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Objectives To systematically review the literature on the unit cost and cost-effectiveness of malaria control. Methods Ten databases and gray literature sources were searched to identify evidence relevant to the period 2005 to 2018. Studies with primary financial or economic cost data from malaria endemic countries that took a provider, provider and household, or societal perspective were included. Results We identified 103 costing studies. The majority of studies focused on individual rather than combined interventions, notably insecticide-treated bed nets and treatment, and commonly took a provider perspective. A third of all studies took place in 3 countries. The median provider economic cost of protecting 1 person per year ranged from $1.18 to $5.70 with vector control and from $0.53 to $5.97 with chemoprevention. The median provider economic cost per case diagnosed with rapid diagnostic tests was $6.06 and per case treated $9.31 or $89.93 depending on clinical severity. Other interventions did not share enough similarities to be summarized. Cost drivers were rarely reported. Cost-effectiveness of malaria control was reiterated, but care in methodological and reporting standards is required to enhance data transferability. Conclusions Important information that can support resource allocation was reviewed. Given the variability in methods and reporting, global efforts to follow existing standards are required for the evidence to be most useful outside their study context, supplemented by guidance on options for transferring existing data across settings.

Introduction Numerous guidelines and policies for ethical research practice have evolved over time, how this translates to global health practice in resource-constrained settings is unclear. The purpose of this paper is to describe how the concept of ancillary care has evolved over time and how it is included in the ethics guidelines and policy documents that guide the conduct of research in the global south with both an international focus and providing a specific example of Malawi, where the first author lives and works, as a case study. Methods Discourse analysis was conducted on 34 international ethics guidelines and policy documents. Documents were purposively selected if they contained a set of key terms that reflect the concept of ancillary care. Following a process of inductive discourse analysis, five key interrelated text phrases relating to ancillary care were extracted from the documents. The evolution of these phrases over time was explored as they represented the development of the concept of ancillary care as a component of ethical health research guidance and practice. Results We found key interrelated phrases that represent discourses regarding the evolution of ancillary care including participant protection; provide care as appropriate; supererogation; patient needs prevail over science; and ancillary care as an obligation. Arguments for the provision of ancillary care were characterised by safeguarding the safety, health rights and well-being of study participants. However, despite the evolution of discourse around ethical obligations to provide ancillary care, this is rarely made explicit within guidance documents, leaving interpretive space for differential application in practice. Conclusion While there have been major changes to the ethics guidance that reflect significant evolution in the ethical conduct of research, the specific vocabulary or language used to explain the ethics of researchers' ancillary care obligations to the health needs of their research participants, lacks clarity and consistency. As a result, the concept of ancillary care continues to be under-represented in local ethical guidelines and regulations, with no clear directives for country-level research ethics committees to apply in regulating ancillary care responsibilities.

Tuberculosis, although curable, frequently leaves the individual with chronic physical and psycho-social impairment, yet these consequences have to-date been largely neglected.\ud The 1st International Post-Tuberculosis Symposium was devoted entirely to impairment after tuberculosis, and covered a number of multi-disciplinary topics. Using the Delphi process, consensus was achieved for the terms “post- tuberculosis”, “post-tuberculosis lung disease/s (PTLD)”, and “post-tuberculosis economic, social and psychological well-being” (Post-TB ESP)”, to overcome the historical challenge of varied terminology in the literature. A minimum case-definition was proposed by consensus for PTLD in adults and children. Lack of sufficient evidence hampered definitive recommendations in most domains, including prevention and treatment of PTLD, but highlighted the dire need for research and priorities were identified. The heterogeneity of respiratory outcomes and previously employed research methodologies complicates the accurate estimation of disease burden. However, consensus was reached proposing a toolkit for future PTLD measurement, and on PTLD patterns to be considered. The importance of extra-pulmonary consequences and progressive impairment throughout the life-course was identified, including tuberculosis recurrence and increased mortality. Patient advocates emphasised the need for addressing the psychological and social impacts post tuberculosis, and called for clinical guidance. Increased awareness and more research addressing post-tuberculosis complications is urgently needed.

Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting is vital to this process; it allows readers to assess the reliability of the findings and repeat or build upon the work of other researchers. The ARRIVE guidelines (Animal Research: Reporting In Vivo Experiments) were developed in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of ARRIVE on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This explanation and elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2.0, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature. This document also covers advice and best practice in the design and conduct of animal studies to support researchers in improving standards from the start of the experimental design process through to publication., The NC3Rs developed the ARRIVE guidelines in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. This article explains the rationale behind each item in the revised and updated ARRIVE guidelines 2019, clarifying key concepts and providing illustrative examples.

Objectives: Clear communication of systematic review findings will help readers and decision makers. We built on previous work to develop an approach that improves the clarity of statements to convey findings and that draws on Grading of Recommendations Assessment,\ud Development and Evaluation (GRADE).\ud \ud Study Design and Setting: We conducted workshops including 80 attendants and a survey of 110 producers and users of systematic reviews. We calculated acceptability of statements and\ud revised the wording of those that were unacceptable to ≥40% of participants.\ud \ud Results: Most participants agreed statements should be based on size of effect and certainty of evidence. Statements for low, moderate and high certainty evidence were acceptable to >60%. Key guidance, for example, includes statements for high, moderate and low certainty for a large effect on intervention x as: x results in a large reduction…; x likely results in a large reduction…; x may result in a large reduction…, respectively.\ud \ud Conclusions: Producers and users of systematic reviews found statements to communicate findings combining size and certainty of an effect acceptable. This article provides GRADE guidance and a wording template to formulate statements in systematic reviews and other\ud decision tools.\ud \ud Keywords: review literature as topic, health communication, Evidence-Based Medicine, Surveys and Questionnaires, Language, persuasive communication

Multi-arm, parallel-group clinical trials are an efficient way of testing several new treatments, treatment regimens or doses. However, guidance on the requirement for statistical adjustment to control for multiple comparisons (type I error) using a shared control group is unclear. We argue, based on current evidence, that adjustment is not always necessary in such situations. We propose that adjustment should not be a requirement in multi-arm, parallel-group trials testing distinct treatments and sharing a control group, and we call for clearer guidance from stakeholders, such as regulators and scientific journals, on the appropriate settings for adjustment of multiplicity.

Objectives AGILE is a Phase Ib/IIa platform for rapidly evaluating COVID-19 treatments. In this trial (NCT04746183) we evaluated the safety and optimal dose of molnupiravir in participants with early symptomatic infection. Methods We undertook a dose-escalating, open-label, randomized-controlled (standard-of-care) Bayesian adaptive Phase I trial at the Royal Liverpool and Broadgreen Clinical Research Facility. Participants (adult outpatients with PCR-confirmed SARS-CoV-2 infection within 5 days of symptom onset) were randomized 2:1 in groups of 6 participants to 300, 600 and 800 mg doses of molnupiravir orally, twice daily for 5 days or control. A dose was judged unsafe if the probability of 30% or greater dose-limiting toxicity (the primary outcome) over controls was 25% or greater. Secondary outcomes included safety, clinical progression, pharmacokinetics and virological responses. Results Of 103 participants screened, 18 participants were enrolled between 17 July and 30 October 2020. Molnupiravir was well tolerated at 300, 600 and 800 mg doses with no serious or severe adverse events. Overall, 4 of 4 (100%), 4 of 4 (100%) and 1 of 4 (25%) of the participants receiving 300, 600 and 800 mg molnupiravir, respectively, and 5 of 6 (83%) controls, had at least one adverse event, all of which were mild (≤grade 2). The probability of ≥30% excess toxicity over controls at 800 mg was estimated at 0.9%. Conclusions Molnupiravir was safe and well tolerated; a dose of 800 mg twice daily for 5 days was recommended for Phase II evaluation.

Previous studies have suggested that the pneumococcal niche changes from the nasopharynx to the oral cavity with age. We use an Experimental Human Pneumococcal Challenge model to investigate pneumococcal colonisation in different anatomical niches with age. Healthy adults (n = 112) were intranasally inoculated with Streptococcus pneumoniae serotype 6B (Spn6B) and were categorised as young 18–55 years (n = 57) or older > 55 years (n = 55). Colonisation status (frequency and density) was determined by multiplex qPCR targeting the lytA and cpsA-6A/B genes in both raw and culture-enriched nasal wash and oropharyngeal swab samples collected at 2-, 7- and 14-days post-exposure. For older adults, raw and culture-enriched saliva samples were also assessed. 64% of NW samples and 54% of OPS samples were positive for Spn6B in young adults, compared to 35% of NW samples, 24% of OPS samples and 6% of saliva samples in older adults. Many colonisation events were only detected in culture-enriched samples. Experimental colonisation was detected in 72% of young adults by NW and 63% by OPS. In older adults, this was 51% by NW, 36% by OPS and 9% by saliva. The nose, as assessed by nasal wash, is the best niche for detection of experimental pneumococcal colonisation in both young and older adults.

Background Snakebite is a priority neglected tropical disease and causes a range of complications that vary depending on the snake species. Randomised clinical trials have used varied outcome measures that do not allow results to be compared or combined. In accordance with the Core Outcomes Measurements in Effectiveness Trials (COMET) initiative, this systematic review aims to support the development of a globally relevant core outcome set for snakebite. Methods All randomised controlled trials, secondary analyses of randomised controlled trials and study protocols investigating the efficacy of therapeutics for human snakebite envenoming were eligible for inclusion. Study screening and data extraction were conducted in duplicate by two independent reviewers. All primary and secondary outcome measures were extracted and compiled, as were adverse event outcome measures. Similar outcome measures were grouped into domains. The study was prospectively registered with PROSPERO: CRD42020196160. Results This systematic review included 43 randomised controlled trials, two secondary analyses and 13 study protocols. A total of 382 outcome measures were extracted and, after duplicates were merged, there were 153 unique outcomes. The most frequently used outcome domain (‘venom antigenaemia’) was included in less than one third of the studies. The unique outcomes were classified into 60 outcome domains. Patient-centred outcomes were used in only three of the studies. Discussion Significant heterogeneity in outcome measures exists in snakebite clinical trials. Consensus is needed to select outcome measures that are valid, reliable, patient-centred and feasible. The results of this systematic review strongly support the development of a core outcome set for use in snakebite clinical trials., Author summary Standardised outcome measures for snakebite randomised controlled trials are needed to enable results to be compared and combined between studies. This systematic review was conducted to understand the variations in outcome measure use in snakebite randomised controlled trials, and to create a comprehensive list of outcome measures from which to develop a core outcome set (COS). A total of 153 unique outcome measures were extracted from the 58 studies identified in this systematic review. Of these 153 unique outcome measures, 91 were used in only in a single study. Although a form of bedside whole blood clotting test was used in 30 of the 58 studies, 18 unique methods of measurement were identified. Only three studies, all conducted in the USA, included patient-centred outcomes. This systematic review demonstrates the strong need for a snakebite core outcome set, which will support the adoption of valid, reproducible, and patient-centred outcome measures, and enable downstream meta-analyses.

Background\ud The burden of maternal and neonatal morbidity and mortality is a global health concern with the highest burden documented after childbirth in women and babies living in sub-Saharan Africa. To date, there is limited information on the quality of postnatal care and/or whether evidence-based interventions to improve postnatal care in a way that meets the specific health needs of each mother and her baby have been lacking. There is also limited data related to how quality of care (respectful or disrespectful) influences women's decision to access postnatal care.\ud \ud Objective\ud To systematically review available qualitative evidence for how quality of care (respectful or disrespectful) influences perceptions and experiences of, and decisions to, access postnatal care for women living in sub-Saharan Africa.\ud \ud Search strategy\ud CINAHL plus, Cochrane library, Global Health, Medline, PubMed, Web of Science were searched from 2009—2019. Grey literature was searched on Google Scholar.\ud \ud Selection criteria\ud Qualitative literature in English describing women’s perceptions and experiences of the quality of care they received after childbirth and how this influenced their perceptions of and decisions to access postnatal care.\ud \ud Data analysis\ud Thematic analysis was performed to extract subthemes and themes. Outcomes were themes from the qualitative data used to form a thematic synthesis.\ud \ud Results\ud Fifteen studies were included with data from 985 women interviewed face-to-face across eight countries. Descriptions of respectful care included healthcare providers being kind, supportive and attentive to women’s needs. Women described preferring healthcare services where the healthcare providers communicated in a respectful and caring manner. Descriptions of disrespectful care included verbal and/or physical abuse and power imbalances between women and healthcare providers. Some women were denied postnatal care when attending a healthcare facility after giving birth at home. There is evidence to suggest that vulnerable women (adolescents; women with poor socioeconomic status; women who are HIV positive) are more likely to receive disrespectful care.\ud \ud Conclusions\ud This systematic review describes how aspects of respectful and disrespectful maternity care influence women’s perceptions and experiences of, and decisions to access postnatal care services. There is a need for a renewed focus to prioritise respectful maternity care and to sustainably provide good quality postnatal care to all women and their babies in a way that meets their expectations and health needs.

Background Individuals infected with SARS-CoV-2 develop neutralising antibodies. We investigated the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how this proportion varies with selected covariates. Methodology/Principal findings This systematic review and meta-analysis examined the proportion of individuals with SARS-CoV-2 neutralising antibodies after infection and how these proportions vary with selected covariates. Three models using the maximum likelihood method assessed these proportions by study group, covariates and individually extracted data (protocol CRD42020208913). A total of 983 reports were identified and 27 were included. The pooled (95%CI) proportion of individuals with neutralising antibodies was 85.3% (83.5–86.9) using the titre cut off >1:20 and 83.9% (82.2–85.6), 70.2% (68.1–72.5) and 54.2% (52.0–56.5) with titres >1:40, >1:80 and >1:160, respectively. These proportions were higher among patients with severe COVID-19 (e.g., titres >1:80, 84.8% [80.0–89.2], >1:160, 74.4% [67.5–79.7]) than those with mild presentation (56.7% [49.9–62.9] and 44.1% [37.3–50.6], respectively) and lowest among asymptomatic infections (28.6% [17.9–39.2] and 10.0% [3.7–20.1], respectively). IgG and neutralising antibody levels correlated poorly. Conclusions/Significance 85% of individuals with proven SARS-CoV-2 infection had detectable neutralising antibodies. This proportion varied with disease severity, study setting, time since infection and the method used to measure antibodies., Author summary Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) elicits adaptive immunological responses, including immunoglobulins A, M, and G and neutralising antibodies. Neutralising antibodies are considered markers of functional immunity and protection. However, not all individuals with proven infections have detectable neutralising antibodies. In this systematic review, we investigated the proportion of individuals with former SARS-CoV-2 infections who develop neutralising antibodies, whether their titres vary with disease severity, and their correlation with Immunoglobulin G. We found that approximately 85% of individuals with SARS-CoV-2 infection have detectable neutralising antibodies. This proportion was higher among patients with severe Coronavirus Disease 19 and lower in asymptomatic infections. The variation across studies reflected the wide range of methods used to measure both immunoglobulins and neutralising antibodies, and highlight the need for an international reference standard to measure SARS-CoV-2 antibodies.

Background: Despite growing calls for the provision of ancillary care to study participants during medical research, there remains a noticeable gap in ethical guidelines for medical researchers in resource-constrained settings (RCS). We reviewed recent studies to determine the extent to which ancillary care is provided in East and Southern Africa and to examine the ethical justifications researchers provide to support their views on ancillary care obligations. Methods: A systematic search for qualitative and mixed methods studies on ancillary care was conducted across MEDLINE, Embase, African Wide Information, PubMed, CINAHL Plus, and Scopus. The National Institutes of Health (NIH) Department of Bioethics and H3 Africa websites and Google Scholar were further searched. Studies conducted in East and Southern Africa between 2004 and 2020, as well as those that reported on ancillary care provided to study participants were included. All studies included in this review were evaluated for methodological quality as well as bias risk. NVivo version 12 was used for thematic analysis. Results: Overall, 4,710 articles were identified by the initial search. After the data extraction and quality assessment, 24 articles were included. Key areas presented include ancillary care approaches and the themes of researcher motivation for providing ancillary care and expectations of participants in medical research. The review shows that while some international researchers do provide ancillary care to their study participants, approaches are not standardised without consistent guidelines for ethical practice for ancillary care. We found limited empirical studies in RCS that report on ancillary care, hence findings in this review are based on single studies rather than a collection of multiple studies. Conclusions: This paper emphasizes the value of establishing ethics guidelines for medical researchers in RCS who consider provision of ancillary care to their participants, and the need to account for these ethical guidelines in medical research.

Background\ud Molecular xenomonitoring (MX), the detection of pathogen DNA in mosquitoes, is a recommended approach to support lymphatic filariasis (LF) elimination efforts. Potential roles of MX include detecting presence of LF in communities and quantifying progress towards elimination of the disease. However, the relationship between MX results and human prevalence is poorly understood.\ud \ud Methods\ud :We conducted a systematic review and meta-analysis from all previously conducted studies that reported the prevalence of filarial DNA in wild-caught mosquitoes (MX rate) and the corresponding prevalence of microfilaria (mf) in humans. We calculated a pooled estimate of MX sensitivity for detecting positive communities at a range of mf prevalence values and mosquito sample sizes. We conducted a linear regression to evaluate the relationship between mf prevalence and MX rate.\ud \ud Results\ud We identified 24 studies comprising 144 study communities. MX had an overall sensitivity of 98.3% (95% CI 41.5, 99.9%) and identified 28 positive communities that were negative in the mf survey. Low sensitivity in some studies was attributed to small mosquito sample sizes (

Background Poor participant understanding of research information can be a problem in community interventional studies with rural African women, whose levels of illiteracy are high. This study aimed to improve the informed consent process for women living in rural eastern Uganda. We assessed the impact of alternative consent models on participants’ understanding of clinical trial information and their contribution to the informed consent process in rural Uganda. Methods The study applied a parallel mixed-methods design for a prospective comparative cohort, nested within a pilot study on the community distribution of an alcohol-based hand rub to prevent neonatal sepsis (BabyGel pilot trial). Women of at least 34 weeks’ pregnancy, suitable for inclusion in the BabyGel pilot trial, were recruited into this study from their homes in 13 villages in Mbale District. As part of the informed consent process, information about the trial was presented using one of three consent methods: standard researcher-read information, a slide show using illustrated text on a flip chart or a video showing the patient information being read as if by a newsreader in either English or the local language. In addition, all women received the patient information sheet in their preferred language. Each information-giving method was used in recruitment for 1 week. Two days after recruitment, women’s understanding of the clinical trial was evaluated using the modified Quality of Informed Consent (QuIC) tool. They were also shown the other two methods and their preference assessed using a 5-point Likert scale. Semi-structured interviews were administered to each participant. The interviews were audio-recorded, transcribed and translated verbatim, and thematically analysed. Results A total of 30 pregnant women in their homes participated in this study. Their recall of the trial information within the planned 48 h was assessed for the majority (90%, 27/30). For all three consent models, women demonstrated a high understanding of the study. There was no statistically significant difference between the slide-show message (mean 4.7; standard deviation, SD 0.47; range 4–5), video message (mean 4.9; SD 0.33; range 4–5) and standard method (mean 4.5; SD 0.53; range 4–5; all one-way ANOVA, p = 0.190). The slide-show message resulted in the most objective understanding of question items with the highest average QuIC score of 100 points. For women who had been recruited using any of the three models, the slide show was the most popular method, with a mean score for all items of not less than 4.2 (mean 4.8; SD 0.6; range 4–5). Most women (63%, 19/30) preferred the slide-show message, compared with 17% (5/30) and 20% (6/30) for the standard and video messages, respectively. The reasons given included the benefits of having pictures to aid understanding and the logical progression of the information. Conclusion Our results from this small study suggest that slide-show messages may be an effective and popular alternative way of presenting trial information to women in rural Uganda, many of whom have little or no literacy. Trial registration ISRCTN, ISRCTN67852437. Registered on 18 March 2018.

BACKGROUND\ud Many nutrients have powerful immunomodulatory actions with the potential to alter susceptibility to coronavirus disease 2019 (COVID-19) infection, progression to symptoms, likelihood of severe disease, and survival.\ud \ud OBJECTIVE\ud The aim was to review the latest evidence on how malnutrition across all its forms (under- and overnutrition and micronutrient status) may influence both susceptibility to, and progression of, COVID-19.\ud \ud METHODS\ud We synthesized information on 13 nutrition-related components and their potential interactions with COVID-19: overweight, obesity, and diabetes; protein-energy malnutrition; anemia; vitamins A, C, D, and E; PUFAs; iron; selenium; zinc; antioxidants; and nutritional support. For each section we provide: 1) a landscape review of pertinent material; 2) a systematic search of the literature in PubMed and EMBASE databases, including a wide range of preprint servers; and 3) a screen of 6 clinical trial registries. All original research was considered, without restriction to study design, and included if it covered: 1) severe acute respiratory syndrome coronavirus (CoV) 2 (SARS-CoV-2), Middle East respiratory syndrome CoV (MERS-CoV), or SARS-CoV viruses and 2) disease susceptibility or 3) disease progression, and 4) the nutritional component of interest. Searches took place between 16 May and 11 August 2020.\ud \ud RESULTS\ud Across the 13 searches, 2732 articles from PubMed and EMBASE, 4164 articles from the preprint servers, and 433 trials were returned. In the final narrative synthesis, we include 22 published articles, 38 preprint articles, and 79 trials.\ud \ud CONCLUSIONS\ud Currently there is limited evidence that high-dose supplements of micronutrients will either prevent severe disease or speed up recovery. However, results of clinical trials are eagerly awaited. Given the known impacts of all forms of malnutrition on the immune system, public health strategies to reduce micronutrient deficiencies and undernutrition remain of critical importance. Furthermore, there is strong evidence that prevention of obesity and type 2 diabetes will reduce the risk of serious COVID-19 outcomes. This review is registered at PROSPERO as CRD42020186194.

Background Rapid antimicrobial susceptibility tests are expected to reduce the time to clinically important results of a blood culture. This might enable clinicians to better target therapy to a person's needs, and thereby, improve health outcomes (mortality, length of hospital stay), and reduce unnecessary prescribing of broad‐spectrum antibiotics; thereby reducing antimicrobial resistance rates. Objectives To assess the effects of rapid susceptibility testing versus standard susceptibility testing for bloodstream infections (BSIs). Search methods To identify studies with selected outcomes, we searched the Cochrane Infectious Diseases Group Specialised Register, CENTRAL, MEDLINE, LILACS, and two trials registries, between 1987 and October 2020. We used 'bloodstream infection' and 'antimicrobial susceptibility tests' as search terms. We had no language or publication status limitations. Selection criteria Randomized controlled trials (RCTs) comparing rapid antimicrobial susceptibility testing (with a time‐to‐result of ≤ 8 hours) versus conventional antimicrobial susceptibility testing in people with a BSI caused by any bacteria, as identified by a positive blood culture. Data collection and analysis Two review authors independently screened references, full‐text reports of potentially relevant studies, extracted data from the studies, and assessed risk of bias. Any disagreement was discussed and resolved with a third review author. For mortality, a dichotomous outcome, we extracted the number of events in each arm, and presented a risk ratio (RR) with 95% confidence interval (CI) to compare rapid susceptibility testing to conventional methods. We used Review Manager 5.4 to meta‐analyse the data. For other outcomes, which are time‐to‐event outcomes (time‐to‐discharge from hospital, time‐to‐first appropriate antibiotic change), we conducted qualitative narrative synthesis, due to heterogeneity of outcome measures. Main results We included six trials, with 1638 participants. For rapid antimicrobial susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.10, 95% CI 0.82 to 1.46; 6 RCTs, 1638 participants; low‐certainty evidence). In subgroup analysis, for rapid genotypic or molecular antimicrobial susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.02, 95% CI 0.69 to 1.49; 4 RCTs, 1074 participants; low‐certainty evidence). For phenotypic rapid susceptibility testing compared to conventional methods, there was little or no difference in mortality between groups (RR 1.37, 95% CI 0.80 to 2.35; 2 RCTs, 564 participants; low‐certainty evidence). In qualitative analysis, rapid susceptibility testing may make little or no difference in time‐to‐discharge (4 RCTs, 1165 participants; low‐certainty evidence). In qualitative analysis, rapid genotypic susceptibility testing compared to conventional testing may make little or no difference in time‐to‐appropriate antibiotic (3 RCTs, 929 participants; low‐certainty evidence). In subgroup analysis, rapid phenotypic susceptibility testing compared to conventional testing may improve time‐to‐appropriate antibiotic (RR ‐17.29, CI ‐45.05 to 10.47; 2 RCTs, 564 participants; low‐certainty evidence). Authors' conclusions The theoretical benefits of rapid susceptibility testing have not been demonstrated to directly improve mortality, time‐to‐discharge, or time‐to‐appropriate antibiotic in these randomized studies. Future large prospective studies should be designed to focus on the most clinically meaningful outcomes, and aim to optimize blood culture pathways., Plain language summary Tests for identifying the most suitable antibiotics for a bacterial blood infection: are rapid tests better than standard tests? What is the aim of this Cochrane Review? People with blood infections need urgent treatment with antibiotics. Identifying the bacteria causing the infection helps ensure the right antibiotic is given. Rapid susceptibility tests are a technology to do this quickly, and aim to improve care. We sought to evaluate whether their use reduce deaths or shortens the illness. Key messages Rapid susceptibility tests to identify an appropriate antibiotic quickly for people with blood sepsis may make little to no difference to: · how many people die within 30 days of diagnosis of blood sepsis; · how long people stay in hospital; · whether given a suitable antibiotic. Larger studies will help determine if using rapid susceptibility tests improves these outcomes. What was studied in this review? Susceptibility tests are done in a laboratory, and measure whether bacteria can grow when exposed to a variety of antibiotics, to assure that the antibiotics given are active against the organism causing the infection. The standard approach is to culture the blood samples, but this takes up to 36 hours to obtain a result. Rapid tests to identify bacteria causing blood infections, and their susceptibilities to antibiotics, provide results in eight hours or less. These rapid susceptibility tests include: · tests that look at the direct effect of antibiotics on bacteria (called phenotypic tests); and · tests that look for particular genes in the bacteria to see if they are susceptible, or resistant, to an antibiotic (called genotypic tests). What are the main results of this review? We found six studies that involved 1638 adults with blood infections. All studies took place in specialized medical centres in high‐income countries in Europe, the USA, and East Asia. Compared with standard tests, rapid susceptibility tests may make little to no difference to · how many people died within 30 days (evidence from six studies in 1638 people); · how long people stayed in hospital (4 studies in 1165 people); or · how long it took for people to be given the right antibiotic to treat the infection (5 studies in 1493 people). Phenotypic rapid susceptibility tests may reduce the time it takes to receive the right antibiotic; but this is uncertain (evidence from 2 studies in 564 people). Genotypic rapid susceptibility tests may make little or no difference to the time it takes to receive the right antibiotic (evidence from 4 studies in 1074 people). Our confidence in the results is limited because: · the numbers of deaths reported in the studies were too low to show an important difference; · the tests used and the results from the studies varied widely; · the studies did not include enough participants to enable firm conclusions. Further research is likely to change these results. How up to date is this review? We included evidence published up to 21 October 2020.

Background The Systolic Blood Pressure Intervention Trial (SPRINT) showed significant reductions in death and cardiovascular disease (CVD) risk with a systolic blood pressure (SBP) goal of, Tao Chen and colleagues estimate the cost-effectiveness of intensive blood pressure intervention in Chinese populations at high risk for cardiovascular disease., Author summary Why was this study done? The Systolic Blood Pressure Intervention Trial (SPRINT) has previously demonstrated significant reductions in death and cardiovascular disease (CVD) risk with a systolic blood pressure (SBP) goal of < 120 mm Hg (intensive treatment) compared with a SBP goal of

Summary box Biomedical interventions, such as therapeutics, vaccines and insecticides, are alone insufficient to achieve Sustainable Development Goal (SDG) 3—healthy lives and well-being for all ages. We also need development interventions to tackle the underlying determinants of ill-health by reducing deprivation and improving living conditions and the environment. This recognition formed the bedrock of early public health, from housing improvements and clean water provision in 19th century Europe and North America,1 to house screening for malaria elimination in the USA and water management for historical vector control in Italy, Sri Lanka, Panama and Zambia.2 Today, development interventions are a basic human right and ever more critical in response to rapid population growth, urbanisation and climate change. Despite their importance, many development interventions remain neglected in global health policy. For example, the World Health Organization (WHO) recognises the need for multisectoral approaches to malaria,3 but based on current evidence is unlikely to be able to make a strong …

Female genital mutilation (FGM) is a global issue, with 200 million women and girls thought to be affected. FGM is defined as removal of female external genitalia, either partial or total, for non-medical purposes. FGM is embedded in tradition, including cultural beliefs about sexual behaviour. Associated risks include haemorrhage, infection, death, dyspareunia, childbirth complications and psychological issues. Although FGM negatively impacts on women’s psychological wellbeing, little is known about the impact on pregnancy experiences. Psychological consequences of FGM are likely to be intensified during pregnancy when women have concerns about their own and their baby’s wellbeing. This mixed-method systematic review aimed to provide insight into the psychological impact of FGM on women who subsequently become pregnant. Nine electronic databases were searched, using a search strategy to identify relevant studies. Studies were considered for inclusion if they were primary studies (qualitative, quantitative or mixed-method) involving pregnant women of any age who have previously undergone FGM. Relevant studies were evaluated using the MMAT appraisal tool. Analysis was guided by the review questions and the evidence identified. One quantitative and 9 qualitative papers were included. Qualitative data were analysed using meta-ethnography. Narrative analysis of the quantitative study was conducted. Findings relate to power of choice linked to reinfibulation, deinfibulation, birth procedures and pain management; importance of knowledgeable and sensitive health care professionals; and relived trauma experienced during childbirth. These findings could inform the development of supportive interventions for women with FGM within maternity services. \ud \ud Keywords: systematic review, FGM, pregnancy, mental health

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the “ARRIVE Essential 10,” which constitutes the minimum requirement, and the “Recommended Set,” which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility., The ARRIVE guidelines detail key information to include in any publication describing animal research. This Perspective article describes how the guidelines have been updated and reorganised to facilitate their use in practice.

Background The clinical and epidemiological significance of HIV-associated Mycobacterium tuberculosis bloodstream infection (BSI) is incompletely understood. We hypothesised that M tuberculosis BSI prevalence has been underestimated, that it independently predicts death, and that sputum Xpert MTB/RIF has suboptimal diagnostic yield for M tuberculosis BSI. Methods We did a systematic review and individual patient data (IPD) meta-analysis of studies performing routine mycobacterial blood culture in a prospectively defined patient population of people with HIV aged 13 years or older. Studies were identified through searching PubMed and Scopus up to Nov 10, 2018, without language or date restrictions and through manual review of reference lists. Risk of bias in the included studies was assessed with an adapted QUADAS-2 framework. IPD were requested for all identified studies and subject to harmonised inclusion criteria: age 13 years or older, HIV positivity, available CD4 cell count, a valid mycobacterial blood culture result (excluding patients with missing data from lost or contaminated blood cultures), and meeting WHO definitions for suspected tuberculosis (presence of screening symptom). Predicted probabilities of M tuberculosis BSI from mixed-effects modelling were used to estimate prevalence. Estimates of diagnostic yield of sputum testing with Xpert (or culture if Xpert was unavailable) and of urine lipoarabinomannan (LAM) testing for M tuberculosis BSI were obtained by two-level random-effect meta-analysis. Estimates of mortality associated with M tuberculosis BSI were obtained by mixed-effect Cox proportional-hazard modelling and of effect of treatment delay on mortality by propensity-score analysis. This study is registered with PROSPERO, number 42016050022. Findings We identified 23 datasets for inclusion (20 published and three unpublished at time of search) and obtained IPD from 20, representing 96·2% of eligible IPD. Risk of bias for the included studies was assessed to be generally low except for on the patient selection domain, which was moderate in most studies. 5751 patients met harmonised IPD-level inclusion criteria. Technical factors such as number of blood cultures done, timing of blood cultures relative to blood sampling, and patient factors such as inpatient setting and CD4 cell count, explained significant heterogeneity between primary studies. The predicted probability of M tuberculosis BSI in hospital inpatients with HIV-associated tuberculosis, WHO danger signs, and a CD4 count of 76 cells per μL (the median for the cohort) was 45% (95% CI 38–52). The diagnostic yield of sputum in patients with M tuberculosis BSI was 77% (95% CI 63–87), increasing to 89% (80–94) when combined with urine LAM testing. Presence of M tuberculosis BSI compared with its absence in patients with HIV-associated tuberculosis increased risk of death before 30 days (adjusted hazard ratio 2·48, 95% CI 2·05–3·08) but not after 30 days (1·25, 0·84–2·49). In a propensity-score matched cohort of participants with HIV-associated tuberculosis (n=630), mortality increased in patients with M tuberculosis BSI who had a delay in anti-tuberculosis treatment of longer than 4 days compared with those who had no delay (odds ratio 3·15, 95% CI 1·16–8·84). Interpretation In critically ill adults with HIV-tuberculosis, M tuberculosis BSI is a frequent manifestation of tuberculosis and predicts mortality within 30 days. Improved diagnostic yield in patients with M tuberculosis BSI could be achieved through combined use of sputum Xpert and urine LAM. Anti-tuberculosis treatment delay might increase the risk of mortality in these patients. Funding This study was supported by Wellcome fellowships 109105Z/15/A and 105165/Z/14/A .

Background Rapid reviews (RRs) have emerged as an efficient alternative to time-consuming systematic reviews—they can help meet the demand for accelerated evidence synthesis to inform decision-making in healthcare. The synthesis of diagnostic evidence has important methodological challenges. Here, we performed an international survey to identify the current practice of producing RRs for diagnostic tests. Methods We developed and administered an online survey inviting institutions that perform RRs of diagnostic tests from all over the world. Results All participants (N = 25) reported the implementation of one or more methods to define the scope of the RR; however, only one strategy (defining a structured question) was used by ≥90% of participants. All participants used at least one methodological shortcut including the use of a previous review as a starting point (92%) and the use of limits on the search (96%). Parallelization and automation of review tasks were not extensively used (48 and 20%, respectively). Conclusion Our survey indicates a greater use of shortcuts and limits for conducting diagnostic test RRs versus the results of a recent scoping review analyzing published RRs. Several shortcuts are used without knowing how their implementation affects the results of the evidence synthesis in the setting of diagnostic test reviews. Thus, a structured evaluation of the challenges and implications of the adoption of these RR methods is warranted.

Tuomas Rissanen and colleagues reported a statistically significantly reduced incidence of major adverse cardiac events in patients with de-novo coronary artery lesions at a high risk of bleeding treated with a drug-coated balloon compared with those treated with a bare-metal stent. In this study, the absolute difference in major adverse cardiac events at 9 months was reported as −13·2 percentage points (95% CI −6·2 to −21·1). Therefore, the authors claimed that percutaneous coronary intervention with drug-coated balloon was superior to bare-metal stent in patients at risk of bleeding. However, we believe that these results should be interpreted with caution.

Humanised xenograft models allow for the analysis of human tissue within a physiological environment in vivo. However, current models often rely on the angiogenesis and ingrowth of recipient vasculature to perfuse tissues, preventing analysis of biological processes and diseases involving human blood vessels. This limits the effectiveness of xenografts in replicating human physiology and may lead to issues with translating findings into human research.\ud We have designed a xenograft model of human vasculature to address this issue. Human subcutaneous fat was cultured in vitro to promote blood vessel outgrowth prior to implantation into immunocompromised mice. We demonstrate that implants survived, retained human vasculature and anastomosed with the circulatory system of the recipient mouse. Significantly, by performing transplants into the ear pinna, this system enabled intravital observation of xenografts by multiphoton microscopy, allowing us to visualise the steps leading to vascular cytoadherence of erythrocytes infected with the human parasite Plasmodium falciparum.\ud This model represents a useful tool for imaging the interactions that occur within human tissues in vivo and permits visualization of blood flow and cellular recruitment in a system which is amenable to intervention for various studies in basic biology together with drug evaluation and mechanism of action studies.

Objective: To explore experts’ views on factors influencing national and global active case-finding (ACF) policy development and implementation, and the use of evidence in these processes. Design: This is an exploratory study based on semistructured expert interviews. Framework analysis was applied. Participants: The study involved a purposive sample of 39 experts from international, non-governmental and non-profit organisations, funders, government institutions, international societies, think tanks, universities and research institutions worldwide. Results: This study highlighted the perceived need among experts for different types of evidence for ACF policy development and implementation, and for stakeholder engagement including researchers and policymakers to foster evidence use. Interviewees stressed the influence of government, donor and non-governmental stakeholders in ACF policy development. Such key stakeholders also influence ACF policy implementation, in addition to available systems and processes in a given health system, and implementers’ motivation and incentives. According to the interviewees, the World Health Organization (WHO) guidelines for systematic screening face the innate challenge of providing guidance to countries across the broad area of ACF in terms of target groups, settings and screening algorithms. The guidelines could be improved by focusing on what should be done rather than what can be done in ACF, and by providing howto examples. Leadership, integration into health systems and long-term financing are key for ACF to be sustainable. Conclusions: We provide new insights into ACF policy processes globally, particularly regarding facilitators for and barriers to ACF policy development, evidence need and use, and donor organisations’ influence. According to expert participants, national and global ACF policy development and implementation can be improved by broadening stakeholder engagement. Meanwhile, using diverse evidence to inform ACF policy development and implementation could mitigate the ‘power plays plus push’ that might otherwise disrupt and mislead these policy processes.

Purpose of Review This paper discusses the current issues in the development of foetal charts and is informed by a scoping review of studies constructing charts between 2012 and 2018. Recent Findings The scoping review of 20 articles revealed that there is still a lack of consensus on how foetal charts should be constructed and whether an international chart that can be applied across populations is feasible. Many of these charts are in clinical use today and directly affect the identification of at risk newborns that require treatment and nutritional strategies. However, there is no agreement on important design features such as inclusion and exclusion criteria; sample size and agreement on definitions such as what constitutes a healthy population of pregnant women that can be used for constructing foetal standards. Summary This paper therefore reiterates some of these current issues and the scoping review showcases the heterogeneity in the studies developing foetal charts between 2012 and 2018. There is no consensus on these pertinent issues and hence if not resolved will lead to continued surge of foetal reference and standard charts which will only exacerbate the current problem of not being able to make direct comparisons of foetal size and growth across populations.

Ethics guidelines emphasise that research should be acceptable to the people invited to take part. However, acceptability is subjective and dependent on context, complicating its assessment and use as an ethical standard. This paper examines the concept of acceptability in relation to parents' perspectives on a paediatric vaccine trial in Malawi. We examined decisions on participation and experiences of the trial through interviews with parents in 41 households invited to enrol their children and participant observation of trial processes. Fieldwork took place in Chikwawa, Southern Malawi from February–October 2016. Parents were not neatly split between those who saw the trial as acceptable and those who did not; instead there were mixed and changing feelings among parents who enrolled their children, and among those who withdrew or did not take part. Some parents agreed to participate but had concerns about the trial, while others expressed satisfaction with the trial but still did not take part. These experiences indicate substantial variation in the nature of acceptance. We describe these variations in relation to six dimensions of acceptability: how acceptable the trial is, what aspects are acceptable, changes over time, circumstances affecting acceptability, variations between people, and reasons for participation or non-participation. The findings illustrate the difficulty of determining whether a trial is sufficiently acceptable to potential participants. We suggest that clarifying definitions of acceptability and examining how acceptability varies in degree, between trial components, over time, and between people and contexts may help researchers generate more nuanced descriptions of acceptability that support responsive and ethical trial design.

Background Programs that integrate tuberculosis (TB) and human immunodeficiency virus (HIV) treatment aim to provide efficient treatment services and maximize successful treatment outcomes through the delivery of both TB and HIV treatment by one provider at the same time and location. However, multi-drug resistant tuberculosis (MDR-TB) is more difficult to treat as compared to drug-sensitive TB, and in low- and middle-income countries (LMICs), the potential of programs integrating TB/HIV treatment to sustain favourable MDR-TB treatment outcomes is poorly elucidated. The objective of this review is to perform a systematic collection, critical appraisal and synthesis of existing evidence on therapeutic outcomes of MDR-TB and their predictors among adults receiving integrated treatment for TB/HIV in LMICs. Methods A systematic review of quantitative evidence from observational cohort studies will be performed. MEDLINE, Embase, and Global Health electronic databases will be searched for relevant studies published from March 2004 to December 2019. Two investigators will independently screen the search output, review the eligible studies, and assess the quality of the eligible studies using quality assessment tools of the National Heart Lung and Blood Institute. Random-effects meta-analysis will be used to obtain summary estimates. Heterogeneity across studies will be assessed using the I2 statistic. The confidence in the summary estimates will be rated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The final review will be reported following the guidelines of the Preferred Reporting System for Systematic Reviews and Meta-analysis, presented at scientific conferences and published in a peer-reviewed journal. Discussion This study is expected to report the performance of integrated TB/HIV treatment programs as regards their potential to uphold successful MDR-TB treatment outcomes in LMICs. Furthermore, the review will indicate patient-related and healthcare-related factors that should be addressed to improve on survival of patients with MDR-TB/HIV co-infection in LMICs. Systematic review registration This review has been registered with the International Prospective Register of Systematic Reviews and the reference ID is CRD42020159745

As demonstrated by the collection of scientific papers published in BMJ Military Health [1–5][1] and elsewhere[6][2] regarding Operation TRENTON and preceding operations, the Defence Medical Services (DMS) are established world leaders in the field of military medical research.[7][3] Many aspiring

Background Despite large-scale efforts to diagnose people living with HIV, 54% remain undiagnosed in sub-Saharan Africa. The gap in knowledge of HIV status and uptake of follow-on services remains wide with much lower rates of HIV testing among men compared to women. Here, we design a study to investigate the effect on uptake of HIV testing and linkage into care or prevention of partner-delivered HIV self-testing alone or with an additional intervention among male partners of pregnant women. Methods A phase II, adaptive, multi-arm, multi-stage cluster randomised trial, randomising antenatal clinic (ANC) days to six different trial arms. Pregnant women accessing ANC in urban Malawi for the first time will be recruited into either the standard of care (SOC) arm (invitation letter to the male partner offering HIV testing) or one of five intervention arms offering oral HIV self-test kits. Three of the five intervention arms will additionally offer the male partner a financial incentive (fixed or lottery amount) conditional on linkage after self-testing with one arm testing phone call reminders. Assuming that 25% of male partners link to care or prevention in the SOC arm, six clinic days, with a harmonic mean of 21 eligible participants, per arm will provide 80% power to detect a 0.15 absolute difference in the primary outcome. Cluster proportions will be analysed by a cluster summaries approach with adjustment for clustering and multiplicity. Discussion This trial applies adaptive methods which are novel and efficient designs. The methodology and lessons learned here will be important as proof of concept of how to design and conduct similar studies in the future. Although small, this trial will potentially present good evidence on the type of effective interventions for improving linkage into ART or prevention. The trial results will also have important policy implications on how to implement HIVST targeting male partners of pregnant women who are accessing ANC for the first time while paying particular attention to safety concerns. Contamination may occur if women in the intervention arms share their self-test kits with women in the SOC arm. Trial registration ISRCTN, ID: 18421340. Registered on 31 March 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2093-2) contains supplementary material, which is available to authorized users.

Summary Adding low-dose primaquine to malaria treatment reduced gametocyte carriage by 73%. Patients who received primaquine had more frequent hemoglobinuria and there was a greater reduction in haemoglobin concentration in G6PD-deficient patients. One patient who received primaquine developed moderately severe anemia., Introduction More information is needed about the safety of low-dose primaquine in populations where G6PD deficiency is common. Methods Adults with Plasmodium falciparum malaria were randomized to receive 1 of 3 artemisinin combination therapies (ACTs) with or without primaquine (0.25 mg/kg). Glucose-6-phosphate dehydrogenase (G6PD) status was determined using a rapid test. Patients were followed for 28 days to record hemoglobin concentration, adverse events, and gametocyte carriage. The primary end point was the change in Hb at day 7. Results In sum, 274 patients were randomized, 139 received an ACT alone, and 135 received an ACT + primaquine. The mean reduction in Hb at day 7 was similar in each group, a difference in the ACT + PQ versus the ACT alone group of −0.04 g/dL (95% confidence interval [CI] −0.23, 0.31), but the effect of primaquine differed according to G6PD status. In G6PD-deficient patients the drop in Hb was 0.63 g/dL (95% CI 0.03, 1.24) greater in those who received primaquine than in those who received an ACT alone. In G6PD-normal patients, the reduction in Hb was 0.22 g/dL (95% CI −0.08, 0.52) less in those who received primaquine (interaction P = .01). One G6PD normal patient who received primaquine developed moderately severe anaemia (Hb < 8 g/dL). Dark urine was more frequent in patients who received primaquine. Primaquine was associated with a 73% (95% CI 24–90) reduction in gametocyte carriage (P = .013). Conclusion Primaquine substantially reduced gametocyte carriage. However, the fall in Hb concentration at day 7 was greater in G6PD-deficient patients who received primaquine than in those who did not and one patient who received primaquine developed moderately severe anemia. Clinical Trial registration PACTR201411000937373 (www.pactr.org)

Background: Cost is a major barrier to maternal health service utilisation for many women in low- and middle-income countries (LMICs). However, comparable evidence of the available cost data in these countries is limited. We conducted a systematic review and comparative analysis of costs of utilising maternal health services in these settings. Methods: We searched peer-reviewed and grey literature databases for articles reporting cost of utilising maternal health services in LMICs published post-2000. All retrieved records were screened and articles meeting the inclusion criteria selected. Quality assessment was performed using the relevant cost-specific criteria of the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. To guarantee comparability, disaggregated costs data were inflated to 2019 US dollar equivalents. Total adjusted costs and cost drivers associated with utilising each service were systematically compared. Where heterogeneity in methods or non-disaggregated costs was observed, narrative synthesis was used to summarise findings. Results: Thirty-six studies met our inclusion criteria. Many of the studies costed multiple services. However, the most frequently costed services were utilisation of normal vaginal delivery (22 studies), caesarean delivery (13), and antenatal care (ANC) (10). The least costed services were post-natal care (PNC) and post-abortion care (PAC) (5 each). Studies used varied methods for data collection and analysis and their quality ranged from low to high with most assessed as average or high. Generally, across all included studies, cost of utilisation progressively increased from ANC and PNC to delivery and PAC, and from public to private providers. Medicines and diagnostics were main cost drivers for ANC and PNC while cost drivers were variable for delivery. Women experienced financial burden of utilising maternal health services and also had to pay some unofficial costs to access care, even where formal exemptions existed. Conclusion: Consensus regarding approach for costing maternal health services will help to improve their relevance for supporting policy-making towards achieving universal health coverage. If indeed the post-2015 mission of the global community is to "leave no one behind," then we need to ensure that women and their families are not facing unnecessary and unaffordable costs that could potentially tip them into poverty.

Background: Extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) threaten human health; and, in areas of sub-Saharan Africa (sSA) where carbapenems are not available, may render ESBL-E infections untreatable. Gut mucosal colonisation probably occurs before infection, making prevention of colonisation an attractive target for intervention, but the epidemiology of ESBL-E in sSA is poorly described.\ud \ud Objectives: Describe ESBL-E colonisation prevalence in sSA and risk factors associated with colonisation.\ud Methods: Studies included were prospective cross-sectional or cohort studies reporting gut mucosal ESBL-E colonisation in any population in sSA. We searched PubMed and Scopus on 18 December 2018. We summarise the range of prevalence across sites and tabulated risk factors for colonisation. The protocol was registered (Prospero ID CRD42019123559).\ud \ud Results: From 2975 abstracts we identified 32 studies including a total of 8619 participants from a range of countries and settings. Six studies were longitudinal; no longitudinal studies followed patients beyond hospital discharge. Prevalence varied between 5 and 84% with a median of 31%, with a relationship to setting: pooled ESBL-E colonisation in community studies was 18% (95% CI 12 to 28, 12 studies); in studies recruiting people at admission to hospital colonisation was 32% (95% CI 24 to 41% 8 studies); and for inpatients, colonisation was 55% (95% CI 49 to 60%, 7 studies). Antimicrobial use was associated with increased risk of ESBL-E colonisation, and protected water sources or water treatment by boiling may reduce risk.\ud \ud Conclusions: ESBL-E colonisation is common in sSA, but how people become carriers and why is not well understood. To inform the design of interventions to interrupt transmission in this setting requires longitudinal, community studies.

Background.\ud Drug efficacy trials monitor the continued efficacy of front-line drugs against falciparum malaria. Over-estimates of efficacy result in a country retaining a failing drug as first-line treatment with associated increases in morbidity and mortality, while under-estimating drug effectiveness leads to removal of an effective treatment with substantial practical and economic implications. Trials are challenging: they require long durations of follow-up to detect drug failures, and patients are frequently re-infected during that period. Molecular correction based on parasite genotypes distinguishes reinfections from drug failures to ensure the accuracy of failure rate estimates. Several molecular correction “algorithms” are proposed, but which is most accurate and/or robust remains unknown.\ud Methods.\ud We used pharmacological modelling to simulate parasite dynamics and genetic signals that occur in patients enrolled in malaria drug clinical trials. We compared estimates of treatment failure obtained from a selection of proposed molecular correction algorithms against the known “true” failure rate in the model. \ud Findings.\ud (i) Molecular correction is essential to avoid substantial over-estimates of drug failure rates. (ii) The current WHO-recommended algorithm consistently under-estimates the true failure rate. (iii) Newly-proposed algorithms produce more accurate failure rate estimates; the most accurate algorithm depends on the choice of drug, trial follow-up length, and transmission intensity. (iv) Long durations of patient follow-up may be counterproductive; large numbers of new infections accumulate and may be misclassified, over-estimating drug failure rate. (v) Our model was highly consistent with existing in vivo data.\ud Interpretation.\ud The current WHO-recommended method for molecular correction and analysis of clinical trials should be re-evaluated and updated.

Background The use of histamine-2 receptor antagonists (H2RA) in neonates is still debated because of possible risk of infection, necrotizing enterocolitis (NEC) and increased mortality. Aim To review whether the use of H2RA in neonates admitted to neonatal intensive care units (NICU) is associated with infection, NEC or mortality. Materials and method We performed a systematic search in PubMed, Web of Science and SCOPUS databases using the terms “histamine-2 receptor antagonists”, “infection”, “necrotizing enterocolitis”, “mortality”, “neonates” and related terms to identify studies published up to April 30, 2017. We included studies conducted in hospitalized neonates and exposed to H2RA. The primary outcomes were infection, NEC and mortality. We included reports of infections with clinical signs and positive culture, and NEC according to Bell stages (stage ≥II) based on standardised clinical and radiologic criteria. Among 1,144 studies identified, 10 fulfilled the selection criteria. Information extracted included study design, sample size and number of participants, along with the outcomes of interest. We conducted a meta-analysis of adjusted data and pooled estimates of infection, NEC and mortality are reported as odds ratios (OR) and 95% confidence intervals (95%CI). Results Ten studies were analysed. There were substantial associations between H2RA and infection (pooled OR: 2.09; 95%CI: 1.35–3.24; P = 0.001) and NEC (pooled OR: 2.81, 95%CI: 1.19–6.64; P = 0.02) but not with the mortality risk (pooled OR: 1.76; 95%CI: 0.50–6.16; P: 0.38). Conclusion Current evidence suggests that H2RA is associated with an increased risk of infection and NEC, but not with mortality in neonates admitted to NICU. The use of H2RA in neonates must be stringently considered when necessary.

Background\ud Research turnover in the HIV field is rapid, and as a result, maintaining high-quality, up-to-date, and relevant systematic reviews is a challenge. One approach is to frequently update published reviews.\ud Methods\ud We evaluated the methods and relevance of all HIV systematic reviews and protocols published in the Cochrane Library over a 16-year period (2000–2016) to determine the need to update published reviews or complete of reviews in progress.\ud Results\ud Of 148 published reviews and protocols, 129 (87%) were identified as not for updating or progression to publication, mostly due to research questions which were either entirely outdated or addressed questions in an outdated manner (N = 89; 60%); this was anticipated for older reviews, but was found also to be the case for recent publications. Some research questions were also inadequately conceptualized, particularly when complex pragmatic trials or behavioral interventions were included.\ud Conclusions\ud We suggest that authors clearly characterize interventions and synthesis approaches in their review protocols. In research fields, such as HIV, where questions change frequently, systematic reviews and protocols should be regularly re-evaluated to ensure relevance to current questions. This process of re-evaluation should be incorporated into the methods of living systematic reviews.

To achieve universal health coverage, the scale-up of high impact public health interventions is essential. However, scale-up is challenging and often not successful. Therefore, a systematic review was conducted to provide insights into the factors influencing the scale-up of public health interventions in low- and middle-income countries (LMICs). Two databases were searched for studies with a qualitative research component. The GRADE-CERQual approach was applied to assess the confidence in the evidence for each key review finding. A multi-level perspective on transition was applied to ensure a focus on vertical scale-up for sustainability. According to this theory, changes in the way of organizing (structure), doing (practice) and thinking (culture) need to take place to ensure the scale-up of an intervention. Among the most prominent factors influencing scale-up through changes in structure was the availability of financial, human and material resources. Inadequate supply chains were often barriers to scale-up. Advocacy activities positively influenced scale-up, and changes in the policy environment hindered or facilitated scale-up. The most outstanding factors influencing scale-up through changes in practice were the availability of a strategic plan for scale-up and the way in which training and supervision was conducted. Furthermore, collaborations such as community participation and partnerships facilitated scale-up, as well as the availability of research and monitoring and evaluation data. Factors influencing scale-up through a change in culture were less prominent in the literature. While some studies articulated the acceptability of the intervention in a given sociocultural environment, more emphasis was placed on the importance of stakeholders feeling a need for a specific intervention to facilitate its scale-up. All identified factors should be taken into account when scaling up public health interventions in LMICs. The different factors are strongly interlinked, and most of them are related to one crucial first step: the development of a scale-up strategy before scaling up.

Background The ability of cluster-randomized trials to capture mass or indirect effects is one reason for their increasing use to test interventions against vector-borne diseases such as malaria and dengue. For the same reason, however, the independence of clusters may be compromised if the distances between clusters is too small to ensure independence. In other words they may be subject to spillover effects. Methods We distinguish two types of spatial spillover effect: between-cluster dependence in outcomes, or spillover dependence; and modification of the intervention effect according to distance to the intervention arm, or spillover indirect effect. We estimate these effects in trial of insecticide-treated materials against the dengue mosquito vector, Aedes aegypti, in Venezuela, the endpoint being the Breteau index. We use a novel random effects Poisson spatial regression model. Spillover dependence is incorporated via an orthogonalized intrinsic conditional autoregression (ICAR) model. Spillover indirect effects are incorporated via the number of locations within a certain radius, set at 200m, that are in the intervention arm. Results From the model with ICAR spatial dependence, and the degree of surroundedness, the intervention effect is estimated as 0.74—favouring the intervention—with a 95% credible interval of 0.34 to 1.69. The point estimates are stronger with increasing surroundedness within intervention locations. Conclusion In this trial there is some evidence of a spillover indirect effect of the intervention, with the Breteau index tending to be lower in locations which are more surrounded by locations in the intervention arm., Author summary Control methods for dengue, and other diseases which are transmitted by mosquitoes, are often tested in cluster-randomized trials. This means that whole groups of people, often defined by geographical area, are randomly allocated to receive the control method or not. These control methods often have a mass effect so that they may be stronger if applied to a whole area together. However, if the areas (clusters) are not very far apart then the effects may ‘spill over’ from one to another. In this paper we use a new spatial statistical method to re-analyse data from a cluster-randomized trial which was done in a town in Venezuela. The idea was to use insecticide treated curtains and water tank covers to try to control the mosquitoes which transmit dengue. To assess the spillover effect we calculate how much each location was surrounded by locations which got the control method. We found some evidence that the greater the surroundedness then the stronger the effect of the intervention.

Background Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). Methods An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. Discussion A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. Trial registration ISRCTN, ISRCTN72509687. Registered on 13 July 2017. Electronic supplementary material The online version of this article (10.1186/s13063-018-3026-4) contains supplementary material, which is available to authorized users.

Controlled human infection (CHI) trials, in which healthy volunteers are experimentally infected, can accelerate the development of novel drugs and vaccines for infectious diseases of global importance. The use of CHI models is expanding from around 60 studies in the 1970s to more than 120 publications in this decade, primarily for influenza, rhinovirus, and malaria. CHI trials have provided landmark data for several registered drugs and vaccines, and have generated unprecedented scientific insights. Because of their invasive nature, CHI studies demand critical ethical review according to established frameworks. CHI-associated serious adverse events are rarely reported. Novel CHI models need standardised safety data from comparable CHI models to facilitate evidence-based risk assessments, as well as funds to produce challenge inoculum according to regulatory requirements. Advances such as the principle of controlled colonisation, the expansion of models to endemic areas, and the use of genetically attenuated strains will further broaden the scope of CHI trials.

Letter to the Editor

Little is known about the perceptions, attitudes and practices of lymphatic filariasis in Conakry, Republic of Guinea. Yet, such knowledge is important for an optimal design and implementation of setting-specific prevention and control measures. We conducted a cross-sectional study using a mixed methods approach. Qualitative data related to people's general experience with lymphatic filariasis, their perception of the causes of the disease, the onset of elephantiasis, care-seeking behaviour and the socioeconomic impact of lymphatic filariasis were collected by in-depth interviews with 85 respondents. Quantitative data related to strategies for prevention and the knowledge of the causes of the disease were collected by interviewing 429 people. A total of 514 individuals (313 females and 201 males), aged 10-84 years, participated. Most participants were well aware of lymphatic filariasis and they recognized the disease mainly by its disfiguring manifestation, collectively termed "elephantiasis" or "leg-swelling disease". Morbidity patterns due to filarial infection showed an increase with age (from 30 to 50 years) independent of sex. Most patients with lymphatic filariasis abandoned their jobs (73.9%) or sought other work (21.7%). The main perceived causes of acquiring lymphatic filariasis were of supernatural origin (as stated by 8.7% of patients and 5.7% of healthy subjects), while mosquito bites were mentioned by fewer participants (4.3% of patients and 4.2% of healthy subjects). A number of other causes were reported that relate to both medical and non-medical conceptions. The study also identified socioeconomic impairments and stigmatization due to elephantiasis. Taken together, community perception of lymphatic filariasis in Conakry is influenced by sociocultural conceptions. Appropriate health education campaigns aimed at enhancing community understanding of the transmission of lymphatic filariasis are required to increase the success of mass drug administration implemented for the elimination of this disease. There is a need for a morbidity management programme to alleviate lymphatic filariasis-related physical and emotional burden in Conakry. [Abstract copyright: Copyright © 2017. Published by Elsevier B.V.]

Background Methodological research into the design, conduct, analysis and reporting of trials is essential to optimise the process. UK specialists in the field have established a set of top priorities in aid of this research. These priorities, however, may not be reflected in the needs of similar research in low- to middle-income countries (LMICs) with different healthcare provision, resources and research infrastructure. The aim of the study was to identify the top priorities for methodological research in LMICs to inform further research and ultimately to improve clinical trials in these regions. Methods An online, two-round survey was conducted from December 2016 to April 2017 amongst researchers and methodologists working on trials in LMICs. The first round required participants to suggest between three and six topics which they felt were priorities for trial methodological research in LMICs. The second round invited participants to grade the importance of a compulsory list of topics suggested by four or more individuals, and an optional list of the remaining topics. Findings Rounds 1 and 2 were completed by 412 and 314 participants, respectively. A wide spread of years of experience, discipline, current country of residence, origin of trials training and area of involvement in trials was reported. The topics deemed most important for methodological research were: choosing appropriate outcomes to measure and training of research staff. Conclusion By presenting these top priorities we have the foundations of a global health trials methodological research agenda which we hope will foster future research in specific areas in order to increase and improve trials in LMICs. Electronic supplementary material The online version of this article (10.1186/s13063-018-2440-y) contains supplementary material, which is available to authorized users.

The worldwide dissemination of Mycobacterium tuberculosis strains has led to the study of their genetic diversity. One of the most used genotyping methods is spoligotyping, based on the detection of spacers in the clustered regularly interspaced short palindromic repeats (CRISPR) locus. This study assessed the performance of a microbead-based spoligotyping assay using samples extracted from Ziehl-Neelsen-stained smear-microscopy preparations and described the genetic diversity of Mycobacterium tuberculosis among new TB patients in Southern Nations, Nationalities and Peoples’ Region (SNNPR) in Ethiopia. Among the 91 samples analysed, 59 (64.8%) generated spoligotyping patterns. Fifty (84.7%) samples were classified into 12 clusters (mostly Lineage 4 or 3) comprising 2–11 samples and nine had unique spoligotyping patterns. Among the 59 spoligotyping patterns, 25 belonged to the T1 sublineage, 11 to the T3-ETH, 5 to the URAL, 4 to the H3 and 14 to other L4 sublineages. There was a remarkable variation in genetic distribution in SNNPR compared to other regions of the country. Microbead-based spoligotyping is an easy-to-perform, high-throughput assay that can generate genotyping information using material obtained from smear microscopy preparations. The method provides an opportunity to obtain data of the M. tuberculosis genetic epidemiology in settings with limited laboratory resources.

Infectious disease models are both concise statements of hypotheses and powerful techniques for creating tools from hypotheses and theories. As such, they have tremendous potential for guiding data collection in experimental and observational studies, leading to more efficient testing of hypotheses and more robust study designs. In numerous instances, infectious disease models have played a key role in informing data collection, including the Garki project studying malaria, the response to the 2009 pandemic of H1N1 influenza in the United Kingdom and studies of T-cell immunodynamics in mammals. However, such synergies remain the exception rather than the rule; and a close marriage of dynamic modeling and empirical data collection is far from the norm in infectious disease research. Overcoming the challenges to using models to inform data collection has the potential to accelerate innovation and to improve practice in how we deal with infectious disease threats.

Important policy questions tend to span a range of academic disciplines, and the relevant research is often carried out in a variety of social, economic and geographic contexts. In efforts to synthesise research to help inform decisions arising from the policy questions, systematic reviews need conceptual frameworks and ways of thinking\ud that combine knowledge drawn from different academic traditions and contexts; in other words, transdisciplinary research. This paper considers how transdisciplinary working can be achieved with: conceptual frameworks that span traditional academic boundaries; methods for shaping review questions and conceptual frameworks; and\ud methods for interpreting the relevance of findings to different contexts. It also discusses the practical challenges and ultimate benefits of transdisciplinary working for systematic reviews.

Background: Evaluating applications for multi-national, multi-disciplinary, dual-purpose research consortia is highly complex. There has been little research on the peer review process for evaluating grant applications and almost none on how applications for multi-national consortia are reviewed. Overseas development investments are increasingly being channelled into international science consortia to generate high-quality research while simultaneously strengthening multi-disciplinary research capacity. We need a better understanding of how such decisions are made and their effectiveness.\ud \ud Methods: An award-making institution planned to fund 10 UK-Africa research consortia. Over two annual rounds, 34 out of 78 eligible applications were shortlisted and reviewed by at least five external reviewers before final selections were made by a face-to-face panel. We used an innovative approach involving structured, overt observations of award-making panel meetings and semi-structured interviews with panel members to explore how assessment criteria concerning research quality and capacity strengthening were applied during the peer review process. Data were coded and analysed using pre-designed matrices which incorporated categories relating to the assessment criteria.\ud \ud Results: In general the process was rigorous and well-managed. However, lack of clarity about differential weighting of criteria and variations in the panel’s understanding of research capacity strengthening resulted in some inconsistencies in use of the assessment criteria. Using the same panel for both rounds had advantages, in that during the second round consensus was achieved more quickly and the panel had increased focus on development aspects.\ud \ud Conclusion: Grant assessment panels for such complex research applications need to have topic- and context-specific expertise. They must also understand research capacity issues and have a flexible but equitable and transparent approach. This study has developed and tested an approach for evaluating the operation of such panels and has generated lessons that can promote coherence and transparency among grant-makers and ultimately make the award-making process more effective.

We read the perspective article “NutriGrade: A Scoring system to Assess and Judge the Meta-Evidence of Randomized Controlled Trials and Cohort Studies in Nutrition Research” published in November 2016 in Advances in Nutrition [1]. We agree it is important to assess the trustworthiness of evidence.

Problem\ud We investigated leukocyte and lymphocyte subsets in HIV-infected or HIV-uninfected, pregnant or non-pregnant Malawian women to explore whether HIV infection and pregnancy may act synergistically to impair cellular immunity.\ud \ud Method of study\ud We recruited 54 pregnant and 48 non-pregnant HIV-uninfected women and 24 pregnant and 20 non-pregnant HIV-infected Malawian women. We compared peripheral blood leukocyte and lymphocyte subsets between women in the four groups.\ud \ud Results\ud Parturient HIV-infected and HIV-uninfected women had more neutrophils (each P

Background\ud \ud Couples' HIV testing and counselling (CHTC) is associated with greater engagement with HIV prevention and care than individual testing and is cost-effective, but uptake remains suboptimal. Initiating discussion of CHTC might result in distrust between partners. Offering incentives for CHTC could change the focus of the pre-test discussion. We aimed to determine the impact of incentives for CHTC on uptake of couples testing and HIV case diagnosis in rural Zimbabwe.\ud \ud Methods\ud \ud In this cluster-randomised trial, 68 rural communities (the clusters) in four districts receiving mobile HIV testing services were randomly assigned (1:1) to incentives for CHTC or not. Allocation was not masked to participants and researchers. Randomisation was stratified by district and proximity to a health facility. Within each stratum random permutation was done to allocate clusters to the study groups. In intervention communities, residents were informed that couples who tested together could select one of three grocery items worth US$1·50. Standard mobilisation for testing was done in comparison communities. The primary outcome was the proportion of individuals testing with a partner. Analysis was by intention to treat. 3 months after CHTC, couple-testers from four communities per group individually completed a telephone survey to evaluate any social harms resulting from incentives or CHTC. The effect of incentives on CHTC was estimated using logistic regression with random effects adjusting for clustering. The trial was registered with the Pan African Clinical Trial Registry, number PACTR201606001630356.\ud \ud Findings\ud \ud From May 26, 2015, to Jan 29, 2016, of 24 679 participants counselled with data recorded, 14 099 (57·1%) were in the intervention group and 10 580 (42·9%) in the comparison group. 7852 (55·7%) testers in the intervention group versus 1062 (10·0%) in the comparison group tested with a partner (adjusted odds ratio 13·5 [95% CI 10·5–17·4]). Among 427 (83·7%) of 510 eligible participants who completed the telephone survey, 11 (2·6%) reported that they were pressured or themselves pressured their partner to test together; none regretted couples' testing. Relationship unrest was reported by eight individuals (1·9%), although none attributed this to incentives.