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The COVID-19 pandemic has led to far-reaching disruptions to health systems, including preventative and curative services for malaria. The aim of this study was to estimate the magnitude of disruptions in malaria case management in sub-Saharan Africa and their impact on malaria burden during the COVID-19 pandemic. We used survey data collected by the World Health Organization, in which individual country stakeholders reported on the extent of disruptions to malaria diagnosis and treatment. The relative disruption values were then applied to estimates of antimalarial treatment rates and used as inputs to an established spatiotemporal Bayesian geostatistical framework to generate annual malaria burden estimates with case management disruptions. This enabled an estimation of the additional malaria burden attributable to pandemic-related impacts on treatment rates in 2020 and 2021. Our analysis found that disruptions in access to antimalarial treatment in sub-Saharan Africa likely resulted in approximately 5.9 (4.4-7.2 95% CI) million more malaria cases and 76 (20-132) thousand additional deaths in the 2020-2021 period within the study region, equivalent to approximately 1.2% (0.3-2.1 95% CI) greater clinical incidence of malaria and 8.1% (2.1-14.1 95% CI) greater malaria mortality than expected in the absence of the disruptions to malaria case management. The available evidence suggests that access to antimalarials was disrupted to a significant degree and should be considered an area of focus to avoid further escalations in malaria morbidity and mortality. The results from this analysis were used to estimate cases and deaths in the World Malaria Report 2022 during the pandemic years.

The purpose of this study is to investigate healthcare access disparity that will cause delayed and unmet healthcare needs for the elderly, and to examine health inequality and healthcare cost burden for the elderly. To produce clear policy applications, this study adapts a modified PRECEDE-PROCEED model for framing theoretical and experimental approaches. Data were collected from a large collection of the Community Tracking Study Household Survey 2003–2004 of the USA. Reliability and construct validity are examined for internal consistency and estimation of disparity and inequality are analyzed by using probit/ols regressions. The results show that predisposing factors (e.g., attitude, beliefs, and perception by socio-demographic differences) are negatively associated with delayed healthcare. A 10% increase in enabling factors (e.g., availability of health insurance coverage, and usual sources of healthcare providers) are significantly associated with a 1% increase in healthcare financing factors. In addition, information through a socio-economic network and support system has a 5% impact on an access disparity. Income, health status, and health inequality are exogenously determined. Designing and implementing easy healthcare accessibility (healthcare system) and healthcare financing methods, and developing a socio-economic support network (including public health information) are essential in reducing delayed healthcare and health inequality.

Plasmodium vivax exacts a significant toll on health worldwide, yet few efforts to date have quantified the extent and temporal trends of its global distribution. Given the challenges associated with the proper diagnosis and treatment of P vivax, national malaria programmes—particularly those pursuing malaria elimination strategies—require up to date assessments of P vivax endemicity and disease impact. This study presents the first global maps of P vivax clinical burden from 2000 to 2017. In this spatial and temporal modelling study, we adjusted routine malariometric surveillance data for known biases and used socioeconomic indicators to generate time series of the clinical burden of P vivax. These data informed Bayesian geospatial models, which produced fine-scale predictions of P vivax clinical incidence and infection prevalence over time. Within sub-Saharan Africa, where routine surveillance for P vivax is not standard practice, we combined predicted surfaces of Plasmodium falciparum with country-specific ratios of P vivax to P falciparum. These results were combined with surveillance-based outputs outside of Africa to generate global maps. We present the first high-resolution maps of P vivax burden. These results are combined with those for P falciparum (published separately) to form the malaria estimates for the Global Burden of Disease 2017 study. The burden of P vivax malaria decreased by 41·6%, from 24·5 million cases (95% uncertainty interval 22·5–27·0) in 2000 to 14·3 million cases (13·7–15·0) in 2017. The Americas had a reduction of 56·8% (47·6–67·0) in total cases since 2000, while South-East Asia recorded declines of 50·5% (50·3–50·6) and the Western Pacific regions recorded declines of 51·3% (48·0–55·4). Europe achieved zero P vivax cases during the study period. Nonetheless, rates of decline have stalled in the past five years for many countries, with particular increases noted in regions affected by political and economic instability. Our study highlights important spatial and temporal patterns in the clinical burden and prevalence of P vivax. Amid substantial progress worldwide, plateauing gains and areas of increased burden signal the potential for challenges that are greater than expected on the road to malaria elimination. These results support global monitoring systems and can inform the optimisation of diagnosis and treatment where P vivax has most impact. Bill & Melinda Gates Foundation and the Wellcome Trust.

Since 2000, the scale-up of malaria control interventions has substantially reduced morbidity and mortality caused by the disease globally, fuelling bold aims for disease elimination. In tandem with increased availability of geospatially resolved data, malaria control programmes increasingly use high-resolution maps to characterise spatially heterogeneous patterns of disease risk and thus efficiently target areas of high burden. We updated and refined the Plasmodium falciparum parasite rate and clinical incidence models for sub-Saharan Africa, which rely on cross-sectional survey data for parasite rate and intervention coverage. For malaria endemic countries outside of sub-Saharan Africa, we produced estimates of parasite rate and incidence by applying an ecological downscaling approach to malaria incidence data acquired via routine surveillance. Mortality estimates were derived by linking incidence to systematically derived vital registration and verbal autopsy data. Informed by high-resolution covariate surfaces, we estimated P falciparum parasite rate, clinical incidence, and mortality at national, subnational, and 5 × 5 km pixel scales with corresponding uncertainty metrics. We present the first global, high-resolution map of P falciparum malaria mortality and the first global prevalence and incidence maps since 2010. These results are combined with those for Plasmodium vivax (published separately) to form the malaria estimates for the Global Burden of Disease 2017 study. The P falciparum estimates span the period 2000–17, and illustrate the rapid decline in burden between 2005 and 2017, with incidence declining by 27·9% and mortality declining by 42·5%. Despite a growing population in endemic regions, P falciparum cases declined between 2005 and 2017, from 232·3 million (95% uncertainty interval 198·8–277·7) to 193·9 million (156·6–240·2) and deaths declined from 925 800 (596 900–1 341 100) to 618 700 (368 600–952 200). Despite the declines in burden, 90·1% of people within sub-Saharan Africa continue to reside in endemic areas, and this region accounted for 79·4% of cases and 87·6% of deaths in 2017. High-resolution maps of P falciparum provide a contemporary resource for informing global policy and malaria control planning, programme implementation, and monitoring initiatives. Amid progress in reducing global malaria burden, areas where incidence trends have plateaued or increased in the past 5 years underscore the fragility of hard-won gains against malaria. Efforts towards elimination should be strengthened in such areas, and those where burden remained high throughout the study period. Bill & Melinda Gates Foundation.

The mammalian cortex is a laminar structure containing many areas and cell types that are densely interconnected in complex ways, and for which generalizable principles of organization remain mostly unknown. Here we describe a major expansion of the Allen Mouse Brain Connectivity Atlas resource 1 , involving around a thousand new tracer experiments in the cortex and its main satellite structure, the thalamus. We used Cre driver lines (mice expressing Cre recombinase) to comprehensively and selectively label brain-wide connections by layer and class of projection neuron. Through observations of axon termination patterns, we have derived a set of generalized anatomical rules to describe corticocortical, thalamocortical and corticothalamic projections. We have built a model to assign connection patterns between areas as either feedforward or feedback, and generated testable predictions of hierarchical positions for individual cortical and thalamic areas and for cortical network modules. Our results show that cell-class-specific connections are organized in a shallow hierarchy within the mouse corticothalamic network. Using mouse lines in which subsets of neurons are genetically labelled, the authors provide generalized anatomical rules for connections within and between the cortex and thalamus.

Methods for profiling DNA methylation differ in the physical principles used to detect modified cytosines. Harris et al . compare the performances of four sequencing-based technologies for genome-wide analysis of DNA methylation and combine two methods to enable detection of allelic differences in epigenetic marks. Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression.

In recent years, many countries have adopted universal health coverage (UHC) as a national aspiration. In response to increasing demand for a systematic assessment of global experiences with UHC, the Government of Japan and the World Bank collaborated on a 2-year multicountry research programme to analyse the processes of moving towards UHC. The programme included 11 countries (Bangladesh, Brazil, Ethiopia, France, Ghana, Indonesia, Japan, Peru, Thailand, Turkey, and Vietnam), representing diverse geographical, economic, and historical contexts. The study identified common challenges and opportunities and useful insights for how to move towards UHC. The study showed that UHC is a complex process, fraught with challenges, many possible pathways, and various pitfalls—but is also feasible and achievable. Movement towards UHC is a long-term policy engagement that needs both technical knowledge and political know-how. Technical solutions need to be accompanied by pragmatic and innovative strategies that address the national political economy context.

Despite calls for improved responses to emerging infectious diseases in wildlife, management is seldom considered until a disease has been detected in affected populations. Reactive approaches may limit the potential for control and increase total response costs. An alternative, proactive management framework can identify immediate actions that reduce future impacts even before a disease is detected, and plan subsequent actions that are conditional on disease emergence. We identify four main obstacles to developing proactive management strategies for the newly discovered salamander pathogen Batrachochytrium salamandrivorans (Bsal). Given that uncertainty is a hallmark of wildlife disease management and that associated decisions are often complicated by multiple competing objectives, we advocate using decision analysis to create and evaluate trade-offs between proactive (pre-emergence) and reactive (post-emergence) management options. Policy makers and natural resource agency personnel can apply principles from decision analysis to improve strategies for countering emerging infectious diseases.

DNA methylation plays an important role in the regulation of transcription. Genetic control of DNA methylation is a potential candidate for explaining the many identified SNP associations with disease that are not found in coding regions. We replicated 52,916 cis and 2,025 trans DNA methylation quantitative trait loci (mQTL) using methylation from whole blood measured on Illumina HumanMethylation450 arrays in the Brisbane Systems Genetics Study (n = 614 from 177 families) and the Lothian Birth Cohorts of 1921 and 1936 (combined n = 1366). The trans mQTL SNPs were found to be over-represented in 1 Mbp subtelomeric regions, and on chromosomes 16 and 19. There was a significant increase in trans mQTL DNA methylation sites in upstream and 5′ UTR regions. The genetic heritability of a number of complex traits and diseases was partitioned into components due to mQTL and the remainder of the genome. Significant enrichment was observed for height (p = 2.1 × 10 −10 ), ulcerative colitis (p = 2 × 10 −5 ), Crohn’s disease (p = 6 × 10 −8 ) and coronary artery disease (p = 5.5 × 10 −6 ) when compared to a random sample of SNPs with matched minor allele frequency, although this enrichment is explained by the genomic location of the mQTL SNPs.

Since 2001, the United States has been engaged in the longest and most expensive overseas conflict in its history. Sleep disorders, especially insomnia and obstructive sleep apnea (OSA), are common in service members and appear related to deployment and combat exposure, but this has not been systematically examined. Therefore, the incidence of clinically diagnosed insomnia and OSA from 1997 to 2011 in the entire population of US Army soldiers was determined and associations of these disorders with deployment and combat exposure examined. This observational retrospective cohort study linked medical, demographic, deployment, and combat casualty data from all active duty US Army soldiers serving from 1997 to 2011 (n = 1 357 150). The mediating effects of multiple known comorbid conditions were considered. From 2003 to 2011, there were extraordinary increases in incidence of insomnia (652%) and OSA (600%). Factors increasing insomnia risk were deployment (risk ratio [RR] [deployed/not deployed] = 2.06; 95% confidence interval [CI], 2.04–2.08) and combat exposure (RR [exposed/not exposed] = 1.20; 95% CI, 1.19–1.22). Risk of OSA was increased by deployment (RR [deployed/not deployed] = 2.14; 95% CI, 2.11–2.17), but not combat exposure (RR [exposed/not exposed] = 1.00; 95% CI, 0.98–1.02). These relationships remained after accounting for other factors in multivariable analyses. A number of comorbid medical conditions such as posttraumatic stress disorder and traumatic brain injury mediated a portion of the association between the sleep disorders and deployment. It is essential to determine underlying mechanisms responsible for these very large increases in insomnia and OSA and introduce effective preventive measures.