Variation in Specificity of HIV Rapid Diagnostic Tests over Place and Time: An Analysis of Discordancy Data Using a Bayesian Approach

BACKGROUND Recent trends to earlier access to anti-retroviral treatment underline the importance of accurate HIV diagnosis. The WHO HIV testing strategy recommends the use of two or three rapid diagnostic tests (RDTs) combined in an algorithm and assume a population is serologically stable over time. Yet RDTs are prone to cross reactivity which can lead to false positive or discordant results. This paper uses discordancy data from Médecins Sans Frontières (MSF) programmes to test the hypothesis that the specificity of RDTs change over place and time. METHODS Data was drawn from all MSF test centres in 2007-8 using a parallel testing algorithm. A Bayesian approach was used to derive estimates of disease prevalence, and of test sensitivity and specificity using the software WinBUGS. A comparison of models with different levels of complexity was performed to assess the evidence for changes in test characteristics by location and over time. RESULTS 106, 035 individuals were included from 51 centres in 10 countries using 7 different RDTs. Discordancy patterns were found to vary by location and time. Model fit statistics confirmed this, with improved fit to the data when test specificity and sensitivity were allowed to vary by centre and over time. Two examples show evidence of variation in specificity between different testing locations within a single country. Finally, within a single test centre, variation in specificity was seen over time with one test becoming more specific and the other less specific. CONCLUSION This analysis demonstrates the variable specificity of multiple HIV RDTs over geographic location and time. This variability suggests that cross reactivity is occurring and indicates a higher than previously appreciated risk of false positive HIV results using the current WHO testing guidelines. Given the significant consequences of false HIV diagnosis, we suggest that current testing and evaluation strategies be reviewed.The authors have no funding or support to report

Transformation in a changing climate: a research agenda

The concept of transformation in relation to climate and other global change is increasingly receiving attention. The concept provides important opportunities to help examine how rapid and fundamental change to address contemporary global challenges can be facilitated. This paper contributes to discussions about transformation by providing a social science, arts and humanities perspective to open up discussion and set out a research agenda about what it means to transform and the dimensions, limitations and possibilities for transformation. Key focal areas include: (1) change theories, (2) knowing whether transformation has occurred or is occurring; (3) knowledge production and use; (4), governance; (5) how dimensions of social justice inform transformation; (6) the limits of human nature; (7) the role of the utopian impulse; (8) working with the present to create new futures; and (9) human consciousness. In addition to presenting a set of research questions around these themes the paper highlights that much deeper engagement with complex social processes is required; that there are vast opportunities for social science, humanities and the arts to engage more directly with the climate challenge; that there is a need for a massive upscaling of efforts to understand and shape desired forms of change; and that, in addition to helping answer important questions about how to facilitate change, a key role of the social sciences, humanities and the arts in addressing climate change is to critique current societal patterns and to open up new thinking. Through such critique and by being more explicit about what is meant by transformation, greater opportunities will be provided for opening up a dialogue about change, possible futures and about what it means to re-shape the way in which people live

Perinatal outcomes after admission with COVID-19 in pregnancy:a UK national cohort study

There are few population-based studies of sufficient size and follow-up duration to have reliably assessed perinatal outcomes for pregnant women hospitalised with SARS-CoV-2 infection. The United Kingdom Obstetric Surveillance System (UKOSS) covers all 194 consultant-led UK maternity units and included all pregnant women admitted to hospital with an ongoing SARS-CoV-2 infection. Here we show that in this large national cohort comprising two years’ active surveillance over four SARS-CoV-2 variant periods and with near complete follow-up of pregnancy outcomes for 16,627 included women, severe perinatal outcomes were more common in women with moderate to severe COVID-19, during the delta dominant period and among unvaccinated women. We provide strong evidence to recommend continuous surveillance of pregnancy outcomes in future pandemics and to continue to recommend SARS-CoV-2 vaccination in pregnancy to protect both mothers and babies

Estimating the incidence of acute infectious intestinal disease in the community in the UK:A retrospective telephone survey

Objectives: To estimate the burden of intestinal infectious disease (IID) in the UK and determine whether disease burden estimations using a retrospective study design differ from those using a prospective study design. Design/Setting: A retrospective telephone survey undertaken in each of the four countries comprising the United Kingdom. Participants were randomly asked about illness either in the past 7 or 28 days. Participants: 14,813 individuals for all of whom we had a legible recording of their agreement to participate Outcomes: Self-reported IID, defined as loose stools or clinically significant vomiting lasting less than two weeks, in the absence of a known non-infectious cause. Results: The rate of self-reported IID varied substantially depending on whether asked for illness in the previous 7 or 28 days. After standardising for age and sex, and adjusting for the number of interviews completed each month and the relative size of each UK country, the estimated rate of IID in the 7-day recall group was 1,530 cases per 1,000 person-years (95% CI: 1135 – 2113), while in the 28-day recall group it was 533 cases per 1,000 person-years (95% CI: 377 – 778). There was no significant variation in rates between the four countries. Rates in this study were also higher than in a related prospective study undertaken at the same time. Conclusions: The estimated burden of disease from IID varied dramatically depending on study design. Retrospective studies of IID give higher estimates of disease burden than prospective studies. Of retrospective studies longer recall periods give lower estimated rates than studies with short recall periods. Caution needs to be exercised when comparing studies of self-reported IID as small changes in study design or case definition can markedly affect estimated rates

“I didn’t realise I was such a sausage”: Men’s Accounts of Whole-body Scanning, Body Image, and Expected Changes in Health-related Behaviours

Objective: Whole-body scanning is now available in stores to assist buyers in choosing well-fitting clothes. This study was designed to investigate men’s accounts of scanning, body image, and expectations of behaviour change. Design: Ten men aged 18-39 years without histories of eating disorders or previous experience of whole-body scanning, took part in semi-structured interviews before and after scanning. Data were analysed using inductive thematic analysis. Results: Pre-scan, men’s body ideals were tall, slender, and relatively muscular. Post-scan, seven reported looking shorter, fatter, thinner, and/or less symmetrical than they hoped; three were pleasantly surprised by the images. Men were interested in scans as an objective view of their bodies and as a “wake-up call” to motivate healthy behaviours. Five men intended to change their behaviour as a result of scanning, and repeat scanning was seen as a good way to monitor behavioural changes. Participants suggested that scanning may raise body concerns in other men, though downplayed impacts on their own body image. Conclusion: Whole-body scanning may encourage men to exercise and eat more healthily. However, men became more negative about their bodies as a result of seeing their body scans, so scanning needs to be carried out with supervision and support

Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial

Background Treatment of chronic lymphocytic leukaemia (CLL) has seen a substantial improvement over the last few years. Combination immunochemotherapy, such as fludarabine, cyclophosphamide and rituximab (FCR), is now standard first-line therapy. However, the majority of patients relapse and require further therapy, and so new, effective, targeted therapies that improve remission rates, reduce relapses, and have fewer side effects, are required. The FLAIR trial will assess whether ibrutinib plus rituximab (IR) is superior to FCR in terms of progression-free survival (PFS). Methods/design FLAIR is a phase III, multicentre, randomised, controlled, open, parallel-group trial in patients with previously untreated CLL. A total of 754 participants will be randomised on a 1:1 basis to receive standard therapy with FCR or IR. Participants randomised to FCR will receive a maximum of six 28-day treatment cycles. Participants randomised to IR will receive six 28-day cycles of rituximab, and ibrutinib taken daily for 6 years until minimal residual disease (MRD) negativity has been recorded for the same amount of time as it took to become MRD negative, or until disease progression. The primary endpoint is PFS according to the International Workshop on CLL (IWCLL) criteria. Secondary endpoints include: overall survival; proportion of participants with undetectable MRD; response to therapy by IWCLL criteria; safety and toxicity; health-related quality of life (QoL); and cost-effectiveness. Discussion The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of PFS, and whether toxicity rates are favourable. Trial registration ISRCTN01844152. Registered on 8 August 2014, EudraCT number 2013-001944-76. Registered on 26 April 2013

GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) trial: study protocol for a phase II/III randomised controlled trial

Background: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Achieving minimal residual disease (MRD) negativity in CLL is an independent predictor of survival even with a variety of different treatment approaches and regardless of the line of therapy. Methods/design: GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) is a seamless phase II/III, multi-centre, randomised, controlled, open, parallel-group trial for patients with CLL who have recently responded to chemotherapy. Participants will be randomised to receive either obinutuzumab (GA-101) consolidation or no treatment (as is standard). The phase II trial will assess safety and short-term efficacy in order to advise on continuation to a phase III trial. The primary objective for phase III is to assess the effect of consolidation therapy on progression-free survival (PFS). One hundred eighty-eight participants are planned to be recruited from forty research centres in the United Kingdom. Discussion: There is evidence that achieving MRD eradication with alemtuzumab consolidation is associated with improvements in survival and time to progression. This trial will assess whether obinutuzumab is safe in a consolidation setting and effective at eradicating MRD and improving PFS. Trial registration: ISRCTN, 64035629. Registered on 12 January 2015. EudraCT, 2014-000880-42. Registered on 12 November 2014

epiCaPture: a urine DNA methylation test for early detection of aggressive prostate cancer

Purpose Liquid biopsies that noninvasively detect molecular correlates of aggressive prostate cancer (PCa) could be used to triage patients, reducing the burdens of unnecessary invasive prostate biopsy and enabling early detection of high-risk disease. DNA hypermethylation is among the earliest and most frequent aberrations in PCa. We investigated the accuracy of a six-gene DNA methylation panel (Epigenetic Cancer of the Prostate Test in Urine [epiCaPture]) at detecting PCa, high-grade (Gleason score greater than or equal to 8) and high-risk (D'Amico and Cancer of the Prostate Risk Assessment] PCa from urine. Patients and Methods Prognostic utility of epiCaPture genes was first validated in two independent prostate tissue cohorts. epiCaPture was assessed in a multicenter prospective study of 463 men undergoing prostate biopsy. epiCaPture was performed by quantitative methylation-specific polymerase chain reaction in DNA isolated from prebiopsy urine sediments and evaluated by receiver operating characteristic and decision curves (clinical benefit). The epiCaPture score was developed and validated on a two thirds training set to one third test set. Results Higher methylation of epiCaPture genes was significantly associated with increasing aggressiveness in PCa tissues. In urine, area under the receiver operating characteristic curve was 0.64, 0.86, and 0.83 for detecting PCa, high-grade PCa, and highrisk PCa, respectively. Decision curves revealed a net benefit across relevant threshold probabilities. Independent analysis of two epiCaPture genes in the same clinical cohort provided analytical validation. Parallel epiCaPture analysis in urine and matched biopsy cores showed added value of a liquid biopsy. Conclusion epiCaPture is a urine DNA methylation test for high-risk PCa. Its tumor specificity out-performs that of prostate-specific antigen (greater than 3 ng/mL). Used as an adjunct to prostate-specific antigen, epiCaPture could aid patient stratification to determine need for biopsy

Obesity Prevalence and Dietary Factors Among Preschool-Aged Head Start Children in Remote Alaska Native Communities: Baseline Data from the ‘‘Got Neqpiaq?’’ Study

Background: American Indian and Alaska Native preschool-aged children experience a high prevalence of obesity, yet are underrepresented in obesity prevention research. This study examined obesity prevalence and dietary risk factors among Alaska Native preschool-aged children in southwest Alaska. Methods: The study used baseline data from ‘‘Got Neqpiaq?’’ a culturally centered multilevel intervention focused on Yup’ik Alaska Native children, aged 3–5 years, enrolled in Head Start in 12 communities in southwest Alaska (n = 155). The primary outcomes were BMI percentile, overweight, and obesity. Dietary factors of interest were measured using biomarkers: traditional food intake (nitrogen stable isotope ratio biomarker), ultraprocessed food intake (carbon stable isotope ratio biomarker), and vegetable and fruit intake (skin carotenoid status biomarker measured by the Veggie Meter). Cardiometabolic markers (glycated hemoglobin [HbA1c] and blood cholesterol) were also measured. Results: Among the Yup’ik preschool-aged children in the study, the median BMI percentile was 91, and the prevalence of overweight or obesity was 70%. The traditional food intake biomarker was negatively associated with BMI, whereas the ultraprocessed foods and vegetable and fruit biomarkers were not associated with BMI. HbA1c and blood cholesterol were within healthy levels. Conclusions: The burden of overweight and obesity is high among Yup’ik preschool-aged children. Traditional food intake is inversely associated with BMI, which underscores the need for culturally grounded interventions that emphasize traditional values and knowledge to support the traditional food systems in Alaska Native communities in southwest Alaska. Registered with ClinicalTrials.gov #NCT03601299.Ye

Cytomegalovirus distribution and evolution in hominines

Herpesviruses are thought to have evolved in very close association with their hosts. This is notably the case for cytomegaloviruses (CMVs; genus Cytomegalovirus) infecting primates, which exhibit a strong signal of co-divergence with their hosts. Some herpesviruses are however known to have crossed species barriers. Based on a limited sampling of CMV diversity in the hominine (African great ape and human) lineage, we hypothesized that chimpanzees and gorillas might have mutually exchanged CMVs in the past. Here, we performed a comprehensive molecular screening of all 9 African great ape species/subspecies, using 675 fecal samples collected from wild animals. We identified CMVs in eight species/subspecies, notably generating the first CMV sequences from bonobos. We used this extended dataset to test competing hypotheses with various degrees of co-divergence/number of host switches while simultaneously estimating the dates of these events in a Bayesian framework. The model best supported by the data involved the transmission of a gorilla CMV to the panine (chimpanzee and bonobo) lineage and the transmission of a panine CMV to the gorilla lineage prior to the divergence of chimpanzees and bonobos, more than 800,000 years ago. Panine CMVs then co-diverged with their hosts. These results add to a growing body of evidence suggesting that viruses with a double-stranded DNA genome (including other herpesviruses, adenoviruses, and papillomaviruses) often jumped between hominine lineages over the last few million years.Peer Reviewe