyme that some viruses, including SARS-CoV-2, use to replicate. In February, researchers showed that the drug reduces viral infection in human cells grown in a laboratory. Gilead began to ramp up production of remdesivir well before the NIAID results. By the end of March, the company had produced enough to treat 30,000 patients.

    By streamlining its manufacturing process and finding new sources of raw materials, Gilead announced that it hoped to produce enough remdesivir to treat more than a million people by the end of the year. That calculation was based on the assumption that people would take the drug for 10 days, but the results announced from Gilead’s trial today suggest that a 5-day course of treatment could work just as well. If so, that would effectively double the number of people who could be treated, says Porges. Many drugs needed In the long term, clinicians will likely want a bevy of anti-viral drugs—with different ways of disabling the virus—in their arsenal, says Timothy Sheahan, a virologist at the University of North Carolina in Chapel Hill, who has teamed up with Gilead researchers to study remdesivir. €œThere is always the potential for antiviral resistance,” he says.

    €œAnd to hedge against that potential, it’s good to have not only a first-line, but also a second-, third-, fourth-, fifth-line antiviral.” Researchers are furiously testing a wide range of therapies, but early results, while not yet definitive, have not been encouraging. The malaria drugs chloroquine and hydroxychloroquine, both of which also have anti-inflammatory effects, drew so much attention from physicians and the public that some countries have depleted their supplies of the drugs. Yet studies in humans have failed to show a consistent benefit, and some have highlighted the risks posed by side effects of the drugs on the heart. Early interest in a mix of two HIV drugs called lopinavir and ritonavir flagged when a clinical trial in nearly 200 people did not find any benefit of the mix for those with severe COVID-19. Another promising therapeutic hypothesis—that inhibiting the action of an immune system regulator called IL-6 could reduce the severe inflammation seen in some people with severe COVID-19—has met with mixed results thus far.

    Still, a host of other therapies are being tested in people, and many researchers are hunting for new drugs at the bench. Sheahan and his colleagues have found a compound that is active against SARS-CoV-2 and other coronaviruses, including a remdesivir-resistant variant of a coronavirus, when tested in laboratory-grown human cells. But much more testing would need to be done before the compound could be tried in people. €œWhat we’re doing now will hopefully have an impact on the current pandemic,” he says. €œBut maybe more importantly, it could position us to better respond more quickly in the future.” This article is reproduced with permission and was first published on April 29 2020.

    Read more about the coronavirus outbreak here.During a press conference in early September, President Donald Trump was asked when he thought a vaccine for COVID-19 might become available. His prediction was upbeat. €œWe’re going to have a vaccine very soon,” Trump said. €œMaybe even before a very special day—you know what day I’m talking about.” Trump was referring, of course, to the presidential election on November 3. But the odds of a vaccine materializing for public use before then appear slim.

    New drugs and vaccines ordinarily go through a lengthy review process prior to regulatory approval. Vaccines for COVID-19, however, are widely expected to be released under emergency use authorization (EUA) protocols, which allow for the sale of unapproved medical products during national health crises. On October 6 the White House agreed to new EUA guidelines that call on COVID-19 vaccine developers to monitor their phase III clinical trial subjects for at least two months for side effects and severe disease. The U.S. Food and Drug Administration, which administers EUAs, will host a widely anticipated meeting on October 22 to address standards for efficacy, safety and manufacturing of COVID-19 vaccines.

    But the FDA’s recommended two-month observation period puts a preelection vaccine approval out of reach. EUAs could, however, make the first successful COVID-19 vaccines available to frontline workers by the start of 2021, although distribution in the general U.S. Population will take longer, starting with elderly and other high-risk groups and then younger, healthier people who may not have access to them until late in the year, according to Paul Offit, a pediatrician and director of the Vaccine Education Center at Children’s Hospital of Philadelphia. The FDA has already granted hundreds of COVID-related EUAs for products such as diagnostic tests, medical devices and therapies—including for convalescent plasma and hydroxychloroquine (the latter was later revoked). €œAll the COVID-19 vaccine developers are going for an EUA first,” says Eric Topol, a cardiologist and head of the Scripps Research Translational Institute in La Jolla, Calif., who has directed numerous multinational clinical trials (although none for vaccines).

    €œIt makes no sense to wait for formal licensure.” Defining Success Obtaining an EUA hinges on how independent reviewers judge a vaccine’s performance during periodic readouts of phase III clinical trial data. The trials are each enrolling tens of thousands of people and are also double-blinded—meaning that neither the subjects nor the experimenters know which participants got a vaccine versus a placebo. They were designed to continue until the number of symptomatic infections reaches 150 in the vaccinated and control groups combined. If a vaccine halves the risk of symptomatic infections among the vaccinated group, it will meet the FDA’s minimum bar for approval. Reviewers examining the interim data readouts will be looking for better protection than that.

    Pfizer, which began a phase III trial for its vaccine on July 27, plans to conduct its first readout when the number of symptomatic cases reaches 32. The company expects that could happen this month, making it first in line for a potential EUA. Statistical thresholds are set such that if COVID case numbers in the vaccinated group are, at that point, at least five times lower than they are among vaccinated subjects, then reviewers can declare overwhelming efficacy. In that event, the company will “consult with regulatory authorities about next steps,” which could include an EUA, says a Pfizer spokesperson. In an October 16 open letter, Pfizer chairman and CEO Albert Bourla wrote that if the efficacy data are positive, the company will apply for an EUA in the U.S.

    €œsoon after the safety milestone is achieved in the third week of November.” The company’s study protocol also includes data readouts at 62, 92 and 120 cases, respectively, although the amount of protection the vaccine has to achieve at each step declines progressively until it reaches the FDA’s minimum target of 50 percent. Other companies racing to develop COVID-19 vaccines are taking a less aggressive approach. Cambridge, Mass.–based Moderna, for instance, plans for a first data readout when it reaches 53 cases among its study subjects and another at 106 cases. The company anticipates filing for an EUA in late November. Meanwhile Johnson &.

    Johnson recently paused its clinical trials after a participant got sick. This delay follows a similar pause by AstraZeneca, which has since resumed its trials outside of the U.S. What Happens Postapproval A significant issue is how vaccine developers will continue to assess safety and efficacy after an EUA. The FDA has said they should include strategies for monitoring a vaccine’s long-term performance in their EUA applications and generate the data needed to support future licensing. The agency has also stressed that companies should continue collecting placebo-controlled trial data for as long as feasible.

    Yet Pfizer representatives said in an e-mail that if an interim readout shows overwhelming efficacy, they have the option to unblind the data, vaccinate placebo recipients and then follow all the subjects in an unblinded fashion—meaning experimenters and participants would know who got the vaccine. (A Pfizer spokesperson later said the company would only unblind the study with regulatory approval.) The problem with unblinding the data is that a compromised control group “makes it harder to ascertain a vaccine’s risks and benefits and, in particular, how well it protects against severe disease—which isn’t as common as milder infections,” says Peter Gilbert, a biostatistician at the Fred Hutchinson Cancer Research Center in Seattle, who helped design clinical trials for the leading U.S. Candidates. Topol argues that with a few more weeks, developers could amass the 150 cases that might allow them to more fully assess protection from severe disease, especially in elderly and other vulnerable populations. €œThere shouldn’t be any shortcuts,” he says.

    €œWe’re talking about giving these vaccines to billions of people. You can’t risk compromising public trust.” Echoing those concerns, Patricia Whitley-Williams, an infectious disease specialist at Rutgers University’s Robert Wood Johnson Medical School, worries that doctors who mainly treat African-Americans and other people of color might be reluctant to recommend vaccines that they believe have not been adequately tested in these populations. Black Americans are hospitalized with COVID-19 at nearly three times the rate white Americans are, so with vaccination, “we need time to look at potential harms in all ethnic, age and gender groups,” she says. Still, if a vaccine’s interim review shows very high efficacy—say, 90 percent or greater—there will be “appropriate pressure to offer it to control groups immediately,” Gilbert says. These sorts of scenarios are under discussion now, he says, and what is unknown is how many control subjects will opt to be vaccinated if given the opportunity.

    Gilbert adds that more safety and efficacy data will come from so-called phase IV studies, which monitor immunized people after a vaccine has reached the market. One way to conduct these studies is for researchers to scour health data for cases of severe COVID-19 and assess vaccination histories among them. Vaccine developers are already gearing up for what is expected to be the largest immunization program in history. Larry St. Onge, president of life sciences and health care at the global shipping company DHL, says the “mRNA vaccines” developed by Pfizer and Moderna, which need to be stored at temperatures below –70 degrees Celsius, will face the greatest distribution challenges, especially in parts of the developing world where climates are harsh.

    Even as vaccine manufacturing ramps up to meet global demand, the logistics industry is building the capacity for vaccine delivery that “we don’t currently have in some countries,” St. Onge says. €œThis takes a lot of planning and forethought. But the world fully understands how important it is to get these vaccines out here so we can achieve some level of normalcy.” Read more about the coronavirus outbreak from Scientific American here. And read coverage from our international network of magazines here.In this time-lapse video, mathematicians at New York University immersed a block of blue candy in water and filmed it as it dissolved.

    The candy surface sunk unevenly as some areas melted faster than others, creating ever sharper and longer shards. Eventually the forest of candy spikes toppled as each “tree” fell.The researchers were aiming to mimic the natural processes that form stone forests—stunning rocky pinnacles of limestone—such as the famous Stone Forestin Kunming, China.The formation processes behind these “tall, slender, and sharply tipped” rock spires “remain unclear,” the scientists wrote in a paper published on September 22 in the Proceedings of the National Academy of Sciences USA. Though the geologic mechanisms are complex, the study showed that the relatively simple process of melting a solid in a liquid produced strikingly similar spikes. The scientists hope that by clarifying how stone forests might form, they can aid conservation efforts. Science in Images is a new category of articles featuring photographs and videos from all the disciplines of science.

    Click on the button below to see the full collection. Science in Images.

    Antabuse medical alert bracelet

    Current management of calcific aortic valve stenosis (CAVS) is limited to palliation of end-stage disease with antabuse medical alert bracelet valve replacement to relieve left ventricular outflow obstruction. Rather than treating the mechanical consequences of severe CAVS, identification of causal disease pathways at the tissue level might lead to medical therapies that could actually prevent or delay the pathological changes in the valve leaflets. Serum levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity are associated with the presence of CAVS.

    However, it has been unclear whether this association is due to antabuse medical alert bracelet a cause–effect relationship. In this issue of Heart, Perrot and colleagues1 used genetic association studies from eight cohorts to show that CAVS was not associated with any of four single nucleotide polymorphisms that are associated with Lp-PLA2 activity or mass. These findings suggest that although Lp-PLA2 activity is a biomarker for CAVS unfortunately, it is unlikely to be a therapeutic target (figure 1).Higher Lp-PLA2 activity is significantly associated with the presence of CAVS in patients with heart disease, but variants influencing Lp-PLA2 mass or activity are not associated with CAVS in this large genetic association study.

    CAVS, calcific antabuse medical alert bracelet aortic valve stenosis. Lp-PLA2, lipoprotein-associated phospholipase A2." data-icon-position data-hide-link-title="0">Figure 1 Higher Lp-PLA2 activity is significantly associated with the presence of CAVS in patients with heart disease, but variants influencing Lp-PLA2 mass or activity are not associated with CAVS in this large genetic association study. CAVS, calcific aortic valve stenosis.

    Lp-PLA2, lipoprotein-associated phospholipase A2.In an editorial, Zheng and Dweck2 discuss this article, summarise current ongoing trials of antabuse medical alert bracelet medical therapy for CAVS (table 1) and comment. €˜Strong evidence points towards elevated Lp(a) levels and its associated oxidised phospholipids (OxPL) as causal risk factors for CAVS, suggesting that targeting this lipid-driven, inflammatory pathway has a real chance to translate into therapy capable of mitigating disease. The current study suggests that this association is not mediated by Lp-PLA2 and underlines the importance of scrutinising whether biological factors within pathophysiological pathways are merely biomarkers or actually represent a feasible and causal target.’View this table:Table 1 Ongoing randomised clinical trials of medical therapies in aortic stenosisRheumatic heart disease (RHD) remains the primary cause of valve disease worldwide and contributes significantly to maternal and fetal morbidity and mortality.

    In a study by Baghel and colleagues3 of 681 pregnant women with RHD, adverse cardiovascular evens occurred antabuse medical alert bracelet in about 15% of pregnancies. Multivariable predictors of adverse outcomes during pregnancy were prior adverse cardiovascular events, lack of appropriate medical therapy, severity of mitral stenosis, valve replacement and pulmonary hypertension. Based on this analysis, the authors propose a risk score from pregnant women with RHD (table 2).View this table:Table 2 New prognostic score (DEVI’s score) to predict composite adverse cardiac outcome in pregnant women with rheumatic valvular heart diseaseCommenting on this paper, Elkayam and Shmueli4 point out that in about one-fourth of women, the diagnosis of RHD was not known prior to pregnancy and that a late diagnosis often was associated with adverse outcomes.

    Their editorial provides antabuse medical alert bracelet a concise summary of optimal management of pregnant women with RHD. They conclude ‘With proper evaluation and risk stratification prior to pregnancy, a close multidisciplinary follow-up during pregnancy, and close monitoring during labour and delivery as well as the early postpartum period most complications can be prevented.’The importance of psychosocial factors in cardiovascular disease (CVD) prevalence and outcomes is increasingly recognised. Using data from the English Longitudinal Study of Ageing, Bu and colleagues5 found that loneliness was associated with CVD, independent of possible confounders and other risk factors, with a 30% higher risk of a new CVD diagnosis in the most lonely people compared with the least lonely people.

    As O’Keefe and colleagues6 point out, this data is especially important now in the context of social distancing and stay-at-home recommendations and they offer several approaches to mitigating loneliness during the COVID-19 pandemic.The Education in Heart article7 in this issue focuses on the antabuse medical alert bracelet clinical use and prognostic implications of echocardiographic speckle tracking measurements of global longitudinal strain to detect and quantify early systolic dysfunction of the left ventricle (figure 2).Left ventricular global longitudinal strain to differentiate between mutation-positive sarcomeric hypertrophic cardiomyopathy and cardiac amyloidosis. (A) Apical four-chamber view of a 66-year-old patient known with mutation-positive hypertrophic cardiomyopathy. The thickness of the septum was 28 mm and the left ventricular ejection fraction was 55%.

    (B) The polar map shows markedly impaired longitudinal strain in the septal mid and basal areas and the global longitudinal antabuse medical alert bracelet strain is impaired (−13.6%). (C) Apical four-chamber view of a 75-year-old patient diagnosed with light chain amyloidosis. There is concentric hypertrophy of the left ventricle and the ejection fraction is 56%.

    Based on speckle tracking echocardiography analysis, the left ventricular global longitudinal strain is impaired (−12.2%), with typical sparing of the longitudinal strain values in the antabuse medical alert bracelet apical segments (D). ANT, anterior. ANT SEPT, anteroseptal.

    GS, global strain. INF, inferior antabuse medical alert bracelet. LAT, lateral.

    POST, posterior. SEPT, septal." data-icon-position data-hide-link-title="0">Figure 2 Left ventricular global longitudinal strain to differentiate between mutation-positive sarcomeric hypertrophic cardiomyopathy antabuse medical alert bracelet and cardiac amyloidosis. (A) Apical four-chamber view of a 66-year-old patient known with mutation-positive hypertrophic cardiomyopathy.

    The thickness of the septum was 28 mm and the left ventricular ejection fraction was 55%. (B) The antabuse medical alert bracelet polar map shows markedly impaired longitudinal strain in the septal mid and basal areas and the global longitudinal strain is impaired (−13.6%). (C) Apical four-chamber view of a 75-year-old patient diagnosed with light chain amyloidosis.

    There is concentric hypertrophy of the left ventricle and the ejection fraction is 56%. Based on speckle tracking antabuse medical alert bracelet echocardiography analysis, the left ventricular global longitudinal strain is impaired (−12.2%), with typical sparing of the longitudinal strain values in the apical segments (D). ANT, anterior.

    ANT SEPT, anteroseptal. GS, global strain antabuse medical alert bracelet. INF, inferior.

    LAT, lateral. POST, posterior antabuse medical alert bracelet. SEPT, septal.Our Cardiology-in-Focus article by Hudson and Pettit8 provides a clear-eyed but brief discussion and outstanding graphic of the challenges in reconciling the varying definitions of the ‘normal’ values for left ventricular ejection fraction, as stated in different guidelines (figure 3).Categories of left ventricular ejection fraction.

    EF, ejection fraction. HF, heart antabuse medical alert bracelet failure. LVEF, left ventricular ejection fraction." data-icon-position data-hide-link-title="0">Figure 3 Categories of left ventricular ejection fraction.

    EF, ejection fraction. HF, heart antabuse medical alert bracelet failure. LVEF, left ventricular ejection fraction.Loneliness is an unpleasant emotional state induced by perceived isolation.

    Until about 200 years ago, the English word for being on one’s own was ‘oneliness’, a term that connoted solitude, and was generally considered an essential and positive experience in life. However, solitude antabuse medical alert bracelet and loneliness are not synonymous. Loneliness is also described as ‘social pain’ from an unwanted lack of connection and intimacy.

    Artists have likened loneliness to hunger, not only because we can feel it physically, sometimes described as an ache, a hollowness or a sense of coldness, but also because these physical sensations might be the body’s way of telling us that we are missing something that is important to our survival and flourishing.In this issue of Heart, Bu and colleagues,1 in a prospective observational study that comprised approximately 5000 adults followed for about 10 years, found that individuals reporting high levels of loneliness had 30%–48% increased risks of developing cardiovascular disease (CVD) and CVD-related hospital admission, respectively, even after adjusting for the usual cardiovascular risk factors.1 This major study has three implications. (1) loneliness should be considered among the most dangerous CVD risk factors.

    Rather than antabuse rash treating the mechanical consequences of severe CAVS, identification of causal disease pathways at the tissue level how to buy cheap antabuse might lead to medical therapies that could actually prevent or delay the pathological changes in the valve leaflets. Serum levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity are associated with the presence of CAVS. However, it has been unclear whether this association is due to a cause–effect relationship. In this issue of Heart, Perrot how to buy cheap antabuse and colleagues1 used genetic association studies from eight cohorts to show that CAVS was not associated with any of four single nucleotide polymorphisms that are associated with Lp-PLA2 activity or mass. These findings suggest that although Lp-PLA2 activity is a biomarker for CAVS unfortunately, it is unlikely to be a therapeutic target (figure 1).Higher Lp-PLA2 activity is significantly associated with the presence of CAVS in patients with heart disease, but variants influencing Lp-PLA2 mass or activity are not associated with CAVS in this large genetic association study.

    CAVS, calcific aortic valve stenosis. Lp-PLA2, lipoprotein-associated phospholipase A2." data-icon-position data-hide-link-title="0">Figure 1 Higher Lp-PLA2 activity is significantly associated with the presence of CAVS in patients with heart disease, but variants how to buy cheap antabuse influencing Lp-PLA2 mass or activity are not associated with CAVS in this large genetic association study. CAVS, calcific aortic valve stenosis. Lp-PLA2, lipoprotein-associated phospholipase A2.In an editorial, Zheng and Dweck2 discuss this article, summarise current ongoing trials of medical therapy for CAVS (table 1) and comment. €˜Strong evidence points towards elevated Lp(a) levels and its associated how to buy cheap antabuse oxidised phospholipids (OxPL) as causal risk factors for CAVS, suggesting that targeting this lipid-driven, inflammatory pathway has a real chance to translate into therapy capable of mitigating disease.

    The current study suggests that this association is not mediated by Lp-PLA2 and underlines the importance of scrutinising whether biological factors within pathophysiological pathways are merely biomarkers or actually represent a feasible and causal target.’View this table:Table 1 Ongoing randomised clinical trials of medical therapies in aortic stenosisRheumatic heart disease (RHD) remains the primary cause of valve disease worldwide and contributes significantly to maternal and fetal morbidity and mortality. In a study by Baghel and colleagues3 of 681 pregnant women with RHD, adverse cardiovascular evens occurred in about 15% of pregnancies. Multivariable predictors how to buy cheap antabuse of adverse outcomes during pregnancy were prior adverse cardiovascular events, lack of appropriate medical therapy, severity of mitral stenosis, valve replacement and pulmonary hypertension. Based on this analysis, the authors propose a risk score from pregnant women with RHD (table 2).View this table:Table 2 New prognostic score (DEVI’s score) to predict composite adverse cardiac outcome in pregnant women with rheumatic valvular heart diseaseCommenting on this paper, Elkayam and Shmueli4 point out that in about one-fourth of women, the diagnosis of RHD was not known prior to pregnancy and that a late diagnosis often was associated with adverse outcomes. Their editorial provides a concise summary of optimal management of pregnant women with RHD.

    They conclude ‘With proper evaluation and risk stratification prior to pregnancy, a close multidisciplinary follow-up during pregnancy, and close monitoring how to buy cheap antabuse during labour and delivery as well as the early postpartum period most complications can be prevented.’The importance of psychosocial factors in cardiovascular disease (CVD) prevalence and outcomes is increasingly recognised. Using data from the English Longitudinal Study of Ageing, Bu and colleagues5 found that loneliness was associated with CVD, independent of possible confounders and other risk factors, with a 30% higher risk of a new CVD diagnosis in the most lonely people compared with the least lonely people. As O’Keefe and colleagues6 point out, this data is especially important now in the context of social distancing and stay-at-home recommendations and they offer several approaches to mitigating loneliness during the COVID-19 pandemic.The Education in Heart article7 in this issue focuses on the clinical use and prognostic implications of echocardiographic speckle tracking measurements of global longitudinal strain to detect and quantify early systolic dysfunction of the left ventricle (figure 2).Left ventricular global longitudinal strain to differentiate between mutation-positive sarcomeric hypertrophic cardiomyopathy and cardiac amyloidosis. (A) Apical four-chamber view of a 66-year-old patient how to buy cheap antabuse known with mutation-positive hypertrophic cardiomyopathy. The thickness of the septum was 28 mm and the left ventricular ejection fraction was 55%.

    (B) The polar map shows markedly impaired longitudinal strain in the septal mid and basal areas and the global longitudinal strain is impaired (−13.6%). (C) Apical four-chamber view of a 75-year-old patient how to buy cheap antabuse diagnosed with light chain amyloidosis. There is concentric hypertrophy of the left ventricle and the ejection fraction is 56%. Based on speckle tracking echocardiography analysis, the left ventricular global longitudinal strain is impaired (−12.2%), with typical sparing of the longitudinal strain values in the apical segments (D). ANT, anterior how to buy cheap antabuse.

    ANT SEPT, anteroseptal. GS, global strain. INF, inferior. LAT, lateral how to buy cheap antabuse antabuse pill price. POST, posterior.

    SEPT, septal." data-icon-position data-hide-link-title="0">Figure 2 Left ventricular global longitudinal strain to differentiate between mutation-positive sarcomeric hypertrophic cardiomyopathy and cardiac amyloidosis. (A) Apical four-chamber view how to buy cheap antabuse of a 66-year-old patient known with mutation-positive hypertrophic cardiomyopathy. The thickness of the septum was 28 mm and the left ventricular ejection fraction was 55%. (B) The polar map shows markedly impaired longitudinal strain in the septal mid and basal areas and the global longitudinal strain is impaired (−13.6%). (C) Apical four-chamber view of a 75-year-old how to buy cheap antabuse patient diagnosed with light chain amyloidosis.

    There is concentric hypertrophy of the left ventricle and the ejection fraction is 56%. Based on speckle tracking echocardiography analysis, the left ventricular global longitudinal strain is impaired (−12.2%), with typical sparing of the longitudinal strain values in the apical segments (D). ANT, anterior how to buy cheap antabuse. ANT SEPT, anteroseptal. GS, global strain.

    INF, inferior how to buy cheap antabuse. LAT, lateral. POST, posterior. SEPT, septal.Our Cardiology-in-Focus article by Hudson and Pettit8 provides a clear-eyed but brief discussion and outstanding graphic of the challenges how to buy cheap antabuse in reconciling the varying definitions of the ‘normal’ values for left ventricular ejection fraction, as stated in different guidelines (figure 3).Categories of left ventricular ejection fraction. EF, ejection fraction.

    HF, heart failure. LVEF, left ventricular ejection fraction." data-icon-position data-hide-link-title="0">Figure 3 Categories of left how to buy cheap antabuse ventricular ejection fraction. EF, ejection fraction. HF, heart failure. LVEF, left how to buy cheap antabuse ventricular ejection fraction.Loneliness is an unpleasant emotional state induced by perceived isolation.

    Until about 200 years ago, the English word for being on one’s own was ‘oneliness’, a term that connoted solitude, and was generally considered an essential and positive experience in life. However, solitude and loneliness are not synonymous. Loneliness is also described as ‘social pain’ from an unwanted lack of how to buy cheap antabuse connection and intimacy. Artists have likened loneliness to hunger, not only because we can feel it physically, sometimes described as an ache, a hollowness or a sense of coldness, but also because these physical sensations might be the body’s way of telling us that we are missing something that is important to our survival and flourishing.In this issue of Heart, Bu and colleagues,1 in a prospective observational study that comprised approximately 5000 adults followed for about 10 years, found that individuals reporting high levels of loneliness had 30%–48% increased risks of developing cardiovascular disease (CVD) and CVD-related hospital admission, respectively, even after adjusting for the usual cardiovascular risk factors.1 This major study has three implications. (1) loneliness should be considered among the most dangerous CVD risk factors.

    (2) feeling lonely is a highly modifiable state that would seemingly respond to lifestyle adjustments as compared with the other foremost psychosocial CVD risk factors—depression and stress/anxiety—which typically require prescription medication or exercise2.

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    Ensure consistency by using the same media/tubes for each specimen within a clinical evaluation. Validate the chosen V/UTM media/tubes to show they will not interfere best place to buy antabuse online with the PCR test results. For example, allowing 7 days of swab positive specimen incubation with the chosen media/vial is considered a worst-case transportation scenario to evaluate maximal leaching/interaction potential). Use a single PCR test platform throughout each clinical evaluation. The platform should have been best place to buy antabuse online previously authorized by HC or another jurisdiction.

    Location (for example, left vs right nostril) and order of sampling (for example, control vs. Test swab) can affect specimen quality and results variability. Location and swab sampling order should be randomized.For additional information on collecting, handling, and testing COVID-19 specimens, please refer to the Centers for Disease Control and Prevention (CDC) Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for COVID-19.Previous clinical dataPreviously obtained clinical data may be best place to buy antabuse online submitted in lieu of clinical testing. Those data should demonstrate the safe and effective use of a swab of identical design and materials in human subjects. The proposed swab should be compared against a best place to buy antabuse online flocked swab commercially available in Canada with respect to.

    flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement) using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Sterility Provide sterilization validation data in a summary report. It should demonstrate that the chosen sterilization method will achieve a minimum Sterility Assurance Level (SAL) of 10-6 for the proposed swab, using an appropriate biological indicator (BI) organism (see below). If the swab will be sterilized using an ethylene oxide (EtO) method, you should best place to buy antabuse online demonstrate that EtO and ethylene chlorohydrin (ECH) residuals meet the tolerable contact limits (TCL) specified in ISO 10993-7. Commonly used swab materials, compatible sterilization methods, and appropriate biological indicators are described below. Sterilization Method Swab Materials EtO(for example, ISO 11135) Gamma Irradiation(ISO 11137) Polystyrene handle, polyester bicomponent fiber tipFootnote * X(for example, Puritan 25-3316-H/U) Not applicable Polystyrene handle, nylon flocked fiber tipFootnote * X(for example, Copan 503CS01) X(for example, BD 220252) Footnote * The CDC provides guidance on the types of swabs that should be used for optimal specimen collection for PCR testing.

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    Regulatory authorization Most PPE, including face shields, are Class I medical devices if they are manufactured, sold or represented for use for reducing the risk of or preventing the user from infection. This includes COVID-19. Face shields best place to buy antabuse online may be authorized for sale or import into Canada through the following regulatory pathways. Pathway 1. Interim order authorization to import and sell medical devices related to COVID-19.

    Pathway 2 best place to buy antabuse online. Expedited review and issuance of Medical Device Establishment Licences (MDEL) related to COVID-19. MDEL holders that import and sell face shields should take best place to buy antabuse online measures to ensure they are safe and effective. Pathway 3. Exceptional importation and sale of certain non-compliant medical devices related to COVID-19.

    Note that a sale generally requires the transfer of ownership of a device from one best place to buy antabuse online party to another and does not necessitate any transfer of money. Applicants should carefully review the pathways and select the most appropriate authorization route for their product. For more information, see Personal protective equipment (COVID-19). How to best place to buy antabuse online get authorization. If you intend to manufacture 3D print face shields in response to the COVID-19 crisis, see.

    3D printing and other manufacturing of personal protective equipment in response to COVID-19 Feedback If you have any questions or comments about this notice, contact the Medical Devices Directorate at hc.meddevices-instrumentsmed.sc@canada.ca R. J. Roberge, "Face shields for infection control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.

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    Date published how to buy cheap antabuse. August 26, 2020On this page BackgroundCOVID-19 is an infectious disease caused by the SARS-CoV-2 coronavirus. The World Health Organization declared a global pandemic in March 2020, and the Minister of Health signed the Interim Order Respecting the Importation and Sale of Medical Devices for Use in Relation to how to buy cheap antabuse COVID-19 on March 18, 2020. The Interim Order (IO) allows us to quickly address large-scale public health emergencies.This IO allows for faster authorization of Class I-IV medical devices for COVID-19.This document presents the criteria for safety and effectiveness that apply to test swabs used for COVID-19 sampling. It also provides guidance on how to meet these criteria in an application under the IO pathway.

    Diagnostic testing is a key element in both how to buy cheap antabuse. identifying cases of infection preventing the spread of the coronavirus A test swab may be used to collect a sample for either Polymerase Chain Reaction (PCR) laboratory testing or point-of-care testing. Point-of-care testing can be done directly in a hospital or doctor’s office. Once the sample has been taken, the swab is either placed in a preserving liquid and sent to a laboratory for testing, or placed directly in how to buy cheap antabuse a testing device (point-of-care).Swabs may be packaged in a variety of virus transport media (VTM). Specifications for individual VTMs are beyond the scope of this document.

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    It should be read in conjunction with this document. We are processing applications as quickly as possible. To avoid delays, please ensure you have completed your application properly.Medical Devices Regulations (MDR) classification In the Canadian regulatory framework, Class how to buy cheap antabuse I devices present the lowest potential risk and Class IV the highest. Swabs are classified according to their labelling and intended use. For example, if a swab is labelled for nasopharyngeal (NP) or oropharyngeal (OP) use only, it will be classified as a Class I medical device according to Classification Rule 2(2) of the MDR.

    If a swab is not exclusively for use in oral or nasal cavities, or its use is not explicitly stated, how to buy cheap antabuse it will be classified as a Class II device by Rule 2(1). These swabs belong to a higher risk class because their use in other body orifices for the collection of tissue samples (for example, to test for chlamydia or ureaplasma) is associated with greater risk. Rule 2 Subject to subrules (2) to (4), all invasive devices that penetrate the body through a body orifice or that how to buy cheap antabuse come into contact with the surface of the eye are classified as Class II. A device described in subrule (1) that is intended to be placed in the oral or nasal cavities as far as the pharynx or in the ear canal up to the ear drum is classified as Class I.Regulatory pathways for COVID-19 devicesManufacturers of Class I swabs may seek authorization to import and sell their products under either. A Medical Device Establishment Licence (MDEL) MDEL is an establishment oversight framework that is not product-specific and not designed to assess safety and effectiveness an IO authorization information on safety and effectiveness are required as part of the application Health Canada is encouraging a sub-group of swab manufacturers to use the IO authorization pathway for Class I swabs, especially if they are.

    New to the manufacturing of swabs and manufacturing in Canada (such as a company that has re-tooled to manufacture), or using a new manufacturing process or design for swabs (such as 3D printing or honeycomb design)IO applications for swabs should include how to buy cheap antabuse the following information.Device description The device description should include. A picture and/or engineering drawing identification of all materials used in the production of the swab the intended use(s) (for example, NP swabs)Quality manufacturingManufacturers must either. demonstrate compliance with Quality Manufacturing Systems (for example, ISO 13485 certificate) applicable to the swab, or provide a clear description of the planned quality manufacturing systems that are consistent with similar existing manufacturing systemsDesign verificationProvide swab design verification (bench testing) data in a summary report. It should show that the essential minimum design characteristics are met how to buy cheap antabuse. These data should be based on test samples representative of finished swabs that have undergone sterilization prior to bench testing.Dimensions Swabs should have minimum length specifications and minimum and maximum head diameter specifications in order to be safe and effective.

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    Regulatory authorization Most PPE, including face shields, are Class I medical devices if they are manufactured, sold or represented for use for reducing the risk of or preventing the user from infection. This includes COVID-19. Face shields may be authorized for sale or import into Canada how to buy cheap antabuse through the following regulatory pathways. Pathway 1. Interim order authorization to import and sell medical devices related to COVID-19.

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    Note that a sale generally requires the transfer of ownership of a device from one party to another how to buy cheap antabuse and does not necessitate any transfer of money. Applicants should carefully review the pathways and select the most appropriate authorization route for their product. For more information, see Personal protective equipment (COVID-19). How to how to buy cheap antabuse get authorization. If you intend to manufacture 3D print face shields in response to the COVID-19 crisis, see.

    3D printing and other manufacturing of personal protective equipment in response to COVID-19 Feedback If you have any questions or comments about this notice, contact the Medical Devices Directorate at hc.meddevices-instrumentsmed.sc@canada.ca R. J. Roberge, "Face shields for infection control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.

    Related links FootnotesFootnote 1 R. J. Roberge, "Face shields for infection control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.Return to footnote 1 referrer.

    Antabuse medication

    How to cite this article:Singh antabuse medication O P. Aftermath of celebrity suicide – Media coverage and role of psychiatrists. Indian J Psychiatry 2020;62:337-8Celebrity suicide is one of the highly publicized antabuse medication events in our country. Indians got a glimpse of this following an unfortunate incident where a popular Hindi film actor died of suicide.

    As expected, the media antabuse medication went into a frenzy as newspapers, news channels, and social media were full of stories providing minute details of the suicidal act. Some even going as far as highlighting the color of the cloth used in the suicide as well as showing the lifeless body of the actor. All kinds of personal details were dug up, and speculations and hypotheses became the order of the day in the next few days that followed. In the process, reputations of many people associated with the actor were besmirched and their private and personal details were freely and blatantly broadcast and discussed antabuse medication on electronic, print, and social media.

    We understand that media houses have their own need and duty to report and sensationalize news for increasing their visibility (aka TRP), but such reporting has huge impacts on the mental health of the vulnerable population.The impact of this was soon realized when many incidents of copycat suicide were reported from all over the country within a few days of the incident. Psychiatrists suddenly antabuse medication started getting distress calls from their patients in despair with increased suicidal ideation. This has become a major area of concern for the psychiatry community.The Indian Psychiatric Society has been consistently trying to engage with media to promote ethical reporting of suicide. Section 24 (1) of Mental Health Care Act, 2017, forbids antabuse medication publication of photograph of mentally ill person without his consent.[1] The Press Council of India has adopted the guidelines of World Health Organization report on Preventing Suicide.

    A resource for media professionals, which came out with an advisory to be followed by media in reporting cases of suicide. It includes points forbidding them from putting stories in prominent positions and unduly repeating them, explicitly describing the method used, providing details about the site/location, using sensational headlines, or using photographs and video footage of the incident.[2] Unfortunately, the advisory seems to have little effect in the aftermath of celebrity suicides. Channels were full of antabuse medication speculations about the person's mental condition and illness and also his relationships and finances. Many fictional accounts of his symptoms and illness were touted, which is not only against the ethics but is also contrary to MHCA, 2017.[1]It went to the extent that the name of his psychiatrist was mentioned and quotes were attributed to him without taking any account from him.

    The Indian Psychiatric Society has written to the Press Council of India underlining this concern and asking for measures to ensure ethics in reporting suicide.While there is a need for engagement with media to make them aware of the grave impact of negative suicide reporting on the lives of many vulnerable persons, there antabuse medication is even a more urgent need for training of psychiatrists regarding the proper way of interaction with media. This has been amply brought out in the aftermath of this incident. Many psychiatrists and mental health professionals were called by media houses to comment antabuse medication on the episode. Many psychiatrists were quoted, or “misquoted,” or “quoted out of context,” commenting on the life of a person whom they had never examined and had no “professional authority” to do so.

    There were even stories with byline of a psychiatrist where the content provided was not only unscientific but also way beyond the expertise of a psychiatrist. These types of viewpoints perpetuate stigma, myths, and “misleading concepts” about psychiatry and are detrimental to the image of psychiatry in addition to doing harm and injustice to our patients antabuse medication. Hence, the need to formulate a guideline for interaction of psychiatrists with the media is imperative.In the infamous Goldwater episode, 12,356 psychiatrists were asked to cast opinion about the fitness of Barry Goldwater for presidential candidature. Out of 2417 respondents, 1189 psychiatrists reported him to be mentally unfit while none had actually examined him.[3] This led to the formulation of “The Goldwater Rule” by the American Psychiatric Association in 1973,[4] but we have witnessed the same phenomenon at the time of presidential candidature of Donald Trump.Psychiatrists should be encouraged to interact with media to provide scientific information about mental illnesses and reduction of stigma, but “statements to the media” can be a double-edged sword, and we should antabuse medication know about the rules of engagements and boundaries of interactions.

    Methods and principles of interaction with media should form a part of our training curriculum. Many professional societies antabuse medication have guidelines and resource books for interacting with media, and psychiatrists should familiarize themselves with these documents. The Press Council guideline is likely to prompt reporters to seek psychiatrists for their expert opinion. It is useful for them to have a template ready with suicide rates, emphasizing multicausality of suicide, role of mental disorders, as well as help available.[5]It is about time that the Indian Psychiatric Society formulated its own guidelines laying down the broad principles and boundaries governing the interaction of Indian psychiatrists with the media.

    Till then, it is desirable to be guided by the following broad principles:It should be assumed that no statement goes “off the record” as the media person is most likely recording the interview, and we should also record any such conversation from our endIt should be clarified in which capacity comments are being made – professional, personal, or as a representative of an organizationOne should not comment on any person whom he has not examinedPsychiatrists should take any such opportunity to educate the public about mental health issuesThe comments should be justified and limited by the boundaries of scientific antabuse medication knowledge available at the moment. References Correspondence Address:Dr. O P SinghAA 304, Ashabari Apartments, O/31, Baishnabghata, Patuli Township, Kolkata antabuse medication - 700 094, West Bengal IndiaSource of Support. None, Conflict of Interest.

    NoneDOI. 10.4103/psychiatry.IndianJPsychiatry_816_20Abstract Electroconvulsive therapy (ECT) is an effective modality of treatment for a variety of psychiatric disorders. However, it has always been accused of being a coercive, unethical, and dangerous modality of treatment. The dangerousness of ECT has been mainly attributed to its claimed ability to cause brain damage.

    This narrative review aims to provide an update of the evidence with regard to whether the practice of ECT is associated with damage to the brain. An accepted definition of brain damage remains elusive. There are also ethical and technical problems in designing studies that look at this question specifically. Thus, even though there are newer technological tools and innovations, any review attempting to answer this question would have to take recourse to indirect methods.

    These include structural, functional, and metabolic neuroimaging. Body fluid biochemical marker studies. And follow-up studies of cognitive impairment and incidence of dementia in people who have received ECT among others. The review of literature and present evidence suggests that ECT has a demonstrable impact on the structure and function of the brain.

    However, there is a lack of evidence at present to suggest that ECT causes brain damage.Keywords. Adverse effect, brain damage, electroconvulsive therapyHow to cite this article:Jolly AJ, Singh SM. Does electroconvulsive therapy cause brain damage. An update.

    Indian J Psychiatry 2020;62:339-53 Introduction Electroconvulsive therapy (ECT) as a modality of treatment for psychiatric disorders has existed at least since 1938.[1] ECT is an effective modality of treatment for various psychiatric disorders. However, from the very beginning, the practice of ECT has also faced resistance from various groups who claim that it is coercive and harmful.[2] While the ethical aspects of the practice of ECT have been dealt with elsewhere, the question of harmfulness or brain damage consequent upon the passage of electric current needs to be examined afresh in light of technological advances and new knowledge.[3]The question whether ECT causes brain damage was reviewed in a holistic fashion by Devanand et al. In the mid-1990s.[4],[5] The authors had attempted to answer this question by reviewing the effect of ECT on the brain in various areas – cognitive side effects, structural neuroimaging studies, neuropathologic studies of patients who had received ECT, autopsy studies of epileptic patients, and finally animal ECS studies. The authors had concluded that ECT does not produce brain damage.This narrative review aims to update the evidence with regard to whether ECT causes brain damage by reviewing relevant literature from 1994 to the present time.

    Framing the Question The Oxford Dictionary defines damage as physical harm that impairs the value, usefulness, or normal function of something.[6] Among medical dictionaries, the Peter Collins Dictionary defines damage as harm done to things (noun) or to harm something (verb).[7] Brain damage is defined by the British Medical Association Medical Dictionary as degeneration or death of nerve cells and tracts within the brain that may be localized to a particular area of the brain or diffuse.[8] Going by such a definition, brain damage in the context of ECT should refer to death or degeneration of brain tissue, which results in the impairment of functioning of the brain. The importance of precisely defining brain damage shall become evident subsequently in this review.There are now many more tools available to investigate the structure and function of brain in health and illness. However, there are obvious ethical issues in designing human studies that are designed to answer this specific question. Therefore, one must necessarily take recourse to indirect evidences available through studies that have been designed to answer other research questions.

    These studies have employed the following methods:Structural neuroimaging studiesFunctional neuroimaging studiesMetabolic neuroimaging studiesBody fluid biochemical marker studiesCognitive impairment studies.While the early studies tended to focus more on establishing the safety of ECT and finding out whether ECT causes gross microscopic brain damage, the later studies especially since the advent of advanced neuroimaging techniques have been focusing more on a mechanistic understanding of ECT. Hence, the primary objective of the later neuroimaging studies has been to look for structural and functional brain changes which might explain how ECT acts rather than evidence of gross structural damage per se. However, put together, all these studies would enable us to answer our titular question to some satisfaction. [Table 1] and [Table 2] provide an overview of the evidence base in this area.

    Structural and Functional Neuroimaging Studies Devanand et al. Reviewed 16 structural neuroimaging studies on the effect of ECT on the brain.[4] Of these, two were pneumoencephalography studies, nine were computed tomography (CT) scan studies, and five were magnetic resonance imaging (MRI) studies. However, most of these studies were retrospective in design, with neuroimaging being done in patients who had received ECT in the past. In the absence of baseline neuroimaging, it would be very difficult to attribute any structural brain changes to ECT.

    In addition, pneumoencephalography, CT scan, and even early 0.3 T MRI provided images with much lower spatial resolution than what is available today. The authors concluded that there was no evidence to show that ECT caused any structural damage to the brain.[4] Since then, at least twenty more MRI-based structural neuroimaging studies have studied the effect of ECT on the brain. The earliest MRI studies in the early 1990s focused on detecting structural damage following ECT. All of these studies were prospective in design, with the first MRI scan done at baseline and a second MRI scan performed post ECT.[9],[11],[12],[13],[41] While most of the studies imaged the patient once around 24 h after receiving ECT, some studies performed multiple post ECT neuroimaging in the first 24 h after ECT to better capture the acute changes.

    A single study by Coffey et al. Followed up the patients for a duration of 6 months and repeated neuroimaging again at 6 months in order to capture any long-term changes following ECT.[10]The most important conclusion which emerged from this early series of studies was that there was no evidence of cortical atrophy, change in ventricle size, or increase in white matter hyperintensities.[4] The next major conclusion was that there appeared to be an increase in the T1 and T2 relaxation time immediately following ECT, which returned to normal within 24 h. This supported the theory that immediately following ECT, there appears to be a temporary breakdown of the blood–brain barrier, leading to water influx into the brain tissue.[11] The last significant observation by Coffey et al. In 1991 was that there was no significant temporal changes in the total volumes of the frontal lobes, temporal lobes, or amygdala–hippocampal complex.[10] This was, however, something which would later be refuted by high-resolution MRI studies.

    Nonetheless, one inescapable conclusion of these early studies was that there was no evidence of any gross structural brain changes following administration of ECT. Much later in 2007, Szabo et al. Used diffusion-weighted MRI to image patients in the immediate post ECT period and failed to observe any obvious brain tissue changes following ECT.[17]The next major breakthrough came in 2010 when Nordanskog et al. Demonstrated that there was a significant increase in the volume of the hippocampus bilaterally following a course of ECT in a cohort of patients with depressive illness.[18] This contradicted the earlier observations by Coffey et al.

    That there was no volume increase in any part of the brain following ECT.[10] This was quite an exciting finding and was followed by several similar studies. However, the perspective of these studies was quite different from the early studies. In contrast to the early studies looking for the evidence of ECT-related brain damage, the newer studies were focused more on elucidating the mechanism of action of ECT. Further on in 2014, Nordanskog et al.

    In a follow-up study showed that though there was a significant increase in the volume of the hippocampus 1 week after a course of ECT, the hippocampal volume returned to the baseline after 6 months.[19] Two other studies in 2013 showed that in addition to the hippocampus, the amygdala also showed significant volume increase following ECT.[20],[21] A series of structural neuroimaging studies after that have expanded on these findings and as of now, gray matter volume increase following ECT has been demonstrated in the hippocampus, amygdala, anterior temporal pole, subgenual cortex,[21] right caudate nucleus, and the whole of the medial temporal lobe (MTL) consisting of the hippocampus, amygdala, insula, and the posterosuperior temporal cortex,[24] para hippocampi, right subgenual anterior cingulate gyrus, and right anterior cingulate gyrus,[25] left cerebellar area VIIa crus I,[29] putamen, caudate nucleus, and nucleus acumbens [31] and clusters of increased cortical thickness involving the temporal pole, middle and superior temporal cortex, insula, and inferior temporal cortex.[27] However, the most consistently reported and replicated finding has been the bilateral increase in the volume of the hippocampus and amygdala. In light of these findings, it has been tentatively suggested that ECT acts by inducing neuronal regeneration in the hippocampus – amygdala complex.[42],[43] However, there are certain inconsistencies to this hypothesis. Till date, only one study – Nordanskog et al., 2014 – has followed study patients for a long term – 6 months in their case. And significantly, the authors found out that after increasing immediately following ECT, the hippocampal volume returns back to baseline by 6 months.[19] This, however, was not associated with the relapse of depressive symptoms.

    Another area of significant confusion has been the correlation of hippocampal volume increase with improvement of depressive symptoms. Though almost all studies demonstrate a significant increase in hippocampal volume following ECT, a majority of studies failed to demonstrate a correlation between symptom improvement and hippocampal volume increase.[19],[20],[22],[24],[28] However, a significant minority of volumetric studies have demonstrated correlation between increase in hippocampal and/or amygdala volume and improvement of symptoms.[21],[25],[30]Another set of studies have used diffusion tensor imaging, functional MRI (fMRI), anatomical connectome, and structural network analysis to study the effect of ECT on the brain. The first of these studies by Abbott et al. In 2014 demonstrated that on fMRI, the connectivity between right and left hippocampus was significantly reduced in patients with severe depression.

    It was also shown that the connectivity was normalized following ECT, and symptom improvement was correlated with an increase in connectivity.[22] In a first of its kind DTI study, Lyden et al. In 2014 demonstrated that fractional anisotropy which is a measure of white matter tract or fiber density is increased post ECT in patients with severe depression in the anterior cingulum, forceps minor, and the dorsal aspect of the left superior longitudinal fasciculus. The authors suggested that ECT acts to normalize major depressive disorder-related abnormalities in the structural connectivity of the dorsal fronto-limbic pathways.[23] Another DTI study in 2015 constructed large-scale anatomical networks of the human brain – connectomes, based on white matter fiber tractography. The authors found significant reorganization in the anatomical connections involving the limbic structure, temporal lobe, and frontal lobe.

    It was also found that connection changes between amygdala and para hippocampus correlated with reduction in depressive symptoms.[26] In 2016, Wolf et al. Used a source-based morphometry approach to study the structural networks in patients with depression and schizophrenia and the effect of ECT on the same. It was found that the medial prefrontal cortex/anterior cingulate cortex (ACC/MPFC) network, MTL network, bilateral thalamus, and left cerebellar regions/precuneus exhibited significant difference between healthy controls and the patient population. It was also demonstrated that administration of ECT leads to significant increase in the network strength of the ACC/MPFC network and the MTL network though the increase in network strength and symptom amelioration were not correlated.[32]Building on these studies, a recently published meta-analysis has attempted a quantitative synthesis of brain volume changes – focusing on hippocampal volume increase following ECT in patients with major depressive disorder and bipolar disorder.

    The authors initially selected 32 original articles from which six articles met the criteria for quantitative synthesis. The results showed significant increase in the volume of the right and left hippocampus following ECT. For the rest of the brain regions, the heterogeneity in protocols and imaging techniques did not permit a quantitative analysis, and the authors have resorted to a narrative review similar to the present one with similar conclusions.[44] Focusing exclusively on hippocampal volume change in ECT, Oltedal et al. In 2018 conducted a mega-analysis of 281 patients with major depressive disorder treated with ECT enrolled at ten different global sites of the Global ECT-MRI Research Collaboration.[45] Similar to previous studies, there was a significant increase in hippocampal volume bilaterally with a dose–response relationship with the number of ECTs administered.

    Furthermore, bilateral (B/L) ECT was associated with an equal increase in volume in both right and left hippocampus, whereas right unilateral ECT was associated with greater volume increase in the right hippocampus. Finally, contrary to expectation, clinical improvement was found to be negatively correlated with hippocampal volume.Thus, a review of the current evidence amply demonstrates that from looking for ECT-related brain damage – and finding none, we have now moved ahead to looking for a mechanistic understanding of the effect of ECT. In this regard, it has been found that ECT does induce structural changes in the brain – a fact which has been seized upon by some to claim that ECT causes brain damage.[46] Such statements should, however, be weighed against the definition of damage as understood by the scientific medical community and patient population. Neuroanatomical changes associated with effective ECT can be better described as ECT-induced brain neuroplasticity or ECT-induced brain neuromodulation rather than ECT-induced brain damage.

    Metabolic Neuroimaging Studies. Magnetic Resonance Spectroscopic Imaging Magnetic resonance spectroscopic imaging (MRSI) uses a phase-encoding procedure to map the spatial distribution of magnetic resonance (MR) signals of different molecules. The crucial difference, however, is that while MRI maps the MR signals of water molecules, MRSI maps the MR signals generated by different metabolites – such as N-acetyl aspartate (NAA) and choline-containing compounds. However, the concentration of these metabolites is at least 10,000 times lower than water molecules and hence the signal strength generated would also be correspondingly lower.

    However, MRSI offers us the unique advantage of studying in vivo the change in the concentration of brain metabolites, which has been of great significance in fields such as psychiatry, neurology, and basic neuroscience research.[47]MRSI studies on ECT in patients with depression have focused largely on four metabolites in the human brain – NAA, choline-containing compounds (Cho) which include majorly cell membrane compounds such as glycerophosphocholine, phosphocholine and a miniscule contribution from acetylcholine, creatinine (Cr) and glutamine and glutamate together (Glx). NAA is located exclusively in the neurons, and is suggested to be a marker of neuronal viability and functionality.[48] Choline-containing compounds (Cho) mainly include the membrane compounds, and an increase in Cho would be suggestive of increased membrane turnover. Cr serves as a marker of cellular energy metabolism, and its levels are usually expected to remain stable. The regions which have been most widely studied in MRSI studies include the bilateral hippocampus and amygdala, dorsolateral prefrontal cortex (DLPFC), and ACC.Till date, five MRSI studies have measured NAA concentration in the hippocampus before and after ECT.

    Of these, three studies showed that there is no significant change in the NAA concentration in the hippocampus following ECT.[33],[38],[49] On the other hand, two recent studies have demonstrated a statistically significant reduction in NAA concentration in the hippocampus following ECT.[39],[40] The implications of these results are of significant interest to us in answering our titular question. A normal level of NAA following ECT could signify that there is no significant neuronal death or damage following ECT, while a reduction would signal the opposite. However, a direct comparison between these studies is complicated chiefly due to the different ECT protocols, which has been used in these studies. It must, however, be acknowledged that the three older studies used 1.5 T MRI, whereas the two newer studies used a higher 3 T MRI which offers betters signal-to-noise ratio and hence lesser risk of errors in the measurement of metabolite concentrations.

    The authors of a study by Njau et al.[39] argue that a change in NAA levels might reflect reversible changes in neural metabolism rather than a permanent change in the number or density of neurons and also that reduced NAA might point to a change in the ratio of mature to immature neurons, which, in fact, might reflect enhanced adult neurogenesis. Thus, the authors warn that to conclude whether a reduction in NAA concentration is beneficial or harmful would take a simultaneous measurement of cognitive functioning, which was lacking in their study. In 2017, Cano et al. Also demonstrated a significant reduction in NAA/Cr ratio in the hippocampus post ECT.

    More significantly, the authors also showed a significant increase in Glx levels in the hippocampus following ECT, which was also associated with an increase in hippocampal volume.[40] To explain these three findings, the authors proposed that ECT produces a neuroinflammatory response in the hippocampus – likely mediated by Glx, which has been known to cause inflammation at higher concentrations, thereby accounting for the increase in hippocampal volume with a reduction in NAA concentration. The cause for the volume increase remains unclear – with the authors speculating that it might be due to neuronal swelling or due to angiogenesis. However, the same study and multiple other past studies [21],[25],[30] have demonstrated that hippocampal volume increase was correlated with clinical improvement following ECT. Thus, we are led to the hypothesis that the same mechanism which drives clinical improvement with ECT is also responsible for the cognitive impairment following ECT.

    Whether this is a purely neuroinflammatory response or a neuroplastic response or a neuroinflammatory response leading to some form of neuroplasticity is a critical question, which remains to be answered.[40]Studies which have analyzed NAA concentration change in other brain areas have also produced conflicting results. The ACC is another area which has been studied in some detail utilizing the MRSI technique. In 2003, Pfleiderer et al. Demonstrated that there was no significant change in the NAA and Cho levels in the ACC following ECT.

    This would seem to suggest that there was no neurogenesis or membrane turnover in the ACC post ECT.[36] However, this finding was contested by Merkl et al. In 2011, who demonstrated that NAA levels were significantly reduced in the left ACC in patients with depression and that these levels were significantly elevated following ECT.[37] This again is contested by Njau et al. Who showed that NAA levels are significantly reduced following ECT in the left dorsal ACC.[39] A direct comparison of these three studies is complicated by the different ECT and imaging parameters used and hence, no firm conclusion can be made on this point at this stage. In addition to this, one study had demonstrated increased NAA levels in the amygdala following administration of ECT,[34] with a trend level increase in Cho levels, which again is suggestive of neurogenesis and/or neuroplasticity.

    A review of studies on the DLPFC reveals a similarly confusing picture with one study, each showing no change, reduction, and elevation of concentration of NAA following ECT.[35],[37],[39] Here, again, a direct comparison of the three studies is made difficult by the heterogeneous imaging and ECT protocols followed by them.A total of five studies have analyzed the concentration of choline-containing compounds (Cho) in patients undergoing ECT. Conceptually, an increase in Cho signals is indicative of increased membrane turnover, which is postulated to be associated with synaptogenesis, neurogenesis, and maturation of neurons.[31] Of these, two studies measured Cho concentration in the B/L hippocampus, with contrasting results. Ende et al. In 2000 demonstrated a significant elevation in Cho levels in B/L hippocampus after ECT, while Jorgensen et al.

    In 2015 failed to replicate the same finding.[33],[38] Cho levels have also been studied in the amygdala, ACC, and the DLPFC. However, none of these studies showed a significant increase or decrease in Cho levels before and after ECT in the respective brain regions studied. In addition, no significant difference was seen in the pre-ECT Cho levels of patients compared to healthy controls.[34],[36],[37]In review, we must admit that MRSI studies are still at a preliminary stage with significant heterogeneity in ECT protocols, patient population, and regions of the brain studied. At this stage, it is difficult to draw any firm conclusions except to acknowledge the fact that the more recent studies – Njau et al., 2017, Cano, 2017, and Jorgensen et al., 2015 – have shown decrease in NAA concentration and no increase in Cho levels [38],[39],[40] – as opposed to the earlier studies by Ende et al.[33] The view offered by the more recent studies is one of a neuroinflammatory models of action of ECT, probably driving neuroplasticity in the hippocampus.

    This would offer a mechanistic understanding of both clinical response and the phenomenon of cognitive impairment associated with ECT. However, this conclusion is based on conjecture, and more work needs to be done in this area. Body Fluid Biochemical Marker Studies Another line of evidence for analyzing the effect of ECT on the human brain is the study of concentration of neurotrophins in the plasma or serum. Neurotrophins are small protein molecules which mediate neuronal survival and development.

    The most prominent among these is brain-derived neurotrophic factor (BDNF) which plays an important role in neuronal survival, plasticity, and migration.[50] A neurotrophic theory of mood disorders was suggested which hypothesized that depressive disorders are associated with a decreased expression of BDNF in the limbic structures, resulting in the atrophy of these structures.[51] It was also postulated that antidepressant treatment has a neurotrophic effect which reverses the neuronal cell loss, thereby producing a therapeutic effect. It has been well established that BDNF is decreased in mood disorders.[52] It has also been shown that clinical improvement of depression is associated with increase in BDNF levels.[53] Thus, serum BDNF levels have been tentatively proposed as a biomarker for treatment response in depression. Recent meta-analytic evidence has shown that ECT is associated with significant increase in serum BDNF levels in patients with major depressive disorder.[54] Considering that BDNF is a potent stimulator of neurogenesis, the elevation of serum BDNF levels following ECT lends further credence to the theory that ECT leads to neurogenesis in the hippocampus and other limbic structures, which, in turn, mediates the therapeutic action of ECT. Cognitive Impairment Studies Cognitive impairment has always been the single-most important side effect associated with ECT.[55] Concerns regarding long-term cognitive impairment surfaced soon after the introduction of ECT and since then has grown to become one of the most controversial aspects of ECT.[56] Anti-ECT groups have frequently pointed out to cognitive impairment following ECT as evidence of ECT causing brain damage.[56] A meta-analysis by Semkovska and McLoughlin in 2010 is one of the most detailed studies which had attempted to settle this long-standing debate.[57] The authors reviewed 84 studies (2981 participants), which had used a combined total of 22 standardized neuropsychological tests assessing various cognitive functions before and after ECT in patients diagnosed with major depressive disorder.

    The different cognitive domains reviewed included processing speed, attention/working memory, verbal episodic memory, visual episodic memory, spatial problem-solving, executive functioning, and intellectual ability. The authors concluded that administration of ECT for depression is associated with significant cognitive impairment in the first few days after ECT administration. However, it was also seen that impairment in cognitive functioning resolved within a span of 2 weeks and thereafter, a majority of cognitive domains even showed mild improvement compared to the baseline performance. It was also demonstrated that not a single cognitive domain showed persistence of impairment beyond 15 days after ECT.Memory impairment following ECT can be analyzed broadly under two conceptual schemes – one that classifies memory impairment as objective memory impairment and subjective memory impairment and the other that classifies it as impairment in anterograde memory versus impairment in retrograde memory.

    Objective memory can be roughly defined as the ability to retrieve stored information and can be measured by various standardized neuropsychological tests. Subjective memory or meta-memory, on the other hand, refers to the ability to make judgments about one's ability to retrieve stored information.[58] As described previously, it has been conclusively demonstrated that anterograde memory impairment does not persist beyond 2 weeks after ECT.[57] However, one of the major limitations of this meta-analysis was the lack of evidence on retrograde amnesia following ECT. This is particularly unfortunate considering that it is memory impairment – particularly retrograde amnesia which has received the most attention.[59] In addition, reports of catastrophic retrograde amnesia have been repeatedly held up as sensational evidence of the lasting brain damage produced by ECT.[59] Admittedly, studies on retrograde amnesia are fewer and less conclusive than on anterograde amnesia.[60],[61] At present, the results are conflicting, with some studies finding some impairment in retrograde memory – particularly autobiographical retrograde memory up to 6 months after ECT.[62],[63],[64],[65] However, more recent studies have failed to support this finding.[66],[67] While they do demonstrate an impairment in retrograde memory immediately after ECT, it was seen that this deficit returned to pre-ECT levels within a span of 1–2 months and improved beyond baseline performance at 6 months post ECT.[66] Adding to the confusion are numerous factors which confound the assessment of retrograde amnesia. It has been shown that depressive symptoms can produce significant impairment of retrograde memory.[68],[69] It has also been demonstrated that sine-wave ECT produces significantly more impairment of retrograde memory as compared to brief-pulse ECT.[70] However, from the 1990s onward, sine-wave ECT has been completely replaced by brief-pulse ECT, and it is unclear as to the implications of cognitive impairment from the sine-wave era in contemporary ECT practice.Another area of concern are reports of subjective memory impairment following ECT.

    One of the pioneers of research into subjective memory impairment were Squire and Chace who published a series of studies in the 1970s demonstrating the adverse effect of bilateral ECT on subjective assessment of memory.[62],[63],[64],[65] However, most of the studies conducted post 1980 – from when sine-wave ECT was replaced by brief-pulse ECT report a general improvement in subjective memory assessments following ECT.[71] In addition, most of the recent studies have failed to find a significant association between measures of subjective and objective memory.[63],[66],[70],[72],[73],[74] It has also been shown that subjective memory impairment is strongly associated with the severity of depressive symptoms.[75] In light of these facts, the validity and value of measures of subjective memory impairment as a marker of cognitive impairment and brain damage following ECT have been questioned. However, concerns regarding subjective memory impairment and catastrophic retrograde amnesia continue to persist, with significant dissonance between the findings of different research groups and patient self-reports in various media.[57]Some studies reported the possibility of ECT being associated with the development of subsequent dementia.[76],[77] However, a recent large, well-controlled prospective Danish study found that the use of ECT was not associated with elevated incidence of dementia.[78] Conclusion Our titular question is whether ECT leads to brain damage, where damage indicates destruction or degeneration of nerves or nerve tracts in the brain, which leads to loss of function. This issue was last addressed by Devanand et al. In 1994 since which time our understanding of ECT has grown substantially, helped particularly by the advent of modern-day neuroimaging techniques which we have reviewed in detail.

    And, what these studies reveal is rather than damaging the brain, ECT has a neuromodulatory effect on the brain. The various lines of evidence – structural neuroimaging studies, functional neuroimaging studies, neurochemical and metabolic studies, and serum BDNF studies all point toward this. These neuromodulatory changes have been localized to the hippocampus, amygdala, and certain other parts of the limbic system. How exactly these changes mediate the improvement of depressive symptoms is a question that remains unanswered.

    However, there is little by way of evidence from neuroimaging studies which indicates that ECT causes destruction or degeneration of neurons. Though cognitive impairment studies do show that there is objective impairment of certain functions – particularly memory immediately after ECT, these impairments are transient with full recovery within a span of 2 weeks. Perhaps, the single-most important unaddressed concern is retrograde amnesia, which has been shown to persist for up to 2 months post ECT. In this regard, the recent neurometabolic studies have offered a tentative mechanism of action of ECT, producing a transient inflammation in the limbic cortex, which, in turn, drives neurogenesis, thereby exerting a neuromodulatory effect.

    This hypothesis would explain both the cognitive adverse effects of ECT – due to the transient inflammation – and the long-term improvement in mood – neurogenesis in the hippocampus. Although unproven at present, such a hypothesis would imply that cognitive impairment is tied in with the mechanism of action of ECT and not an indicator of damage to the brain produced by ECT.The review of literature suggests that ECT does cause at least structural and functional changes in the brain, and these are in all probability related to the effects of the ECT. However, these cannot be construed as brain damage as is usually understood. Due to the relative scarcity of data that directly examines the question of whether ECT causes brain damage, it is not possible to conclusively answer this question.

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    Electroconvulsive therapy and risk of dementia in patients with affective disorders. A cohort study. Lancet Psychiatry 2018;5:348-56. Correspondence Address:Dr.

    Shubh Mohan SinghDepartment of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh IndiaSource of Support. None, Conflict of Interest. NoneDOI. 10.4103/psychiatry.IndianJPsychiatry_239_19 Tables [Table 1], [Table 2].

    How to cite http://www.amisdepasteur.fr/antabuse-cost-walmart/ this article:Singh O how to buy cheap antabuse P. Aftermath of celebrity suicide – Media coverage and role of psychiatrists. Indian J Psychiatry how to buy cheap antabuse 2020;62:337-8Celebrity suicide is one of the highly publicized events in our country. Indians got a glimpse of this following an unfortunate incident where a popular Hindi film actor died of suicide. As expected, the media went into a frenzy as newspapers, news how to buy cheap antabuse channels, and social media were full of stories providing minute details of the suicidal act.

    Some even going as far as highlighting the color of the cloth used in the suicide as well as showing the lifeless body of the actor. All kinds of personal details were dug up, and speculations and hypotheses became the order of the day in the next few days that followed. In the process, reputations of many people associated with the actor were besmirched and their private and personal details were freely and blatantly broadcast and discussed on how to buy cheap antabuse electronic, print, and social media. We understand that media houses have their own need and duty to report and sensationalize news for increasing their visibility (aka TRP), but such reporting has huge impacts on the mental health of the vulnerable population.The impact of this was soon realized when many incidents of copycat suicide were reported from all over the country within a few days of the incident. Psychiatrists suddenly how to buy cheap antabuse started getting distress calls from their patients in despair with increased suicidal ideation.

    This has become a major area of concern for the psychiatry community.The Indian Psychiatric Society has been consistently trying to engage with media to promote ethical reporting of suicide. Section 24 (1) of Mental Health Care Act, 2017, forbids how to buy cheap antabuse publication of photograph of mentally ill person without his consent.[1] The Press Council of India has adopted the guidelines of World Health Organization report on Preventing Suicide. A resource for media professionals, which came out with an advisory to be followed by media in reporting cases of suicide. It includes points forbidding them from putting stories in prominent positions and unduly repeating them, explicitly describing the method used, providing details about the site/location, using sensational headlines, or using photographs and video footage of the incident.[2] Unfortunately, the advisory seems to have little effect in the aftermath of celebrity suicides. Channels were full of speculations about the person's mental condition how to buy cheap antabuse and illness and also his relationships and finances.

    Many fictional accounts of his symptoms and illness were touted, which is not only against the ethics but is also contrary to MHCA, 2017.[1]It went to the extent that the name of his psychiatrist was mentioned and quotes were attributed to him without taking any account from him. The Indian Psychiatric Society has written to the Press Council of India underlining this concern and asking for measures to ensure ethics in reporting suicide.While there is a need for engagement with media to make them aware how to buy cheap antabuse of the grave impact of negative suicide reporting on the lives of many vulnerable persons, there is even a more urgent need for training of psychiatrists regarding the proper way of interaction with media. This has been amply brought out in the aftermath of this incident. Many psychiatrists and mental health professionals were called by media houses to comment how to buy cheap antabuse on the episode. Many psychiatrists were quoted, or “misquoted,” or “quoted out of context,” commenting on the life of a person whom they had never examined and had no “professional authority” to do so.

    There were even stories with byline of a psychiatrist where the content provided was not only unscientific but also way beyond the expertise of a psychiatrist. These types of viewpoints perpetuate stigma, myths, and “misleading concepts” about psychiatry and are detrimental to the image of psychiatry in addition to doing harm and injustice to how to buy cheap antabuse our patients. Hence, the need to formulate a guideline for interaction of psychiatrists with the media is imperative.In the infamous Goldwater episode, 12,356 psychiatrists were asked to cast opinion about the fitness of Barry Goldwater for presidential candidature. Out of 2417 respondents, 1189 psychiatrists reported him to be mentally unfit while none had actually examined him.[3] This led to the formulation of “The Goldwater Rule” by the American Psychiatric Association in 1973,[4] but we have witnessed the same phenomenon at the time of presidential candidature of Donald Trump.Psychiatrists should be encouraged to interact how to buy cheap antabuse with media to provide scientific information about mental illnesses and reduction of stigma, but “statements to the media” can be a double-edged sword, and we should know about the rules of engagements and boundaries of interactions. Methods and principles of interaction with media should form a part of our training curriculum.

    Many professional societies have guidelines and resource books for interacting with media, how to buy cheap antabuse and psychiatrists should familiarize themselves with these documents. The Press Council guideline is likely to prompt reporters to seek psychiatrists for their expert opinion. It is useful for them to have a template ready with suicide rates, emphasizing multicausality of suicide, role of mental disorders, as well as help available.[5]It is about time that the Indian Psychiatric Society formulated its own guidelines laying down the broad principles and boundaries governing the interaction of Indian psychiatrists with the media. Till then, it is desirable to be guided by the following broad principles:It should be assumed that no statement goes “off the record” as the media person is most likely recording the interview, and we should also record any such conversation from our endIt how to buy cheap antabuse should be clarified in which capacity comments are being made – professional, personal, or as a representative of an organizationOne should not comment on any person whom he has not examinedPsychiatrists should take any such opportunity to educate the public about mental health issuesThe comments should be justified and limited by the boundaries of scientific knowledge available at the moment. References Correspondence Address:Dr.

    O P SinghAA 304, Ashabari Apartments, O/31, Baishnabghata, how to buy cheap antabuse Patuli Township, Kolkata - 700 094, West Bengal IndiaSource of Support. None, Conflict of Interest. NoneDOI. 10.4103/psychiatry.IndianJPsychiatry_816_20Abstract Electroconvulsive therapy (ECT) is an effective modality of treatment for a variety of psychiatric disorders. However, it has always been accused of being a coercive, unethical, and dangerous modality of treatment.

    The dangerousness of ECT has been mainly attributed to its claimed ability to cause brain damage. This narrative review aims to provide an update of the evidence with regard to whether the practice of ECT is associated with damage to the brain. An accepted definition of brain damage remains elusive. There are also ethical and technical problems in designing studies that look at this question specifically. Thus, even though there are newer technological tools and innovations, any review attempting to answer this question would have to take recourse to indirect methods.

    These include structural, functional, and metabolic neuroimaging. Body fluid biochemical marker studies. And follow-up studies of cognitive impairment and incidence of dementia in people who have received ECT among others. The review of literature and present evidence suggests that ECT has a demonstrable impact on the structure and function of the brain. However, there is a lack of evidence at present to suggest that ECT causes brain damage.Keywords.

    Adverse effect, brain damage, electroconvulsive therapyHow to cite this article:Jolly AJ, Singh SM. Does electroconvulsive therapy cause brain damage. An update. Indian J Psychiatry 2020;62:339-53 Introduction Electroconvulsive therapy (ECT) as a modality of treatment for psychiatric disorders has existed at least since 1938.[1] ECT is an effective modality of treatment for various psychiatric disorders. However, from the very beginning, the practice of ECT has also faced resistance from various groups who claim that it is coercive and harmful.[2] While the ethical aspects of the practice of ECT have been dealt with elsewhere, the question of harmfulness or brain damage consequent upon the passage of electric current needs to be examined afresh in light of technological advances and new knowledge.[3]The question whether ECT causes brain damage was reviewed in a holistic fashion by Devanand et al.

    In the mid-1990s.[4],[5] The authors had attempted to answer this question by reviewing the effect of ECT on the brain in various areas – cognitive side effects, structural neuroimaging studies, neuropathologic studies of patients who had received ECT, autopsy studies of epileptic patients, and finally animal ECS studies. The authors had concluded that ECT does not produce brain damage.This narrative review aims to update the evidence with regard to whether ECT causes brain damage by reviewing relevant literature from 1994 to the present time. Framing the Question The Oxford Dictionary defines damage as physical harm that impairs the value, usefulness, or normal function of something.[6] Among medical dictionaries, the Peter Collins Dictionary defines damage as harm done to things (noun) or to harm something (verb).[7] Brain damage is defined by the British Medical Association Medical Dictionary as degeneration or death of nerve cells and tracts within the brain that may be localized to a particular area of the brain or diffuse.[8] Going by such a definition, brain damage in the context of ECT should refer to death or degeneration of brain tissue, which results in the impairment of functioning of the brain. The importance of precisely defining brain damage shall become evident subsequently in this review.There are now many more tools available to investigate the structure and function of brain in health and illness. However, there are obvious ethical issues in designing human studies that are designed to answer this specific question.

    Therefore, one must necessarily take recourse to indirect evidences available through studies that have been designed to answer other research questions. These studies have employed the following methods:Structural neuroimaging studiesFunctional neuroimaging studiesMetabolic neuroimaging studiesBody fluid biochemical marker studiesCognitive impairment studies.While the early studies tended to focus more on establishing the safety of ECT and finding out whether ECT causes gross microscopic brain damage, the later studies especially since the advent of advanced neuroimaging techniques have been focusing more on a mechanistic understanding of ECT. Hence, the primary objective of the later neuroimaging studies has been to look for structural and functional brain changes which might explain how ECT acts rather than evidence of gross structural damage per se. However, put together, all these studies would enable us to answer our titular question to some satisfaction. [Table 1] and [Table 2] provide an overview of the evidence base in this area.

    Structural and Functional Neuroimaging Studies Devanand et al. Reviewed 16 structural neuroimaging studies on the effect of ECT on the brain.[4] Of these, two were pneumoencephalography studies, nine were computed tomography (CT) scan studies, and five were magnetic resonance imaging (MRI) studies. However, most of these studies were retrospective in design, with neuroimaging being done in patients who had received ECT in the past. In the absence of baseline neuroimaging, it would be very difficult to attribute any structural brain changes to ECT. In addition, pneumoencephalography, CT scan, and even early 0.3 T MRI provided images with much lower spatial resolution than what is available today.

    The authors concluded that there was no evidence to show that ECT caused any structural damage to the brain.[4] Since then, at least twenty more MRI-based structural neuroimaging studies have studied the effect of ECT on the brain. The earliest MRI studies in the early 1990s focused on detecting structural damage following ECT. All of these studies were prospective in design, with the first MRI scan done at baseline and a second MRI scan performed post ECT.[9],[11],[12],[13],[41] While most of the studies imaged the patient once around 24 h after receiving ECT, some studies performed multiple post ECT neuroimaging in the first 24 h after ECT to better capture the acute changes. A single study by Coffey et al. Followed up the patients for a duration of 6 months and repeated neuroimaging again at 6 months in order to capture any long-term changes following ECT.[10]The most important conclusion which emerged from this early series of studies was that there was no evidence of cortical atrophy, change in ventricle size, or increase in white matter hyperintensities.[4] The next major conclusion was that there appeared to be an increase in the T1 and T2 relaxation time immediately following ECT, which returned to normal within 24 h.

    This supported the theory that immediately following ECT, there appears to be a temporary breakdown of the blood–brain barrier, leading to water influx into the brain tissue.[11] The last significant observation by Coffey et al. In 1991 was that there was no significant temporal changes in the total volumes of the frontal lobes, temporal lobes, or amygdala–hippocampal complex.[10] This was, however, something which would later be refuted by high-resolution MRI studies. Nonetheless, one inescapable conclusion of these early studies was that there was no evidence of any gross structural brain changes following administration of ECT. Much later in 2007, Szabo et al. Used diffusion-weighted MRI to image patients in the immediate post ECT period and failed to observe any obvious brain tissue changes following ECT.[17]The next major breakthrough came in 2010 when Nordanskog et al.

    Demonstrated that there was a significant increase in the volume of the hippocampus bilaterally following a course of ECT in a cohort of patients with depressive illness.[18] This contradicted the earlier observations by Coffey et al. That there was no volume increase in any part of the brain following ECT.[10] This was quite an exciting finding and was followed by several similar studies. However, the perspective of these studies was quite different from the early studies. In contrast to the early studies looking for the evidence of ECT-related brain damage, the newer studies were focused more on elucidating the mechanism of action of ECT. Further on in 2014, Nordanskog et al.

    In a follow-up study showed that though there was a significant increase in the volume of the hippocampus 1 week after a course of ECT, the hippocampal volume returned to the baseline after 6 months.[19] Two other studies in 2013 showed that in addition to the hippocampus, the amygdala also showed significant volume increase following ECT.[20],[21] A series of structural neuroimaging studies after that have expanded on these findings and as of now, gray matter volume increase following ECT has been demonstrated in the hippocampus, amygdala, anterior temporal pole, subgenual cortex,[21] right caudate nucleus, and the whole of the medial temporal lobe (MTL) consisting of the hippocampus, amygdala, insula, and the posterosuperior temporal cortex,[24] para hippocampi, right subgenual anterior cingulate gyrus, and right anterior cingulate gyrus,[25] left cerebellar area VIIa crus I,[29] putamen, caudate nucleus, and nucleus acumbens [31] and clusters of increased cortical thickness involving the temporal pole, middle and superior temporal cortex, insula, and inferior temporal cortex.[27] However, the most consistently reported and replicated finding has been the bilateral increase in the volume of the hippocampus and amygdala. In light of these findings, it has been tentatively suggested that ECT acts by inducing neuronal regeneration in the hippocampus – amygdala complex.[42],[43] However, there are certain inconsistencies to this hypothesis. Till date, only one study – Nordanskog et al., 2014 – has followed study patients for a long term – 6 months in their case. And significantly, the authors found out that after increasing immediately following ECT, the hippocampal volume returns back to baseline by 6 months.[19] This, however, was not associated with the relapse of depressive symptoms. Another area of significant confusion has been the correlation of hippocampal volume increase with improvement of depressive symptoms.

    Though almost all studies demonstrate a significant increase in hippocampal volume following ECT, a majority of studies failed to demonstrate a correlation between symptom improvement and hippocampal volume increase.[19],[20],[22],[24],[28] However, a significant minority of volumetric studies have demonstrated correlation between increase in hippocampal and/or amygdala volume and improvement of symptoms.[21],[25],[30]Another set of studies have used diffusion tensor imaging, functional MRI (fMRI), anatomical connectome, and structural network analysis to study the effect of ECT on the brain. The first of these studies by Abbott et al. In 2014 demonstrated that on fMRI, the connectivity between right and left hippocampus was significantly reduced in patients with severe depression. It was also shown that the connectivity was normalized following ECT, and symptom improvement was correlated with an increase in connectivity.[22] In a first of its kind DTI study, Lyden et al. In 2014 demonstrated that fractional anisotropy which is a measure of white matter tract or fiber density is increased post ECT in patients with severe depression in the anterior cingulum, forceps minor, and the dorsal aspect of the left superior longitudinal fasciculus.

    The authors suggested that ECT acts to normalize major depressive disorder-related abnormalities in the structural connectivity of the dorsal fronto-limbic pathways.[23] Another DTI study in 2015 constructed large-scale anatomical networks of the human brain – connectomes, based on white matter fiber tractography. The authors found significant reorganization in the anatomical connections involving the limbic structure, temporal lobe, and frontal lobe. It was also found that connection changes between amygdala and para hippocampus correlated with reduction in depressive symptoms.[26] In 2016, Wolf et al. Used a source-based morphometry approach to study the structural networks in patients with depression and schizophrenia and the effect of ECT on the same. It was found that the medial prefrontal cortex/anterior cingulate cortex (ACC/MPFC) network, MTL network, bilateral thalamus, and left cerebellar regions/precuneus exhibited significant difference between healthy controls and the patient population.

    It was also demonstrated that administration of ECT leads to significant increase in the network strength of the ACC/MPFC network and the MTL network though the increase in network strength and symptom amelioration were not correlated.[32]Building on these studies, a recently published meta-analysis has attempted a quantitative synthesis of brain volume changes – focusing on hippocampal volume increase following ECT in patients with major depressive disorder and bipolar disorder. The authors initially selected 32 original articles from which six articles met the criteria for quantitative synthesis. The results showed significant increase in the volume of the right and left hippocampus following ECT. For the rest of the brain regions, the heterogeneity in protocols and imaging techniques did not permit a quantitative analysis, and the authors have resorted to a narrative review similar to the present one with similar conclusions.[44] Focusing exclusively on hippocampal volume change in ECT, Oltedal et al. In 2018 conducted a mega-analysis of 281 patients with major depressive disorder treated with ECT enrolled at ten different global sites of the Global ECT-MRI Research Collaboration.[45] Similar to previous studies, there was a significant increase in hippocampal volume bilaterally with a dose–response relationship with the number of ECTs administered.

    Furthermore, bilateral (B/L) ECT was associated with an equal increase in volume in both right and left hippocampus, whereas right unilateral ECT was associated with greater volume increase in the right hippocampus. Finally, contrary to expectation, clinical improvement was found to be negatively correlated with hippocampal volume.Thus, a review of the current evidence amply demonstrates that from looking for ECT-related brain damage – and finding none, we have now moved ahead to looking for a mechanistic understanding of the effect of ECT. In this regard, it has been found that ECT does induce structural changes in the brain – a fact which has been seized upon by some to claim that ECT causes brain damage.[46] Such statements should, however, be weighed against the definition of damage as understood by the scientific medical community and patient population. Neuroanatomical changes associated with effective ECT can be better described as ECT-induced brain neuroplasticity or ECT-induced brain neuromodulation rather than ECT-induced brain damage. Metabolic Neuroimaging Studies.

    Magnetic Resonance Spectroscopic Imaging Magnetic resonance spectroscopic imaging (MRSI) uses a phase-encoding procedure to map the spatial distribution of magnetic resonance (MR) signals of different molecules. The crucial difference, however, is that while MRI maps the MR signals of water molecules, MRSI maps the MR signals generated by different metabolites – such as N-acetyl aspartate (NAA) and choline-containing compounds. However, the concentration of these metabolites is at least 10,000 times lower than water molecules and hence the signal strength generated would also be correspondingly lower. However, MRSI offers us the unique advantage of studying in vivo the change in the concentration of brain metabolites, which has been of great significance in fields such as psychiatry, neurology, and basic neuroscience research.[47]MRSI studies on ECT in patients with depression have focused largely on four metabolites in the human brain – NAA, choline-containing compounds (Cho) which include majorly cell membrane compounds such as glycerophosphocholine, phosphocholine and a miniscule contribution from acetylcholine, creatinine (Cr) and glutamine and glutamate together (Glx). NAA is located exclusively in the neurons, and is suggested to be a marker of neuronal viability and functionality.[48] Choline-containing compounds (Cho) mainly include the membrane compounds, and an increase in Cho would be suggestive of increased membrane turnover.

    Cr serves as a marker of cellular energy metabolism, and its levels are usually expected to remain stable. The regions which have been most widely studied in MRSI studies include the bilateral hippocampus and amygdala, dorsolateral prefrontal cortex (DLPFC), and ACC.Till date, five MRSI studies have measured NAA concentration in the hippocampus before and after ECT. Of these, three studies showed that there is no significant change in the NAA concentration in the hippocampus following ECT.[33],[38],[49] On the other hand, two recent studies have demonstrated a statistically significant reduction in NAA concentration in the hippocampus following ECT.[39],[40] The implications of these results are of significant interest to us in answering our titular question. A normal level of NAA following ECT could signify that there is no significant neuronal death or damage following ECT, while a reduction would signal the opposite. However, a direct comparison between these studies is complicated chiefly due to the different ECT protocols, which has been used in these studies.

    It must, however, be acknowledged that the three older studies used 1.5 T MRI, whereas the two newer studies used a higher 3 T MRI which offers betters signal-to-noise ratio and hence lesser risk of errors in the measurement of metabolite concentrations. The authors of a study by Njau et al.[39] argue that a change in NAA levels might reflect reversible changes in neural metabolism rather than a permanent change in the number or density of neurons and also that reduced NAA might point to a change in the ratio of mature to immature neurons, which, in fact, might reflect enhanced adult neurogenesis. Thus, the authors warn that to conclude whether a reduction in NAA concentration is beneficial or harmful would take a simultaneous measurement of cognitive functioning, which was lacking in their study. In 2017, Cano et al. Also demonstrated a significant reduction in NAA/Cr ratio in the hippocampus post ECT.

    More significantly, the authors also showed a significant increase in Glx levels in the hippocampus following ECT, which was also associated with an increase in hippocampal volume.[40] To explain these three findings, the authors proposed that ECT produces a neuroinflammatory response in the hippocampus – likely mediated by Glx, which has been known to cause inflammation at higher concentrations, thereby accounting for the increase in hippocampal volume with a reduction in NAA concentration. The cause for the volume increase remains unclear – with the authors speculating that it might be due to neuronal swelling or due to angiogenesis. However, the same study and multiple other past studies [21],[25],[30] have demonstrated that hippocampal volume increase was correlated with clinical improvement following ECT. Thus, we are led to the hypothesis that the same mechanism which drives clinical improvement with ECT is also responsible for the cognitive impairment following ECT. Whether this is a purely neuroinflammatory response or a neuroplastic response or a neuroinflammatory response leading to some form of neuroplasticity is a critical question, which remains to be answered.[40]Studies which have analyzed NAA concentration change in other brain areas have also produced conflicting results.

    The ACC is another area which has been studied in some detail utilizing the MRSI technique. In 2003, Pfleiderer et al. Demonstrated that there was no significant change in the NAA and Cho levels in the ACC following ECT. This would seem to suggest that there was no neurogenesis or membrane turnover in the ACC post ECT.[36] However, this finding was contested by Merkl et al. In 2011, who demonstrated that NAA levels were significantly reduced in the left ACC in patients with depression and that these levels were significantly elevated following ECT.[37] This again is contested by Njau et al.

    Who showed that NAA levels are significantly reduced following ECT in the left dorsal ACC.[39] A direct comparison of these three studies is complicated by the different ECT and imaging parameters used and hence, no firm conclusion can be made on this point at this stage. In addition to this, one study had demonstrated increased NAA levels in the amygdala following administration of ECT,[34] with a trend level increase in Cho levels, which again is suggestive of neurogenesis and/or neuroplasticity. A review of studies on the DLPFC reveals a similarly confusing picture with one study, each showing no change, reduction, and elevation of concentration of NAA following ECT.[35],[37],[39] Here, again, a direct comparison of the three studies is made difficult by the heterogeneous imaging and ECT protocols followed by them.A total of five studies have analyzed the concentration of choline-containing compounds (Cho) in patients undergoing ECT. Conceptually, an increase in Cho signals is indicative of increased membrane turnover, which is postulated to be associated with synaptogenesis, neurogenesis, and maturation of neurons.[31] Of these, two studies measured Cho concentration in the B/L hippocampus, with contrasting results. Ende et al.

    In 2000 demonstrated a significant elevation in Cho levels in B/L hippocampus after ECT, while Jorgensen et al. In 2015 failed to replicate the same finding.[33],[38] Cho levels have also been studied in the amygdala, ACC, and the DLPFC. However, none of these studies showed a significant increase or decrease in Cho levels before and after ECT in the respective brain regions studied. In addition, no significant difference was seen in the pre-ECT Cho levels of patients compared to healthy controls.[34],[36],[37]In review, we must admit that MRSI studies are still at a preliminary stage with significant heterogeneity in ECT protocols, patient population, and regions of the brain studied. At this stage, it is difficult to draw any firm conclusions except to acknowledge the fact that the more recent studies – Njau et al., 2017, Cano, 2017, and Jorgensen et al., 2015 – have shown decrease in NAA concentration and no increase in Cho levels [38],[39],[40] – as opposed to the earlier studies by Ende et al.[33] The view offered by the more recent studies is one of a neuroinflammatory models of action of ECT, probably driving neuroplasticity in the hippocampus.

    This would offer a mechanistic understanding of both clinical response and the phenomenon of cognitive impairment associated with ECT. However, this conclusion is based on conjecture, and more work needs to be done in this area. Body Fluid Biochemical Marker Studies Another line of evidence for analyzing the effect of ECT on the human brain is the study of concentration of neurotrophins in the plasma or serum. Neurotrophins are small protein molecules which mediate neuronal survival and development. The most prominent among these is brain-derived neurotrophic factor (BDNF) which plays an important role in neuronal survival, plasticity, and migration.[50] A neurotrophic theory of mood disorders was suggested which hypothesized that depressive disorders are associated with a decreased expression of BDNF in the limbic structures, resulting in the atrophy of these structures.[51] It was also postulated that antidepressant treatment has a neurotrophic effect which reverses the neuronal cell loss, thereby producing a therapeutic effect.

    It has been well established that BDNF is decreased in mood disorders.[52] It has also been shown that clinical improvement of depression is associated with increase in BDNF levels.[53] Thus, serum BDNF levels have been tentatively proposed as a biomarker for treatment response in depression. Recent meta-analytic evidence has shown that ECT is associated with significant increase in serum BDNF levels in patients with major depressive disorder.[54] Considering that BDNF is a potent stimulator of neurogenesis, the elevation of serum BDNF levels following ECT lends further credence to the theory that ECT leads to neurogenesis in the hippocampus and other limbic structures, which, in turn, mediates the therapeutic action of ECT. Cognitive Impairment Studies Cognitive impairment has always been the single-most important side effect associated with ECT.[55] Concerns regarding long-term cognitive impairment surfaced soon after the introduction of ECT and since then has grown to become one of the most controversial aspects of ECT.[56] Anti-ECT groups have frequently pointed out to cognitive impairment following ECT as evidence of ECT causing brain damage.[56] A meta-analysis by Semkovska and McLoughlin in 2010 is one of the most detailed studies which had attempted to settle this long-standing debate.[57] The authors reviewed 84 studies (2981 participants), which had used a combined total of 22 standardized neuropsychological tests assessing various cognitive functions before and after ECT in patients diagnosed with major depressive disorder. The different cognitive domains reviewed included processing speed, attention/working memory, verbal episodic memory, visual episodic memory, spatial problem-solving, executive functioning, and intellectual ability. The authors concluded that administration of ECT for depression is associated with significant cognitive impairment in the first few days after ECT administration.

    However, it was also seen that impairment in cognitive functioning resolved within a span of 2 weeks and thereafter, a majority of cognitive domains even showed mild improvement compared to the baseline performance. It was also demonstrated that not a single cognitive domain showed persistence of impairment beyond 15 days after ECT.Memory impairment following ECT can be analyzed broadly under two conceptual schemes – one that classifies memory impairment as objective memory impairment and subjective memory impairment and the other that classifies it as impairment in anterograde memory versus impairment in retrograde memory. Objective memory can be roughly defined as the ability to retrieve stored information and can be measured by various standardized neuropsychological tests. Subjective memory or meta-memory, on the other hand, refers to the ability to make judgments about one's ability to retrieve stored information.[58] As described previously, it has been conclusively demonstrated that anterograde memory impairment does not persist beyond 2 weeks after ECT.[57] However, one of the major limitations of this meta-analysis was the lack of evidence on retrograde amnesia following ECT. This is particularly unfortunate considering that it is memory impairment – particularly retrograde amnesia which has received the most attention.[59] In addition, reports of catastrophic retrograde amnesia have been repeatedly held up as sensational evidence of the lasting brain damage produced by ECT.[59] Admittedly, studies on retrograde amnesia are fewer and less conclusive than on anterograde amnesia.[60],[61] At present, the results are conflicting, with some studies finding some impairment in retrograde memory – particularly autobiographical retrograde memory up to 6 months after ECT.[62],[63],[64],[65] However, more recent studies have failed to support this finding.[66],[67] While they do demonstrate an impairment in retrograde memory immediately after ECT, it was seen that this deficit returned to pre-ECT levels within a span of 1–2 months and improved beyond baseline performance at 6 months post ECT.[66] Adding to the confusion are numerous factors which confound the assessment of retrograde amnesia.

    It has been shown that depressive symptoms can produce significant impairment of retrograde memory.[68],[69] It has also been demonstrated that sine-wave ECT produces significantly more impairment of retrograde memory as compared to brief-pulse ECT.[70] However, from the 1990s onward, sine-wave ECT has been completely replaced by brief-pulse ECT, and it is unclear as to the implications of cognitive impairment from the sine-wave era in contemporary ECT practice.Another area of concern are reports of subjective memory impairment following ECT. One of the pioneers of research into subjective memory impairment were Squire and Chace who published a series of studies in the 1970s demonstrating the adverse effect of bilateral ECT on subjective assessment of memory.[62],[63],[64],[65] However, most of the studies conducted post 1980 – from when sine-wave ECT was replaced by brief-pulse ECT report a general improvement in subjective memory assessments following ECT.[71] In addition, most of the recent studies have failed to find a significant association between measures of subjective and objective memory.[63],[66],[70],[72],[73],[74] It has also been shown that subjective memory impairment is strongly associated with the severity of depressive symptoms.[75] In light of these facts, the validity and value of measures of subjective memory impairment as a marker of cognitive impairment and brain damage following ECT have been questioned. However, concerns regarding subjective memory impairment and catastrophic retrograde amnesia continue to persist, with significant dissonance between the findings of different research groups and patient self-reports in various media.[57]Some studies reported the possibility of ECT being associated with the development of subsequent dementia.[76],[77] However, a recent large, well-controlled prospective Danish study found that the use of ECT was not associated with elevated incidence of dementia.[78] Conclusion Our titular question is whether ECT leads to brain damage, where damage indicates destruction or degeneration of nerves or nerve tracts in the brain, which leads to loss of function. This issue was last addressed by Devanand et al. In 1994 since which time our understanding of ECT has grown substantially, helped particularly by the advent of modern-day neuroimaging techniques which we have reviewed in detail.

    And, what these studies reveal is rather than damaging the brain, ECT has a neuromodulatory effect on the brain. The various lines of evidence – structural neuroimaging studies, functional neuroimaging studies, neurochemical and metabolic studies, and serum BDNF studies all point toward this. These neuromodulatory changes have been localized to the hippocampus, amygdala, and certain other parts of the limbic system. How exactly these changes mediate the improvement of depressive symptoms is a question that remains unanswered. However, there is little by way of evidence from neuroimaging studies which indicates that ECT causes destruction or degeneration of neurons.

    Though cognitive impairment studies do show that there is objective impairment of certain functions – particularly memory immediately after ECT, these impairments are transient with full recovery within a span of 2 weeks. Perhaps, the single-most important unaddressed concern is retrograde amnesia, which has been shown to persist for up to 2 months post ECT. In this regard, the recent neurometabolic studies have offered a tentative mechanism of action of ECT, producing a transient inflammation in the limbic cortex, which, in turn, drives neurogenesis, thereby exerting a neuromodulatory effect. This hypothesis would explain both the cognitive adverse effects of ECT – due to the transient inflammation – and the long-term improvement in mood – neurogenesis in the hippocampus. Although unproven at present, such a hypothesis would imply that cognitive impairment is tied in with the mechanism of action of ECT and not an indicator of damage to the brain produced by ECT.The review of literature suggests that ECT does cause at least structural and functional changes in the brain, and these are in all probability related to the effects of the ECT.

    However, these cannot be construed as brain damage as is usually understood. Due to the relative scarcity of data that directly examines the question of whether ECT causes brain damage, it is not possible to conclusively answer this question. However, in light of enduring ECT survivor accounts, there is a need to design studies that specifically answer this question.Financial support and sponsorshipNil.Conflicts of interestThere are no conflicts of interest. References 1.Payne NA, Prudic J. Electroconvulsive therapy.

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