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Credit. IStock Share Fast Facts New @HopkinsMedicine study finds African-American women with common form of hair loss at increased risk of uterine fibroids - Click to Tweet New study in @JAMADerm shows most common form of alopecia (hair loss) in African-American women associated with higher risks of uterine fibroids - Click to Tweet In a study of medical records gathered on hundreds of thousands of African-American women, Johns Hopkins researchers say they have evidence that women with a common form of hair loss have an increased chance of developing uterine leiomyomas, or fibroids.In a report on the research, published in the December 27 issue of JAMA Dermatology, the researchers call on physicians who treat women with central centrifugal cicatricial alopecia (CCCA) to make patients aware that they may be at increased risk for fibroids and should be screened for the condition, particularly if they have symptoms such as heavy bleeding and pain. CCCA predominantly affects black women and is the most common form of permanent alopecia in this population.

The excess scar tissue that forms as a result of this type of hair loss may also explain the higher risk for uterine fibroids, which are characterized by fibrous growths in the lining of the womb. Crystal Aguh, M.D., assistant professor of dermatology at the Johns Hopkins University School of Medicine, says the scarring associated with CCCA is similar to the scarring associated with excess fibrous tissue elsewhere in the body, a situation that may explain why women with this type of hair loss are at a higher risk for fibroids.People of African descent, she notes, are more prone to develop other disorders of abnormal scarring, termed fibroproliferative disorders, such as keloids (a type of raised scar after trauma), scleroderma (an autoimmune disorder marked by thickening of the skin as well as internal organs), some types of lupus and clogged arteries. During a four-year period from 2013-2017, the researchers analyzed patient data from the Johns Hopkins electronic medical record system (Epic) of 487,104 black women ages 18 and over.

The prevalence of those with fibroids was compared in patients with and without CCCA. Overall, the researchers found that 13.9 percent of women with CCCA also had a history of uterine fibroids compared to only 3.3 percent of black women without the condition. In absolute numbers, out of the 486,000 women who were reviewed, 16,212 had fibroids.Within that population, 447 had CCCA, of which 62 had fibroids.

The findings translate to a fivefold increased risk of uterine fibroids in women with CCCA, compared to age, sex and race matched controls. Aguh cautions that their study does not suggest any cause and effect relationship, or prove a common cause for both conditions. €œThe cause of the link between the two conditions remains unclear,” she says.

However, the association was strong enough, she adds, to recommend that physicians and patients be made aware of it. Women with this type of scarring alopecia should be screened not only for fibroids, but also for other disorders associated with excess fibrous tissue, Aguh says. An estimated 70 percent of white women and between 80 and 90 percent of African-American women will develop fibroids by age 50, according to the NIH, and while CCCA is likely underdiagnosed, some estimates report a prevalence of rates as high as 17 percent of black women having this condition.

The other authors on this paper were Ginette A. Okoye, M.D. Of Johns Hopkins and Yemisi Dina of Meharry Medical College.Credit.

The New England Journal of Medicine Share Fast Facts This study clears up how big an effect the mutational burden has on outcomes to immune checkpoint inhibitors across many different cancer types. - Click to Tweet The number of mutations in a tumor’s DNA is a good predictor of whether it will respond to a class of cancer immunotherapy drugs known as checkpoint inhibitors. - Click to Tweet The “mutational burden,” or the number of mutations present in a tumor’s DNA, is a good predictor of whether that cancer type will respond to a class of cancer immunotherapy drugs known as checkpoint inhibitors, a new study led by Johns Hopkins Kimmel Cancer Center researchers shows.

The finding, published in the Dec. 21 New England Journal of Medicine, could be used to guide future clinical trials for these drugs. Checkpoint inhibitors are a relatively new class of drug that helps the immune system recognize cancer by interfering with mechanisms cancer cells use to hide from immune cells.

As a result, the drugs cause the immune system to fight cancer in the same way that it would fight an . These medicines have had remarkable success in treating some types of cancers that historically have had poor prognoses, such as advanced melanoma and lung cancer. However, these therapies have had little effect on other deadly cancer types, such as pancreatic cancer and glioblastoma.

The mutational burden of certain tumor types has previously been proposed as an explanation for why certain cancers respond better than others to immune checkpoint inhibitors says study leader Mark Yarchoan, M.D., chief medical oncology fellow. Work by Dung Le, M.D., associate professor of oncology, and other researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Cancer Institute for Cancer Immunotherapy showed that colon cancers that carry a high number of mutations are more likely to respond to checkpoint inhibitors than those that have fewer mutations. However, exactly how big an effect the mutational burden has on outcomes to immune checkpoint inhibitors across many different cancer types was unclear.

To investigate this question, Yarchoan and colleagues Alexander Hopkins, Ph.D., research fellow, and Elizabeth Jaffee, M.D., co-director of the Skip Viragh Center for Pancreas Cancer Clinical Research and Patient Care and associate director of the Bloomberg~Kimmel Institute, combed the medical literature for the results of clinical trials using checkpoint inhibitors on various different types of cancer. They combined these findings with data on the mutational burden of thousands of tumor samples from patients with different tumor types. Analyzing 27 different cancer types for which both pieces of information were available, the researchers found a strong correlation.

The higher a cancer type’s mutational burden tends to be, the more likely it is to respond to checkpoint inhibitors. More than half of the differences in how well cancers responded to immune checkpoint inhibitors could be explained by the mutational burden of that cancer. €œThe idea that a tumor type with more mutations might be easier to treat than one with fewer sounds a little counterintuitive.

It’s one of those things that doesn’t sound right when you hear it,” says Hopkins. €œBut with immunotherapy, the more mutations you have, the more chances the immune system has to recognize the tumor.” Although this finding held true for the vast majority of cancer types they studied, there were some outliers in their analysis, says Yarchoan. For example, Merkel cell cancer, a rare and highly aggressive skin cancer, tends to have a moderate number of mutations yet responds extremely well to checkpoint inhibitors.

However, he explains, this cancer type is often caused by a propecia, which seems to encourage a strong immune response despite the cancer’s lower mutational burden. In contrast, the most common type of colorectal cancer has moderate mutational burden, yet responds poorly to checkpoint inhibitors for reasons that are still unclear. Yarchoan notes that these findings could help guide clinical trials to test checkpoint inhibitors on cancer types for which these drugs haven’t yet been tried.

Future studies might also focus on finding ways to prompt cancers with low mutational burdens to behave like those with higher mutational burdens so that they will respond better to these therapies. He and his colleagues plan to extend this line of research by investigating whether mutational burden might be a good predictor of whether cancers in individual patients might respond well to this class of immunotherapy drugs. €œThe end goal is precision medicine—moving beyond what’s true for big groups of patients to see whether we can use this information to help any given patient,” he says.

Yarchoan receives funding from the Norman &. Ruth Rales Foundation and the Conquer Cancer Foundation. Through a licensing agreement with Aduro Biotech, Jaffee has the potential to receive royalties in the future..

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About This TrackerThis tracker provides the number of Generic cialis order online confirmed cases and deaths from novel hair loss by country, the trend in confirmed case and death counts by country, propecia for women reviews and a global map showing which countries have confirmed cases and deaths. The data are drawn from the Johns Hopkins University (JHU) hair loss Resource Center’s hair loss treatment Map and the World Health Organization’s (WHO) hair loss Disease propecia for women reviews (hair loss treatment-2019) situation reports.This tracker will be updated regularly, as new data are released.Related Content. About hair loss treatment hair lossIn late 2019, a new hair loss emerged in central China to cause disease in humans. Cases of propecia for women reviews this disease, known as hair loss treatment, have since been reported across around the globe.

On January 30, 2020, the World Health Organization (WHO) declared the propecia represents a public health emergency of international concern, and on January 31, 2020, the U.S. Department of Health and Human Services declared it to be a health emergency for the United States.With schools nationwide preparing for fall and the federal government encouraging in-person classes, key concerns for school officials, teachers and parents include the risks that hair loss poses to children and their role in transmission of the disease.A new KFF brief examines the propecia for women reviews latest available data and evidence about the issues around hair loss treatment and children and what they suggest about the risks posed for reopening classrooms. The review concludes that while children are much less likely than propecia for women reviews adults to become severely ill, they can transmit the propecia. Key findings include:Disease severity is significantly less in children, though rarely some do get very sick.

Children under age 18 account for 22% of the propecia for women reviews population but account for just 7% of the more than 4 million hair loss treatment cases and less than 1% of deaths.The evidence is mixed about whether children are less likely than adults to become infected when exposed. While one prominent study estimates children and teenagers are half as likely as adults over age 20 to catch the propecia, other studies find children and adults are about equally likely to have antibodies that develop after a hair loss treatment .While children do transmit to others, more evidence is needed on the frequency and extent of that transmission. A number of studies find children are less likely than adults to be the source of s in households and other settings, though this could occur because of differences in testing, the severity of the disease, and the impact of earlier school closures.Most countries that have reopened schools have not experienced outbreaks, but almost all had significantly lower propecia for women reviews rates of community transmission. Some countries, including Canada, Chile, France, and Israel did experience school-based outbreaks, sometimes significant ones, that required schools to close a second time.The analysis concludes that there is a risk of spread associated with reopening schools, particularly in states and communities where there is already widespread community transmission, that should be weighed carefully against the benefits of in-person education..

About This TrackerThis tracker provides the number of confirmed cases and deaths from novel hair loss by country, the trend in confirmed case and death counts by country, and a buy generic propecia online global map showing which countries have confirmed https://wine-showroom.com/generic-cialis-order-online/ cases and deaths. The data are drawn from the Johns Hopkins University (JHU) hair loss Resource Center’s hair loss treatment Map buy generic propecia online and the World Health Organization’s (WHO) hair loss Disease (hair loss treatment-2019) situation reports.This tracker will be updated regularly, as new data are released.Related Content. About hair loss treatment hair lossIn late 2019, a new hair loss emerged in central China to cause disease in humans. Cases of this disease, known as hair loss treatment, have since been reported buy generic propecia online across around the globe. On January 30, 2020, the World Health Organization (WHO) declared the propecia represents a public health emergency of international concern, and on January 31, 2020, the U.S.

Department of Health buy generic propecia online and Human Services declared it to be a health emergency for the United States.With schools nationwide preparing for fall and the federal government encouraging in-person classes, key concerns for school officials, teachers and parents include the risks that hair loss poses to children and their role in transmission of the disease.A new KFF brief examines the latest available data and evidence about the issues around hair loss treatment and children and what they suggest about the risks posed for reopening classrooms. The review concludes that while buy generic propecia online children are much less likely than adults to become severely ill, they can transmit the propecia. Key findings include:Disease severity is significantly less in children, though rarely some do get very sick. Children under age 18 account for 22% of the population buy generic propecia online but account for just 7% of the more than 4 million hair loss treatment cases and less than 1% of deaths.The evidence is mixed about whether children are less likely than adults to become infected when exposed. While one prominent study estimates children and teenagers are half as likely as adults over age 20 to catch the propecia, other studies find children and adults are about equally likely to have antibodies that develop after a hair loss treatment .While children do transmit to others, more evidence is needed on the frequency and extent of that transmission.

A number of studies find children are less likely than adults to be the source of s in buy generic propecia online households and other settings, though this could occur because of differences in testing, the severity of the disease, and the impact of earlier school closures.Most countries that have reopened schools have not experienced outbreaks, but almost all had significantly lower rates of community transmission. Some countries, including Canada, Chile, France, and Israel did experience school-based outbreaks, sometimes significant ones, that required schools to close a second time.The analysis concludes that there is a risk of spread associated with reopening schools, particularly in states and communities where there is already widespread community transmission, that should be weighed carefully against the benefits of in-person education..

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FINASTERIDE is used for the treatment of certain types of male hair loss (Alopecia). Finasteride is not for use in women.

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IntroductionEarly life is propecia crack ho blind date regarded as propecia tablets online canada a crucial period of neurobiological, emotional, social and physical development in all animal species and may have long-term implications for health across the life course. The first studies examining the preadult origins of chronic disease were probably published more propecia crack ho blind date than 50 years ago and based on rodent models.1 By briefly administering a suboptimal diet to newborn mice, Dubos and others1 demonstrated a marked impact on subsequent growth and resistance to . In the 1970s, Forsdahl,2 using infant mortality rates as a proxy for living conditions at birth, arguably provided the first evidence in humans for an association with heart disease in later life. In the last two decades, findings from longitudinal studies with extended mortality and morbidity surveillance have implicated a host of preadult characteristics as potential risk factors for several chronic disease outcomes, including perinatal and postnatal growth,3 coordination,4 intelligence,5 6 mental health,7 overweight,8 9 physical stature,10 raised blood pressure,11 12 cigarette propecia crack ho blind date smoking,13 physical strength14 and diet15 among many others.16An array of prospective studies has also demonstrated associations of childhood socioeconomic disadvantage–indexed by paternal social class or education, the presence of household amenities and domestic overcrowding—with somatic health outcomes in adulthood, chiefly premature mortality and cardiovascular disease.17 18 Parallel work has been undertaken by psychologists and psychiatrists exploring the consequences of childhood maeatment for later psychopathologies—perhaps the most well examined health endpoint in this context.19 20 Collectively, these early life circumstances have been more widely defined to comprise the separate themes of material deprivation (eg, economic hardship and long-term unemployment). Stressful family dynamics (eg, physical and emotional abuse, psychiatric illness or substance abuse by propecia crack ho blind date a family member).

Loss or threat of loss (eg, death or serious illness …INTRODUCTIONSevere acute respiratory syndrome hair loss 2 (hair loss), causative agent of hair loss disease (hair loss treatment), emerged in Wuhan, China, in late 2019. On 11 March 2020, the World Health Organization (WHO) declared hair loss treatment a propecia, with over 10 million confirmed cases as of the beginning of July 2020.1 2 The first patient in the Netherlands was confirmed on 27 February 2020.3 Cases primarily clustered in the southeastern part of propecia crack ho blind date the country, but were reported in other regions quickly hereafter. Multi-pronged interventions to suppress the spread of the propecia, including social distancing, school and bar/restaurant closure, and stringent advice to home quarantine when feeling ill and work from home, were implemented on 16 March 2020—and were relaxed gradually since 1 June 2020. By 1 July 2020, 50 273 cases, 11 877 hospitalisations, and 6113 related propecia crack ho blind date deaths were reported in the Netherlands.3Supplemental materialReported hair loss treatment cases worldwide are an underestimation of the true magnitude of the propecia. The scope of undetected cases remains largely unknown due to difference in restrictive testing policy and registration across countries, and occurrence of asymptomatic s.4 5 Large-scale nationwide serosurveillance studies measuring hair loss-specific serum antibodies could help to better assess the number of s, propecia crack ho blind date viral spread, and groups at risk of in the general population by incorporating extensive questionnaire data, for example, on lifestyle, behaviour and profession.

This might yield different factors than those identified for (severely-ill) clinical cases investigated more frequently up until now.6 7 Unfortunately, such nationwide studies (eg, in Spain8 and Iceland,9) also referred to as Unity Studies by the WHO,10 are scarce and mainly set up through convenience sampling.Therefore, a nationwide serosurveillance study (PIENTER-Corona, PICO) was initiated quickly after the lockdown was in effect. This cohort is unique as it comprises data available from a previous serosurvey established in 2016/17 (PIENTER-3) of a randomised nationwide sample of Dutch citizens, across all ages and a separate sample enriched for Orthodox-Reformed Protestants, whom might have been exposed to hair loss more frequently due to their socio-geographical-clustered lifestyle.11 12 The presented serological framework and findings of our first round of inclusion can support public health policy in the Netherlands as well as internationally.METHODSStudy designIn 2016/17, propecia crack ho blind date the National Institute for Public Health and the Environment of the Netherlands (RIVM) initiated a large-scale nationwide serosurveillance study (PIENTER-3) (n=7600. Age-range 0–89 years). The primary aim was to propecia crack ho blind date obtain insights into the protection against treatment-preventable diseases offered by the National Immunisation Programme in the Netherlands. A comprehensive description of PIENTER-3 has been published previously.13 Briefly, participants were selected via a two-stage cluster design, propecia crack ho blind date comprising 40 municipalities in five regions nationwide (henceforth ‘national sample’, NS), and nine municipalities in the low vaccination coverage municipalities (LVC), inhabited by a relative large proportion of Orthodox-Reformed Protestants (figure 1).

Among other materials, sera and questionnaire data had been collected from all participants. Hence, the PIENTER-3 study acted as baseline sample of the Dutch population for the present cross-sectional PICO-study since 6102 participants (80%) consented to be approached for follow-up (after updating addresses and screening of possible deaths) propecia crack ho blind date. The study was powered to estimate an overall seroprevalence with a precision of at least 2.5%.13 The PICO-study protocol was approved by the Medical Ethics Committee MEC-U, the Netherlands (Clinical Trial Registration NTR8473), and conformed to the principles embodied in the Declaration of Helsinki.Geographical representation of number of participants in the PICO-study, the Netherlands, first round of inclusion, per municipality. The size of the dots reflect the absolute number of propecia crack ho blind date participants. Thicker grey and smaller light grey boundaries represent provinces and municipalities, respectively, and orange and blue propecia crack ho blind date boundaries characterise municipalities from the national and low vaccination coverage sample, respectively." data-icon-position data-hide-link-title="0">Figure 1 Geographical representation of number of participants in the PICO-study, the Netherlands, first round of inclusion, per municipality.

The size of the dots reflect the absolute number of participants. Thicker grey propecia crack ho blind date and smaller light grey boundaries represent provinces and municipalities, respectively, and orange and blue boundaries characterise municipalities from the national and low vaccination coverage sample, respectively.Study population and materialsOn 25 March 2020, an invitation letter was sent. Invitees (age-range 2–92 years) willing to participate registered online. After enrolment, participants received an instruction letter on how to self-collect a fingerstick blood sample in a microtainer (maximum propecia crack ho blind date of 0.3 mL). Blood samples were returned to the RIVM-laboratory in safety propecia crack ho blind date envelopes.

Serum samples were stored at −20°C awaiting analyses. Materials were collected between March 31 propecia crack ho blind date and May 11, with the majority (80%) in the first week of April 2020 (median collection date April 3). Simultaneous with the blood collection, participants were asked to complete an (online) questionnaire, including questions regarding sociodemographic characteristics, hair loss treatment-related symptoms, and potential other determinants for hair loss seropositivity, such as comorbidities, medication use and behavioural factors. All participants provided written informed consent.Laboratory methodsSerum samples (diluted 1:200) were tested for the presence of hair loss spike S1-specific IgG antibodies using a validated fluorescent bead-based multiplex-immunoassay as described.14 A cut-off concentration propecia crack ho blind date for seropositivity (2.37 AU/mL. With specificity of 99% and sensitivity of 84.4%) was determined by ROC-analysis of 400 pre-propecia control samples (including a nationwide random cross-sectional sample (n=108)) as well as patients with confirmed influenza-like illnesses caused by hair losses and other propeciaes, and a selection of sera from 115 PCR-confirmed propecia crack ho blind date hair loss treatment cases with mild, or severe disease symptoms.

Seropositive PICO-samples and those with a concentration 25% below the cut-off were retested (n=138), and the geometric mean concentration (GMC) was calculated. Paired pre-propecia PIENTER-3-samples of these retested PICO-samples (available from 129/138) were tested correspondingly as described above propecia crack ho blind date to correct for false-positive results (online supplemental figure S1A).Statistical analysesStudy population, hair loss treatment-related symptoms and antibody responsesData management and analyses were conducted in SAS v.9.4 (SAS Institute Inc., USA) and R v.3.6. P values <0.05 were considered statistically significant. Sociodemographic characteristics and hair loss treatment-related symptoms (general, respiratory, and gastrointestinal) developed since the start of the epidemic were stratified by sample (NS vs propecia crack ho blind date LVC), or sex, respectively, and described for seropositive and seronegative participants. Differences were tested via Pearson’s χ², or Fisher’s propecia crack ho blind date exact test if appropriate.

Differences in GMC between reported symptoms in seropositive participants were determined by calculating the difference in log-transformed concentrations of those who developed symptoms at least 4 weeks prior to the sampling—ensuring a plateaued response—and tested by means of a Mann-Whitney U-test.Seroprevalence estimatesSeroprevalence estimates (with 95% Wilson CIs (CI)) for hair loss-specific antibodies were calculated taking into account the survey design (ie, controlling for region and municipality) and weighted by sex, age, ethnic background and degree of urbanisation to match the distribution of the general Dutch population in both the NS and LVC sample. Estimates were corrected for test performance propecia crack ho blind date via the Rogan &. Gladen bias correction (with sensitivity of 84.4% and assuming a specificity of 100% after cross-validation with pre-sera).15 Smooth age-specific seroprevalence estimates were obtained with a logistic regression in a Generalised Additive Model using penalised splines.16Risk factors for hair loss seropositivityA random-effects logistic regression model was used to identify risk factors for hair loss seropositivity, applying a full case analysis (n=3100. Values were missing for <5% of the propecia crack ho blind date participants). Potential risk factors included sociodemographic characteristics (sex, age group, region, ethnic background, Orthodox-Reformed Protestants, educational level, household size, (parent with a) contact profession, healthcare worker), and hair loss treatment-related factors (contact with a hair loss treatment confirmed case, number of persons contacted yesterday, working from home (normally and in the last week), comorbidities (combining diabetes, history of malignancy, immunodeficiency, cardio-vascular, propecia crack ho blind date kidney and chronic lung disease (note.

As a sensitivity analysis, comorbidities were also included separately)), and use of blood pressure medication, immunosuppressants, statins and antivirals/antibiotics in the last month). Models included propecia crack ho blind date a random intercept, potential clustering by municipality and region was accounted for, and odds ratios (OR) in univariable analyses were a priori adjusted for sex and age. Variables with p<0.10 were entered in the multivariable analysis, and backward selection was performed—manually dropping variables one-by-one based on p≥0.05—to identify significant risk factors. Adjusted ORs and corresponding 95% CIs were propecia crack ho blind date provided.RESULTSStudy populationOf 6102 invitees, 3207 (53%) donated a serum sample and filled-out the questionnaire, of which 2637 persons from the NS and 570 from the LVC. Participants from across the country participated (figure 1), with age ranging from 2 to 90 years propecia crack ho blind date (table 1).

In the NS, slightly more women (55%) participated, most (88%) were of Dutch descent, nearly half had a high educational level, and 45% was religious. 20 percent of persons between age 25–66 years were healthcare workers and 56% of the (parents of) participants reported to have had daily contact with patients, clients and/or propecia crack ho blind date children in their profession/volunteer work normally. Over half of the participants lived in a ≥2-person household, and 78% reported to have had physical contact with <5 people outside their own household yesterday (during lockdown), of which more than half with nobody. Comorbidities most propecia crack ho blind date frequently reported included chronic lung and cardiovascular disease (both 13%), and a history of malignancy (5%). In line with the population distribution, the LVC sample was characterised by a relative high proportion of Orthodox-Reformed propecia crack ho blind date Protestants from Dutch descent (table 1).

Sociodemographic characteristics between responders and non-responders are provided in online supplemental table S1.View this table:Table 1 Sociodemographic characteristics of participants in the PICO-study and weighted seroprevalence in the general population of the Netherlands, first round of inclusion, by national sample and low vaccination coverage sampleSupplemental materialhair loss treatment-related symptoms and antibody responsesIn total, 63% of participants reported to have had ≥1 hair loss treatment-related symptom(s) since the start of the epidemic, with runny nose (37%), headache (33%), and cough (30%) being most common (table 2). All reported symptoms were significantly higher propecia crack ho blind date in seropositive compared to seronegative persons, except for stomach ache. The majority of propecia crack ho blind date those seropositive (93%) reported to have had symptoms (90% of men vs 95% of women), of whom three already in mid-February, 2 weeks prior to the official first notification. Median duration of illness in the seropositive participants was 8.5 days (IQR. 4.0–12.5), 16% propecia crack ho blind date (n=12) visited ageneral practitioner and one was admitted to the hospital.

Among seropositive persons, most reported to have had ≥1 respiratory symptom(s) (86%), with runny nose and cough (both 61%) most regularly, and ≥1 general (84%) symptom(s), of which anosmia/ageusia (53%) was most discriminative as compared to the seronegative participants (4%, p<0.0001) (table 2). Symptoms were more common in women, except for anosmia/ageusia, cough and irritable/confusion propecia crack ho blind date. Almost 75% of the seropositive participants met the hair loss treatment case definition of fever propecia crack ho blind date and/or cough and/or dyspnoea, which improved to 80% when anosmia/ageusia was included—while remaining 36% in those seronegative. GMC was significantly higher among seropositive persons with fever vs without (48.2 vs 11.6 AU/mL, p=0.01), and with dyspnoea vs without (78.6 vs 13.5 AU/mL, p=0.04).View this table:Table 2 hair loss treatment-related symptoms since the start of the epidemic among all participants in the PICO-study reporting symptoms (n=3147), first round of inclusionSeroprevalence estimatesOverall weighted seroprevalence in the NS was 2.8% (95% CI 2.1 to 3.7), did not differ between sexes or ethnic backgrounds (table 1), and was not higher among healthcare workers (2.7% vs non-healthcare workers 2.5%). Seroprevalence was propecia crack ho blind date lowest in the northern region (1.3%) and highest in the mid-west (4.0%).

Estimates were lowest in children—gradually increasing from below 1% at age 2 years to 3% at 17 years—was highest in age group 18–39 years (4.9%) and ranged between 2 and 4% up to 90 years of age (figure 2). In both samples, seroprevalence was highest in Orthodox-Reformed Protestants (>7%) (table propecia crack ho blind date 1). Online supplement figure S1B displays the distribution of IgG propecia crack ho blind date concentrations for all participants by age, and online supplemental figure S2 ⇓shows the seroprevalence smoothed by age in the LVC.Smooth age-specific hair loss seroprevalence in the general population of the Netherlands, beginning of April 2020." data-icon-position data-hide-link-title="0">Figure 2 Smooth age-specific hair loss seroprevalence in the general population of the Netherlands, beginning of April 2020.Risk factors for hair loss seropositivityVariables that were associated with hair loss seropositivity in univariable analyses included age group, Orthodox-Reformed Protestant, had been in contact with a hair loss treatment case, use of immunosuppressants, and antibiotic/antiviral medication in the last month (table 3). In multivariable analysis, substantial higher odds were observed for those who took immunosuppressants the last month, were Orthodox-Reformed Protestant, had been in contact with a hair loss treatment confirmed case, and from age groups 18–24 and 25–39 years (compared to 2–12 years).View this table:Table 3 Risk factor analysis for hair loss seropositivity among all participants (n=3100. Full case analysis) in the PICO-study, first round of inclusionDISCUSSIONHere, we have estimated the seroprevalence of hair loss-specific antibodies and identified risk factors for seropositivity in the general population of the Netherlands during the first epidemic wave in propecia crack ho blind date April 2020.

Although overall seroprevalence was still low at this phase, important risk factors for seropositivity could be identified, including adults aged 18–39 years, persons using immunosuppressants, and Orthodox-Reformed Protestants. These data can guide future interventions, including strategies for vaccination, believed to be a realistic solution to overcome this propecia.This PICO-study revealed that 2.8% (95% CI 2.1 to 3.7) of the Dutch population had detectable hair loss-specific serum IgG antibodies, suggesting that almost half a million inhabitants (of in propecia crack ho blind date total 17 423 98117) were infected (487 871 (95% CI 365 904 to 644 687)) in mid-March, 2020 (taking into account the median time to seroconvert18). Several seropositive participants reported to have had hair loss treatment-related symptoms back in mid-February, suggesting the propecia crack ho blind date propecia circulated in our country at the beginning of February already. Our overall estimate is in line with preliminary results from another study conducted in the Netherlands in the beginning of April which found 2.7% to be seropositive, although this study was performed in healthy blood donors aged 18–79 years.19 Worldwide, various seroprevalence studies are ongoing. A large nationwide study in Spain showed that around 5% (ranging between 3.7% and 6.2%) was seropositive, indicating that only a small proportion of the population had been infected in one propecia crack ho blind date of the hardest hit countries in Europe.

Current studies in literature mostly cover hair loss treatment hotspots or specific regions—with possibly bias in selection of participants and/or smaller age-ranges—with rates ranging between 1–7% in April (eg, in Los Angeles County (CA, USA)20 or ten other sites in the USA,21 Geneva (Switzerland),22 and Luxembourg23). Estimates also very much depend propecia crack ho blind date on test performances. Particularly, when seroprevalence is relatively low, specificity of the assay should approach near 100% to diminish false-positive propecia crack ho blind date results and minimise overestimation. Although we cannot rule-out false-positive samples completely, our assay was validated using a broad range of positive and negative hair loss samples. PICO-samples were propecia crack ho blind date cross-linked to pre-propecia concentration.

And bias correction for test performance was applied to represent most accurate estimates. In addition, future studies should establish whether epidemiologically dominant genetic changes in the spike protein of hair loss influence binding to spike S1 used in our and other assays.Seroprevalence was highest in adults aged 18–39 years, which is in line with the serosurvey among blood donors in the Netherlands, but contrary to the low incidence rate as reported in Dutch surveillance, caused by restrictive testing propecia crack ho blind date of risk groups and healthcare workers at the beginning of the epidemic, primarily identifying severe cases.3 19 The elevation in these younger adults may be explained by increased social contacts typical for this age group, in addition to specific social activities in February, such as skiing holidays in the Alps (from where the propecia disseminated quickly across Europe), or carnival festivities in the Netherlands (ie, multiple superspreading events primarily in the mid and Southern part, explaining local elevation in seroprevalence). In correspondence with other nationwide studies8 propecia crack ho blind date 9 and reports from the Dutch government,3 24 seroprevalence was lowest in children. Although some rare events of paediatric inflammatory multisystem syndrome have been reported, this group seems to be at decreased risk for developing (severe) hair loss treatment in general, which may be explained by less severe possibly resulting in a limited humoral response.25 26 Further, significantly higher odds for seropositivity were seen in Orthodox-Reformed Protestants. This community lives socio-geographically clustered in the Netherlands, that is, work, school, leisure and church are intertwined propecia crack ho blind date heavily.

As observed in other countries, particularly frequent attendance of church with close distance to others, including singing activities, might have fuelled the spread of hair loss within this community in the beginning of the epidemic.11 12 Whereas the comorbidities with possible increased risk of severe hair loss treatment were not associated with seropositivity in this study, immunosuppressants use did display higher odds (note. We did not propecia crack ho blind date have information of specific drugs). Recent data indicate that immunosuppressive treatment is not associated with worse hair loss treatment outcomes,27 28 yet continued surveillance is warranted as these patients might be more prone to (future) , for instance due propecia crack ho blind date to a possible attenuated humoral immune response.29The majority of seropositive participants exhibited ≥1 symptom(s), mostly general and respiratory. A recent meta-analysis found a pooled asymptomatic proportion of 16%,5 hence the observed overall fraction in the present study (7%) might be a conservative estimate as the self-reported symptoms could have been due to other reasons or circulating pathogens along the recalled period (ie, 62% of the seronegative participants reported symptoms too). The asymptomatic proportion might be different across ages5 and should be explored further along with propecia crack ho blind date elucidating the overall contribution of asymptomatic transmission via well-designed contact-tracing studies.

Interestingly, clinical studies have observed anosmia/ageusia to be associated with hair loss , and this notion is supported here at a population-based level.30 In the propecia context, sudden onset of anosmia/ageusia seems to be a useful surveillance tool, which can contribute to early disease recognition and minimise transmission by rapid self-isolation.This study has some limitations. First, although half of the total municipalities in the Netherlands were included, some hair loss treatment hotspots might be missed due to the study propecia crack ho blind date design. Second, our study population consisted of more Dutch (88%) than non-Dutch persons and relative more healthcare workers (20%) when propecia crack ho blind date compared to the general population (76% and 14%, respectively).17 Healthcare workers in the Netherlands do not seem to have had a higher likelihood of , and transmission seems to have taken place mostly in household settings.3 31 Although selectivity in response was minimised by weighting our study sample on a set of sociodemographic characters to match the Dutch population, seroprevalence might still be slightly influenced. Third, some potential determinants for seropositivity could have been missed as we might have been underpowered to detect small differences given the low prevalence in this phase, or because these questions had not been included in the questionnaire (as it was designed in the very beginning of the epidemic). Finally, at this stage the proportion of infected individuals that fail to show detectable seroconversion is unknown, potentially leading to underestimation of the percentage propecia crack ho blind date of infected persons.To conclude, we estimated that 2.8% of the Dutch inhabitants, that is, nearly half a million, were infected with hair loss amidst the first epidemic wave in the beginning of April 2020.

This is in striking contrast with the 30-fold lower number of reported cases (of approximately 15 000)3, and underlines the importance of seroepidemiological studies to estimate the true propecia size. The proportion of persons still susceptible to hair loss is high and IFR is substantial.4 Globally, nationwide seroepidemiological studies are urgently needed for better understanding of related risk factors, viral spread, and measures applied to mitigate dissemination.7 The prospective nature of our study will enable us to gain key insights on the duration and quality of antibody responses in infected persons, and hence possible protection of disease by antibodies.6 Serosurveys will thus play a major role in guiding future interventions, such as strategies for vaccination (of risk groups), since even when treatments become available, initial treatment availability will be limited.What is already known on this topicReported hair loss treatment cases worldwide are an underestimation of the true magnitude of the propecia as the scope of undetected cases remains largely unknown.Various symptoms and risk factors have been identified in patients seeking medical advice, however, these may not be representative for s in the general population.Seroepidemiological studies in outbreak settings have been performed, however, studies on a nationwide level covering all ages remain limited.What this study addsThis nationwide seroepidemiological study covering all ages reveals that 2.8% of the Dutch population had been infected with hair loss at the beginning of April 2020, that is, 30 times higher than the official cases reported, leaving a large proportion of the population still susceptible for .The highest seroprevalence was observed in young adults from 18 to 39 years of age and lowest in children aged 2 to 17 years, indicating marginal hair loss s among children in general.Persons taking immunosuppressants as propecia crack ho blind date well as those from the Orthodox-Reformed Protestant community had over four times higher odds of being seropositive compared to others.The extend of the spread of hair loss and the risk groups identified here, can inform monitoring strategies and guide future interventions internationally.AcknowledgmentsFirst of all, we gratefully acknowledge the participants of the PICO-study. Secondly, this study would not have been possible without the instrumental contribution of colleagues from the National Institute of Public Health and Environment (RIVM), Bilthoven, the Netherlands, more specially the department of Immunology of Infectious Diseases and treatments, regarding logistics and/or laboratory analyses (Marjan propecia crack ho blind date Bogaard-van Maurik, Annemarie Buisman, Pieter van Gageldonk, Hinke ten Hulscher-van Overbeek, Petra Jochemsen, Deborah Kleijne, Jessica Loch, Marjan Kuijer, Milou Ohm, Hella Pasmans, Lia de Rond, Debbie van Rooijen, Liza Tymchenko, Esther van Woudenbergh, and Mary-lene de Zeeuw-Brouwer), the Epidemiology and Surveillance department concerning logistics (Francoise van Heiningen, Alies van Lier, Jeanet Kemmeren, Joske Hoes, Maarten Immink, Marit Middeldorp, Christiaan Oostdijk, Ilse Schinkel-Gordijn, Yolanda van Weert, and Anneke Westerhof), methodological insights (Hendriek Boshuizen, Susan Hahné, Scott McDonald, Rianne van Gageldonk-Lafeber, Jan van de Kassteele, and Maarten Schipper) and manuscript reviewing (Susan van den Hof, and Don Klinkenberg), department of IT and Communication for help with the invitations (Luppo de Vries, Daphne Gijselaar, and Maaike Mathu), student interns for additional support (Stijn Andeweg for creating online supplemental figures 1A and 1B. Janine Wolf, Natasha Kaagman, and Demi Wagenaar for logistics. And Lisette van Cooten for data entry of paper questionnaires), and Sidekick-IT, Breda, propecia crack ho blind date the Netherlands, regarding data flow (Tim de Hoog).

This study was funded by the ministry of Health, Welfare and Sports (VWS), the Netherlands..

IntroductionEarly life click here now is regarded as a crucial period of neurobiological, emotional, social and physical development in all animal buy generic propecia online species and may have long-term implications for health across the life course. The first studies examining the preadult origins of chronic disease were probably published more than 50 years ago and based on rodent models.1 By briefly administering a suboptimal diet to newborn buy generic propecia online mice, Dubos and others1 demonstrated a marked impact on subsequent growth and resistance to . In the 1970s, Forsdahl,2 using infant mortality rates as a proxy for living conditions at birth, arguably provided the first evidence in humans for an association with heart disease in later life.

In the last two decades, findings from longitudinal studies with extended mortality and morbidity surveillance have implicated a host of preadult characteristics as potential risk factors for several chronic disease outcomes, including perinatal and postnatal growth,3 coordination,4 intelligence,5 6 mental health,7 overweight,8 9 physical stature,10 raised blood pressure,11 12 cigarette smoking,13 physical strength14 and diet15 among many others.16An array of prospective studies has also demonstrated associations of childhood socioeconomic disadvantage–indexed by paternal social class or education, the presence of household amenities and domestic overcrowding—with somatic health outcomes in adulthood, chiefly premature mortality and cardiovascular disease.17 18 Parallel work has been undertaken by psychologists and psychiatrists exploring the consequences of childhood maeatment for later psychopathologies—perhaps the most well examined health endpoint in this context.19 20 Collectively, these early life circumstances have been more widely defined to comprise the separate themes buy generic propecia online of material deprivation (eg, economic hardship and long-term unemployment). Stressful family dynamics (eg, physical and emotional abuse, psychiatric illness or substance abuse by a family buy generic propecia online member). Loss or threat of loss (eg, death or serious illness …INTRODUCTIONSevere acute respiratory syndrome hair loss 2 (hair loss), causative agent of hair loss disease (hair loss treatment), emerged in Wuhan, China, in late 2019.

On 11 March 2020, the World Health Organization (WHO) declared hair loss treatment a propecia, with over 10 million confirmed cases as of the beginning of July 2020.1 2 The first patient in the Netherlands was buy generic propecia online confirmed on 27 February 2020.3 Cases primarily clustered in the southeastern part of the country, but were reported in other regions quickly hereafter. Multi-pronged interventions to suppress the spread of the propecia, including social distancing, school and bar/restaurant closure, and stringent advice to home quarantine when feeling ill and work from home, were implemented on 16 March 2020—and were relaxed gradually since 1 June 2020. By 1 July buy generic propecia online 2020, 50 273 cases, 11 877 hospitalisations, and 6113 related deaths were reported in the Netherlands.3Supplemental materialReported hair loss treatment cases worldwide are an underestimation of the true magnitude of the propecia.

The scope of undetected cases remains largely unknown due to difference in restrictive testing policy and registration across buy generic propecia online countries, and occurrence of asymptomatic s.4 5 Large-scale nationwide serosurveillance studies measuring hair loss-specific serum antibodies could help to better assess the number of s, viral spread, and groups at risk of in the general population by incorporating extensive questionnaire data, for example, on lifestyle, behaviour and profession. This might yield different factors than those identified for (severely-ill) clinical cases investigated more frequently up until now.6 7 Unfortunately, such nationwide studies (eg, in Spain8 and Iceland,9) also referred to as Unity Studies by the WHO,10 are scarce and mainly set up through convenience sampling.Therefore, a nationwide serosurveillance study (PIENTER-Corona, PICO) was initiated quickly after the lockdown was in effect. This cohort is unique as it comprises data available from a previous serosurvey established in 2016/17 (PIENTER-3) of a randomised nationwide sample of Dutch citizens, across all ages and a separate buy generic propecia online sample enriched for Orthodox-Reformed Protestants, whom might have been exposed to hair loss more frequently due to their socio-geographical-clustered lifestyle.11 12 The presented serological framework and findings of our first round of inclusion can support public health policy in the Netherlands as well as internationally.METHODSStudy designIn 2016/17, the National Institute for Public Health and the Environment of the Netherlands (RIVM) initiated a large-scale nationwide serosurveillance study (PIENTER-3) (n=7600.

Age-range 0–89 years). The primary aim was to obtain insights into the protection against treatment-preventable diseases buy generic propecia online offered by the National Immunisation Programme in the Netherlands. A comprehensive description of PIENTER-3 has been published previously.13 Briefly, participants were selected via a two-stage cluster design, comprising 40 municipalities in five regions nationwide (henceforth ‘national sample’, NS), and nine municipalities in the low vaccination coverage municipalities (LVC), inhabited by a relative large proportion of Orthodox-Reformed Protestants (figure buy generic propecia online 1).

Among other materials, sera and questionnaire data had been collected from all participants. Hence, the PIENTER-3 study acted as baseline sample of the Dutch population for the present cross-sectional PICO-study since 6102 participants (80%) consented to be approached for follow-up (after updating addresses and screening of possible deaths) buy generic propecia online. The study was powered to estimate an overall seroprevalence with a precision of at least 2.5%.13 The PICO-study protocol was approved by the Medical Ethics Committee MEC-U, the Netherlands (Clinical Trial Registration NTR8473), and conformed to the principles embodied in the Declaration of Helsinki.Geographical representation of number of participants in the PICO-study, the Netherlands, first round of inclusion, per municipality.

The size buy generic propecia online of the dots reflect the absolute number of participants. Thicker grey and smaller light grey boundaries represent provinces and municipalities, respectively, and orange and blue boundaries characterise municipalities from the national and buy generic propecia online low vaccination coverage sample, respectively." data-icon-position data-hide-link-title="0">Figure 1 Geographical representation of number of participants in the PICO-study, the Netherlands, first round of inclusion, per municipality. The size of the dots reflect the absolute number of participants.

Thicker grey and smaller light grey boundaries represent provinces and municipalities, respectively, and orange and blue boundaries characterise municipalities from buy generic propecia online the national and low vaccination coverage sample, respectively.Study population and materialsOn 25 March 2020, an invitation letter was sent. Invitees (age-range 2–92 years) willing to participate registered online. After enrolment, participants received an instruction letter on how to self-collect a fingerstick blood sample in a microtainer (maximum of buy generic propecia online 0.3 mL).

Blood samples were returned to the RIVM-laboratory in safety buy generic propecia online envelopes. Serum samples were stored at −20°C awaiting analyses. Materials were collected between March 31 and May 11, with the majority (80%) in the first week of April buy generic propecia online 2020 (median collection date April 3).

Simultaneous with the blood collection, participants were asked to complete an (online) questionnaire, including questions regarding sociodemographic characteristics, hair loss treatment-related symptoms, and potential other determinants for hair loss seropositivity, such as comorbidities, medication use and behavioural factors. All participants provided written informed consent.Laboratory methodsSerum samples (diluted 1:200) were tested for the presence of hair loss spike S1-specific IgG antibodies using a validated fluorescent bead-based multiplex-immunoassay as described.14 A cut-off concentration for seropositivity buy generic propecia online (2.37 AU/mL. With specificity of 99% and sensitivity of 84.4%) was determined by ROC-analysis of 400 pre-propecia control samples (including a nationwide random cross-sectional buy generic propecia online sample (n=108)) as well as patients with confirmed influenza-like illnesses caused by hair losses and other propeciaes, and a selection of sera from 115 PCR-confirmed hair loss treatment cases with mild, or severe disease symptoms.

Seropositive PICO-samples and those with a concentration 25% below the cut-off were retested (n=138), and the geometric mean concentration (GMC) was calculated. Paired pre-propecia PIENTER-3-samples of these retested PICO-samples (available from 129/138) were tested correspondingly as described above to correct for false-positive results (online supplemental figure S1A).Statistical analysesStudy population, hair loss treatment-related symptoms and antibody responsesData management and buy generic propecia online analyses were conducted in SAS v.9.4 (SAS Institute Inc., USA) and R v.3.6. P values <0.05 were considered statistically significant.

Sociodemographic characteristics and hair loss treatment-related symptoms (general, respiratory, and gastrointestinal) buy generic propecia online developed since the start of the epidemic were stratified by sample (NS vs LVC), or sex, respectively, and described for seropositive and seronegative participants. Differences were buy generic propecia online tested via Pearson’s χ², or Fisher’s exact test if appropriate. Differences in GMC between reported symptoms in seropositive participants were determined by calculating the difference in log-transformed concentrations of those who developed symptoms at least 4 weeks prior to the sampling—ensuring a plateaued response—and tested by means of a Mann-Whitney U-test.Seroprevalence estimatesSeroprevalence estimates (with 95% Wilson CIs (CI)) for hair loss-specific antibodies were calculated taking into account the survey design (ie, controlling for region and municipality) and weighted by sex, age, ethnic background and degree of urbanisation to match the distribution of the general Dutch population in both the NS and LVC sample.

Estimates were corrected for test performance via buy generic propecia online the Rogan &. Gladen bias correction (with sensitivity of 84.4% and assuming a specificity of 100% after cross-validation with pre-sera).15 Smooth age-specific seroprevalence estimates were obtained with a logistic regression in a Generalised Additive Model using penalised splines.16Risk factors for hair loss seropositivityA random-effects logistic regression model was used to identify risk factors for hair loss seropositivity, applying a full case analysis (n=3100. Values were missing for <5% of buy generic propecia online the participants).

Potential risk factors included sociodemographic characteristics (sex, age group, region, ethnic background, Orthodox-Reformed Protestants, educational level, household size, (parent with a) contact profession, healthcare worker), and hair loss treatment-related factors (contact with a hair loss treatment confirmed case, number of persons contacted yesterday, working from home (normally and in the last week), comorbidities (combining buy generic propecia online diabetes, history of malignancy, immunodeficiency, cardio-vascular, kidney and chronic lung disease (note. As a sensitivity analysis, comorbidities were also included separately)), and use of blood pressure medication, immunosuppressants, statins and antivirals/antibiotics in the last month). Models included a random intercept, potential clustering by buy generic propecia online municipality and region was accounted for, and odds ratios (OR) in univariable analyses were a priori adjusted for sex and age.

Variables with p<0.10 were entered in the multivariable analysis, and backward selection was performed—manually dropping variables one-by-one based on p≥0.05—to identify significant risk factors. Adjusted ORs and corresponding 95% CIs were provided.RESULTSStudy populationOf 6102 invitees, 3207 (53%) donated a serum sample and filled-out the questionnaire, of which 2637 persons from the NS and buy generic propecia online 570 from the LVC. Participants from across the country participated (figure 1), with age ranging from buy generic propecia online 2 to 90 years (table 1).

In the NS, slightly more women (55%) participated, most (88%) were of Dutch descent, nearly half had a high educational level, and 45% was religious. 20 percent of persons between age 25–66 years were healthcare workers buy generic propecia online and 56% of the (parents of) participants reported to have had daily contact with patients, clients and/or children in their profession/volunteer work normally. Over half of the participants lived in a ≥2-person household, and 78% reported to have had physical contact with <5 people outside their own household yesterday (during lockdown), of which more than half with nobody.

Comorbidities most frequently reported included chronic lung and cardiovascular disease (both 13%), and a buy generic propecia online history of malignancy (5%). In line with the population distribution, the LVC sample buy generic propecia online was characterised by a relative high proportion of Orthodox-Reformed Protestants from Dutch descent (table 1). Sociodemographic characteristics between responders and non-responders are provided in online supplemental table S1.View this table:Table 1 Sociodemographic characteristics of participants in the PICO-study and weighted seroprevalence in the general population of the Netherlands, first round of inclusion, by national sample and low vaccination coverage sampleSupplemental materialhair loss treatment-related symptoms and antibody responsesIn total, 63% of participants reported to have had ≥1 hair loss treatment-related symptom(s) since the start of the epidemic, with runny nose (37%), headache (33%), and cough (30%) being most common (table 2).

All reported buy generic propecia online symptoms were significantly higher in seropositive compared to seronegative persons, except for stomach ache. The majority of those seropositive (93%) reported to have had symptoms (90% of men vs 95% of women), of buy generic propecia online whom three already in mid-February, 2 weeks prior to the official first notification. Median duration of illness in the seropositive participants was 8.5 days (IQR.

4.0–12.5), 16% (n=12) visited ageneral practitioner and one buy generic propecia online was admitted to the hospital. Among seropositive persons, most reported to have had ≥1 respiratory symptom(s) (86%), with runny nose and cough (both 61%) most regularly, and ≥1 general (84%) symptom(s), of which anosmia/ageusia (53%) was most discriminative as compared to the seronegative participants (4%, p<0.0001) (table 2). Symptoms were more common in women, except buy generic propecia online for anosmia/ageusia, cough and irritable/confusion.

Almost 75% of the seropositive participants met the hair loss treatment buy generic propecia online case definition of fever and/or cough and/or dyspnoea, which improved to 80% when anosmia/ageusia was included—while remaining 36% in those seronegative. GMC was significantly higher among seropositive persons with fever vs without (48.2 vs 11.6 AU/mL, p=0.01), and with dyspnoea vs without (78.6 vs 13.5 AU/mL, p=0.04).View this table:Table 2 hair loss treatment-related symptoms since the start of the epidemic among all participants in the PICO-study reporting symptoms (n=3147), first round of inclusionSeroprevalence estimatesOverall weighted seroprevalence in the NS was 2.8% (95% CI 2.1 to 3.7), did not differ between sexes or ethnic backgrounds (table 1), and was not higher among healthcare workers (2.7% vs non-healthcare workers 2.5%). Seroprevalence was lowest in the northern region (1.3%) buy generic propecia online and highest in the mid-west (4.0%).

Estimates were lowest in children—gradually increasing from below 1% at age 2 years to 3% at 17 years—was highest in age group 18–39 years (4.9%) and ranged between 2 and 4% up to 90 years of age (figure 2). In both samples, seroprevalence was highest in Orthodox-Reformed Protestants buy generic propecia online (>7%) (table 1). Online supplement figure S1B displays the distribution of IgG concentrations for all participants by age, and online supplemental figure S2 ⇓shows the seroprevalence smoothed by age in the LVC.Smooth age-specific hair loss seroprevalence in the general population of the Netherlands, beginning of April 2020." data-icon-position data-hide-link-title="0">Figure 2 Smooth age-specific hair loss seroprevalence in the general population of the Netherlands, beginning of buy generic propecia online April 2020.Risk factors for hair loss seropositivityVariables that were associated with hair loss seropositivity in univariable analyses included age group, Orthodox-Reformed Protestant, had been in contact with a hair loss treatment case, use of immunosuppressants, and antibiotic/antiviral medication in the last month (table 3).

In multivariable analysis, substantial higher odds were observed for those who took immunosuppressants the last month, were Orthodox-Reformed Protestant, had been in contact with a hair loss treatment confirmed case, and from age groups 18–24 and 25–39 years (compared to 2–12 years).View this table:Table 3 Risk factor analysis for hair loss seropositivity among all participants (n=3100. Full case analysis) in the PICO-study, first round of inclusionDISCUSSIONHere, we have estimated the seroprevalence of hair loss-specific antibodies and identified risk factors for seropositivity in the general population of the Netherlands during the first epidemic wave in buy generic propecia online April 2020. Although overall seroprevalence was still low at this phase, important risk factors for seropositivity could be identified, including adults aged 18–39 years, persons using immunosuppressants, and Orthodox-Reformed Protestants.

These data can guide future interventions, including strategies for vaccination, believed to be a realistic solution to overcome this propecia.This PICO-study revealed that 2.8% (95% CI 2.1 to 3.7) of the Dutch buy generic propecia online population had detectable hair loss-specific serum IgG antibodies, suggesting that almost half a million inhabitants (of in total 17 423 98117) were infected (487 871 (95% CI 365 904 to 644 687)) in mid-March, 2020 (taking into account the median time to seroconvert18). Several seropositive participants reported to have had hair loss treatment-related symptoms back in mid-February, suggesting the propecia circulated in our country at the beginning of February already buy generic propecia online. Our overall estimate is in line with preliminary results from another study conducted in the Netherlands in the beginning of April which found 2.7% to be seropositive, although this study was performed in healthy blood donors aged 18–79 years.19 Worldwide, various seroprevalence studies are ongoing.

A large nationwide study in Spain showed that around 5% (ranging between 3.7% and 6.2%) was seropositive, indicating that only a small proportion buy generic propecia online of the population had been infected in one of the hardest hit countries in Europe. Current studies in literature mostly cover hair loss treatment hotspots or specific regions—with possibly bias in selection of participants and/or smaller age-ranges—with rates ranging between 1–7% in April (eg, in Los Angeles County (CA, USA)20 or ten other sites in the USA,21 Geneva (Switzerland),22 and Luxembourg23). Estimates also very much depend on buy generic propecia online test performances.

Particularly, when seroprevalence buy generic propecia online is relatively low, specificity of the assay should approach near 100% to diminish false-positive results and minimise overestimation. Although we cannot rule-out false-positive samples completely, our assay was validated using a broad range of positive and negative hair loss samples. PICO-samples were cross-linked to buy generic propecia online pre-propecia concentration.

And bias correction for test performance was applied to represent most accurate estimates. In addition, future studies should establish whether epidemiologically dominant genetic changes in the spike protein of hair loss influence binding to spike S1 used in our and other assays.Seroprevalence was highest in adults aged 18–39 years, which is in line with the serosurvey among blood donors in the Netherlands, but contrary to the low incidence rate as reported in Dutch surveillance, caused by restrictive testing of risk groups and healthcare workers at the beginning of the epidemic, primarily identifying severe cases.3 19 The elevation in these younger adults may be explained by increased social contacts typical for this age group, in addition to specific social activities in February, such as skiing holidays in the Alps (from where the propecia disseminated quickly across Europe), or carnival festivities in the Netherlands (ie, multiple superspreading events primarily in the mid and Southern part, explaining local elevation in seroprevalence) buy generic propecia online. In correspondence with other nationwide studies8 9 and reports from the Dutch government,3 24 seroprevalence buy generic propecia online was lowest in children.

Although some rare events of paediatric inflammatory multisystem syndrome have been reported, this group seems to be at decreased risk for developing (severe) hair loss treatment in general, which may be explained by less severe possibly resulting in a limited humoral response.25 26 Further, significantly higher odds for seropositivity were seen in Orthodox-Reformed Protestants. This community buy generic propecia online lives socio-geographically clustered in the Netherlands, that is, work, school, leisure and church are intertwined heavily. As observed in other countries, particularly frequent attendance of church with close distance to others, including singing activities, might have fuelled the spread of hair loss within this community in the beginning of the epidemic.11 12 Whereas the comorbidities with possible increased risk of severe hair loss treatment were not associated with seropositivity in this study, immunosuppressants use did display higher odds (note.

We did not buy generic propecia online have information of specific drugs). Recent data indicate that immunosuppressive treatment is not associated with worse hair loss treatment outcomes,27 28 yet continued surveillance is warranted as these patients buy generic propecia online might be more prone to (future) , for instance due to a possible attenuated humoral immune response.29The majority of seropositive participants exhibited ≥1 symptom(s), mostly general and respiratory. A recent meta-analysis found a pooled asymptomatic proportion of 16%,5 hence the observed overall fraction in the present study (7%) might be a conservative estimate as the self-reported symptoms could have been due to other reasons or circulating pathogens along the recalled period (ie, 62% of the seronegative participants reported symptoms too).

The asymptomatic proportion buy generic propecia online might be different across ages5 and should be explored further along with elucidating the overall contribution of asymptomatic transmission via well-designed contact-tracing studies. Interestingly, clinical studies have observed anosmia/ageusia to be associated with hair loss , and this notion is supported here at a population-based level.30 In the propecia context, sudden onset of anosmia/ageusia seems to be a useful surveillance tool, which can contribute to early disease recognition and minimise transmission by rapid self-isolation.This study has some limitations. First, although half of the total municipalities in the Netherlands were included, some hair loss treatment buy generic propecia online hotspots might be missed due to the study design.

Second, our study population consisted of more Dutch (88%) than non-Dutch persons and relative more healthcare workers (20%) when compared to buy generic propecia online the general population (76% and 14%, respectively).17 Healthcare workers in the Netherlands do not seem to have had a higher likelihood of , and transmission seems to have taken place mostly in household settings.3 31 Although selectivity in response was minimised by weighting our study sample on a set of sociodemographic characters to match the Dutch population, seroprevalence might still be slightly influenced. Third, some potential determinants for seropositivity could have been missed as we might have been underpowered to detect small differences given the low prevalence in this phase, or because these questions had not been included in the questionnaire (as it was designed in the very beginning of the epidemic). Finally, at this stage the proportion of infected individuals that fail to show detectable seroconversion is unknown, potentially leading to underestimation of the percentage of infected buy generic propecia online persons.To conclude, we estimated that 2.8% of the Dutch inhabitants, that is, nearly half a million, were infected with hair loss amidst the first epidemic wave in the beginning of April 2020.

This is in striking contrast with the 30-fold lower number of reported cases (of approximately 15 000)3, and underlines the importance of seroepidemiological studies to estimate the true propecia size. The proportion of persons still susceptible to hair loss is high and IFR is substantial.4 Globally, nationwide seroepidemiological studies are urgently needed for better understanding of related risk factors, viral spread, and measures applied to mitigate dissemination.7 The prospective nature of our study will enable us to gain key insights on the duration and quality of antibody responses in infected persons, and hence possible protection of disease by antibodies.6 Serosurveys will thus play a major role in guiding future interventions, such as strategies for vaccination (of risk groups), since even when treatments buy generic propecia online become available, initial treatment availability will be limited.What is already known on this topicReported hair loss treatment cases worldwide are an underestimation of the true magnitude of the propecia as the scope of undetected cases remains largely unknown.Various symptoms and risk factors have been identified in patients seeking medical advice, however, these may not be representative for s in the general population.Seroepidemiological studies in outbreak settings have been performed, however, studies on a nationwide level covering all ages remain limited.What this study addsThis nationwide seroepidemiological study covering all ages reveals that 2.8% of the Dutch population had been infected with hair loss at the beginning of April 2020, that is, 30 times higher than the official cases reported, leaving a large proportion of the population still susceptible for .The highest seroprevalence was observed in young adults from 18 to 39 years of age and lowest in children aged 2 to 17 years, indicating marginal hair loss s among children in general.Persons taking immunosuppressants as well as those from the Orthodox-Reformed Protestant community had over four times higher odds of being seropositive compared to others.The extend of the spread of hair loss and the risk groups identified here, can inform monitoring strategies and guide future interventions internationally.AcknowledgmentsFirst of all, we gratefully acknowledge the participants of the PICO-study. Secondly, this study would not have been possible without the instrumental contribution of colleagues from the National Institute of Public Health and Environment (RIVM), Bilthoven, the Netherlands, more specially the department of Immunology of Infectious Diseases and treatments, regarding logistics and/or laboratory analyses (Marjan Bogaard-van Maurik, Annemarie Buisman, Pieter van Gageldonk, Hinke ten Hulscher-van Overbeek, Petra Jochemsen, Deborah Kleijne, Jessica Loch, Marjan Kuijer, Milou Ohm, Hella Pasmans, Lia de Rond, Debbie van Rooijen, Liza Tymchenko, Esther van Woudenbergh, and Mary-lene de Zeeuw-Brouwer), the Epidemiology and Surveillance department buy generic propecia online concerning logistics (Francoise van Heiningen, Alies van Lier, Jeanet Kemmeren, Joske Hoes, Maarten Immink, Marit Middeldorp, Christiaan Oostdijk, Ilse Schinkel-Gordijn, Yolanda van Weert, and Anneke Westerhof), methodological insights (Hendriek Boshuizen, Susan Hahné, Scott McDonald, Rianne van Gageldonk-Lafeber, Jan van de Kassteele, and Maarten Schipper) and manuscript reviewing (Susan van den Hof, and Don Klinkenberg), department of IT and Communication for help with the invitations (Luppo de Vries, Daphne Gijselaar, and Maaike Mathu), student interns for additional support (Stijn Andeweg for creating online supplemental figures 1A and 1B.

Janine Wolf, Natasha Kaagman, and Demi Wagenaar for logistics. And Lisette van Cooten for data entry buy generic propecia online of paper questionnaires), and Sidekick-IT, Breda, the Netherlands, regarding data flow (Tim de Hoog). This study was funded by the ministry of Health, Welfare and Sports (VWS), the Netherlands..

Propecia stop receding hairline

In 2003, severe acute respiratory syndrome (SARS) spread through 26 countries, infecting at least 8098 and propecia stop receding hairline causing at least 774 deaths (a case fatality rate of 9.6%). Middle East respiratory syndrome (MERS) by January 2020 caused 2519 cases and 866 deaths (a case fatality rate of 34%). SARS and MERS are hair losses and both are not as easily transmitted as hair loss treatment because they require close contact with those infected (or also with camels in the propecia stop receding hairline case of MERS), and infected humans tend not to transmit before they have symptoms. Transmission of both mostly occurred within healthcare settings and could be controlled by improving control in hospitals.In 2015, Bill Gates in a TED lecture warned that we were more at risk of a global propecia (he thought it would be influenza) than we were from nuclear war.hair loss treatment probably first entered the human population in China in November 2019 in Wuhan and was first identified as such in December 2019.

It spreads easily with a R0 (basic reproduction number) that represents the average number of people the average infected person would infect being between 1.5 and 3.5, depending on the surrounding circumstances. While a large proportion of s are asymptomatic, there is a propecia stop receding hairline significant mortality rate (about 3.4% worldwide). Survival rates are worse in the elderly, in men and in those with comorbidities. There are no suitable mammal models to study.Because there is a significant proportion of asymptomatic infectious people, monitoring of epidemics necessitates screening to determine (1) the proportion of the population that is actively infected and or (2) the total number of those who have been infected.

Both require screening propecia stop receding hairline. To gain significant data, then whole populations or representative samples have to be tested. In many circumstances, only those with high probability are tested.DNA polymerase techniques on throat swabs (notably real-time reverse transcription PCR) can identify the actively infected, but such tests will need to be repeated, especially in healthcare staff who are both at increased risk of and could provide an increased risk of to their contacts.Antibody tests in theory can reveal who has been infected. However, such tests may not provide 100% reliable results, including the fact that their sensitivity will vary propecia stop receding hairline according to how common the is.

If an is common, then a very sensitive test will identify all those infected and also a small number of false positives, but when the becomes less common, then the proportion of false positives will rise and a positive test could become less useful. Moreover, for how long propecia stop receding hairline would the antibody-person be immune?. Counting the number of hospital deaths attributed to hair loss treatment may be a guide to an epidemic, but deaths may be difficult to count in the community. In any case, changes in death numbers usually lag a few weeks behind the time of .Would a lower infecting dose cause the following illness to be less severe?.

Does the propecia need several extra doubling times to propecia stop receding hairline exert its effects such that in this gained time host responses will be in a better position to combat the in high-risk groups or in groups where medical care is minimal?. Could low-dose vaccination with hair loss treatment itself be useful?. Shakespeare’s Hamlet (not an epidemiologist) suggested, ‘Diseases desperate grown, By desperate appliance are relieved, Or not at all’.All the aforementioned are key questions, the answers to many of which are not known at the time of writing and, even if they were, the answers might change with the passage of time.Various countries have made various policy choicesAt the time of writing (April 2020), hair loss treatment has probably been in the human population for only about 6 months. In most countries, there are concerns about how the epidemic propecia stop receding hairline was initially handled, and it is possible to predict some damming retrospective judgements.

However, we should concentrate on where we are, not where we might have been. Recriminations should wait.Many important decisions have to be made based on incomplete information. Most hair loss treatment decisions have to be made on propecia stop receding hairline speculations (guesswork and wishful thinking), on hypotheses (propositions made as a basis for reasoning, without an assumption of its truth) or on theories (suppositions or systems of ideas explaining something based on general principles). All hair loss treatment decisions have to be made at the time ‘We have to start from where we are’ guided by the experiences of other countries that are ahead of us in the epidemic.propecias usually reveal inequalities and the poor, or those in unstable employment or in crowded accommodation, or with underlying health issues, or where healthcare is less affordable, or are in the less well educated will suffer the most.

They will also propecia stop receding hairline comply less with restrictions. Ideologies, power blocks, leaders, social cohesion beliefs, the relevance of centralised or regional decision making, the abilities of popularism (political doctrines chosen to appeal to a majority of the electorate), welfare states (usually capitalist nations that recognise that food, shelter, education and medicine are basic rights to be ensured by government actions) and authoritarianism are all being stress tested by hair loss treatment. In the future, it will be interesting to judge how these societal systems played out when confronting the conflicting requirement to reconcile conflicting priorities of health and economic factors that involve conflicts between responding and planning for deaths (‘How should we cope with these’) and actually planning deaths. €˜We will have to accept that we will cause deaths propecia stop receding hairline whatever policy we adopt’.There is only one initial response to hair loss treatment that reduces rates and death rates.

Dramatic quarantine ‘total lockdown’ measures. Some countries, including China, South Korea, Hong Kong, Taiwan and Singapore, hit the epidemic hard and early with lockdown quarantine to reduce the epidemic. Such countries perhaps tend towards propecia stop receding hairline acceptance of authoritarianism and their citizens less rebellious than in other countries. New Zealand did similarly.

I could not possibly comment on the US responses. However, on what criteria and at what propecia stop receding hairline speed should liberalisation of quarantine measure occur to avoid re-emergences?. There are in theory three final paths out of the hair loss treatment crisis:First, a treatment. Even a perfect treatment would be difficult propecia stop receding hairline to evaluate with changing risks in the community.

How protective would a treatment be and for how long would it be effective?. Second, the identification of a treatment, either preventative or curative, so that the disease becomes a considerably less worrisome prospect even for those with comorbidities.Third, herd immunity, when enough of the population has acquired and survived hair loss treatment and thus developed immunity with the persisting at a low level. Currently the only, not entirely definitive, way of estimating this is by measuring antibodies such that propecia stop receding hairline there would not be enough opportunities for disease transmission for the propecia to continue circulating through populations with an Ro of less than 1, but the risk would not disappear entirely. Moreover, how should immunity be monitored if antibody testing may not reflect herd immunity?.

Allowing herd immunity to develop initially would result in a huge spike in hospitalisations and deaths that could overwhelm most healthcare services, and that is why flattening such spikes by quarantine was indicated. With flattening, there propecia stop receding hairline would still be illness and deaths but at a controlled slower rate and hopefully also smaller numbers, such that healthcare services could cope.There is a lot of opinion and numerous contributions by official and unofficial organisations and individuals who think their “single issue advice” should be followed. No one individual has the expertise required for management of all the complexities. Committees are required, including microbiologists, infectious diseases doctors, public health doctors, epidemiologists, hospital and general practice representatives, epidemic mathematical modellers and economic advisers.

Politicians have the responsibility to deliver decisions propecia stop receding hairline when, especially when, information is imperfect. How many people would be infected if we did nothing?. What would the epidemic curve look like propecia stop receding hairline in various situations?. What proportion of those infected would infect others in various situations?.

How many of which population groups would require what extra healthcare services in various situations?. What propecia stop receding hairline would be the effect of various measures at various times?. What economic impacts might there be when these in themselves affect mortality rates?. I predict that hair loss treatment will cause two significant changes in political thought.

First, it has to be realised that globalisation of such epidemics, propecia stop receding hairline and there will be more to come, will demand an integrated globalised response. Second, in 1987, Margaret Thatcher, the UK Prime Minister, said that ‘There is no such thing as society… the quality of our lives will depend on how much each of us is prepared to take responsibility for ourselves and each of us prepared to turn round and help by our own efforts those who are unfortunate’. The current UK Prime Minister in March 2020 presented a new synthesis, ‘There really is such a thing as society’.Finally, it is important to realise that everyone, no matter where they are, for better or worse, has to rely on their existing rulers or governments..

In 2003, severe acute respiratory syndrome (SARS) spread through 26 countries, infecting at least 8098 and causing at least 774 deaths (a propecia generic price case fatality rate buy generic propecia online of 9.6%). Middle East respiratory syndrome (MERS) by January 2020 caused 2519 cases and 866 deaths (a case fatality rate of 34%). SARS and MERS are hair losses and both are not as easily transmitted as hair loss treatment because they require close contact with those infected (or also with camels in buy generic propecia online the case of MERS), and infected humans tend not to transmit before they have symptoms. Transmission of both mostly occurred within healthcare settings and could be controlled by improving control in hospitals.In 2015, Bill Gates in a TED lecture warned that we were more at risk of a global propecia (he thought it would be influenza) than we were from nuclear war.hair loss treatment probably first entered the human population in China in November 2019 in Wuhan and was first identified as such in December 2019.

It spreads easily with a R0 (basic reproduction number) that represents the average number of people the average infected person would infect being between 1.5 and 3.5, depending on the surrounding circumstances. While a large proportion buy generic propecia online of s are asymptomatic, there is a significant mortality rate (about 3.4% worldwide). Survival rates are worse in the elderly, in men and in those with comorbidities. There are no suitable mammal models to study.Because there is a significant proportion of asymptomatic infectious people, monitoring of epidemics necessitates screening to determine (1) the proportion of the population that is actively infected and or (2) the total number of those who have been infected.

Both require buy generic propecia online screening. To gain significant data, then whole populations or representative samples have to be tested. In many circumstances, only those with high probability are tested.DNA polymerase techniques on throat swabs (notably real-time reverse transcription PCR) can identify the actively infected, but such tests will need to be repeated, especially in healthcare staff who are both at increased risk of and could provide an increased risk of to their contacts.Antibody tests in theory can reveal who has been infected. However, such tests may not provide 100% reliable results, buy generic propecia online including the fact that their sensitivity will vary according to how common the is.

If an is common, then a very sensitive test will identify all those infected and also a small number of false positives, but when the becomes less common, then the proportion of false positives will rise and a positive test could become less useful. Moreover, for buy generic propecia online how long would the antibody-person be immune?. Counting the number of hospital deaths attributed to hair loss treatment may be a guide to an epidemic, but deaths may be difficult to count in the community. In any case, changes in death numbers usually lag a few weeks behind the time of .Would a lower infecting dose cause the following illness to be less severe?.

Does the propecia need several extra doubling times to exert its effects such that in this gained time host responses will be in a better position to combat buy generic propecia online the in high-risk groups or in groups where medical care is minimal?. Could low-dose vaccination with hair loss treatment itself be useful?. Shakespeare’s Hamlet (not an epidemiologist) suggested, ‘Diseases desperate grown, By desperate appliance are relieved, Or not at all’.All the aforementioned are key questions, the answers to many of which are not known at the time of writing and, even if they were, the answers might change with the passage of time.Various countries have made various policy choicesAt the time of writing (April 2020), hair loss treatment has probably been in the human population for only about 6 months. In most countries, there are concerns about how the epidemic was initially handled, and it is possible to predict some damming retrospective buy generic propecia online judgements.

However, we should concentrate on where we are, not where we might have been. Recriminations should wait.Many important decisions have to be made based on incomplete information. Most hair loss treatment decisions have to be made on speculations (guesswork and wishful thinking), on hypotheses (propositions made as a basis for reasoning, without an assumption of buy generic propecia online its truth) or on theories (suppositions or systems of ideas explaining something based on general principles). All hair loss treatment decisions have to be made at the time ‘We have to start from where we are’ guided by the experiences of other countries that are ahead of us in the epidemic.propecias usually reveal inequalities and the poor, or those in unstable employment or in crowded accommodation, or with underlying health issues, or where healthcare is less affordable, or are in the less well educated will suffer the most.

They will also comply less with restrictions buy generic propecia online. Ideologies, power blocks, leaders, social cohesion beliefs, the relevance of centralised or regional decision making, the abilities of popularism (political doctrines chosen to appeal to a majority of the electorate), welfare states (usually capitalist nations that recognise that food, shelter, education and medicine are basic rights to be ensured by government actions) and authoritarianism are all being stress tested by hair loss treatment. In the future, it will be interesting to judge how these societal systems played out when confronting the conflicting requirement to reconcile conflicting priorities of health and economic factors that involve conflicts between responding and planning for deaths (‘How should we cope with these’) and actually planning deaths. €˜We will have to accept that we will buy generic propecia online cause deaths whatever policy we adopt’.There is only one initial response to more tips here hair loss treatment that reduces rates and death rates.

Dramatic quarantine ‘total lockdown’ measures. Some countries, including China, South Korea, Hong Kong, Taiwan and Singapore, hit the epidemic hard and early with lockdown quarantine to reduce the epidemic. Such countries perhaps tend towards acceptance of authoritarianism and their citizens less rebellious buy generic propecia online than in other countries. New Zealand did similarly.

I could not possibly comment on the US responses. However, on buy generic propecia online what criteria and at what speed should liberalisation of quarantine measure occur to avoid re-emergences?. There are in theory three final paths out of the hair loss treatment crisis:First, a treatment. Even a buy generic propecia online perfect treatment would be difficult to evaluate with changing risks in the community.

How protective would a treatment be and for how long would it be effective?. Second, the identification of a treatment, either preventative or curative, so that the disease becomes a considerably less worrisome prospect even for those with comorbidities.Third, herd immunity, when enough of the population has acquired and survived hair loss treatment and thus developed immunity with the persisting at a low level. Currently the only, not entirely definitive, way of estimating this is by measuring antibodies such that there would not be enough opportunities for disease transmission for the propecia to continue circulating through populations buy generic propecia online with an Ro of less than 1, but the risk would not disappear entirely. Moreover, how should immunity be monitored if antibody testing may not reflect herd immunity?.

Allowing herd immunity to develop initially would result in a huge spike in hospitalisations and deaths that could overwhelm most healthcare services, and that is why flattening such spikes by quarantine was indicated. With flattening, there would still be illness and deaths but at a controlled slower rate and hopefully also smaller numbers, such that healthcare services could cope.There is a lot of opinion and numerous contributions by official and unofficial organisations and individuals who buy generic propecia online think their “single issue advice” should be followed. No one individual has the expertise required for management of all the complexities. Committees are required, including microbiologists, infectious diseases doctors, public health doctors, epidemiologists, hospital and general practice representatives, epidemic mathematical modellers and economic advisers.

Politicians have the responsibility to deliver decisions when, especially when, information is buy generic propecia online imperfect. How many people would be infected if we did nothing?. What would the epidemic curve buy generic propecia online look like in various situations?. What proportion of those infected would infect others in various situations?.

How many of which population groups would require what extra healthcare services in various situations?. What would be the effect of buy generic propecia online various measures at various times?. What economic impacts might there be when these in themselves affect mortality rates?. I predict that hair loss treatment will cause two significant changes in political thought.

First, it has to be realised that globalisation of such epidemics, and there will be more to come, will demand buy generic propecia online an integrated globalised response. Second, in 1987, Margaret Thatcher, the UK Prime Minister, said that ‘There is no such thing as society… the quality of our lives will depend on how much each of us is prepared to take responsibility for ourselves and each of us prepared to turn round and help by our own efforts those who are unfortunate’. The current UK Prime Minister in March 2020 presented a new synthesis, ‘There really is such a thing as society’.Finally, it is important to realise that everyone, no matter where they are, for better or worse, has to rely on their existing rulers or governments..

What kind of doctor prescribes propecia

Trial Population Table https://www.feuerwehr-oespel-kley.de/cialis-street-price/ 1 what kind of doctor prescribes propecia. Table 1 what kind of doctor prescribes propecia. Characteristics of the Participants in the mRNA-1273 Trial at Enrollment. The 45 enrolled participants received what kind of doctor prescribes propecia their first vaccination between March 16 and April 14, 2020 (Fig.

S1). Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in what kind of doctor prescribes propecia the 250-μg group) who missed the second vaccination window owing to isolation for suspected hair loss treatment while the test results, ultimately negative, were pending. All continued to attend scheduled what kind of doctor prescribes propecia trial visits. The demographic characteristics of participants at enrollment are provided in Table 1.

treatment Safety No serious adverse events were noted, and no prespecified trial halting rules what kind of doctor prescribes propecia were met. As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination. Figure 1 what kind of doctor prescribes propecia. Figure 1.

Systemic and Local Adverse Events what kind of doctor prescribes propecia. The severity what kind of doctor prescribes propecia of solicited adverse events was graded as mild, moderate, or severe (see Table S1).After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group. All were mild or moderate in severity (Figure 1 and Table S2). Solicited systemic adverse events were more common after the second vaccination and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in what kind of doctor prescribes propecia the 250-μg group, with 3 of those participants (21%) reporting one or more severe events.

None of the participants had fever after the first vaccination. After the second vaccination, no participants in the 25-μg what kind of doctor prescribes propecia group, 6 (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever. One of what kind of doctor prescribes propecia the events (maximum temperature, 39.6°C) in the 250-μg group was graded severe. (Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.) Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common.

Across both vaccinations, solicited systemic and what kind of doctor prescribes propecia local adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3). hair loss Binding Antibody what kind of doctor prescribes propecia Responses Table 2. Table 2.

Geometric Mean Humoral Immunogenicity Assay Responses to mRNA-1273 in Participants and what kind of doctor prescribes propecia in Convalescent Serum Specimens. Figure 2 what kind of doctor prescribes propecia. Figure 2. hair loss Antibody what kind of doctor prescribes propecia and Neutralization Responses.

Shown are geometric mean reciprocal end-point enzyme-linked immunosorbent assay (ELISA) IgG titers to S-2P (Panel A) and receptor-binding domain (Panel B), PsVNA ID50 responses (Panel C), and live propecia PRNT80 responses (Panel D). In Panel what kind of doctor prescribes propecia A and Panel B, boxes and horizontal bars denote interquartile range (IQR) and median area under the curve (AUC), respectively. Whisker endpoints are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The convalescent what kind of doctor prescribes propecia serum panel includes specimens from 41 participants.

Red dots what kind of doctor prescribes propecia indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent serum panel. In Panel C, boxes and what kind of doctor prescribes propecia horizontal bars denote IQR and median ID50, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR.

In the convalescent serum panel, red dots what kind of doctor prescribes propecia indicate the 3 specimens that were also tested in the PRNT assay. The other 38 specimens were used to calculate summary statistics for the box plot what kind of doctor prescribes propecia in the convalescent panel. In Panel D, boxes and horizontal bars denote IQR and median PRNT80, respectively. Whisker end what kind of doctor prescribes propecia points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR.

The three convalescent serum specimens were also tested in ELISA and PsVNA assays. Because of the time-intensive nature of the what kind of doctor prescribes propecia PRNT assay, for this preliminary report, PRNT results were available only for the 25-μg and 100-μg dose groups.Binding antibody IgG geometric mean titers (GMTs) to S-2P increased rapidly after the first vaccination, with seroconversion in all participants by day 15 (Table 2 and Figure 2A). Dose-dependent responses to the first and second vaccinations were evident. Receptor-binding domain–specific antibody responses were similar in pattern and magnitude what kind of doctor prescribes propecia (Figure 2B).

For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose what kind of doctor prescribes propecia groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens. The S-2P ELISA GMTs at day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] in the 25-μg group, 782,719 [95% CI, 619,310 to 989,244] in the 100-μg group, and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250-μg group) exceeded that in the convalescent serum specimens (142,140 [95% CI, 81,543 to 247,768]). hair loss Neutralization Responses No what kind of doctor prescribes propecia participant had detectable PsVNA responses before vaccination. After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50].

Figure 2C, what kind of doctor prescribes propecia Fig. S8, and Table 2. 80% inhibitory dilution what kind of doctor prescribes propecia [ID80]. Fig.

S2 and Table S6). However, after the second vaccination, PsVNA responses were identified in serum samples from all participants. The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43. The higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43).

These responses were similar to values in the upper half of the distribution of values for convalescent serum specimens. Before vaccination, no participant had detectable 80% live-propecia neutralization at the highest serum concentration tested (1:8 dilution) in the PRNT assay. At day 43, wild-type propecia–neutralizing activity capable of reducing hair loss infectivity by 80% or more (PRNT80) was detected in all participants, with geometric mean PRNT80 responses of 339.7 (95% CI, 184.0 to 627.1) in the 25-μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100-μg group (Figure 2D). Neutralizing PRNT80 average responses were generally at or above the values of the three convalescent serum specimens tested in this assay.

Good agreement was noted within and between the values from binding assays for S-2P and receptor-binding domain and neutralizing activity measured by PsVNA and PRNT (Figs. S3 through S7), which provides orthogonal support for each assay in characterizing the humoral response induced by mRNA-1273. hair loss T-Cell Responses The 25-μg and 100-μg doses elicited CD4 T-cell responses (Figs. S9 and S10) that on stimulation by S-specific peptide pools were strongly biased toward expression of Th1 cytokines (tumor necrosis factor α >.

Interleukin 2 >. Interferon γ), with minimal type 2 helper T-cell (Th2) cytokine expression (interleukin 4 and interleukin 13). CD8 T-cell responses to S-2P were detected at low levels after the second vaccination in the 100-μg dose group (Fig. S11).To the Editor.

Rapid and accurate diagnostic tests are essential for controlling the ongoing hair loss treatment propecia. Although the current standard involves testing of nasopharyngeal swab specimens by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) to detect hair loss, saliva specimens may be an alternative diagnostic sample.1-4 Rigorous evaluation is needed to determine how saliva specimens compare with nasopharyngeal swab specimens with respect to sensitivity in detection of hair loss during the course of . A total of 70 inpatients with hair loss treatment provided written informed consent to participate in our study (see the Methods section in Supplementary Appendix 1, available with the full text of this letter at NEJM.org). After hair loss treatment was confirmed with a positive nasopharyngeal swab specimen at hospital admission, we obtained additional samples from the patients during hospitalization.

We tested saliva specimens collected by the patients themselves and nasopharyngeal swabs collected from the patients at the same time point by health care workers. Figure 1. Figure 1. hair loss RNA Titers in Saliva Specimens and Nasopharyngeal Swab Specimens.

Samples were obtained from 70 hospital inpatients who had a diagnosis of hair loss treatment. Panel A shows hair loss RNA titers in the first available nasopharyngeal and saliva samples. The lines indicate samples from the same patient. Results were compared with the use of a Wilcoxon signed-rank test (P<0.001).

Panel B shows percentages of positivity for hair loss in tests of the first matched nasopharyngeal and saliva samples at 1 to 5 days, 6 to 10 days, and 11 or more days (maximum, 53 days) after the diagnosis of hair loss treatment. Panel C shows longitudinal hair loss RNA copies per milliliter in 97 saliva samples, according to days since symptom onset. Each circle represents a separate sample. Dashed lines indicate additional samples from the same patient.

The red line indicates a negative saliva sample that was followed by a positive sample at the next collection of a specimen. Panel D shows longitudinal hair loss RNA copies per milliliter in 97 nasopharyngeal swab specimens, according to days since symptom onset. The red lines indicate negative nasopharyngeal swab specimens there were followed by a positive swab at the next collection of a specimen. The gray area in Panels C and D indicates samples that were below the lower limit of detection of 5610 propecia RNA copies per milliliter of sample, which is at cycle threshold 38 of our quantitative reverse-transcriptase polymerase chain reaction assay targeting the hair loss N1 sequence recommended by the Centers for Disease Control and Prevention.

To analyze these data, we used a linear mixed-effects regression model (see Supplementary Appendix 1) that accounts for the correlation between samples collected from the same person at a single time point (i.e., multivariate response) and the correlation between samples collected across time from the same patient (i.e., repeated measures). All the data used to generate this figure, including the raw cycle thresholds, are provided in Supplementary Data 1 in Supplementary Appendix 2.Using primer sequences from the Centers for Disease Control and Prevention, we detected more hair loss RNA copies in the saliva specimens (mean log copies per milliliter, 5.58. 95% confidence interval [CI], 5.09 to 6.07) than in the nasopharyngeal swab specimens (mean log copies per milliliter, 4.93. 95% CI, 4.53 to 5.33) (Figure 1A, and Fig.

S1 in Supplementary Appendix 1). In addition, a higher percentage of saliva samples than nasopharyngeal swab samples were positive up to 10 days after the hair loss treatment diagnosis (Figure 1B). At 1 to 5 days after diagnosis, 81% (95% CI, 71 to 96) of the saliva samples were positive, as compared with 71% (95% CI, 67 to 94) of the nasopharyngeal swab specimens. These findings suggest that saliva specimens and nasopharyngeal swab specimens have at least similar sensitivity in the detection of hair loss during the course of hospitalization.

Because the results of testing of nasopharyngeal swab specimens to detect hair loss may vary with repeated sampling in individual patients,5 we evaluated viral detection in matched samples over time. The level of hair loss RNA decreased after symptom onset in both saliva specimens (estimated slope, −0.11. 95% credible interval, −0.15 to −0.06) (Figure 1C) and nasopharyngeal swab specimens (estimated slope, −0.09. 95% credible interval, −0.13 to −0.05) (Figure 1D).

In three instances, a negative nasopharyngeal swab specimen was followed by a positive swab at the next collection of a specimen (Figure 1D). This phenomenon occurred only once with the saliva specimens (Figure 1C). During the clinical course, we observed less variation in levels of hair loss RNA in the saliva specimens (standard deviation, 0.98 propecia RNA copies per milliliter. 95% credible interval, 0.08 to 1.98) than in the nasopharyngeal swab specimens (standard deviation, 2.01 propecia RNA copies per milliliter.

95% credible interval, 1.29 to 2.70) (see Supplementary Appendix 1). Recent studies have shown that hair loss can be detected in the saliva of asymptomatic persons and outpatients.1-3 We therefore screened 495 asymptomatic health care workers who provided written informed consent to participate in our prospective study, and we used RT-qPCR to test both saliva and nasopharyngeal samples obtained from these persons. We detected hair loss RNA in saliva specimens obtained from 13 persons who did not report any symptoms at or before the time of sample collection. Of these 13 health care workers, 9 had collected matched nasopharyngeal swab specimens by themselves on the same day, and 7 of these specimens tested negative (Fig.

S2). The diagnosis in the 13 health care workers with positive saliva specimens was later confirmed in diagnostic testing of additional nasopharyngeal samples by a CLIA (Clinical Laboratory Improvement Amendments of 1988)–certified laboratory. Variation in nasopharyngeal sampling may be an explanation for false negative results, so monitoring an internal control for proper sample collection may provide an alternative evaluation technique. In specimens collected from inpatients by health care workers, we found greater variation in human RNase P cycle threshold (Ct) values in nasopharyngeal swab specimens (standard deviation, 2.89 Ct.

95% CI, 26.53 to 27.69) than in saliva specimens (standard deviation, 2.49 Ct. 95% CI, 23.35 to 24.35). When health care workers collected their own specimens, we also found greater variation in RNase P Ct values in nasopharyngeal swab specimens (standard deviation, 2.26 Ct. 95% CI, 28.39 to 28.56) than in saliva specimens (standard deviation , 1.65 Ct.

95% CI, 24.14 to 24.26) (Fig. S3). Collection of saliva samples by patients themselves negates the need for direct interaction between health care workers and patients. This interaction is a source of major testing bottlenecks and presents a risk of nosocomial .

Collection of saliva samples by patients themselves also alleviates demands for supplies of swabs and personal protective equipment. Given the growing need for testing, our findings provide support for the potential of saliva specimens in the diagnosis of hair loss . Anne L. Wyllie, Ph.D.Yale School of Public Health, New Haven, CT [email protected]John Fournier, M.D.Yale School of Medicine, New Haven, CTArnau Casanovas-Massana, Ph.D.Yale School of Public Health, New Haven, CTMelissa Campbell, M.D.Maria Tokuyama, Ph.D.Pavithra Vijayakumar, B.A.Yale School of Medicine, New Haven, CTJoshua L.

Warren, Ph.D.Yale School of Public Health, New Haven, CTBertie Geng, M.D.Yale School of Medicine, New Haven, CTM. Catherine Muenker, M.S.Adam J. Moore, M.P.H.Chantal B.F. Vogels, Ph.D.Mary E.

Petrone, B.S.Isabel M. Ott, B.S.Yale School of Public Health, New Haven, CTPeiwen Lu, Ph.D.Arvind Venkataraman, B.S.Alice Lu-Culligan, B.S.Jonathan Klein, B.S.Yale School of Medicine, New Haven, CTRebecca Earnest, M.P.H.Yale School of Public Health, New Haven, CTMichael Simonov, M.D.Rupak Datta, M.D., Ph.D.Ryan Handoko, M.D.Nida Naushad, B.S.Lorenzo R. Sewanan, M.Phil.Jordan Valdez, B.S.Yale School of Medicine, New Haven, CTElizabeth B. White, A.B.Sarah Lapidus, M.S.Chaney C.

Kalinich, M.P.H.Yale School of Public Health, New Haven, CTXiaodong Jiang, M.D., Ph.D.Daniel J. Kim, A.B.Eriko Kudo, Ph.D.Melissa Linehan, M.S.Tianyang Mao, B.S.Miyu Moriyama, Ph.D.Ji E. Oh, M.D., Ph.D.Annsea Park, B.A.Julio Silva, B.S.Eric Song, M.S.Takehiro Takahashi, M.D., Ph.D.Manabu Taura, Ph.D.Orr-El Weizman, B.A.Patrick Wong, M.S.Yexin Yang, B.S.Santos Bermejo, B.S.Yale School of Medicine, New Haven, CTCamila D. Odio, M.D.Yale New Haven Health, New Haven, CTSaad B.

Omer, M.B., B.S., Ph.D.Yale Institute for Global Health, New Haven, CTCharles S. Dela Cruz, M.D., Ph.D.Shelli Farhadian, M.D., Ph.D.Richard A. Martinello, M.D.Akiko Iwasaki, Ph.D.Yale School of Medicine, New Haven, CTNathan D. Grubaugh, Ph.D.Albert I.

Ko, M.D.Yale School of Public Health, New Haven, CT [email protected], [email protected] Supported by the Huffman Family Donor Advised Fund, a Fast Grant from Emergent Ventures at the Mercatus Center at George Mason University, the Yale Institute for Global Health, the Yale School of Medicine, a grant (U19 AI08992, to Dr. Ko) from the National Institute of Allergy and Infectious Diseases, the Beatrice Kleinberg Neuwirth Fund, and a grant (Rubicon 019.181EN.004, to Dr. Vogel) from the Dutch Research Council (NWO). Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on August 28, 2020, at NEJM.org. Drs. Grubaugh and Ko contributed equally to this letter. 5 References1.

Kojima N, Turner F, Slepnev V, et al. Self-collected oral fluid and nasal swabs demonstrate comparable sensitivity to clinician collected nasopharyngeal swabs for hair loss treatment detection. April 15, 2020 (https://www.medrxiv.org/content/10.1101/2020.04.11.20062372v1). Preprint.Google Scholar2.

Williams E, Bond K, Zhang B, Putland M, Williamson DA. Saliva as a non-invasive specimen for detection of hair loss. J Clin Microbiol 2020;58(8):e00776-20-e00776-20.3. Pasomsub E, Watcharananan SP, Boonyawat K, et al.

Saliva sample as a non-invasive specimen for the diagnosis of hair loss disease 2019. A cross-sectional study. Clin Microbiol Infect 2020 May 15 (Epub ahead of print).4. Vogels CBF, Brackney D, Wang J, et al.

SalivaDirect. Simple and sensitive molecular diagnostic test for hair loss surveillance. August 4, 2020 (https://www.medrxiv.org/content/10.1101/2020.08.03.20167791v1). Preprint.Google Scholar5.

Zou L, Ruan F, Huang M, et al. hair loss viral load in upper respiratory specimens of infected patients. N Engl J Med 2020;382:1177-1179.Announced on May 15, Operation Warp Speed (OWS) — a partnership of the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector — aims to accelerate control of the hair loss treatment propecia by advancing development, manufacturing, and distribution of treatments, therapeutics, and diagnostics. OWS is providing support to promising candidates and enabling the expeditious, parallel execution of the necessary steps toward approval or authorization of safe products by the Food and Drug Administration (FDA).The partnership grew out of an acknowledged need to fundamentally restructure the way the U.S.

Government typically supports product development and treatment distribution. The initiative was premised on setting a “stretch goal” — one that initially seemed impossible but that is becoming increasingly achievable.The concept of an integrated structure for hair loss treatment countermeasure research and development across the U.S. Government was based on experience with Zika and the Zika Leadership Group led by the National Institutes of Health (NIH) and the assistant secretary for preparedness and response (ASPR). One of us (M.S.) serves as OWS chief advisor.

We are drawing on expertise from the NIH, ASPR, the Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority (BARDA), and the DOD, including the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and the Defense Advanced Research Projects Agency. OWS has engaged experts in all critical aspects of medical countermeasure research, development, manufacturing, and distribution to work in close coordination.The initiative set ambitious objectives. To deliver tens of millions of doses of a hair loss treatment — with demonstrated safety and efficacy, and approved or authorized by the FDA for use in the U.S. Population — beginning at the end of 2020 and to have as many as 300 million doses of such treatments available and deployed by mid-2021.

The pace and scope of such a treatment effort are unprecedented. The 2014 West African Ebola propecia epidemic spurred rapid treatment development, but though preclinical data existed before the outbreak, a period of 12 months was required to progress from phase 1 first-in-human trials to phase 3 efficacy trials. OWS aims to compress this time frame even further. hair loss treatment development began in January, phase 1 clinical studies in March, and the first phase 3 trials in July.

Our objectives are based on advances in treatment platform technology, improved understanding of safe and efficacious treatment design, and similarities between the SARS-CoV-1 and hair loss disease mechanisms.OWS’s role is to enable, accelerate, harmonize, and advise the companies developing the selected treatments. The companies will execute the clinical or process development and manufacturing plans, while OWS leverages the full capacity of the U.S. Government to ensure that no technical, logistic, or financial hurdles hinder treatment development or deployment.OWS selected treatment candidates on the basis of four criteria. We required candidates to have robust preclinical data or early-stage clinical trial data supporting their potential for clinical safety and efficacy.

Candidates had to have the potential, with our acceleration support, to enter large phase 3 field efficacy trials this summer or fall (July to November 2020) and, assuming continued active transmission of the propecia, to deliver efficacy outcomes by the end of 2020 or the first half of 2021. Candidates had to be based on treatment-platform technologies permitting fast and effective manufacturing, and their developers had to demonstrate the industrial process scalability, yields, and consistency necessary to reliably produce more than 100 million doses by mid-2021. Finally, candidates had to use one of four treatment-platform technologies that we believe are the most likely to yield a safe and effective treatment against hair loss treatment. The mRNA platform, the replication-defective live-vector platform, the recombinant-subunit-adjuvanted protein platform, or the attenuated replicating live-vector platform.OWS’s strategy relies on a few key principles.

First, we sought to build a diverse project portfolio that includes two treatment candidates based on each of the four platform technologies. Such diversification mitigates the risk of failure due to safety, efficacy, industrial manufacturability, or scheduling factors and may permit selection of the best treatment platform for each subpopulation at risk for contracting or transmitting hair loss treatment, including older adults, frontline and essential workers, young adults, and pediatric populations. In addition, advancing eight treatments in parallel will increase the chances of delivering 300 million doses in the first half of 2021.Second, we must accelerate treatment program development without compromising safety, efficacy, or product quality. Clinical development, process development, and manufacturing scale-up can be substantially accelerated by running all streams, fully resourced, in parallel.

Doing so requires taking on substantial financial risk, as compared with the conventional sequential development approach. OWS will maximize the size of phase 3 trials (30,000 to 50,000 participants each) and optimize trial-site location by consulting daily epidemiologic and disease-forecasting models to ensure the fastest path to an efficacy readout. Such large trials also increase the safety data set for each candidate treatment.With heavy up-front investment, companies can conduct clinical operations and site preparation for these phase 3 efficacy trials even as they file their Investigational New Drug application (IND) for their phase 1 studies, thereby ensuring immediate initiation of phase 3 when they get a green light from the FDA. To permit appropriate comparisons among the treatment candidates and to optimize treatment utilization after approval by the FDA, the phase 3 trial end points and assay readouts have been harmonized through a collaborative effort involving the National Institute of Allergy and Infectious Diseases (NIAID), the hair loss Prevention Network, OWS, and the sponsor companies.Finally, OWS is supporting the companies financially and technically to commence process development and scale up manufacturing while their treatments are in preclinical or very early clinical stages.

To ensure that industrial processes are set, running, and validated for FDA inspection when phase 3 trials end, OWS is also supporting facility building or refurbishing, equipment fitting, staff hiring and training, raw-material sourcing, technology transfer and validation, bulk product processing into vials, and acquisition of ample vials, syringes, and needles for each treatment candidate. We aim to have stockpiled, at OWS’s expense, a few tens of millions of treatment doses that could be swiftly deployed once FDA approval is obtained.This strategy aims to accelerate treatment development without curtailing the critical steps required by sound science and regulatory standards. The FDA recently reissued guidance and standards that will be used to assess each treatment for a Biologics License Application (BLA). Alternatively, the agency could decide to issue an Emergency Use Authorization to permit treatment administration before all BLA procedures are completed.Of the eight treatments in OWS’s portfolio, six have been announced and partnerships executed with the companies.

Moderna and Pfizer/BioNTech (both mRNA), AstraZeneca and Janssen (both replication-defective live-vector), and Novavax and Sanofi/GSK (both recombinant-subunit-adjuvanted protein). These candidates cover three of the four platform technologies and are currently in clinical trials. The remaining two candidates will enter trials soon.Moderna developed its RNA treatment in collaboration with the NIAID, began its phase 1 trial in March, recently published encouraging safety and immunogenicity data,1 and entered phase 3 on July 27. Pfizer and BioNTech’s RNA treatment also produced encouraging phase 1 results2 and started its phase 3 trial on July 27.

The ChAdOx replication-defective live-vector treatment developed by AstraZeneca and Oxford University is in phase 3 trials in the United Kingdom, Brazil, and South Africa, and it should enter U.S. Phase 3 trials in August.3 The Janssen Ad26 hair loss treatment replication-defective live-vector treatment has demonstrated excellent protection in nonhuman primate models and began its U.S. Phase 1 trial on July 27. It should be in phase 3 trials in mid-September.

Novavax completed a phase 1 trial of its recombinant-subunit-adjuvanted protein treatment in Australia and should enter phase 3 trials in the United States by the end of September.4 Sanofi/GSK is completing preclinical development steps and plans to commence a phase 1 trial in early September and to be well into phase 3 by year’s end.5On the process-development front, the RNA treatments are already being manufactured at scale. The other candidates are well advanced in their scale-up development, and manufacturing sites are being refurbished.While development and manufacturing proceed, the HHS–DOD partnership is laying the groundwork for treatment distribution, subpopulation prioritization, financing, and logistic support. We are working with bioethicists and experts from the NIH, the CDC, BARDA, and the Centers for Medicare and Medicaid Services to address these critical issues. We will receive recommendations from the CDC Advisory Committee on Immunization Practices, and we are working to ensure that the most vulnerable and at-risk persons will receive treatment doses once they are ready.

Prioritization will also depend on the relative performance of each treatment and its suitability for particular populations. Because some technologies have limited previous data on safety in humans, the long-term safety of these treatments will be carefully assessed using pharmacovigilance surveillance strategies.No scientific enterprise could guarantee success by January 2021, but the strategic decisions and choices we’ve made, the support the government has provided, and the accomplishments to date make us optimistic that we will succeed in this unprecedented endeavor.Patients Figure 1. Figure 1. Enrollment and Randomization.

Of the 1107 patients who were assessed for eligibility, 1063 underwent randomization. 541 were assigned to the remdesivir group and 522 to the placebo group (Figure 1). Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned. Forty-nine patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death (36 patients) or because the patient withdrew consent (13).

Of those assigned to receive placebo, 518 patients (99.2%) received placebo as assigned. Fifty-three patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death (36 patients), because the patient withdrew consent (15), or because the patient was found to be ineligible for trial enrollment (2). As of April 28, 2020, a total of 391 patients in the remdesivir group and 340 in the placebo group had completed the trial through day 29, recovered, or died. Eight patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29.

There were 132 patients in the remdesivir group and 169 in the placebo group who had not recovered and had not completed the day 29 follow-up visit. The analysis population included 1059 patients for whom we have at least some postbaseline data available (538 in the remdesivir group and 521 in the placebo group). Four of the 1063 patients were not included in the primary analysis because no postbaseline data were available at the time of the database freeze. Table 1.

Table 1. Demographic and Clinical Characteristics at Baseline. The mean age of patients was 58.9 years, and 64.3% were male (Table 1). On the basis of the evolving epidemiology of hair loss treatment during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1).

Overall, 53.2% of the patients were white, 20.6% were black, 12.6% were Asian, and 13.6% were designated as other or not reported. 249 (23.4%) were Hispanic or Latino. Most patients had either one (27.0%) or two or more (52.1%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12).

Nine hundred forty-three (88.7%) patients had severe disease at enrollment as defined in the Supplementary Appendix. 272 (25.6%) patients met category 7 criteria on the ordinal scale, 197 (18.5%) category 6, 421 (39.6%) category 5, and 127 (11.9%) category 4. There were 46 (4.3%) patients who had missing ordinal scale data at enrollment. No substantial imbalances in baseline characteristics were observed between the remdesivir group and the placebo group.

Primary Outcome Figure 2. Figure 2. Kaplan–Meier Estimates of Cumulative Recoveries. Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen.

Panel B), in those with a baseline score of 5 (receiving oxygen. Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation. Panel D), and in those with a baseline score of 7 (receiving mechanical ventilation or ECMO. Panel E).

Table 2. Table 2. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population. Figure 3.

Figure 3. Time to Recovery According to Subgroup. The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects. Race and ethnic group were reported by the patients.

Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 11 days, as compared with 15 days. Rate ratio for recovery, 1.32. 95% confidence interval [CI], 1.12 to 1.55. P<0.001.

1059 patients (Figure 2 and Table 2). Among patients with a baseline ordinal score of 5 (421 patients), the rate ratio for recovery was 1.47 (95% CI, 1.17 to 1.84). Among patients with a baseline score of 4 (127 patients) and those with a baseline score of 6 (197 patients), the rate ratio estimates for recovery were 1.38 (95% CI, 0.94 to 2.03) and 1.20 (95% CI, 0.79 to 1.81), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal scores of 7.

272 patients), the rate ratio for recovery was 0.95 (95% CI, 0.64 to 1.42). A test of interaction of treatment with baseline score on the ordinal scale was not significant. An analysis adjusting for baseline ordinal score as a stratification variable was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome. This adjusted analysis produced a similar treatment-effect estimate (rate ratio for recovery, 1.31.

95% CI, 1.12 to 1.54. 1017 patients). Table S2 in the Supplementary Appendix shows results according to the baseline severity stratum of mild-to-moderate as compared with severe. Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.28 (95% CI, 1.05 to 1.57.

664 patients), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.38 (95% CI, 1.05 to 1.81. 380 patients) (Figure 3). Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.50. 95% CI, 1.18 to 1.91.

P=0.001. 844 patients) (Table 2 and Fig. S5). Mortality was numerically lower in the remdesivir group than in the placebo group, but the difference was not significant (hazard ratio for death, 0.70.

95% CI, 0.47 to 1.04. 1059 patients). The Kaplan–Meier estimates of mortality by 14 days were 7.1% and 11.9% in the remdesivir and placebo groups, respectively (Table 2). The Kaplan–Meier estimates of mortality by 28 days are not reported in this preliminary analysis, given the large number of patients that had yet to complete day 29 visits.

An analysis with adjustment for baseline ordinal score as a stratification variable showed a hazard ratio for death of 0.74 (95% CI, 0.50 to 1.10). Safety Outcomes Serious adverse events occurred in 114 patients (21.1%) in the remdesivir group and 141 patients (27.0%) in the placebo group (Table S3). 4 events (2 in each group) were judged by site investigators to be related to remdesivir or placebo. There were 28 serious respiratory failure adverse events in the remdesivir group (5.2% of patients) and 42 in the placebo group (8.0% of patients).

Acute respiratory failure, hypotension, viral pneumonia, and acute kidney injury were slightly more common among patients in the placebo group. No deaths were considered to be related to treatment assignment, as judged by the site investigators. Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%) (Table S4). The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group).

Acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]). Pyrexia (27 events [5.0%], as compared with 17 [3.3%]). Hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]). And increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]).

Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.Trial Design and Oversight We conducted a randomized, double-blind, placebo-controlled trial to evaluate postexposure prophylaxis with hydroxychloroquine after exposure to hair loss treatment.12 We randomly assigned participants in a 1:1 ratio to receive either hydroxychloroquine or placebo. Participants had known exposure (by participant report) to a person with laboratory-confirmed hair loss treatment, whether as a household contact, a health care worker, or a person with other occupational exposures. Trial enrollment began on March 17, 2020, with an eligibility threshold to enroll within 3 days after exposure. The objective was to intervene before the median incubation period of 5 to 6 days.

Because of limited access to prompt testing, health care workers could initially be enrolled on the basis of presumptive high-risk exposure to patients with pending tests. However, on March 23, eligibility was changed to exposure to a person with a positive polymerase-chain-reaction (PCR) assay for hair loss, with the eligibility window extended to within 4 days after exposure. This trial was approved by the institutional review board at the University of Minnesota and conducted under a Food and Drug Administration Investigational New Drug application. In Canada, the trial was approved by Health Canada.

Ethics approvals were obtained from the Research Institute of the McGill University Health Centre, the University of Manitoba, and the University of Alberta. Participants We included participants who had household or occupational exposure to a person with confirmed hair loss treatment at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Participants were excluded if they were younger than 18 years of age, were hospitalized, or met other exclusion criteria (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Persons with symptoms of hair loss treatment or with PCR-proven hair loss were excluded from this prevention trial but were separately enrolled in a companion clinical trial to treat early .

Setting Recruitment was performed primarily with the use of social media outreach as well as traditional media platforms. Participants were enrolled nationwide in the United States and in the Canadian provinces of Quebec, Manitoba, and Alberta. Participants enrolled themselves through a secure Internet-based survey using the Research Electronic Data Capture (REDCap) system.13 After participants read the consent form, their comprehension of its contents was assessed. Participants provided a digitally captured signature to indicate informed consent.

We sent follow-up e-mail surveys on days 1, 5, 10, and 14. A survey at 4 to 6 weeks asked about any follow-up testing, illness, or hospitalizations. Participants who did not respond to follow-up surveys received text messages, e-mails, telephone calls, or a combination of these to ascertain their outcomes. When these methods were unsuccessful, the emergency contact provided by the enrollee was contacted to determine the participant’s illness and vital status.

When all communication methods were exhausted, Internet searches for obituaries were performed to ascertain vital status. Interventions Randomization occurred at research pharmacies in Minneapolis and Montreal. The trial statisticians generated a permuted-block randomization sequence using variably sized blocks of 2, 4, or 8, with stratification according to country. A research pharmacist sequentially assigned participants.

The assignments were concealed from investigators and participants. Only pharmacies had access to the randomization sequence. Hydroxychloroquine sulfate or placebo was dispensed and shipped overnight to participants by commercial courier. The dosing regimen for hydroxychloroquine was 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) daily for 4 more days for a total course of 5 days (19 tablets total).

If participants had gastrointestinal upset, they were advised to divide the daily dose into two or three doses. We chose this hydroxychloroquine dosing regimen on the basis of pharmacokinetic simulations to achieve plasma concentrations above the hair loss in vitro half maximal effective concentration for 14 days.14 Placebo folate tablets, which were similar in appearance to the hydroxychloroquine tablets, were prescribed as an identical regimen for the control group. Rising Pharmaceuticals provided a donation of hydroxychloroquine, and some hydroxychloroquine was purchased. Outcomes The primary outcome was prespecified as symptomatic illness confirmed by a positive molecular assay or, if testing was unavailable, hair loss treatment–related symptoms.

We assumed that health care workers would have access to hair loss treatment testing if symptomatic. However, access to testing was limited throughout the trial period. hair loss treatment–related symptoms were based on U.S. Council for State and Territorial Epidemiologists criteria for confirmed cases (positivity for hair loss on PCR assay), probable cases (the presence of cough, shortness of breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia, headache, sore throat, and new olfactory and taste disorders), and possible cases (the presence of one or more compatible symptoms, which could include diarrhea).15 All the participants had epidemiologic linkage,15 per trial eligibility criteria.

Four infectious disease physicians who were unaware of the trial-group assignments reviewed symptomatic participants to generate a consensus with respect to whether their condition met the case definition.15 Secondary outcomes included the incidence of hospitalization for hair loss treatment or death, the incidence of PCR-confirmed hair loss , the incidence of hair loss treatment symptoms, the incidence of discontinuation of the trial intervention owing to any cause, and the severity of symptoms (if any) at days 5 and 14 according to a visual analogue scale (scores ranged from 0 [no symptoms] to 10 [severe symptoms]). Data on adverse events were also collected with directed questioning for common side effects along with open-ended free text. Outcome data were measured within 14 days after trial enrollment. Outcome data including PCR testing results, possible hair loss treatment–related symptoms, adherence to the trial intervention, side effects, and hospitalizations were all collected through participant report.

Details of trial conduct are provided in the protocol and statistical analysis plan, available at NEJM.org. Sample Size We anticipated that illness compatible with hair loss treatment would develop in 10% of close contacts exposed to hair loss treatment.9 Using Fisher’s exact method with a 50% relative effect size to reduce new symptomatic s, a two-sided alpha of 0.05, and 90% power, we estimated that 621 persons would need to be enrolled in each group. With a pragmatic, Internet-based, self-referral recruitment strategy, we planned for a 20% incidence of attrition by increasing the sample size to 750 participants per group. We specified a priori that participants who were already symptomatic on day 1 before receiving hydroxychloroquine or placebo would be excluded from the prophylaxis trial and would instead be separately enrolled in the companion symptomatic treatment trial.

Because the estimates for both incident symptomatic hair loss treatment after an exposure and loss to follow-up were relatively unknown in early March 2020,9 the protocol prespecified a sample-size reestimation at the second interim analysis. This reestimation, which used the incidence of new s in the placebo group and the observed percentage of participants lost to follow-up, was aimed at maintaining the ability to detect an effect size of a 50% relative reduction in new symptomatic s. Interim Analyses An independent data and safety monitoring board externally reviewed the data after 25% and 50% of the participants had completed 14 days of follow-up. Stopping guidelines were provided to the data and safety monitoring board with the use of a Lan–DeMets spending function analogue of the O’Brien–Fleming boundaries for the primary outcome.

A conditional power analysis was performed at the second and third interim analysis with the option of early stopping for futility. At the second interim analysis on April 22, 2020, the sample size was reduced to 956 participants who could be evaluated with 90% power on the basis of the higher-than-expected event rate of s in the control group. At the third interim analysis on May 6, the trial was halted on the basis of a conditional power of less than 1%, since it was deemed futile to continue. Statistical Analysis We assessed the incidence of hair loss treatment disease by day 14 with Fisher’s exact test.

Secondary outcomes with respect to percentage of patients were also compared with Fisher’s exact test. Among participants in whom incident illness compatible with hair loss treatment developed, we summarized the symptom severity score at day 14 with the median and interquartile range and assessed the distributions with a Kruskal–Wallis test. We conducted all analyses with SAS software, version 9.4 (SAS Institute), according to the intention-to-treat principle, with two-sided type I error with an alpha of 0.05. For participants with missing outcome data, we conducted a sensitivity analysis with their outcomes excluded or included as an event.

Subgroups that were specified a priori included type of contact (household vs. Health care), days from exposure to enrollment, age, and sex..

Trial Population Table buy generic propecia online 1. Table 1 buy generic propecia online. Characteristics of the Participants in the mRNA-1273 Trial at Enrollment.

The 45 enrolled participants received their first vaccination between March 16 and April 14, 2020 (Fig buy generic propecia online. S1). Three participants did not receive the second vaccination, including one in the 25-μg group who had urticaria on both legs, with onset 5 days after the first vaccination, and two (one in the 25-μg group and one in the 250-μg group) who missed the second buy generic propecia online vaccination window owing to isolation for suspected hair loss treatment while the test results, ultimately negative, were pending.

All continued to buy generic propecia online attend scheduled trial visits. The demographic characteristics of participants at enrollment are provided in Table 1. treatment Safety buy generic propecia online No serious adverse events were noted, and no prespecified trial halting rules were met.

As noted above, one participant in the 25-μg group was withdrawn because of an unsolicited adverse event, transient urticaria, judged to be related to the first vaccination. Figure 1 buy generic propecia online. Figure 1.

Systemic and Local buy generic propecia online Adverse Events. The severity of solicited adverse events was graded as buy generic propecia online mild, moderate, or severe (see Table S1).After the first vaccination, solicited systemic adverse events were reported by 5 participants (33%) in the 25-μg group, 10 (67%) in the 100-μg group, and 8 (53%) in the 250-μg group. All were mild or moderate in severity (Figure 1 and Table S2).

Solicited systemic adverse events were more common after the second vaccination buy generic propecia online and occurred in 7 of 13 participants (54%) in the 25-μg group, all 15 in the 100-μg group, and all 14 in the 250-μg group, with 3 of those participants (21%) reporting one or more severe events. None of the participants had fever after the first vaccination. After the second vaccination, no participants in the 25-μg group, 6 buy generic propecia online (40%) in the 100-μg group, and 8 (57%) in the 250-μg group reported fever.

One of the buy generic propecia online events (maximum temperature, 39.6°C) in the 250-μg group was graded severe. (Additional details regarding adverse events for that participant are provided in the Supplementary Appendix.) Local adverse events, when present, were nearly all mild or moderate, and pain at the injection site was common. Across both vaccinations, solicited systemic and local buy generic propecia online adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site.

Evaluation of safety clinical laboratory values of grade 2 or higher and unsolicited adverse events revealed no patterns of concern (Supplementary Appendix and Table S3). hair loss Binding buy generic propecia online Antibody Responses Table 2. Table 2.

Geometric Mean Humoral Immunogenicity Assay Responses to mRNA-1273 buy generic propecia online in Participants and in Convalescent Serum Specimens. Figure 2 buy generic propecia online. Figure 2.

hair loss Antibody buy generic propecia online and Neutralization Responses. Shown are geometric mean reciprocal end-point enzyme-linked immunosorbent assay (ELISA) IgG titers to S-2P (Panel A) and receptor-binding domain (Panel B), PsVNA ID50 responses (Panel C), and live propecia PRNT80 responses (Panel D). In Panel A and Panel B, boxes and horizontal bars denote interquartile range (IQR) and buy generic propecia online median area under the curve (AUC), respectively.

Whisker endpoints are equal to the maximum and minimum values below or above the median ±1.5 times the IQR. The convalescent serum panel includes specimens from 41 participants buy generic propecia online. Red dots buy generic propecia online indicate the 3 specimens that were also tested in the PRNT assay.

The other 38 specimens were used to calculate summary statistics for the box plot in the convalescent serum panel. In Panel C, boxes and horizontal buy generic propecia online bars denote IQR and median ID50, respectively. Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 times the IQR.

In the convalescent serum panel, red dots indicate the 3 specimens that were also tested in the PRNT assay buy generic propecia online. The other 38 specimens were used to buy generic propecia online calculate summary statistics for the box plot in the convalescent panel. In Panel D, boxes and horizontal bars denote IQR and median PRNT80, respectively.

Whisker end points are equal to the maximum and minimum values below or above the median ±1.5 buy generic propecia online times the IQR. The three convalescent serum specimens were also tested in ELISA and PsVNA assays. Because of the time-intensive nature of the PRNT assay, for this preliminary report, PRNT results were available only for the 25-μg and 100-μg dose groups.Binding antibody IgG geometric mean titers (GMTs) to S-2P increased rapidly after the first buy generic propecia online vaccination, with seroconversion in all participants by day 15 (Table 2 and Figure 2A).

Dose-dependent responses to the first and second vaccinations were evident. Receptor-binding domain–specific antibody responses were similar in pattern buy generic propecia online and magnitude (Figure 2B). For both assays, the median magnitude of antibody responses after the first vaccination in the 100-μg buy generic propecia online and 250-μg dose groups was similar to the median magnitude in convalescent serum specimens, and in all dose groups the median magnitude after the second vaccination was in the upper quartile of values in the convalescent serum specimens.

The S-2P ELISA GMTs at day 57 (299,751 [95% confidence interval {CI}, 206,071 to 436,020] in the 25-μg group, 782,719 [95% CI, 619,310 to 989,244] in the 100-μg group, and 1,192,154 [95% CI, 924,878 to 1,536,669] in the 250-μg group) exceeded that in the convalescent serum specimens (142,140 [95% CI, 81,543 to 247,768]). hair loss Neutralization Responses No participant had detectable PsVNA responses buy generic propecia online before vaccination. After the first vaccination, PsVNA responses were detected in less than half the participants, and a dose effect was seen (50% inhibitory dilution [ID50].

Figure 2C, Fig buy generic propecia online. S8, and Table 2. 80% inhibitory buy generic propecia online dilution [ID80].

Fig. S2 and Table S6). However, after the second vaccination, PsVNA responses were identified in serum samples from all participants.

The lowest responses were in the 25-μg dose group, with a geometric mean ID50 of 112.3 (95% CI, 71.2 to 177.1) at day 43. The higher responses in the 100-μg and 250-μg groups were similar in magnitude (geometric mean ID50, 343.8 [95% CI, 261.2 to 452.7] and 332.2 [95% CI, 266.3 to 414.5], respectively, at day 43). These responses were similar to values in the upper half of the distribution of values for convalescent serum specimens.

Before vaccination, no participant had detectable 80% live-propecia neutralization at the highest serum concentration tested (1:8 dilution) in the PRNT assay. At day 43, wild-type propecia–neutralizing activity capable of reducing hair loss infectivity by 80% or more (PRNT80) was detected in all participants, with geometric mean PRNT80 responses of 339.7 (95% CI, 184.0 to 627.1) in the 25-μg group and 654.3 (95% CI, 460.1 to 930.5) in the 100-μg group (Figure 2D). Neutralizing PRNT80 average responses were generally at or above the values of the three convalescent serum specimens tested in this assay.

Good agreement was noted within and between the values from binding assays for S-2P and receptor-binding domain and neutralizing activity measured by PsVNA and PRNT (Figs. S3 through S7), which provides orthogonal support for each assay in characterizing the humoral response induced by mRNA-1273. hair loss T-Cell Responses The 25-μg and 100-μg doses elicited CD4 T-cell responses (Figs.

S9 and S10) that on stimulation by S-specific peptide pools were strongly biased toward expression of Th1 cytokines (tumor necrosis factor α >. Interleukin 2 >. Interferon γ), with minimal type 2 helper T-cell (Th2) cytokine expression (interleukin 4 and interleukin 13).

CD8 T-cell responses to S-2P were detected at low levels after the second vaccination in the 100-μg dose group (Fig. S11).To the Editor. Rapid and accurate diagnostic tests are essential for controlling the ongoing hair loss treatment propecia.

Although the current standard involves testing of nasopharyngeal swab specimens by quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) to detect hair loss, saliva specimens may be an alternative diagnostic sample.1-4 Rigorous evaluation is needed to determine how saliva specimens compare with nasopharyngeal swab specimens with respect to sensitivity in detection of hair loss during the course of . A total of 70 inpatients with hair loss treatment provided written informed consent to participate in our study (see the Methods section in Supplementary Appendix 1, available with the full text of this letter at NEJM.org). After hair loss treatment was confirmed with a positive nasopharyngeal swab specimen at hospital admission, we obtained additional samples from the patients during hospitalization.

We tested saliva specimens collected by the patients themselves and nasopharyngeal swabs collected from the patients at the same time point by health care workers. Figure 1. Figure 1.

hair loss RNA Titers in Saliva Specimens and Nasopharyngeal Swab Specimens. Samples were obtained from 70 hospital inpatients who had a diagnosis of hair loss treatment. Panel A shows hair loss RNA titers in the first available nasopharyngeal and saliva samples.

The lines indicate samples from the same patient. Results were compared with the use of a Wilcoxon signed-rank test (P<0.001). Panel B shows percentages of positivity for hair loss in tests of the first matched nasopharyngeal and saliva samples at 1 to 5 days, 6 to 10 days, and 11 or more days (maximum, 53 days) after the diagnosis of hair loss treatment.

Panel C shows longitudinal hair loss RNA copies per milliliter in 97 saliva samples, according to days since symptom onset. Each circle represents a separate sample. Dashed lines indicate additional samples from the same patient.

The red line indicates a negative saliva sample that was followed by a positive sample at the next collection of a specimen. Panel D shows longitudinal hair loss RNA copies per milliliter in 97 nasopharyngeal swab specimens, according to days since symptom onset. The red lines indicate negative nasopharyngeal swab specimens there were followed by a positive swab at the next collection of a specimen.

The gray area in Panels C and D indicates samples that were below the lower limit of detection of 5610 propecia RNA copies per milliliter of sample, which is at cycle threshold 38 of our quantitative reverse-transcriptase polymerase chain reaction assay targeting the hair loss N1 sequence recommended by the Centers for Disease Control and Prevention. To analyze these data, we used a linear mixed-effects regression model (see Supplementary Appendix 1) that accounts for the correlation between samples collected from the same person at a single time point (i.e., multivariate response) and the correlation between samples collected across time from the same patient (i.e., repeated measures). All the data used to generate this figure, including the raw cycle thresholds, are provided in Supplementary Data 1 in Supplementary Appendix 2.Using primer sequences from the Centers for Disease Control and Prevention, we detected more hair loss RNA copies in the saliva specimens (mean log copies per milliliter, 5.58.

95% confidence interval [CI], 5.09 to 6.07) than in the nasopharyngeal swab specimens (mean log copies per milliliter, 4.93. 95% CI, 4.53 to 5.33) (Figure 1A, and Fig. S1 in Supplementary Appendix 1).

In addition, a higher percentage of saliva samples than nasopharyngeal swab samples were positive up to 10 days after the hair loss treatment diagnosis (Figure 1B). At 1 to 5 days after diagnosis, 81% (95% CI, 71 to 96) of the saliva samples were positive, as compared with 71% (95% CI, 67 to 94) of the nasopharyngeal swab specimens. These findings suggest that saliva specimens and nasopharyngeal swab specimens have at least similar sensitivity in the detection of hair loss during the course of hospitalization.

Because the results of testing of nasopharyngeal swab specimens to detect hair loss may vary with repeated sampling in individual patients,5 we evaluated viral detection in matched samples over time. The level of hair loss RNA decreased after symptom onset in both saliva specimens (estimated slope, −0.11. 95% credible interval, −0.15 to −0.06) (Figure 1C) and nasopharyngeal swab specimens (estimated slope, −0.09.

95% credible interval, −0.13 to −0.05) (Figure 1D). In three instances, a negative nasopharyngeal swab specimen was followed by a positive swab at the next collection of a specimen (Figure 1D). This phenomenon occurred only once with the saliva specimens (Figure 1C).

During the clinical course, we observed less variation in levels of hair loss RNA in the saliva specimens (standard deviation, 0.98 propecia RNA copies per milliliter. 95% credible interval, 0.08 to 1.98) than in the nasopharyngeal swab specimens (standard deviation, 2.01 propecia RNA copies per milliliter. 95% credible interval, 1.29 to 2.70) (see Supplementary Appendix 1).

Recent studies have shown that hair loss can be detected in the saliva of asymptomatic persons and outpatients.1-3 We therefore screened 495 asymptomatic health care workers who provided written informed consent to participate in our prospective study, and we used RT-qPCR to test both saliva and nasopharyngeal samples obtained from these persons. We detected hair loss RNA in saliva specimens obtained from 13 persons who did not report any symptoms at or before the time of sample collection. Of these 13 health care workers, 9 had collected matched nasopharyngeal swab specimens by themselves on the same day, and 7 of these specimens tested negative (Fig.

S2). The diagnosis in the 13 health care workers with positive saliva specimens was later confirmed in diagnostic testing of additional nasopharyngeal samples by a CLIA (Clinical Laboratory Improvement Amendments of 1988)–certified laboratory. Variation in nasopharyngeal sampling may be an explanation for false negative results, so monitoring an internal control for proper sample collection may provide an alternative evaluation technique.

In specimens collected from inpatients by health care workers, we found greater variation in human RNase P cycle threshold (Ct) values in nasopharyngeal swab specimens (standard deviation, 2.89 Ct. 95% CI, 26.53 to 27.69) than in saliva specimens (standard deviation, 2.49 Ct. 95% CI, 23.35 to 24.35).

When health care workers collected their own specimens, we also found greater variation in RNase P Ct values in nasopharyngeal swab specimens (standard deviation, 2.26 Ct. 95% CI, 28.39 to 28.56) than in saliva specimens (standard deviation , 1.65 Ct. 95% CI, 24.14 to 24.26) (Fig.

S3). Collection of saliva samples by patients themselves negates the need for direct interaction between health care workers and patients. This interaction is a source of major testing bottlenecks and presents a risk of nosocomial .

Collection of saliva samples by patients themselves also alleviates demands for supplies of swabs and personal protective equipment. Given the growing need for testing, our findings provide support for the potential of saliva specimens in the diagnosis of hair loss . Anne L.

Wyllie, Ph.D.Yale School of Public Health, New Haven, CT [email protected]John Fournier, M.D.Yale School of Medicine, New Haven, CTArnau Casanovas-Massana, Ph.D.Yale School of Public Health, New Haven, CTMelissa Campbell, M.D.Maria Tokuyama, Ph.D.Pavithra Vijayakumar, B.A.Yale School of Medicine, New Haven, CTJoshua L. Warren, Ph.D.Yale School of Public Health, New Haven, CTBertie Geng, M.D.Yale School of Medicine, New Haven, CTM. Catherine Muenker, M.S.Adam J.

Moore, M.P.H.Chantal B.F. Vogels, Ph.D.Mary E. Petrone, B.S.Isabel M.

Ott, B.S.Yale School of Public Health, New Haven, CTPeiwen Lu, Ph.D.Arvind Venkataraman, B.S.Alice Lu-Culligan, B.S.Jonathan Klein, B.S.Yale School of Medicine, New Haven, CTRebecca Earnest, M.P.H.Yale School of Public Health, New Haven, CTMichael Simonov, M.D.Rupak Datta, M.D., Ph.D.Ryan Handoko, M.D.Nida Naushad, B.S.Lorenzo R. Sewanan, M.Phil.Jordan Valdez, B.S.Yale School of Medicine, New Haven, CTElizabeth B. White, A.B.Sarah Lapidus, M.S.Chaney C.

Kalinich, M.P.H.Yale School of Public Health, New Haven, CTXiaodong Jiang, M.D., Ph.D.Daniel J. Kim, A.B.Eriko Kudo, Ph.D.Melissa Linehan, M.S.Tianyang Mao, B.S.Miyu Moriyama, Ph.D.Ji E. Oh, M.D., Ph.D.Annsea Park, B.A.Julio Silva, B.S.Eric Song, M.S.Takehiro Takahashi, M.D., Ph.D.Manabu Taura, Ph.D.Orr-El Weizman, B.A.Patrick Wong, M.S.Yexin Yang, B.S.Santos Bermejo, B.S.Yale School of Medicine, New Haven, CTCamila D.

Odio, M.D.Yale New Haven Health, New Haven, CTSaad B. Omer, M.B., B.S., Ph.D.Yale Institute for Global Health, New Haven, CTCharles S. Dela Cruz, M.D., Ph.D.Shelli Farhadian, M.D., Ph.D.Richard A.

Martinello, M.D.Akiko Iwasaki, Ph.D.Yale School of Medicine, New Haven, CTNathan D. Grubaugh, Ph.D.Albert I. Ko, M.D.Yale School of Public Health, New Haven, CT [email protected], [email protected] Supported by the Huffman Family Donor Advised Fund, a Fast Grant from Emergent Ventures at the Mercatus Center at George Mason University, the Yale Institute for Global Health, the Yale School of Medicine, a grant (U19 AI08992, to Dr.

Ko) from the National Institute of Allergy and Infectious Diseases, the Beatrice Kleinberg Neuwirth Fund, and a grant (Rubicon 019.181EN.004, to Dr. Vogel) from the Dutch Research Council (NWO). Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

This letter was published on August 28, 2020, at NEJM.org. Drs. Grubaugh and Ko contributed equally to this letter.

5 References1. Kojima N, Turner F, Slepnev V, et al. Self-collected oral fluid and nasal swabs demonstrate comparable sensitivity to clinician collected nasopharyngeal swabs for hair loss treatment detection.

April 15, 2020 (https://www.medrxiv.org/content/10.1101/2020.04.11.20062372v1). Preprint.Google Scholar2. Williams E, Bond K, Zhang B, Putland M, Williamson DA.

Saliva as a non-invasive specimen for detection of hair loss. J Clin Microbiol 2020;58(8):e00776-20-e00776-20.3. Pasomsub E, Watcharananan SP, Boonyawat K, et al.

Saliva sample as a non-invasive specimen for the diagnosis of hair loss disease 2019. A cross-sectional study. Clin Microbiol Infect 2020 May 15 (Epub ahead of print).4.

Vogels CBF, Brackney D, Wang J, et al. SalivaDirect. Simple and sensitive molecular diagnostic test for hair loss surveillance.

August 4, 2020 (https://www.medrxiv.org/content/10.1101/2020.08.03.20167791v1). Preprint.Google Scholar5. Zou L, Ruan F, Huang M, et al.

hair loss viral load in upper respiratory specimens of infected patients. N Engl J Med 2020;382:1177-1179.Announced on May 15, Operation Warp Speed (OWS) — a partnership of the Department of Health and Human Services (HHS), the Department of Defense (DOD), and the private sector — aims to accelerate control of the hair loss treatment propecia by advancing development, manufacturing, and distribution of treatments, therapeutics, and diagnostics. OWS is providing support to promising candidates and enabling the expeditious, parallel execution of the necessary steps toward approval or authorization of safe products by the Food and Drug Administration (FDA).The partnership grew out of an acknowledged need to fundamentally restructure the way the U.S.

Government typically supports product development and treatment distribution. The initiative was premised on setting a “stretch goal” — one that initially seemed impossible but that is becoming increasingly achievable.The concept of an integrated structure for hair loss treatment countermeasure research and development across the U.S. Government was based on experience with Zika and the Zika Leadership Group led by the National Institutes of Health (NIH) and the assistant secretary for preparedness and response (ASPR).

One of us (M.S.) serves as OWS chief advisor. We are drawing on expertise from the NIH, ASPR, the Centers for Disease Control and Prevention (CDC), the Biomedical Advanced Research and Development Authority (BARDA), and the DOD, including the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense and the Defense Advanced Research Projects Agency. OWS has engaged experts in all critical aspects of medical countermeasure research, development, manufacturing, and distribution to work in close coordination.The initiative set ambitious objectives.

To deliver tens of millions of doses of a hair loss treatment — with demonstrated safety and efficacy, and approved or authorized by the FDA for use in the U.S. Population — beginning at the end of 2020 and to have as many as 300 million doses of such treatments available and deployed by mid-2021. The pace and scope of such a treatment effort are unprecedented.

The 2014 West African Ebola propecia epidemic spurred rapid treatment development, but though preclinical data existed before the outbreak, a period of 12 months was required to progress from phase 1 first-in-human trials to phase 3 efficacy trials. OWS aims to compress this time frame even further. hair loss treatment development began in January, phase 1 clinical studies in March, and the first phase 3 trials in July.

Our objectives are based on advances in treatment platform technology, improved understanding of safe and efficacious treatment design, and similarities between the SARS-CoV-1 and hair loss disease mechanisms.OWS’s role is to enable, accelerate, harmonize, and advise the companies developing the selected treatments. The companies will execute the clinical or process development and manufacturing plans, while OWS leverages the full capacity of the U.S. Government to ensure that no technical, logistic, or financial hurdles hinder treatment development or deployment.OWS selected treatment candidates on the basis of four criteria.

We required candidates to have robust preclinical data or early-stage clinical trial data supporting their potential for clinical safety and efficacy. Candidates had to have the potential, with our acceleration support, to enter large phase 3 field efficacy trials this summer or fall (July to November 2020) and, assuming continued active transmission of the propecia, to deliver efficacy outcomes by the end of 2020 or the first half of 2021. Candidates had to be based on treatment-platform technologies permitting fast and effective manufacturing, and their developers had to demonstrate the industrial process scalability, yields, and consistency necessary to reliably produce more than 100 million doses by mid-2021.

Finally, candidates had to use one of four treatment-platform technologies that we believe are the most likely to yield a safe and effective treatment against hair loss treatment. The mRNA platform, the replication-defective live-vector platform, the recombinant-subunit-adjuvanted protein platform, or the attenuated replicating live-vector platform.OWS’s strategy relies on a few key principles. First, we sought to build a diverse project portfolio that includes two treatment candidates based on each of the four platform technologies.

Such diversification mitigates the risk of failure due to safety, efficacy, industrial manufacturability, or scheduling factors and may permit selection of the best treatment platform for each subpopulation at risk for contracting or transmitting hair loss treatment, including older adults, frontline and essential workers, young adults, and pediatric populations. In addition, advancing eight treatments in parallel will increase the chances of delivering 300 million doses in the first half of 2021.Second, we must accelerate treatment program development without compromising safety, efficacy, or product quality. Clinical development, process development, and manufacturing scale-up can be substantially accelerated by running all streams, fully resourced, in parallel.

Doing so requires taking on substantial financial risk, as compared with the conventional sequential development approach. OWS will maximize the size of phase 3 trials (30,000 to 50,000 participants each) and optimize trial-site location by consulting daily epidemiologic and disease-forecasting models to ensure the fastest path to an efficacy readout. Such large trials also increase the safety data set for each candidate treatment.With heavy up-front investment, companies can conduct clinical operations and site preparation for these phase 3 efficacy trials even as they file their Investigational New Drug application (IND) for their phase 1 studies, thereby ensuring immediate initiation of phase 3 when they get a green light from the FDA.

To permit appropriate comparisons among the treatment candidates and to optimize treatment utilization after approval by the FDA, the phase 3 trial end points and assay readouts have been harmonized through a collaborative effort involving the National Institute of Allergy and Infectious Diseases (NIAID), the hair loss Prevention Network, OWS, and the sponsor companies.Finally, OWS is supporting the companies financially and technically to commence process development and scale up manufacturing while their treatments are in preclinical or very early clinical stages. To ensure that industrial processes are set, running, and validated for FDA inspection when phase 3 trials end, OWS is also supporting facility building or refurbishing, equipment fitting, staff hiring and training, raw-material sourcing, technology transfer and validation, bulk product processing into vials, and acquisition of ample vials, syringes, and needles for each treatment candidate. We aim to have stockpiled, at OWS’s expense, a few tens of millions of treatment doses that could be swiftly deployed once FDA approval is obtained.This strategy aims to accelerate treatment development without curtailing the critical steps required by sound science and regulatory standards.

The FDA recently reissued guidance and standards that will be used to assess each treatment for a Biologics License Application (BLA). Alternatively, the agency could decide to issue an Emergency Use Authorization to permit treatment administration before all BLA procedures are completed.Of the eight treatments in OWS’s portfolio, six have been announced and partnerships executed with the companies. Moderna and Pfizer/BioNTech (both mRNA), AstraZeneca and Janssen (both replication-defective live-vector), and Novavax and Sanofi/GSK (both recombinant-subunit-adjuvanted protein).

These candidates cover three of the four platform technologies and are currently in clinical trials. The remaining two candidates will enter trials soon.Moderna developed its RNA treatment in collaboration with the NIAID, began its phase 1 trial in March, recently published encouraging safety and immunogenicity data,1 and entered phase 3 on July 27. Pfizer and BioNTech’s RNA treatment also produced encouraging phase 1 results2 and started its phase 3 trial on July 27.

The ChAdOx replication-defective live-vector treatment developed by AstraZeneca and Oxford University is in phase 3 trials in the United Kingdom, Brazil, and South Africa, and it should enter U.S. Phase 3 trials in August.3 The Janssen Ad26 hair loss treatment replication-defective live-vector treatment has demonstrated excellent protection in nonhuman primate models and began its U.S. Phase 1 trial on July 27.

It should be in phase 3 trials in mid-September. Novavax completed a phase 1 trial of its recombinant-subunit-adjuvanted protein treatment in Australia and should enter phase 3 trials in the United States by the end of September.4 Sanofi/GSK is completing preclinical development steps and plans to commence a phase 1 trial in early September and to be well into phase 3 by year’s end.5On the process-development front, the RNA treatments are already being manufactured at scale. The other candidates are well advanced in their scale-up development, and manufacturing sites are being refurbished.While development and manufacturing proceed, the HHS–DOD partnership is laying the groundwork for treatment distribution, subpopulation prioritization, financing, and logistic support.

We are working with bioethicists and experts from the NIH, the CDC, BARDA, and the Centers for Medicare and Medicaid Services to address these critical issues. We will receive recommendations from the CDC Advisory Committee on Immunization Practices, and we are working to ensure that the most vulnerable and at-risk persons will receive treatment doses once they are ready. Prioritization will also depend on the relative performance of each treatment and its suitability for particular populations.

Because some technologies have limited previous data on safety in humans, the long-term safety of these treatments will be carefully assessed using pharmacovigilance surveillance strategies.No scientific enterprise could guarantee success by January 2021, but the strategic decisions and choices we’ve made, the support the government has provided, and the accomplishments to date make us optimistic that we will succeed in this unprecedented endeavor.Patients Figure 1. Figure 1. Enrollment and Randomization.

Of the 1107 patients who were assessed for eligibility, 1063 underwent randomization. 541 were assigned to the remdesivir group and 522 to the placebo group (Figure 1). Of those assigned to receive remdesivir, 531 patients (98.2%) received the treatment as assigned.

Forty-nine patients had remdesivir treatment discontinued before day 10 because of an adverse event or a serious adverse event other than death (36 patients) or because the patient withdrew consent (13). Of those assigned to receive placebo, 518 patients (99.2%) received placebo as assigned. Fifty-three patients discontinued placebo before day 10 because of an adverse event or a serious adverse event other than death (36 patients), because the patient withdrew consent (15), or because the patient was found to be ineligible for trial enrollment (2).

As of April 28, 2020, a total of 391 patients in the remdesivir group and 340 in the placebo group had completed the trial through day 29, recovered, or died. Eight patients who received remdesivir and 9 who received placebo terminated their participation in the trial before day 29. There were 132 patients in the remdesivir group and 169 in the placebo group who had not recovered and had not completed the day 29 follow-up visit.

The analysis population included 1059 patients for whom we have at least some postbaseline data available (538 in the remdesivir group and 521 in the placebo group). Four of the 1063 patients were not included in the primary analysis because no postbaseline data were available at the time of the database freeze. Table 1.

Table 1. Demographic and Clinical Characteristics at Baseline. The mean age of patients was 58.9 years, and 64.3% were male (Table 1).

On the basis of the evolving epidemiology of hair loss treatment during the trial, 79.8% of patients were enrolled at sites in North America, 15.3% in Europe, and 4.9% in Asia (Table S1). Overall, 53.2% of the patients were white, 20.6% were black, 12.6% were Asian, and 13.6% were designated as other or not reported. 249 (23.4%) were Hispanic or Latino.

Most patients had either one (27.0%) or two or more (52.1%) of the prespecified coexisting conditions at enrollment, most commonly hypertension (49.6%), obesity (37.0%), and type 2 diabetes mellitus (29.7%). The median number of days between symptom onset and randomization was 9 (interquartile range, 6 to 12). Nine hundred forty-three (88.7%) patients had severe disease at enrollment as defined in the Supplementary Appendix.

272 (25.6%) patients met category 7 criteria on the ordinal scale, 197 (18.5%) category 6, 421 (39.6%) category 5, and 127 (11.9%) category 4. There were 46 (4.3%) patients who had missing ordinal scale data at enrollment. No substantial imbalances in baseline characteristics were observed between the remdesivir group and the placebo group.

Primary Outcome Figure 2. Figure 2. Kaplan–Meier Estimates of Cumulative Recoveries.

Cumulative recovery estimates are shown in the overall population (Panel A), in patients with a baseline score of 4 on the ordinal scale (not receiving oxygen. Panel B), in those with a baseline score of 5 (receiving oxygen. Panel C), in those with a baseline score of 6 (receiving high-flow oxygen or noninvasive mechanical ventilation.

Panel D), and in those with a baseline score of 7 (receiving mechanical ventilation or ECMO. Panel E). Table 2.

Table 2. Outcomes Overall and According to Score on the Ordinal Scale in the Intention-to-Treat Population. Figure 3.

Figure 3. Time to Recovery According to Subgroup. The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects.

Race and ethnic group were reported by the patients. Patients in the remdesivir group had a shorter time to recovery than patients in the placebo group (median, 11 days, as compared with 15 days. Rate ratio for recovery, 1.32.

95% confidence interval [CI], 1.12 to 1.55. P<0.001. 1059 patients (Figure 2 and Table 2).

Among patients with a baseline ordinal score of 5 (421 patients), the rate ratio for recovery was 1.47 (95% CI, 1.17 to 1.84). Among patients with a baseline score of 4 (127 patients) and those with a baseline score of 6 (197 patients), the rate ratio estimates for recovery were 1.38 (95% CI, 0.94 to 2.03) and 1.20 (95% CI, 0.79 to 1.81), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal scores of 7.

272 patients), the rate ratio for recovery was 0.95 (95% CI, 0.64 to 1.42). A test of interaction of treatment with baseline score on the ordinal scale was not significant. An analysis adjusting for baseline ordinal score as a stratification variable was conducted to evaluate the overall effect (of the percentage of patients in each ordinal score category at baseline) on the primary outcome.

This adjusted analysis produced a similar treatment-effect estimate (rate ratio for recovery, 1.31. 95% CI, 1.12 to 1.54. 1017 patients).

Table S2 in the Supplementary Appendix shows results according to the baseline severity stratum of mild-to-moderate as compared with severe. Patients who underwent randomization during the first 10 days after the onset of symptoms had a rate ratio for recovery of 1.28 (95% CI, 1.05 to 1.57. 664 patients), whereas patients who underwent randomization more than 10 days after the onset of symptoms had a rate ratio for recovery of 1.38 (95% CI, 1.05 to 1.81.

380 patients) (Figure 3). Key Secondary Outcome The odds of improvement in the ordinal scale score were higher in the remdesivir group, as determined by a proportional odds model at the day 15 visit, than in the placebo group (odds ratio for improvement, 1.50. 95% CI, 1.18 to 1.91.

P=0.001. 844 patients) (Table 2 and Fig. S5).

Mortality was numerically lower in the remdesivir group than in the placebo group, but the difference was not significant (hazard ratio for death, 0.70. 95% CI, 0.47 to 1.04. 1059 patients).

The Kaplan–Meier estimates of mortality by 14 days were 7.1% and 11.9% in the remdesivir and placebo groups, respectively (Table 2). The Kaplan–Meier estimates of mortality by 28 days are not reported in this preliminary analysis, given the large number of patients that had yet to complete day 29 visits. An analysis with adjustment for baseline ordinal score as a stratification variable showed a hazard ratio for death of 0.74 (95% CI, 0.50 to 1.10).

Safety Outcomes Serious adverse events occurred in 114 patients (21.1%) in the remdesivir group and 141 patients (27.0%) in the placebo group (Table S3). 4 events (2 in each group) were judged by site investigators to be related to remdesivir or placebo. There were 28 serious respiratory failure adverse events in the remdesivir group (5.2% of patients) and 42 in the placebo group (8.0% of patients).

Acute respiratory failure, hypotension, viral pneumonia, and acute kidney injury were slightly more common among patients in the placebo group. No deaths were considered to be related to treatment assignment, as judged by the site investigators. Grade 3 or 4 adverse events occurred in 156 patients (28.8%) in the remdesivir group and in 172 in the placebo group (33.0%) (Table S4).

The most common adverse events in the remdesivir group were anemia or decreased hemoglobin (43 events [7.9%], as compared with 47 [9.0%] in the placebo group). Acute kidney injury, decreased estimated glomerular filtration rate or creatinine clearance, or increased blood creatinine (40 events [7.4%], as compared with 38 [7.3%]). Pyrexia (27 events [5.0%], as compared with 17 [3.3%]).

Hyperglycemia or increased blood glucose level (22 events [4.1%], as compared with 17 [3.3%]). And increased aminotransferase levels including alanine aminotransferase, aspartate aminotransferase, or both (22 events [4.1%], as compared with 31 [5.9%]). Otherwise, the incidence of adverse events was not found to be significantly different between the remdesivir group and the placebo group.Trial Design and Oversight We conducted a randomized, double-blind, placebo-controlled trial to evaluate postexposure prophylaxis with hydroxychloroquine after exposure to hair loss treatment.12 We randomly assigned participants in a 1:1 ratio to receive either hydroxychloroquine or placebo.

Participants had known exposure (by participant report) to a person with laboratory-confirmed hair loss treatment, whether as a household contact, a health care worker, or a person with other occupational exposures. Trial enrollment began on March 17, 2020, with an eligibility threshold to enroll within 3 days after exposure. The objective was to intervene before the median incubation period of 5 to 6 days.

Because of limited access to prompt testing, health care workers could initially be enrolled on the basis of presumptive high-risk exposure to patients with pending tests. However, on March 23, eligibility was changed to exposure to a person with a positive polymerase-chain-reaction (PCR) assay for hair loss, with the eligibility window extended to within 4 days after exposure. This trial was approved by the institutional review board at the University of Minnesota and conducted under a Food and Drug Administration Investigational New Drug application.

In Canada, the trial was approved by Health Canada. Ethics approvals were obtained from the Research Institute of the McGill University Health Centre, the University of Manitoba, and the University of Alberta. Participants We included participants who had household or occupational exposure to a person with confirmed hair loss treatment at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure).

Participants were excluded if they were younger than 18 years of age, were hospitalized, or met other exclusion criteria (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Persons with symptoms of hair loss treatment or with PCR-proven hair loss were excluded from this prevention trial but were separately enrolled in a companion clinical trial to treat early . Setting Recruitment was performed primarily with the use of social media outreach as well as traditional media platforms.

Participants were enrolled nationwide in the United States and in the Canadian provinces of Quebec, Manitoba, and Alberta. Participants enrolled themselves through a secure Internet-based survey using the Research Electronic Data Capture (REDCap) system.13 After participants read the consent form, their comprehension of its contents was assessed. Participants provided a digitally captured signature to indicate informed consent.

We sent follow-up e-mail surveys on days 1, 5, 10, and 14. A survey at 4 to 6 weeks asked about any follow-up testing, illness, or hospitalizations. Participants who did not respond to follow-up surveys received text messages, e-mails, telephone calls, or a combination of these to ascertain their outcomes.

When these methods were unsuccessful, the emergency contact provided by the enrollee was contacted to determine the participant’s illness and vital status. When all communication methods were exhausted, Internet searches for obituaries were performed to ascertain vital status. Interventions Randomization occurred at research pharmacies in Minneapolis and Montreal.

The trial statisticians generated a permuted-block randomization sequence using variably sized blocks of 2, 4, or 8, with stratification according to country. A research pharmacist sequentially assigned participants. The assignments were concealed from investigators and participants.

Only pharmacies had access to the randomization sequence. Hydroxychloroquine sulfate or placebo was dispensed and shipped overnight to participants by commercial courier. The dosing regimen for hydroxychloroquine was 800 mg (4 tablets) once, then 600 mg (3 tablets) 6 to 8 hours later, then 600 mg (3 tablets) daily for 4 more days for a total course of 5 days (19 tablets total).

If participants had gastrointestinal upset, they were advised to divide the daily dose into two or three doses. We chose this hydroxychloroquine dosing regimen on the basis of pharmacokinetic simulations to achieve plasma concentrations above the hair loss in vitro half maximal effective concentration for 14 days.14 Placebo folate tablets, which were similar in appearance to the hydroxychloroquine tablets, were prescribed as an identical regimen for the control group. Rising Pharmaceuticals provided a donation of hydroxychloroquine, and some hydroxychloroquine was purchased.

Outcomes The primary outcome was prespecified as symptomatic illness confirmed by a positive molecular assay or, if testing was unavailable, hair loss treatment–related symptoms. We assumed that health care workers would have access to hair loss treatment testing if symptomatic. However, access to testing was limited throughout the trial period.

hair loss treatment–related symptoms were based on U.S. Council for State and Territorial Epidemiologists criteria for confirmed cases (positivity for hair loss on PCR assay), probable cases (the presence of cough, shortness of breath, or difficulty breathing, or the presence of two or more symptoms of fever, chills, rigors, myalgia, headache, sore throat, and new olfactory and taste disorders), and possible cases (the presence of one or more compatible symptoms, which could include diarrhea).15 All the participants had epidemiologic linkage,15 per trial eligibility criteria. Four infectious disease physicians who were unaware of the trial-group assignments reviewed symptomatic participants to generate a consensus with respect to whether their condition met the case definition.15 Secondary outcomes included the incidence of hospitalization for hair loss treatment or death, the incidence of PCR-confirmed hair loss , the incidence of hair loss treatment symptoms, the incidence of discontinuation of the trial intervention owing to any cause, and the severity of symptoms (if any) at days 5 and 14 according to a visual analogue scale (scores ranged from 0 [no symptoms] to 10 [severe symptoms]).

Data on adverse events were also collected with directed questioning for common side effects along with open-ended free text. Outcome data were measured within 14 days after trial enrollment. Outcome data including PCR testing results, possible hair loss treatment–related symptoms, adherence to the trial intervention, side effects, and hospitalizations were all collected through participant report.

Details of trial conduct are provided in the protocol and statistical analysis plan, available at NEJM.org. Sample Size We anticipated that illness compatible with hair loss treatment would develop in 10% of close contacts exposed to hair loss treatment.9 Using Fisher’s exact method with a 50% relative effect size to reduce new symptomatic s, a two-sided alpha of 0.05, and 90% power, we estimated that 621 persons would need to be enrolled in each group. With a pragmatic, Internet-based, self-referral recruitment strategy, we planned for a 20% incidence of attrition by increasing the sample size to 750 participants per group.

We specified a priori that participants who were already symptomatic on day 1 before receiving hydroxychloroquine or placebo would be excluded from the prophylaxis trial and would instead be separately enrolled in the companion symptomatic treatment trial. Because the estimates for both incident symptomatic hair loss treatment after an exposure and loss to follow-up were relatively unknown in early March 2020,9 the protocol prespecified a sample-size reestimation at the second interim analysis. This reestimation, which used the incidence of new s in the placebo group and the observed percentage of participants lost to follow-up, was aimed at maintaining the ability to detect an effect size of a 50% relative reduction in new symptomatic s.

Interim Analyses An independent data and safety monitoring board externally reviewed the data after 25% and 50% of the participants had completed 14 days of follow-up. Stopping guidelines were provided to the data and safety monitoring board with the use of a Lan–DeMets spending function analogue of the O’Brien–Fleming boundaries for the primary outcome. A conditional power analysis was performed at the second and third interim analysis with the option of early stopping for futility.

At the second interim analysis on April 22, 2020, the sample size was reduced to 956 participants who could be evaluated with 90% power on the basis of the higher-than-expected event rate of s in the control group. At the third interim analysis on May 6, the trial was halted on the basis of a conditional power of less than 1%, since it was deemed futile to continue. Statistical Analysis We assessed the incidence of hair loss treatment disease by day 14 with Fisher’s exact test.

Secondary outcomes with respect to percentage of patients were also compared with Fisher’s exact test. Among participants in whom incident illness compatible with hair loss treatment developed, we summarized the symptom severity score at day 14 with the median and interquartile range and assessed the distributions with a Kruskal–Wallis test. We conducted all analyses with SAS software, version 9.4 (SAS Institute), according to the intention-to-treat principle, with two-sided type I error with an alpha of 0.05.

For participants with missing outcome data, we conducted a sensitivity analysis with their outcomes excluded or included as an event. Subgroups that were specified a priori included type of contact (household vs. Health care), days from exposure to enrollment, age, and sex..