Search

Abstract We developed a composite symptom score (CSS) representing disease-related symptom burden over time in patients with malignant pleural mesothelioma (MPM). Longitudinal data were collected from an open-label Phase IIB study in which 239 patients completed the validated MD Anderson Symptom Inventory for MPM (MDASI-MPM). A blinded, independent review committee of external patient-reported outcomes experts advised on MDASI-MPM symptoms to include in the CSS. Through iterative analyses of potential symptom-item combinations, 5 MPM symptoms (pain, fatigue, shortness of breath, muscle weakness, coughing) were selected. The CSS correlated strongly with the full MDASI-MPM symptom set (0.92–0.94) and the Lung Cancer Symptom Scale-Mesothelioma (0.79–0.87) at each co-administration of the scales. The CSS also had good sensitivity to worsening disease and global quality-of-life ratings. The MDASI-MPM CSS can be used as an outcome in MPM clinical trials, including in responder analyses and at the individual patient level. It is brief enough to administer frequently, including electronically, to better capture symptom trajectories during and after a trial and in clinical practice. As a single score, the CSS addresses multiplicity issues that can arise when several symptoms increase due to worsening disease. Our process can be adapted to produce a CSS for other advanced-cancer trials.

Quentin M Anstee,1,2 Kate Hallsworth,1,2 Niall Lynch,3 Adrien Hauvespre,4 Eid Mansour,5 Sam Kozma,5 Juliana Bottomley,6 Gary Milligan,7 James Piercy,8 Victoria Higgins9 1Translational & Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle, Newcastle Upon Tyne, UK; 2Liver Unit, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; 3Global Value and Access, Gilead Sciences, Hayes, Uxbridge, UK; 4Market Access and Reimbursement, Gilead Sciences, Hayes, Uxbridge, UK; 5Pricing and Market Access (Middle East), Gilead Sciences, Dubai, United Arab Emirates; 6Pricing and Market Access, Gilead Sciences, Hayes, Uxbridge, UK; 7Statistics Department, Adelphi Real World, Bollington, UK; 8Scientific Franchise, Adelphi Real World, Bollington, UK; 9Scientific and NASH Franchise, Adelphi Real World, Bollington, UKCorrespondence: Victoria Higgins, Adelphi Real World, Adelphi Mill, Grimshaw Lane, Bollington, SK10 5JB, UK, Tel +44 1625 577233, Email victoria.higgins@adelphigroup.comObjective: Stratifying disease severity in patients with non-alcoholic steatohepatitis (NASH) is essential for appropriate treatment and long-term management. Liver biopsy is the reference standard for fibrosis severity in NASH, but less invasive methods are used, eg, Fibrosis-4 Index (FIB-4) and vibration-controlled transient elastography (VCTE), for which reference thresholds for no/early fibrosis and advanced fibrosis are available. We compared subjective physician assessment of NASH fibrosis versus reference thresholds to understand classification in a real-world setting.Methods: Data were drawn from Adelphi Real World NASH Disease Specific ProgrammeTM conducted in France, Germany, Italy, Spain and UK in 2018. Physicians (diabetologists, gastroenterologists, hepatologists) completed questionnaires for five consecutive NASH patients presenting for routine care. Physician-stated fibrosis score (PSFS) based on available information was compared with clinically defined reference fibrosis stage (CRFS) determined retrospectively using VCTE and FIB-4 data and eight reference thresholds.Results: One thousand two hundred and eleven patients had VCTE (n = 1115) and/or FIB-4 (n = 524). Depending on thresholds, physicians underestimated severity in 16– 33% (FIB-4) and 27– 50% of patients (VCTE). Using VCTE ≥ 12.2, diabetologists, gastroenterologists and hepatologists underestimated disease severity in 35%, 32%, and 27% of patients, respectively, and overestimated fibrosis in 3%, 4%, and 9%, respectively (p = 0.0083 across specialties). Hepatologists and gastroenterologists had higher liver biopsy rates than diabetologists (52%, 56%, 47%, respectively).Conclusion: PSFS did not consistently align with CRFS in this NASH real-world setting. Underestimation was more common than overestimation, potentially leading to undertreatment of patients with advanced fibrosis. More guidance on interpreting test results when classifying fibrosis is needed, thereby improving management of NASH.Keywords: fibrosis staging, non-alcoholic steatohepatitis, clinically derived reference fibrosis score, physician-stated fibrosis score, real-world evidence

Abstract The relatively stable aquatic conditions of irrigated lowland and rainfed rice, which is grown across 145 million hectares in more than 100 countries, are capable of generating large numbers of mosquito vectors of malaria, which causes more than 400,000 deaths per year worldwide. Many methods can control these vectors, but a systematic review has not previously been conducted. This study assesses whether larviciding, fish or intermittent irrigation can significantly reduce malaria vectors in rice fields whilst increasing rice yield. After a literature search for studies reporting the effect of larval control and rice cultivation practices on malaria vector densities in rice fields, 33 studies were eligible for meta-analysis. Larviciding was effective at reducing rice-field malaria vectors. Pooled analysis of five controlled time-series (CTS) studies with chemical insecticides showed an overall combined reduction of larval densities of 77% compared to no larviciding. Eight CTSs with biological larvicides showed a pooled reduction of 60% compared to no larviciding. Cultivating rice and fish together provided good control too: a pooled analysis of three CTSs showed an overall 82% reduction in anopheline larvae compared to no fish. Pooled analysis of four studies suggested that intermittent irrigation (using various timings and frequencies of drainage) is effective at reducing the abundance of late-stage anopheline larvae (pooled reduction = − 35%), but not overall immature abundance, compared to continuous flooding. We conclude that many interventions such as larvicides, fish and intermittent irrigation can provide riceland malaria vector control, but the critical obstacle to wider use is farmer acceptability. Future research should be led by the agricultural sector, with inputs from entomologists, to investigate malaria control co-benefits within high-yielding rice cultivation practices.

Background: The Kilifi Health and Demographic Surveillance System (KHDSS) was established in 2000 to define the incidence and prevalence of local diseases and evaluate the impact of community-based interventions. KHDSS morbidity data have been reported comprehensively but mortality has not been described. This analysis describes mortality in the KHDSS over 16 years. Methods: We calculated mortality rates from 2003–2018 in four intervals of equal duration and assessed differences in mortality across these intervals by age and sex. We calculated the period survival function and median survival using the Kaplan–Meier method and mean life expectancies using abridged life tables. We estimated trend and seasonality by decomposing a time series of monthly mortality rates. We used choropleth maps and random-effects Poisson regression to investigate geographical heterogeneity. Results: Mortality declined by 36% overall between 2003–2018 and by 59% in children aged

Objectives To establish barriers and motivators underlying research engagement among early-career practitioners in nephrology across the UK, in order to guide potential interventions to enhance research involvement in renal units.Design Cross-sectional online survey employing a range of free-text, Likert scale and binomial/multiple-choice responses, distributed via mailing lists and social media. Topics covered research experience, research involvement and barriers, impact of COVID-19 and strategies to improve research engagement. Thematic analysis was used to assess free-text responses.Setting Renal units throughout the UK.Participants Non-consultant healthcare staff self-identifying as working in nephrology were included (n=211), with responses from non-UK respondents or consultant nephrologists excluded (n=12).Results Responses were received from across the multidisciplinary team (physicians (n=83) and nurses (n=83)) and other allied health professionals (n=45). Most were aware of ongoing local research, but under half of them were actively involved. Multivariate analysis indicated employment as a physician, protected time for research activity and provision of appropriate training were associated with greater research experience and output. There was general enthusiasm to undertake research, but perceived barriers included insufficient staffing, lack of time, funding and encouragement. COVID-19 was felt to have further impacted negatively upon opportunities. Among the suggested strategies to promote engagement, mentorship and an online research resource were felt to be of most interest.Conclusions In the first survey of this type in nephrology, we demonstrate differences across the multidisciplinary spectrum in perceived research experience and accessibility, which have been worsened by COVID-19. Our findings will guide strategies to broaden engagement in early-career practitioners and serve as a baseline to assess the impact of these interventions.

Background: Gastrointestinal symptoms are commonly associated with acute Plasmodium spp infection. Malaria-associated enteritis may provide an opportunity for enteric pathogens to breach the intestinal mucosa, resulting in life-threatening systemic infections. Methods: To investigate whether intestinal pathology also occurs during infection with a murine model of mild and resolving malaria, C57BL/6J mice were inoculated with recently mosquito-transmitted Plasmodium chabaudi AS. At schizogony, intestinal tissues were collected for quantification and localisation of immune mediators and malaria parasites, by PCR and immunohistochemistry. Inflammatory proteins were measured in plasma and faeces and intestinal permeability was assessed by FITC-dextran translocation after oral administration. Results: Parasitaemia peaked at approx. 1.5% at day 9 and resolved by day 14, with mice experiencing significant and transient anaemia but no weight loss. Plasma IFNγ, TNFα and IL10 were significantly elevated during peak infection and quantitative RT-PCR of the intestine revealed a significant increase in transcripts for ifng and cxcl10. Histological analysis revealed parasites within blood vessels of both the submucosa and intestinal villi and evidence of mild crypt hyperplasia. In faeces, concentrations of the inflammatory marker lactoferrin were significantly raised on days 9 and 11 and FITC-dextran was detected in plasma on days 7 to 14. At day 11, plasma FITC-dextran concentration was significantly positively correlated with peripheral parasitemia and faecal lactoferrin concentration. Conclusions: In summary, using a relevant, attenuated model of malaria, we have found that acute infection is associated with intestinal inflammation and increased intestinal permeability. This model can now be used to explore the mechanisms of parasite-induced intestinal inflammation and to assess the impact of increased intestinal permeability on translocation of enteropathogens.

BACKGROUND Sudden cardiac death (SCD) remains a worldwide public health problem in need of better noninvasive predictive tools. Current guidelines for primary preventive SCD therapies, such as implantable cardioverter defibrillators (ICDs), are based on left ventricular ejection fraction (LVEF), but these guidelines are imprecise: fewer than 5% of ICDs deliver lifesaving therapy per year. Impaired cardiac metabolism and ATP depletion cause arrhythmias in experimental models, but to our knowledge a link between arrhythmias and cardiac energetic abnormalities in people has not been explored, nor has the potential for metabolically predicting clinical SCD risk.METHODS We prospectively measured myocardial energy metabolism noninvasively with phosphorus magnetic resonance spectroscopy in patients with no history of significant arrhythmias prior to scheduled ICD implantation for primary prevention in the setting of reduced LVEF (≤35%).RESULTS By 2 different analyses, low myocardial ATP significantly predicted the composite of subsequent appropriate ICD firings for life-threatening arrhythmias and cardiac death over approximately 10 years. Life-threatening arrhythmia risk was approximately 3-fold higher in patients with low ATP and independent of established risk factors, including LVEF. In patients with normal ATP, rates of appropriate ICD firings were several-fold lower than reported rates of ICD complications and inappropriate firings.CONCLUSION To the best of our knowledge, these are the first data linking in vivo myocardial ATP depletion and subsequent significant arrhythmic events in people, suggesting an energetic component to clinical life-threatening ventricular arrhythmogenesis. The findings support investigation of metabolic strategies that limit ATP loss to treat or prevent life-threatening cardiac arrhythmias and herald noninvasive metabolic imaging as a complementary SCD risk stratification tool.TRIAL REGISTRATION ClinicalTrials.gov NCT00181233.FUNDING This work was supported by the DW Reynolds Foundation, the NIH (grants HL61912, HL056882, HL103812, HL132181, HL140034), and Russell H. Morgan and Clarence Doodeman endowments at Johns Hopkins.

Abstract Liquid biopsy testing utilising Next Generation Sequencing (NGS) is rapidly moving towards clinical adoption for personalised oncology. However, before NGS can fulfil its potential any novel testing approach must identify ways of reducing errors, allowing separation of true low-frequency mutations from procedural artefacts, and be designed to improve upon current technologies. Popular NGS technologies typically utilise two DNA capture approaches; PCR and ligation, which have known limitations and seem to have reached a development plateau with only small, stepwise improvements being made. To maximise the ultimate utility of liquid biopsy testing we have developed a highly versatile approach to NGS: Adaptor Template Oligo Mediated Sequencing (ATOM-Seq). ATOM-Seq's strengths and versatility avoid the major limitations of both PCR- and ligation-based approaches. This technology is ligation free, simple, efficient, flexible, and streamlined, and it offers novel advantages that make it perfectly suited for use on highly challenging clinical material. Using reference and clinical materials, we demonstrate detection of known SNVs down to allele frequencies of 0.1% using as little as 20–25 ng of cfDNA, as well as the ability to detect fusions from RNA. We illustrate ATOM-Seq’s suitability for clinical testing by showing high concordance rates between paired cfDNA and FFPE clinical samples.

Introduction The high proportion of SARS-CoV-2 infections that have remained undetected presents a challenge to tracking the progress of the pandemic and estimating the extent of population immunity. Methods We used residual blood samples from women attending antenatal care services at three hospitals in Kenya between August 2020 and October 2021and a validated IgG ELISA for SARS-Cov-2 spike protein and adjusted the results for assay sensitivity and specificity. We fitted a two-component mixture model as an alternative to the threshold analysis to estimate of the proportion of individuals with past SARS-CoV-2 infection. Results We estimated seroprevalence in 2,981 women; 706 in Nairobi, 567 in Busia and 1,708 in Kilifi. By October 2021, 13% of participants were vaccinated (at least one dose) in Nairobi, 2% in Busia. Adjusted seroprevalence rose in all sites; from 50% (95%CI 42–58) in August 2020, to 85% (95%CI 78–92) in October 2021 in Nairobi; from 31% (95%CI 25–37) in May 2021 to 71% (95%CI 64–77) in October 2021 in Busia; and from 1% (95% CI 0–3) in September 2020 to 63% (95% CI 56–69) in October 2021 in Kilifi. Mixture modelling, suggests adjusted cross-sectional prevalence estimates are underestimates; seroprevalence in October 2021 could be 74% in Busia and 72% in Kilifi. Conclusions There has been substantial, unobserved transmission of SARS-CoV-2 in Nairobi, Busia and Kilifi Counties. Due to the length of time since the beginning of the pandemic, repeated cross-sectional surveys are now difficult to interpret without the use of models to account for antibody waning.

Recombinant protein-based vaccines are a valid and safer alternative to traditional vaccines based on live-attenuated or killed pathogens. However, the immune response of subunit vaccines is generally lower compared to that elicited by traditional vaccines and usually requires the use of adjuvants. The use of self-assembling protein nanoparticles, as a platform for vaccine antigen presentation, is emerging as a promising approach to enhance the production of protective and functional antibodies. In this work we demonstrated the successful repetitive antigen display of the C-terminal β-barrel domain of factor H binding protein, derived from serogroup B Meningococcus on the surface of different self-assembling nanoparticles using genetic fusion. Six nanoparticle scaffolds were tested, including virus-like particles with different sizes, geometries, and physicochemical properties. Combining computational and structure-based rational design we were able generate antigen-fused scaffolds that closely aligned with three-dimensional structure predictions. The chimeric nanoparticles were produced as recombinant proteins in Escherichia coli and evaluated for solubility, stability, self-assembly, and antigen accessibility using a variety of biophysical methods. Several scaffolds were identified as being suitable for genetic fusion with the β-barrel from fHbp, including ferritin, a de novo designed aldolase from Thermotoga maritima, encapsulin, CP3 phage coat protein, and the Hepatitis B core antigen. In conclusion, a systematic screening of self-assembling nanoparticles has been applied for the repetitive surface display of a vaccine antigen. This work demonstrates the capacity of rational structure-based design to develop new chimeric nanoparticles and describes a strategy that can be utilized to discover new nanoparticle-based approaches in the search for vaccines against bacterial pathogens.

BackgroundThere is an increasing use of cesarean delivery (CD) based on preference rather than on medical indication. However, the extent to which nonmedically indicated CD benefits or harms child survival remains unclear. Our hypothesis was that in groups with a low indication for CD, this procedure would be associated with higher child mortality and in groups with a clear medical indication CD would be associated with improved child survival chances.Methods and findingsWe conducted a population-based cohort study in Brazil by linking routine data on live births between January 1, 2012 and December 31, 2018 and assessing mortality up to 5 years of age. Women with a live birth who contributed records during this period were classified into one of 10 Robson groups based on their pregnancy and delivery characteristics. We used propensity scores to match CD with vaginal deliveries (1:1) and prelabor CD with unscheduled CD (1:1) and estimated associations with child mortality using Cox regressions. A total of 17,838,115 live births were analyzed. After propensity score matching (PSM), we found that live births to women in groups with low expected frequencies of CD (Robson groups 1 to 4) had a higher death rate up to age 5 years if they were born via CD compared with vaginal deliveries (HR = 1.25, 95% CI: 1.22 to 1.28; p < 0.001). The relative rate was greatest in the neonatal period (HR = 1.39, 95% CI: 1.34 to 1.45; p < 0.001). There was no difference in mortality rate when comparing offspring born by a prelabor CD to those born by unscheduled CD. For the live births to women with a CD in a prior pregnancy (Robson group 5), the relative rates for child mortality were similar for those born by CD compared with vaginal deliveries (HR = 1.05, 95% CI: 1.00 to 1.10; p = 0.024). In contrast, for live births to women in groups with high expected rates of CD (Robson groups 6 to 10), the child mortality rate was lower for CD than for vaginal deliveries (HR = 0.90, 95% CI: 0.89 to 0.91; p < 0.001), particularly in the neonatal period (HR = 0.84, 95% CI: 0.83 to 0.85; p < 0.001). Our results should be interpreted with caution in clinical practice, since relevant clinical data on CD indication were not available.ConclusionsIn this study, we observed that in Robson groups with low expected frequencies of CD, this procedure was associated with a 25% increase in child mortality. However, in groups with high expected frequencies of CD, the findings suggest that clinically indicated CD is associated with a reduction in child mortality.

Patient-reported outcomes (PROs) are used in clinical trials to provide valuable evidence on the impact of disease and treatment on patients’ symptoms, function and quality of life. High-quality PRO data from trials can inform shared decision-making, regulatory and economic analyses and health policy. Recent evidence suggests the PRO content of past trial protocols was often incomplete or unclear, leading to research waste. To address this issue, international, consensus-based, PRO-specific guidelines were developed: the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)-PRO Extension. The SPIRIT-PRO Extension is a 16-item checklist which aims to improve the content and quality of aspects of clinical trial protocols relating to PRO data collection to minimise research waste, and ultimately better inform patient-centred care. This SPIRIT-PRO explanation and elaboration (E&E) paper provides information to promote understanding and facilitate uptake of the recommended checklist items, including a comprehensive protocol template. For each SPIRIT-PRO item, we provide a detailed description, one or more examples from existing trial protocols and supporting empirical evidence of the item’s importance. We recommend this paper and protocol template be used alongside the SPIRIT 2013 and SPIRIT-PRO Extension paper to optimise the transparent development and review of trial protocols with PROs.

Staphylococcus aureus bacteremia is a substantial cause of childhood disease and death, but few studies have described its epidemiology in developing countries. Using a population-based surveillance system for pneumonia, sepsis, and meningitis, we estimated S. aureus bacteremia incidence and the case-fatality ratio in children

The COVID-19 pandemic has hugely disrupted healthcare provision, including oncology services. To evaluate the effects of the pandemic on referral routes leading to diagnosis, treatments, and prognosis in patients with pancreatic ductal adenocarcinoma, we performed a retrospective cohort study at a single tertiary centre in the UK. The patients were identified from the weekly hepatopancreatobiliary multidisciplinary team meetings between February 2018 and March 2021. The demographic, referral, and treatment data for each patient and date of death, where applicable, were extracted from the electronic patient record. The patients (n = 203) were divided into “pre-pandemic” and “pandemic” cohorts based on a referral date cut-off of 23rd March 2020. The median survival was 7.4 months [4.9–9.3] in the “pre-pandemic” cohort (n = 125), halving to 3.3 months [2.2–6.0], (p = 0.015) in the “pandemic” cohort (n = 78). There was no significant difference in patient characteristics between the two cohorts. There was a trend toward increased emergency presentations at diagnosis and reduced use of surgical resection in the “pandemic” cohort. This small-scale study suggested that the COVID-19 pandemic is associated with a halving of median survival in pancreatic ductal adenocarcinoma. Urgent further studies are required to confirm these findings and examine corresponding effects in other cancer types.

Objectives To assess if there is any association between hyperemesis gravidarum (HG), psychological morbidity and infant bonding and to quantify any psychosocial consequences of HG.Design Two-point prospective case–control, multicentre survey study with antenatal and postnatal data collection.Setting Three London hospitals.Participants Pregnant women at ≤12 completed weeks gestation recruited consecutively over 2 years. Women with HG were recruited at the time of admission; controls recruited from a low risk antenatal clinic. 106 women were recruited to the case group and 108 to the control. Response rates at antenatal data collection were 87% and 85% in the case and control groups, respectively. Postnatally, the response rate was 90% in both groups.Primary and secondary outcome measures Primary outcomes were psychological morbidity in the antenatal and postnatal periods, infant bonding in the postnatal period and psychosocial implications of HG. Secondary outcomes were the effects of severity and longevity of HG and assessment of correlation between Edinburgh Postnatal Depression Scale scores and maternal-to-infant bonding scores.Results Antenatally, 49% of cases had probable depression compared with 6% of controls (OR 14.4 (5.29 to 39.44)). Postnatally, 29% of cases had probable depression versus 7% of controls (OR 5.2 (1.65 to 17.21)). There was no direct association between HG and infant bonding. 53% of women in the HG group reported needing four or more weeks of sick leave compared with 2% in the control group (OR 60.5 (95% CI 8.4 to 2535.6)).Conclusions Long-lasting psychological morbidity associated with HG was evident. Significantly more women in the case group sought help for mental health symptoms in the antenatal period, however very few were diagnosed with or treated for depression in pregnancy or referred to specialist perinatal mental health services. HG did not directly affect infant bonding. Women in the case group required long periods off work, highlighting the socioeconomic impact of HG.

BACKGROUND Physical frailty in older individuals is characterized by subjective symptoms of fatigue and exercise intolerance (EI). Objective abnormalities in skeletal muscle (SM) mitochondrial high-energy phosphate (HEP) metabolism contribute to EI in inherited myopathies; however, their presence or link to EI in the frail older adult is unknown.METHODS Here, we studied 3 groups of ambulatory, community-dwelling adults with no history of significant coronary disease: frail older (FO) individuals (81 ± 2.7 years, mean ± SEM), nonfrail older (NFO) individuals (79 ± 2.0 years), and healthy middle-aged individuals, who served as controls (CONT, 51 ± 2.1 years). Lower extremity SM HEP levels and mitochondrial function were measured with 31P magnetic resonance (MR) techniques during graded multistage plantar flexion exercise (PFE). EI was quantified by a 6-minute walk (6MW) and peak oxygen consumption during cardiopulmonary testing (peak VO2).RESULTS During graded exercise, FO, NFO, and CONT individuals all fatigued at similar SM HEP levels, as measured by 31P-MR. However, FO individuals fatigued fastest, with several-fold higher rates of PFE-induced HEP decline that correlated closely with shorter exercise duration in the MR scanner and with 6MW distance and lower peak oxygen consumption on cardiopulmonary testing (P < 0.001 for all). SM mitochondrial oxidative capacity was lower in older individuals and correlated with rapid HEP decline but less closely with EI.CONCLUSION Several-fold faster SM energetic decline during exercise occurs in FO individuals and correlates closely with multiple measures of EI. Rapid energetic decline represents an objective, functional measure of SM metabolic changes and a potential new target for mitigating frailty-associated physical limitations.FUNDING This work was supported by NIH R21 AG045634, R01 AG063661, R01 HL61912, the Johns Hopkins University Claude D. Pepper Older Americans Independence Center P30AG021334, and the Clarence Doodeman Endowment in Cardiology at Johns Hopkins.

Adolescents 360 (A360) is a four-year initiative (2016–2020) to increase 15-19-year-old girls’ use of modern contraception in Nigeria, Ethiopia and Tanzania. The innovative A360 approach is led by human-centred design (HCD), combined with social marketing, developmental neuroscience, public health, sociocultural anthropology and youth engagement ‘lenses’, and aims to create context-specific, youth-driven solutions that respond to the needs of adolescent girls. The A360 external evaluation includes a process evaluation, quasi-experimental outcome evaluation, and a cost-effectiveness study. We reflect on evaluation opportunities and challenges associated with measuring the application and impact of this novel HCD-led design approach. For the process evaluation, participant observations were key to capturing the depth of the fast-paced, highly-iterative HCD process, and to understand decision-making within the design process. The evaluation team had to be flexible and align closely with the work plan of the implementers. The HCD process meant that key information such as intervention components, settings, and eligible populations were unclear and changed over outcome evaluation and cost-effectiveness protocol development. This resulted in a more time-consuming and resource-intensive study design process. As much time and resources went into the creation of a new design approach, separating one-off “creation” costs versus those costs associated with actually implementing the programme was challenging. Opportunities included the potential to inform programmatic decision-making in real-time to ensure that interventions adequately met the contextualized needs in targeted areas. Robust evaluation of interventions designed using HCD, a promising and increasingly popular approach, is warranted yet challenging. Future HCD-based initiatives should consider a phased evaluation, focusing initially on programme theory refinement and process evaluation, and then, when the intervention program details are clearer, following with outcome evaluation and cost-effectiveness analysis. A phased approach would delay the availability of evaluation findings but would allow for a more appropriate and tailored evaluation design.

ObjectivesTo describe differences in modern contraceptive use among adolescent women aged 15–19 years according to their marital status and to determine factors associated with modern contraceptive use among sexually active women in this population.DesignCross-sectional analysis of Adolescent 360 evaluation baseline survey.SettingThe 15 urban and semiurban wards of Ilemela district, Mwanza region, North-Western Tanzania.ParticipantsAdolescent women aged 15–19 years who were living in the study site from August 2017 to February 2018 and who provided informed consent. Women were classified as married if they had a husband or were living as married. Unmarried women were classified as sexually active if they reported having sexual intercourse in the last 12 months.Outcome measurePrevalence of modern contraceptive among adolescent women aged 15–19 years.ResultsData were available for 3511 women aged 15–19 years, of which 201 (5.7%) were married and 744 (22.5%) were unmarried-sexually active. We found strong evidence of differences in use of modern contraceptive methods according to marital status of adolescent women. Determinants of modern contraception use among unmarried-sexually active women were increasing age, increasing level of education, being in education, hearing of modern contraception from interpersonal sources or in the media in the last 12 months, perceiving partner and/or friends support for contraceptive use, as well as higher knowledge and self efficacy for contraception.ConclusionsSexual and reproductive health programmes aiming to increase uptake of modern contraceptives in this population of adolescent women should consider the importance of girl’s education and social support for contraceptive use particularly among unmarried-sexually active women.

IntroductionLittle is known about the impact of bladder cancer (BC) and its treatments on health-related quality of life (HRQL). To date, most work has been small in scale or restricted to subsets of patients. Life and bladder cancer is a cross-sectional and longitudinal study collecting patient-reported outcomes within two distinct cohorts.Methods and analysisA longitudinal study will collect patient-reported outcomes at 3-monthly intervals from newly diagnosed patients. Eligible cases will be identified by recruiting hospitals and surveyed at baseline, 6, 9 and 12 months postdiagnosis to explore changes in outcomes over time. A separate cross-sectional cohort of patients diagnosed within the last 10 years across Yorkshire will be identified through cancer registration systems and surveyed once to explore longer-term HRQL in BC survivors. A comprehensive patient-reported outcome measure (PROM) has been developed using generic, cancer-specific and BC-specific instruments. The study will provide evidence about how useful these PROMs are in measuring BC patient HRQL. The outcome data will be linked with administrative health data (eg, treatment information from hospital data).Ethics and disseminationThe study has received the following approvals: Yorkshire and the Humber—South Yorkshire Research Ethics Committee (17/YH/0095), Health Research Authority Confidentiality Advisory Group (17/CAG/0054). Results will be made available to patients, funders, NHS Trusts, Clinical Commissioning Groups, Strategic Clinical Networks and other researchers.

Adolescents 360 (A360) is a four-year initiative (2016–2020) to increase 15-19-year-old girls’ use of modern contraception in Nigeria, Ethiopia and Tanzania. The innovative A360 approach is led by human-centred design (HCD), combined with social marketing, developmental neuroscience, public health, sociocultural anthropology and youth engagement ‘lenses’, and aims to create context-specific, youth-driven solutions that respond to the needs of adolescent girls. The A360 external evaluation includes a process evaluation, quasi-experimental outcome evaluation, and a cost-effectiveness study. We reflect on evaluation opportunities and challenges associated with measuring the application and impact of this novel HCD-led design approach. For the process evaluation, participant observations were key to capturing the depth of the fast-paced, highly-iterative HCD process, and to understand decision-making within the design process. The evaluation team had to be flexible and align closely with the work plan of the implementers. The HCD process meant that key information such as intervention components, settings, and eligible populations were unclear and changed over outcome evaluation and cost-effectiveness protocol development. This resulted in a more time-consuming and resource-intensive study design process. As much time and resources went into the creation of a new design approach, separating one-off “creation” costs versus those costs associated with actually implementing the programme was challenging. Opportunities included the potential to inform programmatic decision-making in real-time to ensure that interventions adequately met the contextualized needs in targeted areas. Robust evaluation of interventions designed using HCD, a promising and increasingly popular approach, is warranted yet challenging. Future HCD-based initiatives should consider a phased evaluation, focusing initially on programme theory refinement and process evaluation, and then, when the intervention program details are clearer, following with outcome evaluation and cost-effectiveness analysis. A phased approach would delay the availability of evaluation findings but would allow for a more appropriate and tailored evaluation design.

Many disciplines of scholarship are interested in the Relative Age Effect (RAE), whereby age-banding confers advantages on older members of the cohort over younger ones. Most research does not test this relationship in a manner consistent with theory (which requires a decline in frequency across the cohort year), instead resorting to non-parametric, non-directional approaches. In this article, the authors address this disconnect, provide an overview of the benefits associated with Poisson regression modelling, and two managerially useful measures for quantifying RAE bias, namely the Indices of Discrimination and Wastage. In a tutorial-like exposition, applications and extensions of this approach are illustrated using data on professional soccer players competing in the top two tiers of the "Big Five" European football leagues in the search to identify paragon clubs, leagues, and countries from which others may learn to mitigate this form of age-discrimination in the talent identification process. As with OLS regression, Poisson regression may include more than one independent variable. In this way we test competing explanations of RAE; control for unwanted sources of covariation; model interaction effects (that different clubs and countries may not all be subject to RAE to the same degree); and test for non-monotonic versions of RAE suggested in the literature.

BackgroundMaternity care services provide critical interventions aimed at improving maternal and newborn health. In this study, we examined determinants of antenatal care (ANC) content in Syria, together with changes over time.MethodsWe analysed two national surveys conducted by the Central Bureau of Statistics in Damascus (PAPFAM 2001 and MICS 2006). Findings of this initial analysis led to a qualitative study on adequacy of antenatal care content in two Syrian governorates, Aleppo and Latakia in 2010, which in turn informed further quantitative analysis. The perspectives and practices of doctors, women, midwives and health officials were explored using in-depth interviews. A framework approach was used to analyse the data.ResultsThe quantitative analysis demonstrated that women's education level, the type of health facility they attended and whether they had experienced health complications were important determinants of adequacy of ANC content received. The qualitative study revealed that additional factors related to supply side and demand side factors (e.g. organization of health services, doctors' selective prescription of ANC tests and women's selective uptake of those tests), influenced the quality of ANC and explained some regional differences between Aleppo and Latakia.ConclusionsThe percentage of women who received adequate ANC content was probably higher in Latakia than in Aleppo because women in Latakia were more educated, and because services were more available, accessible, and acceptable to them.

ObjectiveTo assess the effect of administering an oral dose of 2g of azithromycin in Gambian women during labour on infant growth.MethodsChildren whose mothers had been randomized to receive either an oral dose of 2g of azithromycin or placebo during labour were visited at home at the end of infancy by trained study nurses blind to the treatment allocation. The follow-up visit of these cohorts (exposed and non-exposed to azithromycin), which was not part of the original trial design, was conducted between November 2014 and May 2015 when the infants were 11 to 13 months of age. During visits, nurses recorded anthropometrical measurements and transcribed information from the infants' welfare cards.ResultsFour-hundred and sixty-five (79.6%) of the 584 infants aged 11-13 months at the time of the survey were recruited. The proportion of children with an age-adjusted Z-score ConclusionsOur results show that azithromycin in labour may have a beneficial effect in MUAC among children who are below the curve. Larger studies with closer follow-up are warranted.Trial registration (main trial)ClinicalTrials.gov Identifier NCT01800942.

The paper analyses two datasets of elite soccer players (top 1000 professionals and UEFA Under-19 Youth League). In both, we find a Relative Age Effect (RAE) for frequency, but not for value. That is, while there are more players born at the start of the competition year, their transfer values are no higher, nor are they given more game time. We use Poisson regression to derive a transparent index of the discrimination present in RAE. Also, because Poisson is valid for small frequency counts, it supports analysis at the disaggregated levels of country and club. From this, we conclude there are no paragon clubs or countries immune to RAE; that is clubs and countries do not differ systematically in the RAE they experience; also, that Poisson regression is a powerful and flexible method of analysing RAE data.

BACKGROUND:Radiologically-confirmed pneumonia (RCP) is a specific end-point used in trials of Pneumococcal Conjugate Vaccine (PCV) to estimate vaccine efficacy. However, chest radiograph (CXR) interpretation varies within and between readers. We measured the repeatability and reliability of paediatric CXR interpretation using percent agreement and Cohen's Kappa and the validity of field readings against expert review in a study of the impact of PCV on pneumonia. METHODS:CXRs were obtained from 2716 children admitted between 2006 and 2014 to Kilifi County Hospital, Kilifi, Kenya, with clinically-defined severe or very-severe pneumonia. Five clinicians and radiologists attended a three-day training course on CXR interpretation using a WHO standard. All CXRs were read once by two local primary readers. Discordant readings and 13% of concordant readings were arbitrated by a panel of three expert radiologists. To assess repeatability, a 5% median random sample was presented twice. Sensitivity and specificity of the primary readers' interpretations was estimated against the 'gold-standard' of the arbitrators' results. RESULTS:Of 2716 CXRs, 2 were uninterpretable and 159 were evaluated twice. The percent agreement and Kappa for RCP were 89% and 0.68 and ranged between 84-97% and 0.19-0.68, respectively, for all pathological findings. Intra-observer repeatability was similar to inter-observer reliability. Sensitivities of the primary readers to detect RCP were 69% and 73%; specificities were 96% and 95%. CONCLUSION:Intra- and inter-observer agreements on interpretations of radiologically-confirmed pneumonia are fair to good. Reasonable sensitivity and high specificity make radiologically-confirmed pneumonia, determined in the field, a suitable measure of relative vaccine effectiveness.

Neisserial heparin binding antigen (NHBA) is one of three main recombinant protein antigens in 4CMenB, a vaccine for the prevention of invasive meningococcal disease caused by Neisseria meningitidis serogroup B. NHBA is a surface-exposed lipoprotein composed of a predicted disordered N-terminal region, an arginine-rich region that binds heparin, and a C-terminal domain that folds as an anti-parallel β-barrel and that upon release after cleavage by human proteases alters endothelial permeability. NHBA induces bactericidal antibodies in humans, and NHBA-specific antibodies elicited by the 4CMenB vaccine contribute to serum bactericidal activity, the correlate of protection. To better understand the structural bases of the human antibody response to 4CMenB vaccination and to inform antigen design, we used X-ray crystallography to elucidate the structures of two C-terminal fragments of NHBA, either alone or in complex with the Fab derived from the vaccine-elicited human monoclonal antibody 5H2, and the structure of the unbound Fab 5H2. The structures reveal details on the interaction between an N-terminal β-hairpin fragment and the β-barrel, and explain how NHBA is capable of generating cross-reactive antibodies through an extensive conserved conformational epitope that covers the entire C-terminal face of the β-barrel. By providing new structural information on a vaccine antigen and on the human immune response to vaccination, these results deepen our molecular understanding of 4CMenB, and might also aid future vaccine design projects.

BackgroundImprovements to housing may contribute to malaria control and elimination by reducing house entry by malaria vectors and thus exposure to biting. We tested the hypothesis that the odds of malaria infection are lower in modern, improved housing compared to traditional housing in sub-Saharan Africa (SSA).Methods and findingsWe analysed 15 Demographic and Health Surveys (DHS) and 14 Malaria Indicator Surveys (MIS) conducted in 21 countries in SSA between 2008 and 2015 that measured malaria infection by microscopy or rapid diagnostic test (RDT). DHS/MIS surveys record whether houses are built with finished materials (e.g., metal) or rudimentary materials (e.g., thatch). This information was used to develop a binary housing quality variable where houses built using finished wall, roof, and floor materials were classified as "modern", and all other houses were classified as "traditional". Conditional logistic regression was used to determine the association between housing quality and prevalence of malaria infection in children aged 0-5 y, adjusting for age, gender, insecticide-treated net (ITN) use, indoor residual spraying, household wealth, and geographic cluster. Individual survey odds ratios (ORs) were combined to determine a summary OR using a random effects meta-analysis. Of 284,532 total children surveyed, 139,318 were tested for malaria infection using microscopy (n = 131,652) or RDT (n = 138,540). Within individual surveys, malaria prevalence measured by microscopy ranged from 0.4% (Madagascar 2011) to 45.5% (Burkina Faso 2010) among children living in modern houses and from 0.4% (The Gambia 2013) to 70.6% (Burkina Faso 2010) in traditional houses, and malaria prevalence measured by RDT ranged from 0.3% (Senegal 2013-2014) to 61.2% (Burkina Faso 2010) in modern houses and from 1.5% (The Gambia 2013) to 79.8% (Burkina Faso 2010) in traditional houses. Across all surveys, modern housing was associated with a 9% to 14% reduction in the odds of malaria infection (microscopy: adjusted OR 0.91, 95% CI 0.85-0.97, p = 0.003; RDT: adjusted OR 0.86, 95% CI 0.80-0.92, p < 0.001). This association was consistent regardless of ITN usage. As a comparison, the odds of malaria infection were 15% to 16% lower among ITN users versus non-users (microscopy: adjusted OR 0.84, 95% CI 0.79-0.90, p < 0.001; RDT: adjusted OR 0.85, 95% CI 0.80-0.90, p < 0.001). The main limitation of this study is that residual confounding by household wealth of the observed association between housing quality and malaria prevalence is possible, since the wealth index may not have fully captured differences in socioeconomic position; however, the use of multiple national surveys offers the advantage of a large sample size and the elimination of many biases typically associated with pooling observational data.ConclusionsHousing quality is an important risk factor for malaria infection across the spectrum of malaria endemicity in SSA, with a strength of association between housing quality and malaria similar to that observed between ITN use and malaria. Improved housing should be considered a promising intervention for malaria control and elimination and long-term prevention of reintroduction.

BACKGROUND:Understanding the costs associated with health care delivery strategies is essential for planning. There are few data on health service resources used by patients and their associated costs within antiretroviral (ART) programmes in Africa. MATERIAL AND METHODS:The study was nested within a large trial, which evaluated screening for cryptococcal meningitis and tuberculosis and a short initial period of home-based adherence support for patients initiating ART with advanced HIV disease in Tanzania and Zambia. The economic evaluation was done in Tanzania alone. We estimated costs of providing routine ART services from the health service provider's perspective using a micro-costing approach. Incremental costs for the different novel components of service delivery were also estimated. All costs were converted into US dollars (US$) and based on 2012 prices. RESULTS:Of 870 individuals enrolled in Tanzania, 434 were enrolled in the intervention arm and 436 in the standard care/control arm. Overall, the median (IQR) age and CD4 cell count at enrolment were 38 [31, 44] years and 52 [20, 89] cells/mm3, respectively. The mean per patient costs over the first three months and over a one year period of follow up following ART initiation in the standard care arm were US$ 107 (95%CI 101-112) and US$ 265 (95%CI 254-275) respectively. ART drugs, clinic visits and hospital admission constituted 50%, 19%, and 19% of the total cost per patient year, while diagnostic tests and non-ART drugs (co-trimoxazole) accounted for 10% and 2% of total per patient year costs. The incremental costs of the intervention to the health service over the first three months was US$ 59 (p

The Relative Age Effect (RAE) documents the inherent disadvantages of being younger rather than older in an age-banded cohort, typically a school- or competition-year, to the detriment of career-progression, earnings and wellbeing into adulthood. We develop the Tails of the Travelling Gaussian (TTG) to model the mechanisms behind RAE. TTG has notable advantages over existing approaches, which have been largely descriptive, potentially confounded, and non-comparable across contexts. In Study 1, using data from the UK's Millennium Cohort Study, we investigate the different levels of RAE bias across school-level academic subjects and "personality" traits. Study 2 concerns biased admissions to elite English Premier League soccer academies, and shows the model can still be used with minimal data. We also develop two practical metrics: the discrimination index (ID), to quantify the disadvantages facing cohort-younger children; and the wastage metric (W), to quantify the loss through untapped potential. TTG is sufficiently well-specified to simulate the consequences of ID and W for policy change.