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ObjectiveTo measure the association between self-reported signs and symptoms and SARS-CoV-2 seropositivity.DesignCross-sectional study of three key worker groups.SettingSix acute NHS hospitals and two Police and Fire and Rescue sites in England.ParticipantsIndividuals were recruited from three streams: (A) Police and Fire and Rescue services (n = 1147), (B) healthcare workers (n = 1546) and (C) healthcare workers with previously positive virus detection (n = 154).Main outcome measuresDetection of anti-SARS-CoV-2 antibodies in plasma.Results943 of the 2847 participants (33%) reported belief they had had COVID-19, having experienced compatible symptoms (including 152 from Stream C). Among individuals reporting COVID-19 compatible symptoms, 466 (49%) were seronegative on both Nucleoprotein (Roche) and Spike-protein (EUROIMMUN) antibody assays. However, among the 268 individuals with prior positive SARS-CoV-2 tests, of whom 96% reported symptoms with onset a median of 63 days (IQR 52 – 75 days) prior to venesection, Roche and EUROIMMUN assays had 96.6% (95% CI 93.7% – 98.2%) and 93.3% (95% CI 89.6% – 95.7%) sensitivity respectively. Symptomatic but seronegative individuals had significantly earlier symptom onset dates than the symptomatic seropositive individuals, shorter illness duration and a much lower anosmia reporting frequency.ConclusionsSelf-reported belief of COVID-19 was common among our frontline worker cohort. About half of these individuals were seronegative, despite a high sensitivity of serology in this cohort, at least in individuals with previous positive PCR results. This is compatible with non-COVID-19 respiratory disease during the COVID-19 outbreak having been commonly mistaken for COVID-19 within the key worker cohort studied.What is already known on this topicScreening for SARS-CoV-2 antibodies is under way in some key worker groups; however, how this adds to self-reported COVID-19 illness is unclear. There are limited studies that investigate the association between self-reported belief of COVID-19 illness and seropositivity.What this study addsAbout one third of a large cohort of key frontline workers believed they had had COVID-19 infection. In around half of these there was no serological evidence of infection. Individuals who believed they had previous infection, but were seronegative, differed systematically from the seropositive individuals: disordered sense of taste and smell was less common, illness duration was shorter, and reported onset of illness commonly predated the main COVID-19 epidemic in the UK.Although some individuals with previous COVID-19 may be seronegative, among symptomatic individuals who had PCR-confirmed SARS-CoV-2 within our cohort, sensitivity of the two immunoassays used (Roche Elecsys ® and EUROIMMUN) exceeded 90%. Together, these data indicate that many key workers may falsely believe, based on symptomatic illness experienced during 2020, that they have had COVID-19. Further research investigating the relationship between antibody detection and protection from future infection, with and without a history of COVID-19 disease, will help define the role serological testing can play in clinical practice.

We evaluate the utility of the National Surveys of Attitudes and Sexual Lifestyles (Natsal) undertaken in 2000 and 2010, before and after the introduction of the National Chlamydia Screening Programme, as an evidence source for estimating the change in prevalence ofChlamydia trachomatis(CT) in England, Scotland and Wales. Both the 2000 and 2010 surveys tested urine samples for CT by Nucleic Acid Amplification Tests (NAATs). We examined the sources of uncertainty in estimates of CT prevalence change, including sample size and adjustments for test sensitivity and specificity, survey non-response and informative non-response. In 2000, the unadjusted CT prevalence was 4.22% in women aged 18–24 years; in 2010, CT prevalence was 3.92%, a non-significant absolute difference of 0.30 percentage points (95% credible interval −2.8 to 2.0). In addition to uncertainty due to small sample size, estimates were sensitive to specificity, survey non-response or informative non-response, such that plausible changes in any one of these would be enough to either reverse or double any likely change in prevalence. Alternative ways of monitoring changes in CT incidence and prevalence over time are discussed.

We present the findings and recommendations of a recent NICE Technical Support Document (available from http://www.nicedsu.org.uk/) regarding the use of population-adjusted treatment comparisons in health technology appraisal.Standard methods for indirect comparisons and network meta-analysis are based on aggregate data, with the key assumption that there is no difference between trials in the distribution of effect-modifying variables. Two methods which relax this assumption, Matching-Adjusted Indirect Comparison (MAIC) and Simulated Treatment Comparison (STC), are becoming increasingly common in industry-sponsored treatment comparisons, where a company has access to individual patient data (IPD) from its own trials but only aggregate data from competitor trials. Both methods use IPD to adjust for between-trial differences in covariate distributions. Despite their increasing popularity, there is a distinct lack of clarity about how and when these methods should be applied. We review the properties of these methods, and identify the key assumptions. Notably, there is a fundamental distinction between “anchored” and “unanchored” forms of indirect comparison, where a common comparator arm is or is not utilised to control for between-trial differences in prognostic variables, with the unanchored comparison making assumptions that are infeasibly strong. Furthermore, both MAIC and STC as currently applied can only produce estimates that are valid for the populations in the competitor trials, which do not necessarily represent the decision population. We provide recommendations on how and when population adjustment methods should be used to provide statistically valid, clinically meaningful, transparent and consistent results.

SummaryWe investigate whether Bayesian decision theory, in the form of expected value of partial perfect information (EVPPI) analysis, is a realistic and practical approach to research prioritization. We develop a simple cost-effectiveness analysis of breast cancer screening as a typical case-study, motivated by data from a cluster randomized 2 × 2 factorial trial of interventions to increase uptake. An EVPPI analysis is developed which shows that, on the basis of the evidence that was available beforehand, the trial was cost effective, but that after incorporating the results of the trial it would still be cost effective to carry out research that further reduced decision uncertainty. We identify key conceptual and technical issues: the relationship between the target interventions and the previous evidence, the distinction between variation and uncertainty and methods for correlated parameters. EVPPI methods have clear advantages over current methods of research prioritization, but we suggest that some specific sensitivity analyses are required before they can be used confidently in practice. These have limitations, and there is a need to develop robust methods to optimize research portfolios.

Background— Our objective was to estimate the comparative harms of individual statins using both placebo-controlled and active-comparator trials. Methods and Results— We systematically reviewed randomized trials evaluating different statins in participants with and without cardiovascular disease. We performed random-effects pairwise and network meta-analyses to quantify the relative harms of individual statins. We included 55 two-armed placebo-controlled and 80 two- or multiarmed active-comparator trials including 246 955 individuals. According to pairwise meta-analyses, individual statins were not different than control in terms of myalgia, creatine kinase elevation, cancer, and discontinuations because of adverse events. Statins as a class resulted in significantly higher odds of diabetes mellitus (odds ratio, 1.09; 95% confidence interval, 1.02–1.16) and transaminase elevations (odds ratio, 1.51; 95% confidence interval, 1.24–1.84) compared with control. When individual statins were compared in network meta-analyses, there were numerous statistically detectable differences, favoring simvastatin and pravastatin. According to dose-level comparisons, individual statins resulted in higher odds of discontinuations with higher doses of atorvastatin and rosuvastatin. Similarly, higher doses of atorvasatin, fluvastatin, lovastatin, and simvastatin were associated with higher odds of transaminase elevations. Simvastatin at its highest doses was associated with creatine kinase elevations (odds ratio, 4.14; 95% credible interval, 1.08–16.24). Meta-regression analyses adjusting for study-level age at baseline, low-density lipoprotein cholesterol level, and publication year did not explain heterogeneity. There was no detectable inconsistency in the network. Conclusions— As a class, adverse events associated with statin therapy are not common. Statins are not associated with cancer risk but do result in a higher odds of diabetes mellitus. Among individual statins, simvastatin and pravastatin seem safer and more tolerable than other statins.

Objective : To assess the value of CD4 T cell count in predicting Pneumocystis carinii pneumonia in infants born to mothers infected with HIV, with reference to the guidelines from the Centers for Disease Control on prophylaxis against pneumocystis. Design : Prospective birth cohort study. Setting : Hospitals in 10 European cities participating in the European collaborative study. Subjects : 924 children born to mothers known to be infected with HIV at or before delivery. Main outcome measures - The incidence of P carinii pneumonia. CD4 T cell counts in children before diagnosis of the pneumonia. The proportions of children infected and uninfected with HIV who fulfilled the criteria for primary prophylaxis. Results : Fourteen children were diagnosed with P carinii pneumonia. The cumulative incidence by the age of 6 years was 2% (95% confidence interval 0.9 to 3.0%). Of the 11 children with a CD4 T cell count predating diagnosis, only three fulfilled the criteria from the Centers for Disease Control for prophylaxis. Prophylaxis was indicated by 1 year of age for 62% of infected children who had not developed P carinii pneumonia and for at least 10% of uninfected children. Conclusions : Monitoring CD4 T cell count seems to be of limited value in deciding when to start prophylaxis against P carinii pneumonia in children born to mothers infected with HIV. The alternative approach of giving prophylaxis to all children born to infected mothers would be difficult to justify given the low incidence of the pneumonia.

We share many of Bero’s concerns regarding the industry sponsorship of research.1 2 3 Studies of industry sponsorship bias must take account of real differences between products and doses. We have shown previously that higher dose statins achieve greater cholesterol reductions from baseline than lower dose ones.4 Taking account of dose differences, and thereby comparing like …

Background Chlamydia trachomatis (CT) is an important risk factor for the development of Pelvic Inflammatory Disease (PID), but despite much study the extent of its causal role remains unclear. Knowledge of the role of Chlamydia is critical for assessing the cost-effectiveness of screening programmes. Methods We perform a Bayesian multi-parameter synthesis of evidence from a range of prospective, retrospective, and routine data sources. These were; randomised trials following screened and unscreened women to PID; retrospective studies of Chlamydia in PID cases and controls, from which an etiologic fraction can be estimated; routine data on the number of PID cases diagnosed in England in 1 year; survey data on the probability of diagnosis of PID. We also used information on the incidence and prevalence of CT in England and the clearance rate of asymptomatic infection. Results We found that the different data sources provided consistent estimates of the critical parameters. We estimate the probability an episode of Chlamydia causes an episode of PID to be 0.09 (0.04 to 0.16) and that the Excess fraction of PID cases due to Chlamydia to be 0.20 (0.09 to 0.35). We estimate that prior to the start of the current screening program in the UK the annual population incidence of PID in women in England was 0.022 (0.016 to 0.028) in women aged 16−24 and 0.013 (0.009 to 0.019) in women aged 25−44 and that 42% (31% to 54%) of these cases were diagnosed. Conclusions In the absence of direct data, it is possible to statistically combine evidence from different types of data, to check the consistency of the data sources, and to estimate the relation between CT and PID. In considering the effect on PID risk of treating women who screen positive for Chlamydia, it is important to note that this is a survivor population who acquired CT an unknown time previously and who have not developed PID.

Introduction Biologic therapies are efficacious but costly. A number of health economic models have been developed to determine the most cost-effective way of using them in the treatment pathway. These models have produced conflicting results, driven by differences in assumptions, model structure, and data, which undermine the credibility of funding decisions based on modeling studies. A Consensus Working Party met to discuss recommendations and approaches for future models of biologic therapies. Methods Our working party consisted of clinical specialists, modelers, and policy makers. Two 1-day meetings were held for members to arrive at consensus positions on model structure, assumptions, and appropriate data sources. These views were guided by clinical aspects of rheumatoid and psoriatic arthritis and the principles of evidence-based medicine. Where opinions differed, we sought to identify a research agenda that would generate the evidence needed to reach consensus. Results We gained consensus in four areas of model development: initial response to treatment; long-term disease progression; lifetime costs and benefits; and model structure. Consensus was also achieved on some key parameters such as choices of outcome measures, methods for extrapolation beyond trial data, and treatment switching. A research agenda to support further consensus was also identified. Conclusion Consensus guidance that fully reflects current evidence and clinical understanding was gained successfully. In addition, research needs have been identified. Such guidance can be updated as evidence develops and policy questions change and need not be prescriptive as long as deviations from consensus are clearly explained and justified. Funding Arthritis Research UK and the UK Medical Research Council Network of Hubs for Trials Methodology Research. Electronic supplementary material The online version of this article (doi:10.1007/s40744-015-0020-0) contains supplementary material, which is available to authorized users.

Papua New Guinea (PNG) is one of the world's least “developed” countries. A third of its three million people have only emerged from the neolithic age over the past 40 years. The people are divided by mountain ranges reaching 4,700m, torrential rivers, forests, ravines, seas, malarial swamps and language — more than 700 are spoken. But in the five years since independence from Australia, the government has launched an ambitious Improvement Plan, under which western science and technology are being introduced enthusiastically. All projects are funded by the National Public Expenditure Plan, which absorbs 21% of all spending. The main national aims are equal distribution of development among a population that is 85% rural and largely dependent on subsistence farming and a reduction in the number of western expatriates on whom development still largely depends. Both aims are meeting with mixed results, as Tony Ades reports

Tony Ades reports on unorthodox efforts by radical Dutch scientists to match their work to the needs of society