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Objectives: The survey was to determine Knowledge, attitude, and practices around bronchiectasis, as a starting point for the development of guidelines for care in African Countries. Materials and Methods: This survey was administered to non-specialist physicians in urban health centers in Burkina Faso, Uganda, South Africa, and Ethiopia. Data were anonymized and analyzed at an individual level by country and health-care setting. Results: A total of 388 participants were recruited from Ouagadougou (75/388, 19.3%), Kampala (85/388, 21.9%), Johannesburg (74/388, 19.3%), and Addis Ababa (154/388, 39.6%). Median age was 30 years, and 66% were male, with a median of 3-year medical experience. Knowledge about the definition, clinical presentation, and diagnosis of disease was good. However, guidelines for local practice were largely absent. Wide variation was reported in diagnostic and management practices. Physicians recognized the need for guidelines and further training. Conclusion: This study highlighted the lack of local guidelines for bronchiectasis care in these settings and marked variation in approaches to investigation, diagnosis, and management within and between sites. Context-appropriate guidelines for bronchiectasis care in Sub-Saharan Africa are needed. These must be informed by local epidemiology, should reflect locally available resources and comorbidities including tuberculosis-disease, and should be codeveloped with local practitioners.

[Image: see text] Synthetic endoperoxide antimalarials, such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. However, limited solubility of second-generation analogues in biological-relevant media represents a barrier in clinical development. We present methodology for the synthesis of nonlinear analogues of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced molecular symmetry on in vitro antimalarial activity and physicochemical properties. While maintaining good antimalarial activity and metabolic stability, head-to-head comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF solubility for three of the four analogues studied. Pharmacokinetic studies in rats comparing a selected nonlinear analogue 14a and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% versus 41%). These findings provide support for further in vivo efficacy studies in preclinical animal species.

Background Continuous quality improvement processes in health care were developed for use at health facility level, and that is where they have been used the most, often addressing defined care processes. However, in different settings different factors have been important to support institutionalization. This study explores how continuous quality improvement processes were institutionalized at the district level and at the health facility level in Uganda. Methods This qualitative study was carried out in seven districts in Uganda. Semi-structured interviews with key informants from the district health management teams and document review were conducted. Thematic analysis was used to analyze the data. Results All districts that participated in the study formed Continuous Quality Improvement (CQI) teams both at the district level and at the health facilities. The district CQI teams comprised of members from different departments within the district health office. District level CQI teams were mandated to take the lead in addressing management gaps and follow up CQI activities at the health facility level. Acceptability of quality improvement processes by the district leadership was identified across districts as supporting the successful implementation of CQI. However, high turnover of staff at health facility level was also reported as a detrimental to the successful implementation of quality improvement processes. Also the district health management teams did not engage much in addressing their own roles using continuous quality improvement. Conclusion The leadership and management provided by the district health management team was an important factor for the use of Continuous Quality Improvement principles within the district. The key roles of the district health team revolved around the institutionalisation of CQI at different levels of the health system, monitoring results of continuous quality improvement implementation, mobilising resources and health care delivery hence promoting the culture of quality, direct implementation of CQI, and creating an enabling environment for the lower-level health facilities to engage in CQI. High turnover of staff at health facility level was also reported as one of the challenges to the successful implementation of continuous quality improvement. The DHT did not engage much in addressing gaps in their own roles using continuous quality improvement.

BACKGROUND: Indoor and ambient air pollution exposure is a major risk to respiratory health worldwide, particularly in low- and middle-income countries (LMICs). Interventional trials have mainly focused on alternatives to cooking stoves, with mixed results. Beyond cooking, additional sources of particulate matter also contribute to the burden of air pollution exposure. This review explores evidence from current randomised controlled trials (RCTs) on the clinical effectiveness of interventions to reduce particulate matter in LMICs.METHODS: Twelve databases and the grey literature (e.g., Government reports and policy papers) were searched. Eligible studies were RCTs conducted in LMICs aiming to reduce particulate exposure from any source and reporting on at least one clinical respiratory outcome (respiratory symptoms, lung function or clinical diagnoses). Data from relevant studies were systematically extracted, the risk of bias assessed and narrative synthesis provided.RESULTS: Of the 14 included studies, 12 tested ‘improved' cookstoves, most using biomass, but solar and bioethanol cookers were also included. One trial used solar lamps and another was an integrated intervention incorporating behavioural and environmental components for the treatment and prevention of chronic obstructive pulmonary disease. Of the six studies reporting child pneumonia outcomes, none demonstrated significant benefit in intention-to-treat analysis. Ten studies reported respiratory symptom outcomes with some improvements seen, but self-reporting made these outcomes highly vulnerable to bias. Substantial inter-study clinical and methodological heterogeneity precluded calculation of pooled effect estimates.CONCLUSION: Evidence from the RCTs performed to date suggests that individual household-level interventions for air pollution exposure reduction have limited benefits for respiratory health. More comprehensive approaches to air pollution exposure reduction must be developed so their potential health benefits can be assessed.

Lateral flow device (LFD) rapid tests for SARS-CoV-2 antigens are used for asymptomatic testing (including for people who are presymptomatic or paucisymptomatic) in various settings, including in the UK. As of April 9, 2021, LFD tests were made available for twice per week rapid testing to the general population in England. News articles reported pressures within the UK Government to rescind asymptomatic testing due to concerns that, despite high specificity (estimated to be 99·9%),1 the proportion of people testing positive who had COVID-19 (ie, the positive predictive value) was falling in line with the reducing prevalence, leading to greater proportions of individuals having to unnecessarily isolate because of a false-positive test result.2 Asking people to isolate on the basis of what might be a false-positive result is associated with a perceived unfairness and, in some cases, moral indignation.\ud \ud The risk of people without COVID-19 self-isolating due to false-positive test results is a cost to the individual, their household, and their workplace that needs consideration and mitigation. However, this cost should be considered in the context of the costs of failing to identify true-positive results. In the UK, the epidemic control strategies implemented during the past year, including lockdowns, have all, to varying extents, required people who do not have COVID-19 to isolate or quarantine and to greatly restrict their social contacts, while shutting down entire economic sectors. These restrictions have had massive implications for the incomes, education, and wellbeing of many people, including children and young people.3 Any discussions concerning LFD testing policy should incorporate the trade-off between the negative effects of false positives and the onwards transmission prevented. This trade-off is particularly pertinent when considering the contribution of LFD testing to preventing the need for additional widespread restrictive measures.

Background\ud Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS‐CoV‐2 infection and COVID‐19 treatment is conflicting.\ud \ud Objectives\ud To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID‐19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS‐CoV‐2 (postexposure prophylaxis).\ud \ud Search methods\ud We searched the Cochrane COVID‐19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021.\ud \ud Selection criteria\ud We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID‐19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS‐CoV‐2 infection.\ud \ud Co‐interventions had to be the same in both study arms. \ud \ud We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy.\ud \ud Data collection and analysis\ud We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate‐to‐severe COVID‐19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID‐19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS‐CoV‐2 infection: SARS‐CoV‐2 infection, development of COVID‐19 symptoms, adverse events, mortality, admission to hospital, and quality of life.\ud \ud Main results\ud We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID‐19 in inpatient settings and four treating mild COVID‐19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS‐CoV‐2 infection. Eight studies had an open‐label design, six were double‐blind and placebo‐controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias. \ud \ud Ivermectin doses and treatment duration varied among included studies. \ud \ud We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies.\ud \ud Ivermectin compared to placebo or standard of care for inpatient COVID‐19 treatment\ud \ud We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low‐certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low‐certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low‐certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low‐certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low‐certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low‐certainty evidence) and duration of hospitalization (mean difference (MD) −0.10 days, 95% CI −2.43 to 2.23; 1 study; 45 participants; low‐certainty evidence). No study reported quality of life up to 28 days.\ud \ud Ivermectin compared to placebo or standard of care for outpatient COVID‐19 treatment\ud \ud We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low‐certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low‐certainty evidence) or non‐IMV or high flow oxygen requirement (0 participants required non‐IMV or high flow; 1 study, 398 participants; very low‐certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low‐certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low‐certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low‐certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days.\ud \ud Ivermectin compared to no treatment for prevention of SARS‐CoV‐2 infection\ud \ud We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low‐certainty evidence). The study reported results for development of COVID‐19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS‐CoV‐2 infection, hospital admission, and quality of life up to 14 days.\ud \ud Authors' conclusions\ud Based on the current very low‐ to low‐certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID‐19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID‐19 outside of well‐designed randomized trials.

Highlights • COVID-19 clinical cases were reported in Brazil in February 2020. • SARS-CoV-2 may have circulated before the clinical cases were detected. • We tested serum samples collected in Jan-April 2020 for SARS-CoV-2 antibodies. • 16/989 (1.6%) had antibodies, suggesting an earlier circulation of the virus. • Patients with undetected and reported infection had similar age, sex and residency., We screened stored samples collected before COVID-19 had been reported in Brazil. 989 samples were tested for SAR-CoV-2 antibodies using two different methods; 16 (1.6%) were positive (7 (43.8%) IgM, 3 (18.8%) IgG and 6 (37.5%) IgG/IgM positive), suggesting SARS-CoV-2 had circulated before the first reported COVID-19 case in Brazil.

Purpose Adolescents and young adults (AYA) with Inflammatory Bowel Disease (IBD) report higher depressive symptoms and anxiety compared to healthy controls, with disease severity and abdominal pain being important factors. In the current study, building on what young people had told us in our previous work, we examined whether embarrassment of the condition, social self-efficacy, and friendship quality mediated the relationship between abdominal pain and disease severity, and mental health/well-being. We also included loneliness as a component of well-being. Methods Data on depression, anxiety, loneliness, friendship quality, social self-efficacy, and disease embarrassment were collected from 130 AYA with IBD ages 14–25 years; data on disease severity and abdominal pain were taken from their medical records. Structural Equation Modeling (SEM) was used to test the relationships between the variables. Results Using SEM, we established that higher IBD disease activity negatively impacted how AYA felt about their friendships and how embarrassed they were about their condition; embarrassment then influenced reports of mental health, including loneliness. Abdominal pain, disease onset, and social self-efficacy directly predicted internalising problems. Conclusion In this sample of 14–25-year-old patients with IBD, specifics about the disease (severity and pain) predicted poorer mental health, suggesting discussion of mental health should be part of the clinical dialogue between patient and consultant. In addition, embarrassment about their condition increased depression, anxiety, and loneliness, mediating the relationship between disease severity and well-being. Thus, it is important to consider how perceived stigma affects those with chronic illness, and those issues should be explored in clinic.

BACKGROUND\ud The population impact of pneumococcal conjugate vaccines (PCVs) depends on direct and indirect protection. Following Malawi's introduction of the 13-valent PCV (PCV13) in 2011, we examined its impact on vaccine and non-vaccine serotype invasive pneumococcal disease among vaccine-eligible-age and vaccine-ineligible-age children and adults.\ud \ud METHODS\ud We did a prospective observational time-series analysis and a case-control study. We used data from between Jan 1, 2006, and Dec 31, 2018, from laboratory-based surveillance at a government hospital in Malawi. This period included 6 years before and 7 years after introduction of PCV13. By use of negative-binomial regression, we evaluated secular trend-adjusted incidence rate ratio (IRR) in vaccine serotype and non-vaccine serotype invasive pneumococcal disease before and after introduction of PCV. We compared predicted counterfactual incidence in hypothetical absence of vaccine with empirically observed incidence following vaccine introduction. The case-control study assessed vaccine effectiveness, comparing PCV uptake among cases of vaccine-eligible-age invasive pneumococcal disease versus matched community controls.\ud \ud FINDINGS\ud Surveillance covered 10 281 476 person-years of observation, with 140 498 blood and 63 291 cerebrospinal fluid cultures. A reduction in total (vaccine serotype plus non-vaccine serotype) invasive pneumococcal disease incidence preceded introduction of PCV: 19% (IRR 0·81, 95% CI 0·74 to 0·88, p

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

Background: WHO’s 2015 End TB Strategy advocates social and economic (socioeconomic) support for TB-affected households to improve TB control. However, evidence concerning socioeconomic support for TB-affected households remains limited, especially in low-income countries. Protocol: This mixed-methods study in Nepal will: evaluate the socioeconomic impact of accessing TB diagnosis and care (Project 1); and create a shortlist of feasible, locally-appropriate interventions to mitigate this impact (Project 2). The study will be conducted in the Chitwan, Mahottari, Makawanpur, and Dhanusha districts of Nepal, which have frequent TB and poverty. The study population will include: approximately 200 people with TB (Cases) starting TB treatment with Nepal’s National TB Program and 100 randomly-selected people without TB (Controls) in the same sites (Project 1); and approximately 40 key in-country stakeholders from Nepal including people with TB, community leaders, and TB healthcare professionals (Project 2). During Project 1, visits will be made to people with TB’s households during months 3 and 6 of TB treatment, and a single visit made to Control households. During visits, participants will be asked about: TB-related costs (if receiving treatment), food insecurity, stigma; TB-related knowledge; household poverty level; social capital; and quality of life. During Project 2, stakeholders will be invited to participate in: a survey and focus group discussion (FGD) to characterise socioeconomic impact, barriers and facilitators to accessing and engaging with TB care in Nepal; and a one-day workshop to review FGD findings and suggest interventions to mitigate the barriers identified. Ethics and dissemination: The study has received ethical approval. Results will be disseminated through scientific meetings, open access publications, and a national workshop in Nepal. Conclusions: This research will strengthen understanding of the socioeconomic impact of TB in Nepal and generate a shortlist of feasible and locally-appropriate socioeconomic interventions for TB-affected households for trial evaluation.

ETTING: Eight tuberculosis treatment sites in Cavite Province, the Philippines, including two sites specialising in management of multidrug-resistant tuberculosis (MDR-TB).OBJECTIVE: To evaluate costs incurred by TB patients and to determine the proportion of households that faced catastrophic costs, then to consider cost survey responses alongside results of detailed patient-pathway modelling.DESIGN: Clustered cross-sectional survey using a field testing version of the WHO TB patient-costing tool and protocol; face-to-face interviews with 194 patients conducted in May-August 2016. Costs included direct-medical, direct non-medical and indirect costs using the human capital approach. Patients were deemed to incur catastrophic expenditure if TB-related costs exceeded 20% of annual household income. Patient pathways were modelled following multiple health staff interviews.RESULTS: Estimated mean cost incurred by patients with drug-susceptible TB was US$321 vs. $2356 for MDR-TB patients. Catastrophic costs were suffered by 28% of drug-susceptible and 80% of MDR-TB patients, with lost income being the largest contributor. Patient-pathway modelling suggested most patients had under-reported health visits.CONCLUSION: Survey results indicate that patient costs are large for all patients in Cavite, particularly for MDR-TB patients. Patient-pathway modelling suggests these costs are an underestimate due to poor recollection of health visits, suggesting that the WHO instrument and protocol could be improved to better capture the diagnostic journey.

Antimicrobial resistance (AMR) is a major threat to human health globally. Surveillance is a key activity to determine AMR burden, impacts, and trends and to monitor effects of interventions. Surveillance systems require efficient capture and onward sharing of high-quality laboratory data. Substantial investment is being made to improve laboratory capacity, particularly in low-income and middle-income countries (LMICs) with high disease burdens. However, building capacity for effective laboratory data management remains an under-resourced area, which, unless addressed, will limit progress towards comprehensive AMR surveillance in LMICs. The lack of a fit-for-purpose and open-source laboratory information management system software is of particular concern. In this Personal View, we summarise the technical requirements for microbiology laboratory data management, provide a snapshot of laboratory data management in LMIC laboratories, and describe the key steps required to improve the situation. Without action to improve information technology infrastructure and data management systems in microbiology laboratories, the ongoing efforts to develop capacity for AMR surveillance in LMICs might not realise their full potential.

Introduction: Iron deficiency is a treatable cause of severe anaemia in low-and-middle-income-countries (LMIC). Diagnosing it remains challenging as peripheral blood markers poorly reflect bone-marrow iron deficiency (BM-ID), especially in the context of HIV-infection.\ud Methods: Severely anaemic (haemoglobin ≤70g/l) HIV-infected adults were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. BM-ID was evaluated. Accuracy of blood markers (including hepcidin, mean corpuscular volume, mean cellular haemoglobin concentration, serum iron, serum ferritin, soluble transferrin receptor (sTfR), sTfR -index, sTfR –ratio) to detect BM-ID was evaluated by ROC area under the curve (AUCROC ). \ud Results: Seventy-three patients were enrolled and 35 (48.0%) had BM-ID. Although hepcidin and MCV performed best ( AUCROC of 0.593 and 0.545 respectively), all markers performed poorly in identifying BM-ID (ROC

– Background: To perform a bibliometric analysis and quantify the amount of orthopaedic and trauma\ud literature published from low-income countries (LICs).\ud Methods and methods: The Web of Science database was utilised to identify all indexed orthopaedic journals. All\ud articles published in the 76 orthopaedics journals over the last 10 years were reviewed, to determine their geographic\ud origin.\ud Results: A total of 131 454 articles were published across 76 orthopaedic journals over the last 10 years. Of these,\ud 132 (0.1%) were published from LICs and 3515 (2.7%) were published from lower middle-income countries (LMICs);\ud 85.7% (n = 112 716) of published orthopaedic research was undertaken in a high-income setting. The majority of the\ud studies (n = 90, 74.4%) presented level IV evidence. Only 7.4% (n = 9) were high-quality evidence (level I or II). Additionally, the majority of research (74 articles, 56%) was published in partnership with high-income countries (HICs).\ud Conclusions: There is a stark mismatch between the publication of scientific reports on orthopaedic research and the\ud geographical areas of greatest clinical need. We believe there is an urgent need for orthopaedic research to be carried\ud out in low-income settings to guide treatment and improve outcomes, rather than assuming that evidence from highincome settings will translate into this environment.

IntroductionCalcium dobesilate (CaD) has been used in the treatment of diabetic retinopathy (DR) due to its potential in protecting against retinal vascular damage. However, there is limited evidence exploring its efficacy in combating DR progression. This study is aimed at evaluating whether CaD could prevent DR progression into an advanced stage among Chinese patients with mild-to-moderate non-proliferative DR (NPDR).Methods and analysisThis study is a single-blind, multicentre, cluster-randomised, controlled superiority trial. A total of 1272 patients with mild-to-moderate NPDR will be enrolled and randomly assigned at a 1:1 ratio into the control group (conventional treatment group) and the intervention group (conventional treatment plus CaD (500 mg three times per day) for 12 months). Patients will be followed at 1, 3, 6 and 12 months after randomisation and receiving treatments, with the severity of DR assessed by the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. The primary endpoint is the progression of DR during follow-up, which is defined as an increase of two or more steps in the ETDRS scale. The secondary endpoints include the concomitant changes in visual acuity, presence, number, location and type of retinal lesions, and retinal blood vessel diameter as well as the arteriovenous ratio at different visits.Ethics and disseminationEach local ethics committee (first Vote: Ethical Review Committees of Zhongda Hospital of Southeast University (2019ZDSYLL132-P01)) has approved the study. The results will be published in high impact peer-reviewed scientific journals aimed at the general reader.Trial registration numbersNCT04283162.

Summary Background Maternal and perinatal mortality are still unacceptably high in many countries despite steep increases in facility birth. The evidence that childbirth in facilities reduces mortality is weak, mainly because of the scarcity of robust study designs and data. We aimed to assess this link by quantifying the influence of major determinants of facility birth (cluster-level facility birth, wealth, education, and distance to childbirth care) on several mortality outcomes, while also considering quality of care. Methods Our study is a secondary analysis of surveillance data on 119 244 pregnancies from two large population-based cluster-randomised controlled trials in Brong Ahafo, Ghana. In addition, we specifically collected data to assess quality of care at all 64 childbirth facilities in the study area. Outcomes were direct maternal mortality, perinatal mortality, first-day and early neonatal mortality, and antepartum and intrapartum stillbirth. We calculated cluster-level facility birth as the percentage of facility births in a woman's village over the preceding 2 years, and we computed distances from women's regular residence to health facilities in a geospatial database. Associations between determinants of facility birth and mortality outcomes were assessed in crude and multivariable multilevel logistic regression models. We stratified perinatal mortality effects by three policy periods, using April 1, 2005, and July 1, 2008, as cutoff points, when delivery-fee exemption and free health insurance were introduced in Ghana. These policies increased facility birth and potentially reduced quality of care. Findings Higher proportions of facility births in a cluster were not linked to reductions in any of the mortality outcomes. In women who were wealthier, facility births were much more common than in those who were poorer, but mortality was not lower among them or their babies. Women with higher education had lower mortality risks than less-educated women, except first-day and early neonatal mortality. A substantially higher proportion of women living in areas closer to childbirth facilities had facility births and caesarean sections than women living further from childbirth facilities, but mortality risks were not lower despite this increased service use. Among women who lived in areas closer to facilities offering comprehensive emergency obstetric care (CEmOC), emergency newborn care, or high-quality routine care, or to facilities that had providers with satisfactory competence, we found a lower risk of intrapartum stillbirth (14·2 per 1000 deliveries at >20 km from a CEmOC facility vs 10·4 per 1000 deliveries at ≤1 km; odds ratio [OR] 1·13, 95% CI 1·06–1·21) and of composite mortality outcomes than among women living in areas where these services were further away. Protective effects of facility birth were restricted to the two earlier policy periods (from June 1, 2003, to June 30, 2008), whereas there was evidence for higher perinatal mortality with increasing wealth (OR 1·09, 1·03–1·14) and lower perinatal mortality with increasing distance from childbirth facilities (OR 0·93, 0·89–0·98) after free health insurance was introduced in July 1, 2008. Interpretation Facility birth does not necessarily convey a survival benefit for women or babies and should only be recommended in facilities capable of providing emergency obstetric and newborn care and capable of safe-guarding uncomplicated births. Funding The Baden-Wurttemberg Foundation, the Daimler and Benz Foundation, the European Social Fund and Ministry of Science, Research, and the Arts Baden-Wurttemberg, WHO, US Agency for International Development, Save the Children, the Bill & Melinda Gates Foundation, and the UK Department for International Development.

Typhoid fever is endemic across sub-Saharan Africa. However, estimates of the burden of typhoid are undermined by insufficient blood volumes and lack of sensitivity of blood culture. Here, we aimed to address this limitation by exploiting pre-enrichment culture followed by PCR, alongside routine blood culture to improve typhoid case detection. We carried out a prospective diagnostic cohort study and enrolled children (aged 0–4 years) with non-specific febrile disease admitted to a tertiary hospital in Blantyre, Malawi from August 2014 to July 2016. Blood was collected for culture (BC) and real-time PCR after a pre-enrichment culture in tryptone soy broth and ox-bile. DNA was subjected to PCR for invA (Pan-Salmonella), staG (S. Typhi), and fliC (S. Typhimurium) genes. A positive PCR was defined as invA plus either staG or fliC (CT

Widespread use of Pneumococcal Conjugate Vaccines (PCV) has reduced vaccine-type nasopharyngeal colonisation and invasive pneumococcal disease. In a double-blind, randomised controlled trial using the Experimental Human Pneumococcal Challenge (EHPC) model, PCV-13 (Prevenar-13) conferred 78% protection against colonisation acquisition and reduced bacterial intensity (AUC) as measured by classical culture. We used a multiplex qPCR assay targeting lytA and pneumococcal serotype 6A/B cpsA genes to re-assess the colonisation status of the same volunteers. Increase in detection of low-density colonisation resulted in reduced PCV efficacy against colonisation acquisition (29%), compared to classical culture (83%). For experimentally colonised volunteers, PCV had a pronounced effect on decreasing colonisation density. These results obtained in adults suggest that the success of PCV vaccination could primarily be mediated by the control of colonisation density. Studies assessing the impact of pneumococcal vaccines should allow for density measurements in their design.

Using the 20-meter shuttle run test (20mSRT) as a morbidity metric, we assessed whether Schistosoma mansoni infection was associated with decreased aerobic capacity in Ugandan children across a range of altitudes, either at low (∼600 m) or high (∼1,000 m) altitudes. A total of 305 children were recruited from six schools within the Buliisa District, Lake Albert, Uganda. A subset (n = 96) of these had been previously assessed and treated for schistosomiasis ± malaria 2 weeks prior. Fitness scores on the 20mSRT were translated into VO2max using a standardized equation. Unadjusted and multivariable-adjusted analyses were performed using VO2max as the primary outcome. Analysis of fitness scores from 304 children, inclusive of the subset follow-up cohort, revealed a median VO2max of 45.4 mL kg−1 min−1 (interquartile range: 42.9–48.0 mL kg−1 min−1). Children residing at high altitudes demonstrated increased aerobic capacities (46.3 versus 44.8 mL kg−1 min−1, P = 0.031). The prevalence of stunting, wasting, S. mansoni egg patent infection, malaria, giardiasis, anemia, and fecal occult blood were 36.7%, 16.1%, 44.3%, 65.2%, 21.4%, 50.6%, and 41.2%, respectively. Median VO2max was elevated in those previously treated, compared with those newly recruited (46.3 versus 44 mL kg−1 min−1, P < 0.001). Multivariable-adjusted analysis revealed a strong negative association between S. mansoni egg patent infection and VO2max at low altitude (beta coefficient: −3.96, 95% CI: −6.56 to −137, P = 0.004). This is the first study to document a negative association between S. mansoni infection and aerobic capacity at low altitudes using the 20mSRT.

Background\ud As part of ongoing co-surveillance of intestinal schistosomiasis and malaria in Ugandan school children, a non-invasive detection method for amplification of Plasmodium DNA using real-time (rt)PCR analysis of ethanol preserved faeces (EPF) was assessed. For diagnostic tabulations, results were compared to rtPCR analysis of dried blood spots (DBS) and field-based point-of-care (POC) rapid diagnostic tests (RDTs).\ud Methods\ud A total 247 school children from 5 primary schools along the shoreline of Lake Albert were examined with matched EPF and DBS obtained. Mean prevalence and prevalence by school was calculated by detection of Plasmodium DNA by rtPCR using a 18S rDNA Taqman® probe. Diagnostic sensitivity, specificity, positive and negative predictive values were tabulated and compared against RDTs. \ud Results\ud By rtPCR of EPF and DBS, 158 (63.9%; 95% CI: 57.8–69.7) and 198 (80.1 %, 95% CI: 74.7–84.6) children were positive for Plasmodium spp. By RDT, 138 (55.8%; 95% CI: 49.6– 61.9) and 45 (18.2%; 95% CI: 13.9–23.5) children were positive for Plasmodium falciparum with non-P. falciparum infections, respectively. Using RDT results as a convenient field-based reference, the sensitivity of rtPCR of EPF and DBS was 73.1% (95% CI: 65.2–79.8) and 94.2% (95% CI: 88.9–97.0) while specificity was 47.7% (95% CI: 38.5–57.0) and 37.6% (95% CI: 29.0–46.9), respectively. With one exception, school prevalence estimated by analysis of EPF was higher than that by RDT. Positive and negative predictive values were compared and dicussed.\ud Conclusions\ud In this high transmission setting, EPF sampling by rtPCR has satisfactory diagnostic performance in estimation of mean prevalence and prevalence by school upon direct comparison with POC-RDTs. Although analysis of EPF was judged inferior to that of DBS, it permits an alternative non-invasive sampling regime that could be implemented alongside general monitoring and surveillance for other faecal parasites. EPF analysis may also have future value in passive surveillance of low transmission settings.\ud Keywords Plasmodium; Schistosoma mansoni, real-time PCR; surveillance; RDT; faecal sampling.

Background:Long‑lasting insecticidal nets (LLINs) are the principal tool for malaria control in Africa and are presently treated with a single class of insecticide; however, increasing levels of insecticide resistance threaten their success. In response to this threat nets have been developed that incorporate the synergist, piperonyl butoxide (PBO), which inhibits the activity of cytochrome P450s which is one main mechanisms of insecticide resistance, allowing resistance to pyrethroids to be reversed. However, data on the value and cost effectiveness of these nets is lacking. A large‑scale cluster randomised trial of conventional LLINs and PBO‑LLINs was conducted in Uganda in 104 health sub‑districts (HSDs) in 2017–2019. Prior to the mass distribution of LLINs, a baseline entomological survey was carried out, the results of which are reported herein. Ten households from each HSD were randomly selected for entomological sur‑veillance at baseline which included household mosquito collections.Results:Prior to LLIN distribution entomological collections were carried out in 1029 houses across the 104 HSDs. Anopheles gambiae (s.l.) was the principal vector in all but 9 of the 71 HSDs that yielded vector species. Molecular analysis found An. gambiae (s.s.) to be the predominant vector collected. Plasmodium falciparum was detected in 5.5% of An. gambiae (s.s.) and in 4.0% of An. funestus (s.s.) examined. Infection rates of other plasmodium species (P. vivax, P. ovale and P. malariae) were lower with infection rates of 1.2% and 1.7% for An. gambiae (s.s.) and An. funestus (s.s.), respectively. The knockdown resistance (kdr) mutation Vgsc‑L1014S was found at very high frequency in An. gambiae(s.s.) with the Vgsc‑L1014F mutation at low frequency and the wild‑type allele virtually absent. In An. arabiensis the wild‑type allele was predominant. The resistance‑associated alleles, Cyp4j5‑L43F and Coeae1d were found at moderate frequencies which varied across the study site. Vgsc‑N1575Y mutation was not found in any samples examined.Conclusions:No significant differences between planned intervention arms was observed in vector densities, sporo‑zoite infection rate or insecticide resistance marker frequency across the study site prior to the distribution of LLINs. Very high levels of kdr resistance were observed in all areas; however, the resistance‑associated markers Cyp4j5‑L43F and Coeae1d were found at varying frequencies across the study site which may have implications for the effective‑ness of standard LLINs

\ud \ud Dialogue and exchange between researchers and policy personnel may increase the use of research evidence in policy. We piloted and evaluated a programme of formalised dialogue between researchers and provincial health policymakers in South Africa, called the buddying programme. An external evaluation examined implementation and short-term impact, drawing on documents, in-depth interviews with policymakers, a researcher buddies focus group and our own reflection on what we learnt. We set up buddying with seven policymakers and five researchers on six policy questions. Researchers knew little about policymaking or needs of policymakers. Policymakers respected the contact with researchers, respected researchers’ objectivity and appreciated the formalised approach. Having policymaker champions facilitated the dialogue. Scenarios for policy questions and use were different. One topic was at problem identification stage (contraceptives and HIV risk), four at policy formulation stage (healthy lifestyles, chronic illness medication adherence, integrated care of chronic illness and maternal transmission of HIV to infants) and one at implementation stage (task shifting). Research evidence were used to identify or solve a policy problem (two scenarios), to legitimise a predetermined policy position (three scenarios) or the evidence indirectly influenced the policy (one scenario). The formalised dialogue required in this structured buddying programme took time and commitment from both sides. The programme illustrated the importance of researchers listening, and policymakers understanding what research can offer. Both parties recognised that the structured buddying made the dialogue happen. Often the evidence was helpful in supporting provincial policy decisions that were in the roll-out phase from the national government.

Importance\ud Chronic obstructive pulmonary disease (COPD) is a major global health issue and theophylline is used extensively. Preclinical investigations have demonstrated that low plasma concentrations (1-5 mg/L) of theophylline enhance antiinflammatory effects of corticosteroids in COPD.\ud \ud Objective\ud To investigate the effectiveness of adding low-dose theophylline to inhaled corticosteroids in COPD.\ud \ud Design, Setting, and Participants\ud The TWICS (theophylline with inhaled corticosteroids) trial was a pragmatic, double-blind, placebo-controlled, randomized clinical trial that enrolled patients with COPD between February 6, 2014, and August 31, 2016. Final follow-up ended on August 31, 2017. Participants had a ratio of forced expiratory volume in the first second to forced vital capacity (FEV1/FVC) of less than 0.7 with at least 2 exacerbations (treated with antibiotics, oral corticosteroids, or both) in the previous year and were using an inhaled corticosteroid. This study included 1578 participants in 121 UK primary and secondary care sites.\ud \ud Interventions\ud Participants were randomized to receive low-dose theophylline (200 mg once or twice per day) to provide plasma concentrations of 1 to 5 mg/L (determined by ideal body weight and smoking status) (n = 791) or placebo (n = 787).\ud \ud Main Outcomes and Measures\ud The number of participant-reported moderate or severe exacerbations treated with antibiotics, oral corticosteroids, or both over the 1-year treatment period.\ud \ud Results\ud Of the 1567 participants analyzed, mean (SD) age was 68.4 (8.4) years and 54% (843) were men. Data for evaluation of the primary outcome were available for 1536 participants (98%) (772 in the theophylline group; 764 in the placebo group). In total, there were 3430 exacerbations: 1727 in the theophylline group (mean, 2.24 [95% CI, 2.10-2.38] exacerbations per year) vs 1703 in the placebo group (mean, 2.23 [95% CI, 2.09-2.37] exacerbations per year); unadjusted mean difference, 0.01 (95% CI, -0.19 to 0.21) and adjusted incidence rate ratio, 0.99 (95% CI, 0.91-1.08). Serious adverse events in the theophylline and placebo groups included cardiac, 2.4% vs 3.4%; gastrointestinal, 2.7% vs 1.3%; and adverse reactions such as nausea (10.9% vs 7.9%) and headaches (9.0% vs 7.9%).\ud \ud Conclusions and Relevance\ud Among adults with COPD at high risk of exacerbation treated with inhaled corticosteroids, the addition of low-dose theophylline, compared with placebo, did not reduce the number COPD exacerbations over a 1-year period. The findings do not support the use of low-dose theophylline as adjunctive therapy to inhaled corticosteroids for the prevention of COPD exacerbations.\ud \ud Trial Registration\ud isrctn.org Identifier: ISRCTN27066620.

Tuberculosis (TB), the leading single infectious diseases killer globally, is driven by poverty. Conversely, having TB worsens impoverishment. During TB illness, lost income and out-of-pocket costs can become “catastrophic”, leading patients to abandon treatment, develop drug-resistance, and die. WHO’s 2015 End TB Strategy recommends eliminating catastrophic costs and providing socioeconomic support for TB-affected people. However, there is negligible evidence to guide the design and implementation of such socioeconomic support, especially in low-income, TB-endemic countries. A national, multi-sectoral workshop was held in Kathmandu, Nepal, on the 11th and 12th September 2019, to develop a shortlist of feasible, locally appropriate socioeconomic support interventions for TB-affected households in Nepal, a low-income country with significant TB burden. The workshop brought together key stakeholders in Nepal including from the Ministry of Health and Population, Department of Health Services, Provincial Health Directorate, Health Offices, National TB Program (NTP); and TB/Leprosy Officers, healthcare workers, community health volunteers, TB-affected people, and external development partners (EDP). During the workshop, participants reviewed current Nepal NTP data and strategy, discussed the preliminary results of a mixed-methods study of the socioeconomic determinants and consequences of TB in Nepal, described existing and potential socioeconomic interventions for TB-affected households in Nepal, and selected the most promising interventions for future randomized controlled trial evaluations in Nepal. This report describes the activities, outcomes, and recommendations from the workshop.

BACKGROUND\ud Transmission dynamics, vectorial capacity, and co-infections have substantial impacts on vector-borne diseases (VBDs) affecting urban and suburban populations. Reviewing key factors can provide insight into priority research areas and offer suggestions for potential interventions.\ud \ud MAIN BODY\ud Through a scoping review, we identify knowledge gaps on transmission dynamics, vectorial capacity, and co-infections regarding VBDs in urban areas. Peer-reviewed and grey literature published between 2000 and 2016 was searched. We screened abstracts and full texts to select studies. Using an extraction grid, we retrieved general data, results, lessons learned and recommendations, future research avenues, and practice implications. We classified studies by VBD and country/continent and identified relevant knowledge gaps. Of 773 articles selected for full-text screening, 50 were included in the review: 23 based on research in the Americas, 15 in Asia, 10 in Africa, and one each in Europe and Australia. The largest body of evidence concerning VBD epidemiology in urban areas concerned dengue and malaria. Other arboviruses covered included chikungunya and West Nile virus, other parasitic diseases such as leishmaniasis and trypanosomiasis, and bacterial rickettsiosis and plague. Most articles retrieved in our review combined transmission dynamics and vectorial capacity; only two combined transmission dynamics and co-infection. The review identified significant knowledge gaps on the role of asymptomatic individuals, the effects of co-infection and other host factors, and the impacts of climatic, environmental, and socioeconomic factors on VBD transmission in urban areas. Limitations included the trade-off from narrowing the search strategy (missing out on classical modelling studies), a lack of studies on co-infections, most studies being only descriptive, and few offering concrete public health recommendations. More research is needed on transmission risk in homes and workplaces, given increasingly dynamic and mobile populations. The lack of studies on co-infection hampers monitoring of infections transmitted by the same vector.\ud \ud CONCLUSIONS\ud Strengthening VBD surveillance and control, particularly in asymptomatic cases and mobile populations, as well as using early warning tools to predict increasing transmission, were key strategies identified for public health policy and practice.

ObjectiveTo explore antecedents, components and influencing factors on active case-finding (ACF) policy development and implementation.DesignScoping review, searching MEDLINE, Web of Science, the Cochrane Database of Systematic Reviews and the World Health Organization (WHO) Library from January 1968 to January 2018. We excluded studies focusing on latent tuberculosis (TB) infection, passive case-finding, childhood TB and studies about effectiveness, yield, accuracy and impact without descriptions of how this evidence has/could influence ACF policy or implementation. We included any type of study written in English, and conducted frequency and thematic analyses.ResultsSeventy-three articles fulfilled our eligibility criteria. Most (67%) were published after 2010. The studies were conducted in all WHO regions, but primarily in Africa (22%), Europe (23%) and the Western-Pacific region (12%). Forty-one percent of the studies were classified as quantitative, followed by reviews (22%) and qualitative studies (12%). Most articles focused on ACF for tuberculosis contacts (25%) or migrants (32%). Fourteen percent of the articles described community-based screening of high-risk populations. Fifty-nine percent of studies reported influencing factors for ACF implementation; mostly linked to the health system (eg, resources) and the community/individual (eg, social determinants of health). Only two articles highlighted factors influencing ACF policy development (eg, politics). Six articles described WHO’s ACF-related recommendations as important antecedent for ACF. Key components of successful ACF implementation include health system capacity, mechanisms for integration, education and collaboration for ACF.ConclusionWe identified some main themes regarding the antecedents, components and influencing factors for ACF policy development and implementation. While we know much about facilitators and barriers for ACF policy implementation, we know less abouthowto strengthen those facilitators andhowto overcome those barriers. A major knowledge gap remains when it comes to understanding which contextual factors influence ACF policy development. Research is required to understand, inform and improve ACF policy development and implementation.

Routine laboratory animal tests necessary to assess the toxicity of snake venoms and the preclinical neutralizing ability of antivenoms and other inhibitory substances induce significant pain and distress. This has prompted initiatives to introduce the routine use of analgesia. In this study, the analgesic effect of morphine and tramadol was assessed in tests assessing the lethal, hemorrhagic, myotoxic and edema-forming activities of the venom of the viperid snake Bothrops asper. The Mouse Grimace Scale (MGS) and mouse-exploration activity were used to assess pain and its inhibition by the analgesics. Results demonstrate that tests assessing lethality and myotoxicity induce higher levels of pain than assays quantifying hemorrhagic and edema-forming activities. Our observations also indicate that pretreatment of mice with both analgesics, at the doses used, were similarly effective in reducing the MGS magnitude and increase mouse-exploration activity after the administration of B. asper venom. Moreover, the analgesic effect of both drugs was more evident in the myotoxic and lethality assays. Combined with previous observations showing that these analgesics do not alter the extent of toxic effects induced by B. asper venom, our results strongly indicate that the use of analgesia (using either morphine or tramadol) should be considered in the routine assessment of venom toxicity and antivenom efficacy.

\ud Background: HIV risk remains unacceptably high among adolescent girls and young women (AGYW) in southern\ud and eastern Africa, reflecting structural and social inequities that drive new infections. In 2015, PEPFAR (the United\ud States President’s Emergency Plan for AIDS Relief) with private-sector partners launched the DREAMS Partnership, an\ud ambitious package of interventions in 10 sub-Saharan African countries. DREAMS aims to reduce HIV incidence by\ud 40% among AGYW over two years by addressing multiple causes of AGYW vulnerability. This protocol outlines an\ud impact evaluation of DREAMS in four settings.\ud Methods: To achieve an impact evaluation that is credible and timely, we describe a mix of methods that build on\ud longitudinal data available in existing surveillance sites prior to DREAMS roll-out. In three long-running surveillance\ud sites (in rural and urban Kenya and rural South Africa), the evaluation will measure: (1) population-level changes\ud over time in HIV incidence and socio-economic, behavioural and health outcomes among AGYW and young men\ud (before, during, after DREAMS); and (2) causal pathways linking uptake of DREAMS interventions to ‘mediators’ of\ud change such as empowerment, through to behavioural and health outcomes, using nested cohort studies with\ud samples of ~ 1000–1500 AGYW selected randomly from the general population and followed for two years. In\ud Zimbabwe, where DREAMS includes an offer of pre-exposure HIV prophylaxis (PrEP), cohorts of young women who\ud sell sex will be followed for two years to measure the impact of ‘DREAMS+PrEP’ on HIV incidence among young\ud women at highest risk of HIV. In all four settings, process evaluation and qualitative studies will monitor the delivery\ud and context of DREAMS implementation. The primary evaluation outcome is HIV incidence, and secondary\ud outcomes include indicators of sexual behavior change, and social and biological protection.\ud Discussion: DREAMS is, to date, the most ambitious effort to scale-up combinations or ‘packages’ of multi-sectoral\ud interventions for HIV prevention. Evidence of its effectiveness in reducing HIV incidence among AGYW, and\ud demonstrating which aspects of the lives of AGYW were changed, will offer valuable lessons for replication.\ud Keywords: HIV prevention, Adolescent health, Complex intervention, Impact evaluation, Gender equity, Kenya,\ud South Africa, Zimbabwe

\ud Introduction High asthma prevalence in Latin-American cities is thought to be caused by poor hygiene and infections. This contradicts the widely accepted ‘hygiene hypothesis’ for asthma aetiology.\ud Methods Systematic review of observational studies evaluating the association between poor hygiene exposures or infections and asthma/wheeze among Latin-American children aged 4–16 years. MEDLINE, EMBASE, LILACS and CINAHL electronic databases were searched following a predefined strategy to 18 December 2017. We quantified outcomes measured and reported, assessed risk of bias and tabulated the results.\ud Results Forty-five studies included: 6 cohort, 30 cross-sectional and 9 case–control studies. 26 cross-sectional studies were school-based surveys (14 of over 3000 children), whereas 5 case–control studies were hospital/health centre-based. Exposures measured and reported varied substantially between studies, and current wheeze was the most common outcome reported. Data showed selective reporting based on statistical significance (P value

Lymphatic filariasis (LF) and onchocerciasis are priority neglected tropical diseases targeted for elimination. The only safe drug treatment with substantial curative activity against the filarial nematodes responsible for LF (Brugia malayi, Wuchereria bancrofti) or onchocerciasis (Onchocerca volvulus) is doxycycline. The target of doxycycline is the essential endosymbiont, Wolbachia. Four to six weeks doxycycline therapy achieves >90% depletion of Wolbachia in worm tissues leading to blockade of embryogenesis, adult sterility and premature death 18–24 months post-treatment. Long treatment length and contraindications in children and pregnancy are obstacles to implementing doxycycline as a public health strategy. Here we determine, via preclinical infection models of Brugia malayi or Onchocerca ochengi that elevated exposures of orally-administered rifampicin can lead to Wolbachia depletions from filariae more rapidly than those achieved by doxycycline. Dose escalation of rifampicin achieves >90% Wolbachia depletion in time periods of 7 days in B. malayi and 14 days in O. ochengi. Using pharmacokinetic-pharmacodynamic modelling and mouse-human bridging analysis, we conclude that clinically relevant dose elevations of rifampicin, which have recently been determined as safe in humans, could be administered as short courses to filariasis target populations with potential to reduce anti-Wolbachia curative therapy times to between one and two weeks.

\ud \ud This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:\ud \ud To assess and summarize the effects of the MVA85A vaccine boosting BCG in humans.\ud \ud Background\ud \ud Description of the condition\ud \ud Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis. In 2016, 6.3 million new cases of tuberculosis were reported. Tuberculosis now ranks first, followed by human immunodeficiency virus (HIV), as the leading cause of death from an infectious disease worldwide killing an estimated 1.8 million people in 2016, including 370,000 people living with HIV. Over 95% of these people were living in low- and middle-income countries (WHO 2017).\ud \ud Tuberculosis can be classed as active when people experience signs or symptoms of tuberculosis or have radiological evidence of it. Tuberculosis can also be classified as latent tuberculosis infection (LTBI) where immunological evidence of previous exposure to M. tuberculosis exists without clinical or radiological evidence of the disease (CDC 2000). Of healthy adults with immunological evidence of previous exposure to M. tuberculosis, the overall lifetime risk of progressing to active disease if not treated for the infection is 5% to 10% (Harries 2006). Often this happens months or years after the initial infection in response to a weakening of the body’s immune system. The probability of developing active disease is higher in HIV-positive, diabetic patients, and young children (Baker 2011; Perez-Velez 2012; Tiemersma 2010). Fifty percent of infants with evidence of LTBI will progress to active disease if untreated (Marais 2004). People with LTBI require early diagnosis and treatment to reduce the pool of active tuberculosis cases. This is particularly important in high-risk groups, such as those co-infected with HIV (Sharma 2012). Tuberculosis can be treated with long courses of multiple antibiotics, but the rise of HIV and spread of multi-drug resistant tuberculosis (MDR-TB) means that tuberculosis is still one of the largest threats to public health worldwide (WHO 2017). Structural determinants such as rapid urbanization of populations and economic inequalities, social determinants such as poverty and poor housing, alongside biological factors such as HIV and drug-resistant strains of tuberculosis play a vital role in the spread of tuberculosis through vulnerable populations (Daftary 2012).\ud \ud The Bacillus Calmette–Guérin (BCG) vaccine is currently the only available vaccine. Epidemiological studies indicate that it has a protective effect against tuberculosis disease in children, particularly against the more severe forms of the disease such as tuberculosis meningitis or miliary tuberculosis (Roy 2014). The effectiveness of BCG differs greatly depending on location and site of infection. It has consistent protection against tuberculosis meningitis and miliary disease in children but variable protection against pulmonary tuberculosis (Abubakar 2013; Colditz 1995). As a result, despite many areas achieving high coverage of BCG vaccination, the disease remains a problem, and a new tuberculosis vaccine remains an important global research priority (WHO 2017).\ud \ud Previously it has been impossible to ascertain reliably whether the BCG vaccine protected against active disease or infection with M. tuberculosis. This was due to the tuberculin skin test being unable to distinguish between cases of LTBI and people who had been vaccinated with BCG (Roy 2014). An important development was therefore the development and use of interferon gamma release assays (IGRA), which can distinguish between tuberculosis infection and vaccination. This has allowed researchers to establish that BCG vaccination reduces the risk of Mycobacterium infection in some settings (Eisenhut 2009).

The World Health Organization's (WHO) 2015-2020 Global Strategy on water, sanitation, and hygiene (WASH) and neglected tropical diseases (NTDs) encourages integration, whilst maintaining existing structured NTD investments, and acceleration towards Sustainable Development Goal (SDG) targets. Accordingly, SDG-associated and WASH-NTD indicators have been developed, commencing important intersectoral dialogue, alongside opportunities for future disease-specific refinements. The rationale for soil-transmitted helminthiasis (STH)- and schistosomiasis-specific WASH considerations, and a traffic-light figure, are presented here to indicate where current international definitions may, or may not, suffice. Certain unique aspects in control dynamics and parasitic lifecycles, however, necessitate additional implementation research with more appropriate measurement indicators developed to record programmatic interventions and to define strategic priorities more effectively.

Lymphatic filariasis and onchocerciasis are parasitic helminth diseases, which cause severe morbidities such as elephantiasis, skin disease and blindness, presenting a major public health burden in endemic communities. The anti-Wolbachia consortium (A·WOL: http://www.a-wol.com/) has identified a number of registered antibiotics that target the endosymbiotic bacterium, Wolbachia, delivering macrofilaricidal activity. Here we use pharmacokinetics/pharmacodynamics (PK/PD) analysis to rationally develop an anti-Wolbachia chemotherapy by linking drug exposure to pharmacological effect. We compare the pharmacokinetics and anti-Wolbachia efficacy in a murine Brugia malayi model of minocycline versus doxycycline. Doxycycline exhibits superior PK in comparison to minocycline resulting in a 3-fold greater exposure in SCID mice. Monte-Carlo simulations confirmed that a bi-daily 25-40 mg/Kg regimen is bioequivalent to a clinically effective 100-200 mg/day dose for these tetracyclines. Pharmacodynamic studies showed that minocycline depletes Wolbachia more effectively than doxycycline (99.51% vs. 90.35%) after 28 day 25 mg/Kg bid regimens with a more potent block in microfilarial production. PK/PD analysis predicts that minocycline would be expected to be 1.7 fold more effective than doxycycline in man despite lower exposure in our infection models. Our findings warrant onward clinical investigations to examine the clinical efficacy of minocycline treatment regimens against lymphatic filariasis and onchocerciasis.

Aflatoxin exposure is an important public health concern in sub-Saharan Africa as well as parts of Latin America and Asia. In addition to hepatocellular carcinoma, chronic aflatoxin exposure is believed to play a role in childhood growth impairment. The most reliable biomarker of chronic aflatoxin exposure is the aflatoxin-albumin adduct, as measured by ELISA or isotope dilution mass spectrometry (IDMS). In this report, we have used high resolution LC-MS/MS with IDMS to quantitate AFB1-lysine in an extremely vulnerable population of Nigerian children suffering from severe acute malnutrition. To increase the sensitivity and reliability of the analyses, a labelled AFB1-13C615N2-lysine internal standard was synthesized. AFB1-lysine concentrations in this population ranged between 0.2 and 59.2 pg/mg albumin, with a median value of 2.6 pg/mg albumin. AFB1-lysine concentrations were significantly higher in stunted children (median = 4.6 pg/mg) compared to non-stunted (1.2 pg/mg), as well as in children with severe acute malnutrition (4.3 pg/mg) compared to controls (0.8 pg/mg). The median concentrations were also higher in children with kwashiorkor (6.3 pg/mg) compared to those suffering from marasmus (0.9 pg/mg). This is the first report of the use of high-resolution mass spectrometry to quantitate AFB1-lysine in humans.

Background Provision of routine iron supplements to prevent anaemia could increase the risk for lower genital tract infections as virulence of some pathogens depends on iron availability. This trial in Burkina Faso assessed whether weekly periconceptional iron supplementation increased the risk of lower genital tract infection in young non-pregnant and pregnant women. Methods Genital tract infections were assessed within a double blind, controlled, non-inferiority trial of malaria risk among nulliparous women, randomised to receive either iron and folic acid or folic acid alone, weekly, under direct observation for 18 months. Women conceiving during this period entered the pregnancy cohort. End assessment (FIN) for women remaining non-pregnant was at 18 months. For the pregnancy cohort, end assessment was at the first scheduled antenatal visit (ANC1). Infection markers included Nugent scores for abnormal flora and bacterial vaginosis (BV), T. vaginalis PCR, vaginal microbiota, reported signs and symptoms, and antibiotic and anti-fungal prescriptions. Iron biomarkers were assessed at baseline, FIN and ANC1. Analysis compared outcomes by intention to treat and in iron replete/deficient categories. Results A total of 1954 women (mean 16.8 years) were followed and 478 (24.5%) became pregnant. Median supplement adherence was 79% (IQR 59–90%). Baseline BV prevalence was 12.3%. At FIN and ANC1 prevalence was 12.8% and 7.0%, respectively (P

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.

Neglected tropical diseases (NTDs) affect the poorest of the poor. NTD programmes can and should rise to the challenge of playing a part in promoting more gender equitable societies. Gender equity shapes poverty and the experience of disease in multiple ways; yet to date, there has been little attention paid to gender equity in NTD control efforts. Drawing on a synthesis of relevant literature, the tacit knowledge and experience of the authors, and discussions at a meeting on women, girls and NTDs, this analysis paper distills five key lessons from over 20 years of gender mainstreaming in health. The paper links this learning to NTDs and Mass Drug Administration (MDA). Our first lesson is that tailored gender frameworks support gender analysis within research and programming. We present a gender review framework focusing on different MDA strategies. Second, gender interplays with other axes of inequality, such as disability and geographical location; hence, intersectionality is important for inclusive and responsive NTD programmes. Third, gender, power and positionality shape who is chosen as community drug distributors (CDDs). How CDDs interact with communities and how this interface role is valued and practised needs to be better understood. Fourth, we need to unpack the gender and power dynamics at household level to assess how this impacts MDA coverage and interactions with CDDs. Finally, we need to collect and use sex disaggregated data to support the development of more equitable and sustainable NTD programmes.

In stable transmission areas, malaria is the leading cause of anemia in children. Anemia in children is proposed as an added sensitive indicator for community changes in malaria prevalence. We report short-term temporal variations of malaria and anemia prevalence in rural Malawian children. Data from five repeated cross-sectional surveys conducted over 1 year in rural communities in Chikwawa District, Malawi, were analyzed. Different households were sampled per survey; all children, 6–59 months, in sampled household were tested for malaria parasitemia and hemoglobin levels using malaria rapid diagnostic tests (mRDT) and Hemocue 301, respectively. Malaria symptoms, recent treatment (2 weeks) for malaria, anthropometric measurements, and sociodemographic details were recorded. In total, 894 children were included from 1,377 households. The prevalences of mRDT positive and anemia (Hb < 11 g/dL) were 33.8% and 58.7%, respectively. Temporal trends in anemia and parasite prevalence varied differently. Overall, unadjusted and adjusted relative risks of anemia in mRDT-positive children were 1.31 (95% CI: 1.09–1.57) and 1.36 (1.13–1.63), respectively. Changes in anemia prevalence differed with short-term changes in malaria prevalence, although malaria is an important factor in anemia.

Background Mefloquine is one of four antimalarial agents commonly recommended for preventing malaria in travellers to malaria-endemic areas. Despite its high efficacy, there is controversy about its psychological side effects. Objectives To summarize the efficacy and safety of mefloquine used as prophylaxis for malaria in travellers. Search methods We searched the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published on the Cochrane Library; MEDLINE; Embase (OVID); TOXLINE (https://toxnet.nlm.nih.gov/newtoxnet/toxline.htm); and LILACS. We also searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en/) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home) for trials in progress, using 'mefloquine', 'Lariam', and 'malaria' as search terms. The search date was 22 June 2017. Selection criteria We included randomized controlled trials (for efficacy and safety) and non-randomized cohort studies (for safety). We compared prophylactic mefloquine with placebo, no treatment, or an alternative recommended antimalarial agent. Our study populations included all adults and children, including pregnant women. Data collection and analysis Two review authors independently assessed the eligibility and risk of bias of trials, extracted and analysed data. We compared dichotomous outcomes using risk ratios (RR) with 95% confidence intervals (CI). Prespecified adverse outcomes are included in 'Summary of findings' tables, with the best available estimate of the absolute frequency of each outcome in short-term international travellers. We assessed the certainty of the evidence using the GRADE approach. Main results We included 20 RCTs (11,470 participants); 35 cohort studies (198,493 participants); and four large retrospective analyses of health records (800,652 participants). Nine RCTs explicitly excluded participants with a psychiatric history, and 25 cohort studies stated that the choice of antimalarial agent was based on medical history and personal preference. Most RCTs and cohort studies collected data on self-reported or clinician-assessed symptoms, rather than formal medical diagnoses. Mefloquine efficacy Of 12 trials comparing mefloquine and placebo, none were performed in short-term international travellers, and most populations had a degree of immunity to malaria. The percentage of people developing a malaria episode in the control arm varied from 1% to 82% (median 22%) and 0% to 13% in the mefloquine group (median 1%). In four RCTs that directly compared mefloquine, atovaquone-proguanil and doxycycline in non-immune, short-term international travellers, only one clinical case of malaria occurred (4 trials, 1822 participants). Mefloquine safety versus atovaquone-proguanil Participants receiving mefloquine were more likely to discontinue their medication due to adverse effects than atovaquone-proguanil users (RR 2.86, 95% CI 1.53 to 5.31; 3 RCTs, 1438 participants; high-certainty evidence). There were few serious adverse effects reported with mefloquine (15/2651 travellers) and none with atovaquone-proguanil (940 travellers). One RCT and six cohort studies reported on our prespecified adverse effects. In the RCT with short-term travellers, mefloquine users were more likely to report abnormal dreams (RR 2.04, 95% CI 1.37 to 3.04, moderate-certainty evidence), insomnia (RR 4.42, 95% CI 2.56 to 7.64, moderate-certainty evidence), anxiety (RR 6.12, 95% CI 1.82 to 20.66, moderate-certainty evidence), and depressed mood during travel (RR 5.78, 95% CI 1.71 to 19.61, moderate-certainty evidence). The cohort studies in longer-term travellers were consistent with this finding but most had larger effect sizes. Mefloquine users were also more likely to report nausea (high-certainty evidence) and dizziness (high-certainty evidence). Based on the available evidence, our best estimates of absolute effect sizes for mefloquine versus atovaquone-proguanil are 6% versus 2% for discontinuation of the drug, 13% versus 3% for insomnia, 14% versus 7% for abnormal dreams, 6% versus 1% for anxiety, and 6% versus 1% for depressed mood. Mefloquine safety versus doxycycline No difference was found in numbers of serious adverse effects with mefloquine and doxycycline (low-certainty evidence) or numbers of discontinuations due to adverse effects (RR 1.08, 95% CI 0.41 to 2.87; 4 RCTs, 763 participants; low-certainty evidence). Six cohort studies in longer-term occupational travellers reported our prespecified adverse effects; one RCT in military personnel and one cohort study in short-term travellers reported adverse events. Mefloquine users were more likely to report abnormal dreams (RR 10.49, 95% CI 3.79 to 29.10; 4 cohort studies, 2588 participants, very low-certainty evidence), insomnia (RR 4.14, 95% CI 1.19 to 14.44; 4 cohort studies, 3212 participants, very low-certainty evidence), anxiety (RR 18.04, 95% CI 9.32 to 34.93; 3 cohort studies, 2559 participants, very low-certainty evidence), and depressed mood (RR 11.43, 95% CI 5.21 to 25.07; 2 cohort studies, 2445 participants, very low-certainty evidence). The findings of the single cohort study reporting adverse events in short-term international travellers were consistent with this finding but the single RCT in military personnel did not demonstrate a difference between groups in frequencies of abnormal dreams or insomnia. Mefloquine users were less likely to report dyspepsia (RR 0.26, 95% CI 0.09 to 0.74; 5 cohort studies, 5104 participants, low certainty-evidence), photosensitivity (RR 0.08, 95% CI 0.05 to 0.11; 2 cohort studies, 1875 participants, very low-certainty evidence), vomiting (RR 0.18, 95% CI 0.12 to 0.27; 4 cohort studies, 5071 participants, very low-certainty evidence), and vaginal thrush (RR 0.10, 95% CI 0.06 to 0.16; 1 cohort study, 1761 participants, very low-certainty evidence). Based on the available evidence, our best estimates of absolute effect for mefloquine versus doxycyline were: 2% versus 2% for discontinuation, 12% versus 3% for insomnia, 31% versus 3% for abnormal dreams, 18% versus 1% for anxiety, 11% versus 1% for depressed mood, 4% versus 14% for dyspepsia, 2% versus 19% for photosensitivity, 1% versus 5% for vomiting, and 2% versus 16% for vaginal thrush. Additional analyses, including comparisons of mefloquine with chloroquine, added no new information. Subgroup analysis by study design, duration of travel, and military versus non-military participants, provided no conclusive findings. Authors' conclusions The absolute risk of malaria during short-term travel appears low with all three established antimalarial agents (mefloquine, doxycycline, and atovaquone-proguanil). The choice of antimalarial agent depends on how individual travellers assess the importance of specific adverse effects, pill burden, and cost. Some travellers will prefer mefloquine for its once-weekly regimen, but this should be balanced against the increased frequency of abnormal dreams, anxiety, insomnia, and depressed mood.

A feature of mature Plasmodium falciparum parasitized red blood cells is their ability to bind surface molecules of the microvascular endothelium via the parasite-derived surface protein Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). This ligand is associated with the cytoadherence pathology observed in severe malaria. As pRBC treated with effective anti-malarial drugs are still able to cytoadhere, there is therefore a need to find an adjunct treatment that can inhibit and reverse the adhesion process. One semi-synthetic, sulfated polysaccharide has been identified that is capable of inhibiting and reversing sequestration of pRBC on endothelial cells in vitro under physiological flow conditions. Furthermore, it exhibits low toxicity in the intrinsic (APTT assay) and extrinsic (PT assay) clotting pathways, as well as exhibiting minimal effects on cell (HUVEC) viability (MTT proliferation assay). These findings suggest that carbohydrate-based anti-adhesive candidates may provide potential leads for therapeutics for severe malaria.

Background: While guidance exists for obtaining population size estimates using multiplier methods with respondent-driven sampling surveys, we lack specific guidance for making sample size decisions.\ud \ud Objective: To guide the design of multiplier method population size estimation studies using respondent-driven sampling surveys to reduce the random error around the estimate obtained.\ud \ud Methods: The population size estimate is obtained by dividing the number of individuals receiving a service or the number of unique objects distributed (M) by the proportion of individuals in a representative survey who report receipt of the service or object (P). We have developed an approach to sample size calculation, interpreting methods to estimate the variance around estimates obtained using multiplier methods in conjunction with research into design effects and respondent-driven sampling. We describe an application to estimate the number of female sex workers in Harare, Zimbabwe.\ud \ud Results: There is high variance in estimates. Random error around the size estimate reflects uncertainty from M and P, particularly when the estimate of P in the respondent-driven sampling survey is low. As expected, sample size requirements are higher when the design effect of the survey is assumed to be greater.\ud \ud Conclusions: We suggest a method for investigating the effects of sample size on the precision of a population size estimate obtained using multipler methods and respondent-driven sampling. Uncertainty in the size estimate is high, particularly when P is small, so balancing against other potential sources of bias, we advise researchers to consider longer service attendance reference periods and to distribute more unique objects, which is likely to result in a higher estimate of P in the respondent-driven sampling survey.

Public health strategies for malaria in endemic countries aim to prevent transmission of the disease and control the vector. This historical analysis considers the strategies for vector control developed during the first four decades of the twentieth century. In 1925, policies and technological advances were debated internationally for the first time after the outbreak of malaria in Europe which followed World War I. This dialogue had implications for policies in Europe, Russia and the Middle East, and influenced the broader international control agenda. The analysis draws on the advances made before 1930, and includes the effects of mosquito-proofing of houses; the use of larvicides (Paris Green) and larvivorous fish (Gambusia); the role of large-scale engineering works; and the emergence of biological approaches to malaria. The importance of strong government and civil servant support was outlined. Despite best efforts of public health authorities, it became clear that it was notoriously difficult to interrupt transmission in areas of moderately high transmission. The importance of combining a variety of measures to achieve control became clear and proved successful in Palestine between 1923 and 1925, and improved education, economic circumstances and sustained political commitment emerge as key factors in the longer term control of malaria. The analysis shows that the principles for many of the present public health strategies for malaria have nearly all been defined before 1930, apart from large scale usage of pesticides, which came later at the end of the Second World War. No single intervention provided an effective single answer to preventing transmission, but certainly approaches taken that are locally relevant and applied in combination, are relevant to today’s efforts at elimination.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:\ud \ud Primary objective\ud To evaluate the impact of space spraying on malaria transmission and vector populations, or the incremental impact when applied in combination with other malaria control methods, in comparison to equivalent conditions with no space spraying intervention.\ud Secondary objective\ud To guide future evaluations of strategies for which there is currently insufficient evidence to reliably assess the impact on malaria transmission, by identifying the following.\ud The range of space spraying strategies that have been trialled.\ud Potentially promising strategies that have been used and warrant further evaluation.\ud Strategies that have been used and appear unlikely to warrant further evaluation (for example, because they were found to be infeasible or unacceptable).

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:\ud To evaluate whether indoor residual spraying (IRS) in combination with long-lasting insecticide-treated nets (LLINs)/insecticide-treated nets (ITNs) causes an additional reduction to malaria transmission versus LLINs/ITNs alone.

Background While barriers to uptake of antenatal care (ANC) among pregnant women have been explored, much less is known about how integrating prevention of mother-to-child transmission (PMTCT) programmes within ANC services affects uptake. We explored barriers to uptake of integrated ANC services in a poor Zimbabwean community. Methods A cross-sectional survey was conducted among post-natal women at Mbare Clinic, Harare, between September 2010 and February 2011. Collected data included participant characteristics and ANC uptake. Logistic regression was conducted to determine factors associated with ANC registration. In-depth interviews were held with the first 21 survey participants who either did not register or registered after twenty-four weeks gestation to explore barriers. Interviews were analysed thematically. Results Two hundred and ninety-nine participants (mean age 26.1 years) were surveyed. They came from ultra-poor households, with mean household income of US$181. Only 229 (76.6%) had registered for ANC, at a mean gestation of 29.5 weeks. In multivariable analysis, household income was positively associated with ANC registration, odds ratio (OR) for a $10-increase in household income 1.02 (95% confidence interval, CI, 1.0–1.04), as was education which interacted with having planned the pregnancy (OR for planned pregnancy with completed ordinary level education 3.27 (95%CI 1.55–6.70). Divorced women were less likely to register than married women, OR 0.20 (95%CI 0.07–0.58). In the qualitative study, barriers to either ANC or PMTCT services limited uptake of integrated services. Women understood the importance of integrated services for PMTCT purposes and theirs and the babies’ health and appeared unable to admit to barriers which they deemed “stupid/irresponsible”, namely fear of HIV testing and disrespectful treatment by nurses. They represented these commonly recurring barriers as challenges that “other women” faced. The major proffered personal barrier was unaffordability of user fees, which was sometimes compounded by unsupportive husbands who were the breadwinners. Conclusion Women who delayed/did not register were aware of the importance of ANC and PMTCT but were either unable to afford or afraid to register. Addressing the identified challenges will not only be important for integrated PMTCT/ANC services but will also provide a model for dealing with challenges as countries scale up ‘treat all’ approaches. Electronic supplementary material The online version of this article (10.1186/s12884-018-1898-7) contains supplementary material, which is available to authorized users.

Background Due to outdoor and residual transmission and insecticide resistance, long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) will be insufficient as stand-alone malaria vector control interventions in many settings as programmes shift toward malaria elimination. Combining additional vector control interventions as part of an integrated strategy would potentially overcome these challenges. Larval source management (LSM) and structural house improvements (HI) are appealing as additional components of an integrated vector management plan because of their long histories of use, evidence on effectiveness in appropriate settings, and unique modes of action compared to LLINs and IRS. Implementation of LSM and HI through a community-based approach could provide a path for rolling-out these interventions sustainably and on a large scale. Methods/design We will implement community-based LSM and HI, as additional interventions to the current national malaria control strategies, using a randomised block, 2 × 2 factorial, cluster-randomised design in rural, southern Malawi. These interventions will be continued for two years. The trial catchment area covers about 25,000 people living in 65 villages. Community participation is encouraged by training community volunteers as health animators, and supporting the organisation of village-level committees in collaboration with The Hunger Project, a non-governmental organisation. Household-level cross-sectional surveys, including parasitological and entomological sampling, will be conducted on a rolling, 2-monthly schedule to measure outcomes over two years (2016 to 2018). Coverage of LSM and HI will also be assessed throughout the trial area. Discussion Combining LSM and/or HI together with the interventions currently implemented by the Malawi National Malaria Control Programme is anticipated to reduce malaria transmission below the level reached by current interventions alone. Implementation of LSM and HI through a community-based approach provides an opportunity for optimum adaptation to the local ecological and social setting, and enhances the potential for sustainability. Trial Registration Registered with The Pan African Clinical Trials Registry on 3 March 2016, trial number PACTR201604001501493. Electronic supplementary material The online version of this article (10.1186/s12879-017-2749-2) contains supplementary material, which is available to authorized users.

Introduction\ud In the context of malaria elimination, interventions will need to target high burden areas to further reduce transmission. Current tools to monitor and report disease burden lack the capacity to continuously detect fine-scale spatial and temporal variations of disease distribution exhibited by malaria. These tools use random sampling techniques that are inefficient for capturing underlying heterogeneity while health facility data in resource-limited settings are inaccurate. Continuous community surveys of malaria burden provide real-time results of local spatio-temporal variation. Adaptive geostatistical design (AGD) improves prediction of outcome of interest compared to current random sampling techniques. We present findings of continuous malaria prevalence surveys using an adaptive sampling design. \ud \ud Methods\ud We conducted repeated cross sectional surveys guided by an adaptive sampling design to monitor the prevalence of malaria parasitaemia and anaemia in children below five years old in the communities living around Majete Wildlife Reserve in Chikwawa district, Southern Malawi. AGD sampling uses previously collected data to sample new locations of high prediction variance or, where prediction exceeds a set threshold. We fitted a geostatistical model to predict malaria prevalence in the area.\ud \ud Findings\ud We conducted five rounds of sampling, and tested 876 children aged 6-59 months from 1377 households over a 12-month period. Malaria prevalence prediction maps showed spatial heterogeneity and presence of hotspots – where predicted malaria prevalence was above 30%; predictors of malaria included age, socio-economic status and ownership of insecticide-treated mosquito nets. \ud \ud Conclusions\ud Continuous malaria prevalence surveys using adaptive sampling increased malaria prevalence prediction accuracy. Results from the surveys were readily available after data collection. \ud The tool can assist local managers to target malaria control interventions in areas with the greatest health impact and is ready for assessment in other diseases.

Vector-borne diseases (VBD) transmitted by arthropods are responsible for over 1 billion cases and 1 million deaths every year, corresponding to at least 17% of all infectious diseases in human populations [1]. Among them, we can find malaria, leishmaniasis, onchocerciasis, lymphatic filariasis, Chagas disease, and African trypanosomiases, as well as several arboviral diseases (arthropod-borne virus) such as dengue and Zika virus. Some of these have reemerged in new parts of the world and have become a topic of growing importance in public health and in political and scientific agendas [2]. Several factors are contributing towards the reemergence of VBDs. On the one hand, the spread of resistance to drugs in pathogens has become a major obstacle for the effective treatment of some VBDs [3], and the emergence of new strains of arboviruses (e.g., Zika virus in Brazil) has created new challenges for health care systems [4]. On the other hand, an increase in insecticide resistance is threatening the sustainability of vector control programmes in several tropical regions [5]. Additionally, the expansion of different vector populations due to climate change is becoming a growing concern in temperate countries, where vector control programs have been discontinuous for almost 50 years [6, 7]. The scientific community has been trying to overcome these challenges by creating new strategies and tools to improve the diagnosis and treatment of VBDs and by developing new methodologies and targets for vector control campaigns. This special issue of BioMed Research International compiles nine topical articles that explore recent advances in research of an eclectic range of pathogens, vectors, and human diseases affecting several regions of the world. publishersversion published

Opinion article. The pipeline for new antibiotics is dry. Despite the creation of public/private initiatives like Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (Carb-X) and the Antimicrobial Resistance (AMR) Centre, the current focus on ‘push-pull’ incentives for the pharmaceutical industry still relies on economic return. We propose a joint, internationally-funded antimicrobial development institute that would fund permanent staff to take on roles previously assigned to pharmaceutical companies. This institute would receive ring-fenced, long-term, core funding from participating countries as well as charities, with the aim to focus on transforming the largely dormant antimicrobial pipeline. Resulting drugs would be sold globally and according to a principle of shared burdens. Our proposed model for antimicrobial development aims to maximise society’s investment, through open science, investment in people, and the sharing of intellectual property.