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ABSTRACT Sex‐ratio theory predicts that parents can optimise their fitness by producing offspring of the rare sex, yet there is a dearth of empirical evidence for adaptive sex allocation in response to the adult sex ratio (ASR). This is concerning, as anthropogenic disruption of the sex ratios of reproductive individuals threatens to cause demographic collapse in animal populations. Species with environmental sex determination (ESD) are especially at risk but may possess the capacity to adaptively influence offspring sex via control over the developmental environment. For example, reptiles with temperature‐dependent sex determination (TSD) could conceivably choose nest sites with thermal characteristics that produce offspring of the rare sex. To test this hypothesis, we seeded three secure outdoor ponds with different sex ratios (~M:F 3:1, 1:1, and 1:3) of adult painted turtles (Chrysemys picta), a reptile species with TSD. We then quantified nesting traits that could influence nest temperature and thus offspring sex ratio, including nesting date, nest depth, and nest canopy cover. We found no directional relationship between the ASR treatments and any measured nest traits and thus rejected our hypothesis. Interestingly, increased maternal body size was associated with reduced nest canopy cover, and this trend was more pronounced in the biased ASR treatments. If adaptive sex allocation occurs in this system, it instead may manifest via maternal epigenetic predisposition of offspring sex or in response to a phenomenon other than the ASR.

Despite some progress, universal access to safe water, sanitation and hygiene (WASH) by 2030—a remit of Sustainable Development Goal 6—remains a distant prospect in many countries. Policy-makers and implementers of the WASH sector are challenged to track a new path. This research aimed to identify core orienting themes of the sector, as legacies of past processes, which can provide insights for its future. We reviewed global policy, science and programmatic documents and carried out 19 expert interviews to track the evolution of the global WASH sector over seven decades. We situated this evolution in relation to wider trends in global health and development over the same time period.With transnational flows of concern, expertise and resources from high-income to lower-income countries, the WASH sector evolved over decades of international institutionalisation of health and development with (1) a focus on technologies (technicalisation), (2) a search for generalised solutions (universalisation), (3) attempts to make recipients responsible for environmental health (responsibilisation) and (4) the shaping of programmes around quantifiable outcomes (metricisation). The emergent commitment of the WASH sector to these core themes reflects a pragmatic response in health and development to depoliticise poverty and social inequalities in order to enable action. This leads to questions about what potential solutions have been obscured, a recognition which might be understood as ‘uncomfortable knowledge’—the knowns that have had to be unknown, which resonate with concerns about deep inequalities, shrinking budgets and the gap between what could and has been achieved.

Background: The adoption of e-platforms for use in clinical and administrative processes within health facilities in many African countries has been slow. Objectives: To assess the opinion of physicians on the usefulness and impact of e-platforms in their practice. Materials and Methods: Information was obtained from 236 physicians using an online pre-tested and validated 29-item questionnaire. Results: The majority of the respondents, 57.2% agreed that information and communication technology (ICT) reduced errors in patient records in the clinics and emergency room and 22.8% disagreed, whereas 19.9% were neutral. On whether ICT helped to curb cases of missing medical records, 76.7% agreed and 9.7% disagreed, whereas 13.6% were neutral. Concerning ICT platforms being user-friendly and easy to understand, 64% agreed and 12.3% disagreed, whereas 23.7% were neutral. On whether the clinics experienced faster reviews and turnaround time, 48.4% agreed and 20.8% disagreed, whereas 30.9% were neutral. While 27.1% agreed that excess workload had been reduced in their clinic in the past 3 years because of these new platforms and 28.8% disagreed, 44.1% were neutral. On clinics being less crowded as a result, 28.8% agreed and 32.2% disagreed, whereas 39% were neutral. There was no difference in the responses obtained across the various cadres of physicians or their years of experience. Conclusion: Most respondents agreed that communication with other health facilities and ease of accessing patients′ clinical and laboratory details have been improved by using e-platforms. Responses obtained did not vary across the various cadre of physicians or with their years of experience. Translating these innovations to impact patients’ satisfaction, reduction in workload, and overcrowding are of major importance.

Abstract Analysis of environmental DNA (eDNA) has gained widespread usage for taxonomically based biodiversity assessment. While interest in applying noninvasive eDNA monitoring for population genetic assessments has grown, its usage in this sphere remains limited. One barrier to uptake is that the effectiveness of eDNA detection below the species level remains to be determined for multiple species and environments. Here, we test the utility of this emergent technology to obtain within‐species haplotypic variation of New Zealand (NZ) blackfoot pāua (Haliotis iris). We compare mitochondrial haplotype diversity recovered from marine eDNA samples against traditional tissue samples of blackfoot pāua collected at the same NZ coastal site. Targeting the ATP8‐ATP6 region, we recovered four mitochondrial haplotypes from eDNA versus six haplotypes from tissue samples. Three common haplotypes were recovered with both eDNA and tissue samples, while only one out of three rare haplotypes – represented in tissue samples by one individual each – was recovered with our eDNA methods. We demonstrate that eDNA monitoring is an effective tool for recovering common genetic diversity from pāua, although rare (

Multimorbidity is an emerging challenge for health systems globally. It is commonly defined as the co-occurrence of two or more chronic conditions in one person, but its meaning remains a lively area of academic debate, and the utility of the concept beyond high-income settings is uncertain. This article presents the findings from an interdisciplinary research initiative that drew together 60 academic and applied partners working in 10 African countries to answer the questions: how useful is the concept of multimorbidity within Africa? Can the concept be adapted to context to optimise its transformative potentials? During a three-day concept-building workshop, we investigated how the definition of multimorbidity was understood across diverse disciplinary and regional perspectives, evaluated the utility and limitations of existing concepts and definitions, and considered how to build a more context-sensitive, cross-cutting description of multimorbidity. This iterative process was guided by the principles of grounded theory and involved focus- and whole-group discussions during the workshop, thematic coding of workshop discussions, and further post-workshop development and refinement. Three thematic domains emerged from workshop discussions: the current focus of multimorbidity on constituent diseases; the potential for revised concepts to centre the priorities, needs, and social context of people living with multimorbidity (PLWMM); and the need for revised concepts to respond to varied conceptual priorities amongst stakeholders. These themes fed into the development of an expanded conceptual model that centres the catastrophic impacts multimorbidity can have for PLWMM, families and support structures, service providers, and health systems.

The mass production of antibiotics in the 1940s enabled their travel beyond Europe and America, but to date the significance of the ways in which these medicines co-constituted colonial regimes at the time has not been systematically described. Through a case study of yaws and syphilis, this research article traces arrivals of antibiotics in three countries of Eastern Africa—Malawi, Zimbabwe, and Uganda. We draw attention to the emergent roles of antibiotics at the intersection of colonial governance and humanitarianism in these different settings. Through this analysis of archival and ethnographic materials, we explore how antibiotics became ‘infrastructural’ in material, affective, and political ways. Achieving a better understanding of the entanglement of antibiotics with human systems and lives is crucial to address the pressing issue of antimicrobial resistance (AMR). With this article we join in the global multidisciplinary efforts to tackle AMR, pointing out the often-overlooked role of colonial history in the circulation of antibiotic drugs, and opening a line of research that will provide valuable insights for the development of effective measures to prevent and reduce the spread of antibiotic resistance.

Epigenetic mechanisms allow cells to fine-tune gene expression in response to environmental stimuli. For decades, it has been known that mitochondria have genetic material. Still, only recently have studies shown that epigenetic factors regulate mitochondrial DNA (mtDNA) gene expression. Mitochondria regulate cellular proliferation, apoptosis, and energy metabolism, all critical areas of dysfunction in gliomas. Methylation of mtDNA, alterations in mtDNA packaging via mitochondrial transcription factor A (TFAM), and regulation of mtDNA transcription via the micro-RNAs (mir 23-b) and long noncoding RNAs [RNA mitochondrial RNA processing (RMRP)] have all been identified as contributing to glioma pathogenicity. Developing new interventions interfering with these pathways may improve glioma therapy.

Multimorbidity has been framed as a pressing global health challenge that exposes the limits of systems organised around single diseases. This article seeks to expand and strengthen current thinking around multimorbidity by analysing its construction within the field of global health. We suggest that the significance of multimorbidity lies not only in challenging divisions between disease categories but also in what it reveals about the culture and history of transnational biomedicine. Drawing on social research from sub-Saharan Africa to ground our arguments, we begin by describing the historical processes through which morbidity was made divisible in biomedicine and how the single disease became integral not only to disease control but to the extension of biopolitical power. Multimorbidity, we observe, is hoped to challenge single disease approaches but is assembled from the same problematic, historically-loaded categories that it exposes as breaking down. Next, we highlight the consequences of such classificatory legacies in everyday lives and suggest why frameworks and interventions to integrate care have tended to have limited traction in practice. Finally, we argue that efforts to align priorities and disciplines around a standardised biomedical definition of multimorbidity risks retracing the same steps. We call for transdisciplinary work across the field of global health around a more holistic, reflexive understanding of multimorbidity that foregrounds the culture and history of translocated biomedicine, the intractability of single disease thinking, and its often-adverse consequences in local worlds. We outline key domains within the architecture of global health where transformation is needed, including care delivery, medical training, the organisation of knowledge and expertise, global governance, and financing.

In Guillain-Barré syndrome (GBS), both axonal and demyelinating variants can be mediated by complement-fixing anti–GM1 ganglioside autoantibodies that target peripheral nerve axonal and Schwann cell (SC) membranes, respectively. Critically, the extent of axonal degeneration in both variants dictates long-term outcome. The differing pathomechanisms underlying direct axonal injury and the secondary bystander axonal degeneration following SC injury are unresolved. To investigate this, we generated glycosyltransferase-disrupted transgenic mice that express GM1 ganglioside either exclusively in neurons [GalNAcT–/–-Tg(neuronal)] or glia [GalNAcT–/–-Tg(glial)], thereby allowing anti-GM1 antibodies to solely target GM1 in either axonal or SC membranes, respectively. Myelinated-axon integrity in distal motor nerves was studied in transgenic mice exposed to anti-GM1 antibody and complement in ex vivo and in vivo injury paradigms. Axonal targeting induced catastrophic acute axonal disruption, as expected. When mice with GM1 in SC membranes were targeted, acute disruption of perisynaptic glia and SC membranes at nodes of Ranvier (NoRs) occurred. Following glial injury, axonal disruption at NoRs also developed subacutely, progressing to secondary axonal degeneration. These models differentiate the distinctly different axonopathic pathways under axonal and glial membrane targeting conditions, and provide insights into primary and secondary axonal injury, currently a major unsolved area in GBS research.

Drug resistant infections are increasing across the world and urgent action is required to preserve current classes of antibiotics. Antibiotic use practices in low-and-middle-income countries have gained international attention, especially as antibiotics are often accessed beyond the formal health system. Public awareness campaigns have gained popularity, often conceptualising antimicrobial resistance (AMR) as a problem of excess, precipitated by irrational behaviour. Insufficient attention has been paid to people’s lived experiences of accessing medicines in low-income contexts. In Chikwawa District, Malawi, a place of extreme scarcity, our study aimed to understand the care and medicine use practices of households dependent on subsistence farming. Adopting an anthropological approach, we undertook medicine interviews (100), ethnographic fieldwork (six-month period) and key informant interviews (33) with a range of participants in two villages in rural Chikwawa. The most frequently used drugs were cotrimoxazole and amoxicillin, not considered to be of critical importance to human health. Participants recognised that keeping, sharing, and buying medicines informally was not the “right thing.” However, they described using antibiotics and other medicines in these ways due to conditions of extreme precarity, the costs and limitations of seeking formal care in the public sector, and the inevitability of future illness. Our findings emphasise the need in contexts of extreme scarcity to equip policy actors with interventions to address AMR through strengthening health systems, rather than public awareness campaigns that foreground overuse and the dangers of using antibiotics beyond the formal sector.

Drug resistant infections are increasing across the world and urgent action is required to preserve current classes of antibiotics. Antibiotic use practices in low-and-middle-income countries have gained international attention, especially as antibiotics are often accessed beyond the formal health system. Public awareness campaigns have gained popularity, often conceptualising antimicrobial resistance (AMR) as a problem of excess, precipitated by irrational behaviour. Insufficient attention has been paid to people's lived experiences of accessing medicines in low-income contexts. In Chikwawa District, Malawi, a place of extreme scarcity, our study aimed to understand the care and medicine use practices of households dependent on subsistence farming. Adopting an anthropological approach, we undertook medicine interviews (100), ethnographic fieldwork (six-month period) and key informant interviews (33) with a range of participants in two villages in rural Chikwawa. The most frequently used drugs were cotrimoxazole and amoxicillin, not considered to be of critical importance to human health. Participants recognised that keeping, sharing, and buying medicines informally was not the "right thing." However, they described using antibiotics and other medicines in these ways due to conditions of extreme precarity, the costs and limitations of seeking formal care in the public sector, and the inevitability of future illness. Our findings emphasise the need in contexts of extreme scarcity to equip policy actors with interventions to address AMR through strengthening health systems, rather than public awareness campaigns that foreground overuse and the dangers of using antibiotics beyond the formal sector.

Background As concerns about the prevalence of infections that are resistant to available antibiotics increase, attention has turned toward the use of these medicines both within and outside of formal healthcare settings. Much of what is known about use beyond formal settings is informed by survey-based research. Few studies to date have used comparative, mixed-methods approaches to render visible patterns of use within and between settings as well as wider points of context shaping these patterns.Design This article analyses findings from mixed-methods anthropological studies of antibiotic use in a range of rural and urban settings in Zimbabwe, Malawi and Uganda between 2018 and 2020. All used a ‘drug bag’ survey tool to capture the frequency and types of antibiotics used among 1811 households. We then undertook observations and interviews in residential settings, with health providers and key stakeholders to better understand the stories behind the most-used antibiotics.Results The most self-reported ‘frequently used’ antibiotics across settings were amoxicillin, cotrimoxazole and metronidazole. The stories behind their use varied between settings, reflecting differences in the configuration of health systems and antibiotic supplies. At the same time, these stories reveal cross-cutting features and omissions of contemporary global health programming that shape the contours of antibiotic (over)use at national and local levels.Conclusions Our findings challenge the predominant focus of stewardship frameworks on the practices of antibiotic end users. We suggest future interventions could consider systems—rather than individuals—as stewards of antibiotics, reducing the need to rely on these medicines to fix other issues of inequity, productivity and security.

Addressing antibiotic use is essential to tackle antimicrobial resistance, a major human and animal health challenge. This review seeks to inform stewardship efforts in companion animals by collating research insights regarding antibiotic use in this group and identifying overlooked avenues for future research and stewardship efforts. The development of population-based methods has established that antibiotics are frequently used in companion animal care. Research insights are also contributing toward an in-depth comprehension of the contexts to antibiotic use. Qualitative approaches, for example, have enabled a nuanced understanding in four key areas: interactions with owners, clinical and financial risk management, time pressures, and clinic dynamics. This review identifies that much of the existing research frames antibiotic use as the result of choices made by the individuals at the interface of their use. Future research and policy endeavours could look beyond the moment of prescribing to consider the societal structures and networks in which companion animal antibiotic use is entangled. A diversification in research approaches and frameworks through which antibiotic use is understood will facilitate the identification of additional targets for stewardship initiatives beyond providing information and awareness campaigns.

Environmental disturbances have long been theorized to play a significant role in shaping the diversity and composition of ecosystems. However, an inability to specify the characteristics of a disturbance experimentally has produced an inconsistent picture of diversity-disturbance relationships (DDRs). Here, using a high-throughput programmable culture system, we subjected a soil-derived bacterial community to dilution disturbance profiles with different intensities (mean dilution rates), applied either constantly or with fluctuations of different frequencies. We observed an unexpected U-shaped relationship between community diversity and disturbance intensity in the absence of fluctuations. Adding fluctuations increased community diversity and erased the U-shape. All our results are well-captured by a Monod consumer resource model, which also explains how U-shaped DDRs emerge via a novel ‘niche flip’ mechanism. Broadly, our combined experimental and modeling framework demonstrates how distinct features of an environmental disturbance can interact in complex ways to govern ecosystem assembly and offers strategies for reshaping the composition of microbiomes.

Abstract Background There has been a successful push towards parasitological diagnosis of malaria in Africa, mainly with rapid diagnostic tests (mRDTs), which has reduced over-prescribing of artemisinin-based combination therapies (ACT) to malaria test-negative patients. The effect on prescribing for test-positive patients has received much less attention. Malaria infection in endemic Africa is often most dangerous for young children and those in low-transmission settings. This study examined non-prescription of antimalarials for patients with malaria infection demonstrated by positive mRDT results, and in particular these groups who are most vulnerable to poor outcomes if antimalarials are not given. Methods Analysis of data from 562,762 patients in 8 studies co-designed as part of the ACT Consortium, conducted 2007–2013 in children and adults, in Cameroon, Ghana, Nigeria, Tanzania, and Uganda, in a variety of public and private health care sector settings, and across a range of malaria endemic zones. Results Of 106,039 patients with positive mRDT results (median age 6 years), 7426 (7.0%) were not prescribed an ACT antimalarial. The proportion of mRDT-positive patients not prescribed ACT ranged across sites from 1.3 to 37.1%. For patients under age 5 years, 3473/44,539 (7.8%) were not prescribed an ACT, compared with 3833/60,043 (6.4%) of those aged ≥ 5 years. The proportion of

Abstract Background Intermittent preventive treatment (IPT) of malaria is recommended as policy for certain high-risk populations, but not currently for schoolchildren. A cluster-randomized trial was conducted to evaluate the effect of IPT with dihydroartemisinin–piperaquine (DP) on primary schoolchildren in Jinja, Uganda. Results of the impact of IPT of schoolchildren on community-level transmission have been reported previously. Here, secondary outcomes from a school-based survey are presented. Methods Eighty-four clusters (one primary school plus 100 households) were randomized to intervention and control (1:1 ratio). Participants from intervention schools received monthly IPT with DP for up to 6 rounds (June–December 2014). At endline (November–December 2014), randomly selected children from all 84 schools were surveyed (13 per school) and thick blood smears were done. Those with fever or history of fever were tested with rapid diagnostic tests (RDTs) for malaria. Haemoglobin was measured in every fifth participant. Outcome measures included prevalence of asexual parasites and gametocytes (by microscopy), and prevalence of anaemia. Prevalence outcomes were analysed using generalized linear Poisson models with log link function, incorporating a cluster-level random intercept and quantified using prevalence risk ratios. Results Among 23,280 students listed on the 42 intervention school registers, 10,079 (43.3%) aged 5–20 years were enrolled into the IPT intervention and received at least one dose of DP; of these, 9286 (92.1%) received at least one full (3-day) course. In total, 1092 children were enrolled into the final school survey (546 per arm) and had a thick blood smear done; of these, 255 had haemoglobin measured (129 intervention, 126 control). Children in the intervention arm were less likely to have asexual parasites (9.2% intervention vs 44.1% control, adjusted risk ratio [aRR] 0.22 [95% CI 0.16–0.30] p

Environmental stress can affect the outcome of ecological competition. Here, the authors use theory and experiments with a synthetic microbial community to show that a tradeoff between growth rate and competitive ability determines which species prevails when the population faces variable mortality rates.

Climatic changes and anthropogenic pressures affect biodiversity and community composition. These biodiversity shifts are recognized in marine ecosystems, but the underlying processes are barely understood so far. Importantly, human well-being highly relies on oceanic services, which are affected by anthropogenic pressures. Here, we review how interdisciplinary research approaches, with the incorporation of eDNA (environmental DNA) analyses, can help increase the understanding of complex ecosystem processes and dynamics, and how they affect ecosystem services. We discuss marine conservation issues in the light of life cycle aspects and conclude that eDNA can improve our ecological knowledge in some instances, for example, in tracking migration patterns. We also illustrate and discuss the application of eDNA analysis within the context of population genetics, epigenetics, geochemistry and oceanography. Embedded into an interdisciplinary context, eDNA can be exploited by a huge variety of methodological techniques, and can resolve spatio-temporal patterns of diversity, species, or even populations within ecological, evolutionary, and management frameworks.

There is increasing concern globally about the enormity of the threats posed by antimicrobial resistance (AMR) to human, animal, plant and environmental health. A proliferation of international, national and institutional reports on the problems posed by AMR and the need for antibiotic stewardship have galvanised attention on the global stage. However, the AMR community increasingly laments a lack of action, often identified as an ‘implementation gap’. At a policy level, the design of internationally salient solutions that are able to address AMR’s interconnected biological and social (historical, political, economic and cultural) dimensions is not straightforward. This multidisciplinary paper responds by asking two basic questions: (A) Is a universal approach to AMR policy and antibiotic stewardship possible? (B) If yes, what hallmarks characterise ‘good’ antibiotic policy? Our multistage analysis revealed four central challenges facing current international antibiotic policy: metrics, prioritisation, implementation and inequality. In response to this diagnosis, we propose three hallmarks that can support robust international antibiotic policy. Emerging hallmarks for good antibiotic policies are: Structural, Equitable and Tracked. We describe these hallmarks and propose their consideration should aid the design and evaluation of international antibiotic policies with maximal benefit at both local and international scales.

The effect of environmental fluctuations is a major question in ecology. While it is widely accepted that fluctuations and other types of disturbances can increase biodiversity, there are fewer examples of other types of outcomes in a fluctuating environment. Here we explore this question with laboratory microcosms, using cocultures of two bacterial species, P. putida and P. veronii. At low dilution rates we observe competitive exclusion of P. veronii, whereas at high dilution rates we observe competitive exclusion of P. putida. When the dilution rate alternates between high and low, we do not observe coexistence between the species, but rather alternative stable states, in which only one species survives and initial species' fractions determine the identity of the surviving species. The Lotka-Volterra model with a fluctuating mortality rate predicts that this outcome is independent of the timing of the fluctuations, and that the time-averaged mortality would also lead to alternative stable states, a prediction that we confirm experimentally. Other pairs of species can coexist in a fluctuating environment, and again consistent with the model we observe coexistence in the time-averaged dilution rate. We find a similar time-averaging result holds in a three-species community, highlighting that simple linear models can in some cases provide powerful insight into how communities will respond to environmental fluctuations.

Kynurenine-3-monooxygenase (KMO) is an emerging clinical target for treatment of neurodegenerative diseases and acute pancreatitis. Here, the authors report potent inhibitors that bind KMO in an unexpected conformation, offering structural and mechanistic insights for future drug discovery ventures.

Understanding the prevalence and types of antibiotics used in a given human and/or animal population is important for informing stewardship strategies. Methods used to capture such data often rely on verbal elicitation of reported use that tend to assume shared medical terminology. Studies have shown the category ‘antibiotic’ does not translate well linguistically or conceptually, which limits the accuracy of these reports. This article presents a ‘Drug Bag’ method to study antibiotic use (ABU) in households and on farms, which involves using physical samples of all the antibiotics available within a given study site. We present the conceptual underpinnings of the method, and our experiences of using this method to produce data about antibiotic recognition, use and accessibility in the context of anthropological research in Africa and South-East Asia. We illustrate the kinds of qualitative and quantitative data the method can produce, comparing and contrasting our experiences in different settings. The Drug Bag method can produce accurate antibiotic use data as well as provide a talking point for participants to discuss antibiotic experiences. We propose it can help improve our understanding of antibiotic use in peoples’ everyday lives across different contexts, and our reflections add to a growing conversation around methods to study ABU beyond prescriber settings, where data gaps are currently substantial.

Background: Blindness from glaucoma is associated with socio-economic deprivation, presumed to reflect poor access to care and poor adherence to treatment. Objectives: To determine why people with glaucoma are presenting late for treatment and to understand access to glaucoma care. Additionally, we sought to identify what patients and the community know, do and think about the condition and why the poor are the most affected with glaucoma blindness. Design: Study participants were from four communities and two hospitals in Abuja-FCT and Kaduna State, Nigeria. A total of 120 participants were involved, including 8 focus group discussions, 7 in-depth interviews with blind/visually impaired glaucoma patients, 5 rapid direct observation visits with these patients and 13 exit interviews of glaucoma patients in the hospital. The data were analysed using content analysis, interpreting participant experiences in terms of three key steps conceptualised as important in the care pathway: what it takes to know glaucoma, to reach a diagnosis and to access continued care. Results: This article presents multiple narratives of accessing and maintaining glaucoma care and how people manage and cope with the disease. People may be presenting late due to structural barriers, which include lack of knowledge and awareness about glaucoma and not finding an appropriately equipped health care facility. What keeps glaucoma patients within the care pathway are a good hospital experience; a support structure involving family, counselling and shared patients’ experiences; and an informed choice of treatment, as well as agency. The high cost of purchasing care is a major factor for patients dropping out of treatment. Conclusion: The findings suggest the need to address economic and social structural drivers as glaucoma presents another case study to demonstrate that poverty is a strong driver for blindness. There is also a need for clear glaucoma care pathways with early case finding in the community, two-way referral/feedback systems, well-equipped glaucoma care hospitals and better eye health care financing.

Summary: Background: Intermittent preventive treatment (IPT) is a well established malaria control intervention. Evidence that delivering IPT to schoolchildren could provide community-level benefits is limited. We did a cluster-randomised controlled trial to assess the effect of IPT of primary schoolchildren with dihydroartemisinin-piperaquine (DP) on indicators of malaria transmission in the community, in Jinja, Uganda. Methods: We included 84 clusters, each comprising one primary school and the 100 closest available households. The clusters were randomly assigned 1:1 to receive IPT with DP or standard care (control) by restricted randomisation to ensure balance by geography and school type. Children in intervention schools received IPT monthly for up to six rounds (June to December, 2014). We did cross-sectional community surveys in randomly selected households at baseline and in January to April, 2015, during which we measured participants' temperatures and obtained finger-prick blood smears for measurement of parasite prevalence by microscopy. We also did entomological surveys 1 night per month in households from 20 randomly selected IPT and 20 control clusters. The primary trial outcome was parasite prevalence in the final community survey. The primary entomological survey outcome was the annual entomological inoculation rate (aEIR) from July, 2014, to April, 2015. This trial is registered at ClinicalTrials.gov, number NCT02009215. Findings: Among 23 280 students registered in the 42 intervention schools, 10 079 (43%) aged 5–20 years were enrolled and received at least one dose of DP. 9286 (92%) of 10 079 received at least one full course of DP (three doses). Community-level parasite prevalence was lower in the intervention clusters than in the control clusters (19% vs 23%, adjusted risk ratio 0·85, 95% CI 0·73–1·00, p=0·05). The aEIR was lower in the intervention group than in the control group, but not significantly so (10·1 vs 15·2 infective bites per person, adjusted incidence rate ratio 0·80, 95% CI 0·36–1·80, p=0·59). Interpretation: IPT of schoolchildren with DP might have a positive effect on community-level malaria indicators and be operationally feasible. Studies with greater IPT coverage are needed. Funding: UK Medical Research Council, UK Department for International Development, and Wellcome Trust.

Background: In Uganda, health system challenges limit access to good quality healthcare and contribute to slow progress on malaria control. We developed a complex intervention (PRIME), which was designed to improve quality of care for malaria at public health centres. Objective: Responding to calls for increased transparency, we describe the PRIME intervention's design process, rationale, and final content and reflect on the choices and challenges encountered during the design of this complex intervention. Design: To develop the intervention, we followed a multistep approach, including the following: 1) formative research to identify intervention target areas and objectives; 2) prioritization of intervention components; 3) review of relevant evidence; 4) development of intervention components; 5) piloting and refinement of workshop modules; and 6) consolidation of the PRIME intervention theories of change to articulate why and how the intervention was hypothesized to produce desired outcomes. We aimed to develop an intervention that was evidence-based, grounded in theory, and appropriate for the study context; could be evaluated within a randomized controlled trial; and had the potential to be scaled up sustainably. Results: The process of developing the PRIME intervention package was lengthy and dynamic. The final intervention package consisted of four components: 1) training in fever case management and use of rapid diagnostic tests for malaria (mRDTs); 2) workshops in health centre management; 3) workshops in patient-centred services; and 4) provision of mRDTs and antimalarials when stocks ran low. Conclusions: The slow and iterative process of intervention design contrasted with the continually shifting study context. We highlight the considerations and choices made at each design stage, discussing elements we included and why, as well as those that were ultimately excluded. Reflection on and reporting of ‘behind the scenes’ accounts of intervention design may improve the design, assessment, and generalizability of complex interventions and their evaluations.

Environmental DNA (eDNA) is an increasingly used non-invasive molecular tool for detecting species presence and monitoring populations. In this article, we review the current state of non-avian reptile eDNA work in aquatic systems, and present a field experiment on detecting the presence of painted turtle (Chrysemys picta) eDNA. Thus far, turtle and snake eDNA studies have shown mixed results in detecting the presence of these animals under field conditions. However, some instances of low detection rates and non-detection occur for these non-avian reptiles, especially for squamates. We explored non-avian reptile eDNA quantification by sampling four lentic ponds with different densities (0 kg/ha, 6 kg/ha, 9 kg/ha, and 13 kg/ha) of painted turtles over three months to detect differences in eDNA using a qPCR assay amplifying the COI gene of the mtDNA genome. Only one sample of the highest-density pond amplified eDNA for a positive detection. Yet, estimates of eDNA concentration from pond eDNA were rank-order correlated with turtle density. We present the “shedding hypothesis„—the possibility that animals with hard, keratinized integument do not shed as much DNA as mucus-covered organisms—as a potential challenge for eDNA studies. Despite challenges with eDNA inhibition and availability in water samples, we remain hopeful that eDNA can be used to detect freshwater turtles in the field. We provide key recommendations for biologists wishing to use eDNA methods for detecting non-avian reptiles.

BACKGROUND:Many patients with malaria-like symptoms seek treatment in private medicine retail outlets (PMR) that distribute malaria medicines but do not traditionally provide diagnostic services, potentially leading to overtreatment with antimalarial drugs. To achieve universal access to prompt parasite-based diagnosis, many malaria-endemic countries are considering scaling up malaria rapid diagnostic tests (RDTs) in these outlets, an intervention that may require legislative changes and major investments in supporting programs and infrastructures. This review identifies studies that introduced malaria RDTs in PMRs and examines study outcomes and success factors to inform scale up decisions. METHODS:Published and unpublished studies that introduced malaria RDTs in PMRs were systematically identified and reviewed. Literature published before November 2016 was searched in six electronic databases, and unpublished studies were identified through personal contacts and stakeholder meetings. Outcomes were extracted from publications or provided by principal investigators. RESULTS:Six published and six unpublished studies were found. Most studies took place in sub-Saharan Africa and were small-scale pilots of RDT introduction in drug shops or pharmacies. None of the studies assessed large-scale implementation in PMRs. RDT uptake varied widely from 8%-100%. Provision of artemisinin-based combination therapy (ACT) for patients testing positive ranged from 30%-99%, and was more than 85% in five studies. Of those testing negative, provision of antimalarials varied from 2%-83% and was less than 20% in eight studies. Longer provider training, lower RDT retail prices and frequent supervision appeared to have a positive effect on RDT uptake and provider adherence to test results. Performance of RDTs by PMR vendors was generally good, but disposal of medical waste and referral of patients to public facilities were common challenges. CONCLUSIONS:Expanding services of PMRs to include malaria diagnostic services may hold great promise to improve malaria case management and curb overtreatment with antimalarials. However, doing so will require careful planning, investment and additional research to develop and sustain effective training, supervision, waste-management, referral and surveillance programs beyond the public sector.

BACKGROUND:Rapid diagnostic tests for malaria (mRDTs) have been scaled-up widely across Africa. The PRIME study evaluated an intervention aiming to improve fever case management using mRDTs at public health centers in Uganda. METHODS:A cluster-randomized trial was conducted from 2010-13 in Tororo, a high malaria transmission setting. Twenty public health centers were randomized in a 1:1 ratio to intervention or control. The intervention included training in health center management, fever case management with mRDTs, and patient-centered services; plus provision of mRDTs and artemether-lumefantrine (AL) when stocks ran low. Three rounds of Interviews were conducted with caregivers of children under five years of age as they exited health centers (N = 1400); reference mRDTs were done in children with fever (N = 1336). Health worker perspectives on mRDTs were elicited through semi-structured questionnaires (N = 49) and in-depth interviews (N = 10). The primary outcome was inappropriate treatment of malaria, defined as the proportion of febrile children who were not treated according to guidelines based on the reference mRDT. FINDINGS:There was no difference in inappropriate treatment of malaria between the intervention and control arms (24.0% versus 29.7%, adjusted risk ratio 0.81 [95% CI: 0.56, 1.17] p = 0.24). Most children (76.0%) tested positive by reference mRDT, but many were not prescribed AL (22.5% intervention versus 25.9% control, p = 0.53). Inappropriate treatment of children testing negative by reference mRDT with AL was also common (31.3% invention vs 42.4% control, p = 0.29). Health workers appreciated mRDTs but felt that integrating testing into practice was challenging given constraints on time and infrastructure. CONCLUSIONS:The PRIME intervention did not have the desired impact on inappropriate treatment of malaria for children under five. In this high transmission setting, use of mRDTs did not lead to the reductions in antimalarial prescribing seen elsewhere. Broader investment in health systems, including infrastructure and staffing, will be required to improve fever case management.

Background: The scale-up of malaria rapid diagnostic tests (RDTs) is intended to improve case management of fever and targeting of artemisinin-based combination therapy. Habitual presumptive treatment has hampered these intentions, suggesting a need for strategies to support behaviour change. We aimed to assess the introduction of RDTs when packaged with basic or enhanced clinician training interventions in Cameroon. Methods: We did a three-arm, stratified, cluster-randomised trial at 46 public and mission health facilities at two study sites in Cameroon to compare three approaches to malaria diagnosis. Facilities were randomly assigned by a computer program in a 9:19:19 ratio to current practice with microscopy (widely available, used as a control group); RDTs with a basic (1 day) clinician training intervention; or RDTs with an enhanced (3 days) clinician training intervention. Patients (or their carers) and fieldworkers who administered surveys to obtain outcome data were masked to study group assignment. The primary outcome was the proportion of patients treated in accordance with WHO malaria treatment guidelines, which is a composite indicator of whether patients were tested for malaria and given appropriate treatment consistent with the test result. All analyses were by intention to treat. This study is registered at ClinicalTrials.gov, number NCT01350752. Findings: The study took place between June 7 and Dec 14, 2011. The analysis included 681 patients from nine facilities in the control group, 1632 patients from 18 facilities in the basic-training group, and 1669 from 19 facilities in the enhanced-training group. The proportion of patients treated in accordance with malaria guidelines did not improve with either intervention; the adjusted risk ratio (RR) for basic training compared with control was 1·04 (95% CI 0·53–2·07; p=0·90), and for enhanced training compared with control was 1·17 (0·61–2·25; p=0·62). Inappropriate use of antimalarial drugs after a negative test was reduced from 84% (201/239) in the control group to 52% (413/796) in the basic-training group (unadjusted RR 0·63, 0·28–1·43; p=0·25) and to 31% (232/759) in the enhanced-training group (0·29, 0·11–0·77; p=0·02). Interpretation: Enhanced clinician training, designed to translate knowledge into prescribing practice and improve quality of care, has the potential to halve overtreatment in public and mission health facilities in Cameroon. Basic training is unlikely to be sufficient to support the behaviour change required for the introduction of RDTs. Funding: ACT Consortium (Bill & Melinda Gates Foundation).

The wide-scale roll-out of artemisinin combination therapies (ACTs) for the treatment of malaria should be accompanied by continued surveillance of their safety. Post-marketing pharmacovigilance (PV) relies on adverse event (AE) reporting by clinicians, but as a large proportion of treatments are provided by non-clinicians in low-resource settings, the effectiveness of such PV systems is limited. To facilitate reporting, AE forms should be easily completed; however, most are challenging for lower-level health workers and non-clinicians to complete. Through participatory research, we sought to develop user-friendly AE report forms to capture information on events associated with ACTs.Following situation analysis, we undertook workshops with community medicine distributors and health workers in Jinja, Uganda, to develop a reporting form based on experiences and needs of users, and communication and visual perception principles. Participants gave feedback for revisions of subsequent versions. We then conducted 8 pretesting sessions with 77 potential end users to test and refine passive and active versions of the form.The development process resulted in a form that included a pictorial storyboard to communicate the rationale for the information needed and facilitate rapport between the reporter and the respondent, and a diary format to record the drug administration and event details in chronological relation to each other. Successive rounds of pretesting used qualitative and quantitative feedback to refine the form, with the final round showing over 80% of the form completed correctly by potential end users.We developed novel AE report forms that can be used by non-clinicians to capture pharmacovigilance data for anti-malarial drugs. The participatory approach was effective for developing forms that are intuitive for reporters, and motivating for respondents. The forms, or their key components, could be adapted for use in other low-literacy settings to improve quality and quantity of drug safety reports as new medicines are scaled-up.

Abstract Background The European DISABKIDS project aims to enhance the Health Related Quality of Life (HRQoL) of children and adolescents with chronic medical conditions and their families. We describe the development of the seven cross-nationally tested condition-specific modules of the European DISABKIDS HRQoL instrument in a population of children and adolescents. The condition-specific modules are intended for use in conjunction with the DISABKIDS chronic generic module. Methods Focus groups were used to construct the pilot version of the DISABKIDS condition-specific HRQoL modules for asthma, juvenile idiopathic arthritis, atopic dermatitis, cerebral palsy, cystic fibrosis, diabetes and epilepsy. Analyses were conducted on pilot test data in order to construct field test versions of the modules. A series of factor analyses were run, first, to determine potential structures for each condition-specific module, and, secondly, to select a reduced number of items from the pilot test to be included in the field test. Post-field test analyses were conducted to retest the domain structure for the final DISABKIDS condition-specific modules. Results The DISABKIDS condition-specific modules were tested in a pilot study of 360 respondents, and subsequently in a field test of 1152 respondents in 7 European countries. The final condition-specific modules consist of an 'Impact' domain and an additional domain (e.g. worry, stigma, treatment) with between 10 to 12 items in total. The Cronbach's alpha of the final domains was found to vary from 0.71 to 0.90. Conclusion The condition-specific modules of the DISABKIDS instrument were developed through a step-by-step process including cognitive interview, clinical expertise, factor analysis, correlations and internal consistency. A cross-national pilot and field test were necessary to collect these data. In general, the internal consistency of the domains was satisfactory to high. In future, the DISABKIDS instrument may serve as a useful tool with which to assess HRQoL in children and adolescents with a chronic condition. The condition-specific modules can be used in conjunction with the DISABKIDS chronic generic module.