Community drug distributors for mass drug administration in neglected tropical disease programmes: systematic review and analysis of policy documents

Background Mass drug administration (MDA) programmes for neglected tropical diseases (NTDs) depend on voluntary community drug distributors (CDDs) to deliver drugs, and these volunteer schemes need regular training and supervision. NTD policy now includes integration of multiple disease programmes, but we are unsure if there is clarity in what is currently expected of CDDs and how they are managed. We therefore analysed World Health Organization (WHO) policy, strategy and implementation guidance, and select national NTD programme implementation plans. Methods Included are a) WHO global and WHO-Regional Office for Africa guidelines, strategies, operational manuals and meeting reports published between January 2007 to February 2018 that included policy and plans for CDDs; and b) national NTD programme master plans for Cameroon, Ghana, Liberia and Nigeria. For both review components, we examined the CDD responsibilities through a framework developed iteratively against the documents and prepared a narrative synthesis. Results Twenty WHO policy documents met the inclusion criteria. In the twelve global and eight regional documents, the CDD role was not explicitly or comprehensively defined. Three documents mentioned CDDs will distribute drugs; some mentioned health promotion, data handling and engagement in clinical care. Four WHO documents noted a need for CDD training or management, eight detailed some aspect of this, and one regional document provided a comprehensive overview. In the national plans, additional responsibilities included case management in two countries and transmission control in two countries. Every plan included training and supervision, but this was not always explicit, and details of the purpose and frequency varied. In all national plans, CDD motivation was identified as a challenge but not comprehensively addressed, although one document mentioned provision of bicycles. Conclusions WHO and national policies and plans assume CDDs will implement NTD programmes. However, there is almost no clear delineation of responsibilities, nor is there up-to-date practical guidance to guide managers. This ambiguity, in relation to the lack of explicit policies or programmatic guidance, probably impairs the effectiveness of NTD programmes

WHO guidance for refugees in camps: systematic review

Objectives The circumstances of people living in refugee camps means that they have distinct medical care requirements. Our objective is to describe clinical guidance in published WHO guidelines that refer to people living in refugee camps; and how evidence and context are used and reported in making recommendations. Design Systematic review and analysis of WHO guidelines approved by the organisation’s quality oversight body and published between 2007 and 2018. We sought for key terms related to camps and humanitarian settings, and identified text that included guidance. We compared this to Mèdecins Sans Frontièrs (MSF) guidelines. Results No WHO guideline published in the last 10 years focused exclusively on clinical guidance for healthcare in camp settings. Seven guidelines contained guidance about camps; three made recommendations for camps—but only two used formal evidence summaries. We did not find any structured consideration of the situation in camps used in the decision-making process. We examined seven WHO guidelines and six chapters within guidelines that concerned humanitarian settings: none of these documents contained recommendations based on formal evidence summaries for camp settings. One of the eight MSF guidelines was devoted to clinical care in refugees and the authors had clearly linked the health problems and recommendations to the setting, but this guideline is now >20 years old. Conclusions There is an absence of up-to-date, evidence-based medical treatment guidelines from WHO and MSF that comprehensively address the clinical needs for people living in camps; and there is no common framework to help guideline groups formulate recommendations in these settings. WHO may wish to consider context of special populations more formally in the evidence to decision-making approach for clinical guidelines relevant to primary care

Analytic Tools for Post-traumatic Epileptogenesis Biomarker Search in Multimodal Dataset of an Animal Model and Human Patients

Epilepsy is among the most common serious disabling disorders of the brain, and the global burden of epilepsy exerts a tremendous cost to society. Most people with epilepsy have acquired forms of the disorder, and the development of antiepileptogenic interventions could potentially prevent or cure epilepsy in many of them. However, the discovery of potential antiepileptogenic treatments and clinical validation would require a means to identify populations of patients at very high risk for epilepsy after a potential epileptogenic insult, to know when to treat and to document prevention or cure. A fundamental challenge in discovering biomarkers of epileptogenesis is that this process is likely multifactorial and crosses multiple modalities. Investigators must have access to a large number of high quality, well-curated data points and study subjects for biomarker signals to be detectable above the noise inherent in complex phenomena, such as epileptogenesis, traumatic brain injury (TBI), and conditions of data collection. Additionally, data generating and collecting sites are spread worldwide among different laboratories, clinical sites, heterogeneous data types, formats, and across multi-center preclinical trials. Before the data can even be analyzed, these data must be standardized. The Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) is a multi-center project with the overarching goal that epileptogenesis after TBI can be prevented with specific treatments. The identification of relevant biomarkers and performance of rigorous preclinical trials will permit the future design and performance of economically feasible full-scale clinical trials of antiepileptogenic therapies. We have been analyzing human data collected from UCLA and rat data collected from the University of Eastern Finland, both centers collecting data for EpiBioS4Rx, to identify biomarkers of epileptogenesis. Big data techniques and rigorous analysis are brought to longitudinal data collected from humans and an animal model of TBI, epilepsy, and their interaction. The prolonged continuous data streams of intracranial, cortical surface, and scalp EEG from humans and an animal model of epilepsy span months. By applying our innovative mathematical tools via supervised and unsupervised learning methods, we are able to subject a robust dataset to recently pioneered data analysis tools and visualize multivariable interactions with novel graphical methods

A Comparison of Neuroelectrophysiology Databases

As data sharing has become more prevalent, three pillars - archives, standards, and analysis tools - have emerged as critical components in facilitating effective data sharing and collaboration. This paper compares four freely available intracranial neuroelectrophysiology data repositories: Data Archive for the BRAIN Initiative (DABI), Distributed Archives for Neurophysiology Data Integration (DANDI), OpenNeuro, and Brain-CODE. These archives provide researchers with tools to store, share, and reanalyze neurophysiology data though the means of accomplishing these objectives differ. The Brain Imaging Data Structure (BIDS) and Neurodata Without Borders (NWB) are utilized by these archives to make data more accessible to researchers by implementing a common standard. While many tools are available to reanalyze data on and off the archives' platforms, this article features Reproducible Analysis and Visualization of Intracranial EEG (RAVE) toolkit, developed specifically for the analysis of intracranial signal data and integrated with the discussed standards and archives. Neuroelectrophysiology data archives improve how researchers can aggregate, analyze, distribute, and parse these data, which can lead to more significant findings in neuroscience research.Comment: 25 pages, 8 figures, 1 tabl

Genetic variability and ontogeny predict microbiome structure in a disease-challenged montane amphibian

Amphibian populations worldwide are at risk of extinction from infectious diseases, including chytridiomycosis caused by the fungal pathogen Batrachochytrium dendrobatidis (Bd). Amphibian cutaneous microbiomes interact with Bd and can confer protective benefits to the host. The composition of the microbiome itself is influenced by many environment- and host-related factors. However, little is known about the interacting effects of host population structure, genetic variation and developmental stage on microbiome composition and Bd prevalence across multiple sites. Here we explore these questions in Amietia hymenopus, a disease-affected frog in southern Africa. We use microsatellite genotyping and 16S amplicon sequencing to show that the microbiome associated with tadpole mouthparts is structured spatially, and is influenced by host genotype and developmental stage. We observed strong genetic structure in host populations based on rivers and geographic distances, but this did not correspond to spatial patterns in microbiome composition. These results indicate that demographic and host genetic factors affect microbiome composition within sites, but different factors are responsible for host population structure and microbiome structure at the between-site level. Our results help to elucidate complex within- and among- population drivers of microbiome structure in amphibian populations. That there is a genetic basis to microbiome composition in amphibians could help to inform amphibian conservation efforts against infectious diseases

Current and Historical Drivers of Landscape Genetic Structure Differ in Core and Peripheral Salamander Populations

With predicted decreases in genetic diversity and greater genetic differentiation at range peripheries relative to their cores, it can be difficult to distinguish between the roles of current disturbance versus historic processes in shaping contemporary genetic patterns. To address this problem, we test for differences in historic demography and landscape genetic structure of coastal giant salamanders (Dicamptodon tenebrosus) in two core regions (Washington State, United States) versus the species' northern peripheral region (British Columbia, Canada) where the species is listed as threatened. Coalescent-based demographic simulations were consistent with a pattern of post-glacial range expansion, with both ancestral and current estimates of effective population size being much larger within the core region relative to the periphery. However, contrary to predictions of recent human-induced population decline in the less genetically diverse peripheral region, there was no genetic signature of population size change. Effects of current demographic processes on genetic structure were evident using a resistance-based landscape genetics approach. Among core populations, genetic structure was best explained by length of the growing season and isolation by resistance (i.e. a ‘flat’ landscape), but at the periphery, topography (slope and elevation) had the greatest influence on genetic structure. Although reduced genetic variation at the range periphery of D. tenebrosus appears to be largely the result of biogeographical history rather than recent impacts, our analyses suggest that inherent landscape features act to alter dispersal pathways uniquely in different parts of the species' geographic range, with implications for habitat management

A novel formulation of inhaled sodium cromoglicate (PA101) in idiopathic pulmonary fibrosis and chronic cough: a randomised, double-blind, proof-of-concept, phase 2 trial

Background Cough can be a debilitating symptom of idiopathic pulmonary fibrosis (IPF) and is difficult to treat. PA101 is a novel formulation of sodium cromoglicate delivered via a high-efficiency eFlow nebuliser that achieves significantly higher drug deposition in the lung compared with the existing formulations. We aimed to test the efficacy and safety of inhaled PA101 in patients with IPF and chronic cough and, to explore the antitussive mechanism of PA101, patients with chronic idiopathic cough (CIC) were also studied. Methods This pilot, proof-of-concept study consisted of a randomised, double-blind, placebo-controlled trial in patients with IPF and chronic cough and a parallel study of similar design in patients with CIC. Participants with IPF and chronic cough recruited from seven centres in the UK and the Netherlands were randomly assigned (1:1, using a computer-generated randomisation schedule) by site staff to receive PA101 (40 mg) or matching placebo three times a day via oral inhalation for 2 weeks, followed by a 2 week washout, and then crossed over to the other arm. Study participants, investigators, study staff, and the sponsor were masked to group assignment until all participants had completed the study. The primary efficacy endpoint was change from baseline in objective daytime cough frequency (from 24 h acoustic recording, Leicester Cough Monitor). The primary efficacy analysis included all participants who received at least one dose of study drug and had at least one post-baseline efficacy measurement. Safety analysis included all those who took at least one dose of study drug. In the second cohort, participants with CIC were randomly assigned in a study across four centres with similar design and endpoints. The study was registered with ClinicalTrials.gov (NCT02412020) and the EU Clinical Trials Register (EudraCT Number 2014-004025-40) and both cohorts are closed to new participants. Findings Between Feb 13, 2015, and Feb 2, 2016, 24 participants with IPF were randomly assigned to treatment groups. 28 participants with CIC were enrolled during the same period and 27 received study treatment. In patients with IPF, PA101 reduced daytime cough frequency by 31·1% at day 14 compared with placebo; daytime cough frequency decreased from a mean 55 (SD 55) coughs per h at baseline to 39 (29) coughs per h at day 14 following treatment with PA101, versus 51 (37) coughs per h at baseline to 52 (40) cough per h following placebo treatment (ratio of least-squares [LS] means 0·67, 95% CI 0·48–0·94, p=0·0241). By contrast, no treatment benefit for PA101 was observed in the CIC cohort; mean reduction of daytime cough frequency at day 14 for PA101 adjusted for placebo was 6·2% (ratio of LS means 1·27, 0·78–2·06, p=0·31). PA101 was well tolerated in both cohorts. The incidence of adverse events was similar between PA101 and placebo treatments, most adverse events were mild in severity, and no severe adverse events or serious adverse events were reported. Interpretation This study suggests that the mechanism of cough in IPF might be disease specific. Inhaled PA101 could be a treatment option for chronic cough in patients with IPF and warrants further investigation

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

An immunodominant NP105-113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease.

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: Chinese Academy of Medical Sciences (CAMS); doi: https://doi.org/10.13039/501100005150Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design