Clinical disorders affecting mesopic vision

Vision in the mesopic range is affected by a number of inherited and acquired clinical disorders. We review these conditions and summarize the historical background, describing the clinical characteristics alongside the genetic basis and molecular biological mechanisms giving rise to rod and cone dysfunction relevant to twilight vision. The current diagnostic gold standards for each disease are discussed and curative and symptomatic treatment strategies are summarized

Growth of children receiving a dehydrated potato-soy protein concentrate or corn-soy blend as part of a food aid program in Northern Senegal

Rations distributed by food aid programs are intended to improve the growth of undernourished children. In practice, food programs target individual children and provide a supplement to the family that is intended to increase the energy and nutrient intake of undernourished children. Multiple food rations are available yet few studies have compared their differential effect on the growth of children. The objective of the study was to compare growth in undernourished Senegalese children who received a newly developed dehydrated potato-soy protein concentrate blend (PSB) to those supplemented with the currently available corn-soy blend (CSB). The first child at each site was randomly assigned to receive PSB or CSB and subsequent children alternately received PSB or CSB. Eligibility for obtaining the food ration was basedon criteria determined by the USAID (P.L. 480) Title II Food Aid Program. Children received iso-caloric amounts of the two supplements each month (23,000kcals). Weight, height and mid-upper arm circumference (MUAC) were taken over a fourmonth period. Z-scores were calculated for weight-for-age (WAZ), weight-for-height (WHZ) and for length/height-for-age measures (HAZ).The study was conducted at 7 clinics which served as food distribution sites in northern Senegal. The study enrolled348 children 18-56 months old with a weight-for-age z-score below the �yellow� zone of the locally available growth chart (equivalent to WAZ < -1.0). WAZ and HAZ significantly increased over time but there was no difference between the two ration groups. In a subset of 280 children (145 PSB, 135 CSB) who attended all four appointments and received the full complement of ration, there was significant and equivalent increase for both groups in WAZ and WHZ. These findings indicate thatchildren participating in the food aid program significantly improved their growth over a four-month period. Using the new PSB as a ration had the same impact on growth as the standard CSB and required less fuel to prepare

School-based interventions modestly increase physical activity and cardiorespiratory fitness but are least effective for youth who need them most: an individual participant pooled analysis of 20 controlled trials

OBJECTIVES To determine if subpopulations of students benefit equally from school-based physical activity interventions in terms of cardiorespiratory fitness and physical activity. To examine if physical activity intensity mediates improvements in cardiorespiratory fitness. DESIGN Pooled analysis of individual participant data from controlled trials that assessed the impact of school-based physical activity interventions on cardiorespiratory fitness and device-measured physical activity. PARTICIPANTS Data for 6621 children and adolescents aged 4-18 years from 20 trials were included. MAIN OUTCOME MEASURES Peak oxygen consumption (VO$_{2Peak}$ mL/kg/min) and minutes of moderate and vigorous physical activity. RESULTS Interventions modestly improved students' cardiorespiratory fitness by 0.47 mL/kg/min (95% CI 0.33 to 0.61), but the effects were not distributed equally across subpopulations. Girls and older students benefited less than boys and younger students, respectively. Students with lower levels of initial fitness, and those with higher levels of baseline physical activity benefitted more than those who were initially fitter and less active, respectively. Interventions had a modest positive effect on physical activity with approximately one additional minute per day of both moderate and vigorous physical activity. Changes in vigorous, but not moderate intensity, physical activity explained a small amount (~5%) of the intervention effect on cardiorespiratory fitness. CONCLUSIONS Future interventions should include targeted strategies to address the needs of girls and older students. Interventions may also be improved by promoting more vigorous intensity physical activity. Interventions could mitigate declining youth cardiorespiratory fitness, increase physical activity and promote cardiovascular health if they can be delivered equitably and their effects sustained at the population level

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings: In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice

Amyloids are a class of protein with unique self-aggregation properties, and their aberrant accumulation can lead to cellular dysfunctions associated with neurodegenerative diseases. While genetic and environmental factors can influence amyloid formation, molecular triggers and/or facilitators are not well defined. Growing evidence suggests that non-identical amyloid proteins may accelerate reciprocal amyloid aggregation in a prion-like fashion. While humans encode ~30 amyloidogenic proteins, the gut microbiome also produces functional amyloids. For example, curli are cell surface amyloid proteins abundantly expressed by certain gut bacteria. In mice overexpressing the human amyloid α-synuclein (αSyn), we reveal that colonization with curli-producing Escherichia coli promotes αSyn pathology in the gut and the brain. Curli expression is required for E. coli to exacerbate αSyn-induced behavioral deficits, including intestinal and motor impairments. Purified curli subunits accelerate αSyn aggregation in biochemical assays, while oral treatment of mice with a gut-restricted amyloid inhibitor prevents curli-mediated acceleration of pathology and behavioral abnormalities. We propose that exposure to microbial amyloids in the gastrointestinal tract can accelerate αSyn aggregation and disease in the gut and the brain

Examining the overlap in lymphatic filariasis prevalence and malaria insecticide-treated net access-use in endemic Africa

Eradication and elimination strategies for lymphatic filariasis (LF) primarily rely on multiple rounds of annual mass drug administration (MDA), but also may benefit from vector control interventions conducted by malaria vector control programs. We aim to examine the overlap in LF prevalence and malaria vector control to identify potential gaps in program coverage. We used previously published geospatial estimates of LF prevalence from the Institute for Health Metrics and Evaluation, as well as publicly available insecticide-treated net (ITN) access (proportion of the total population with access to ITNs) and use (proportion of the total population that slept under an ITN) estimates among the total population and malaria Plasmodium falciparum parasite rates (PfPR) from the Malaria Atlas Project (MAP). We aggregated the 5x5 km2 estimates of LF prevalence estimates and ITN estimates to the implementation unit (IU) level using fractional aggregation, for 33 LF and malaria-endemic locations in Africa, and then overlaid the IU-level aggregates. In this analysis, ITN coverage was low in areas where LF is common, with 51.7% (90/174) of high-LF-prevalence-IUs having both access and use estimates under 40%. Most (67.8%; 61/90) of these low-ITN-coverage, high-LF-prevalence locations were also categorized as high- or highest-prevalence for malaria by PfPR, suggesting suboptimal ITN coverage even in some malaria-co-endemic locations. Even in IUs with high LF prevalence but low malaria prevalence, almost half (48.2%; 39/81) had high levels of access to ITNs. When accounting for population, however, gaps in ITN access in such areas were evident: more individuals lived in high-LF, low-malaria IUs with low ITN access (8.68 million) than lived in high-LF, low-malaria IUs with high ITN access (6.76 million). These results suggest that relying on current malaria vector control programs alone may not provide sufficient ITN coverage for high LF prevalence areas. Opportunities for coordinated vector control programs in places where LF and malaria prevalence are high but ITN coverage is low – or additional ITN distribution in high-LF, low-malaria locations - should be explored to help achieve elimination goals

Global chemical effects of the microbiome include new bile-acid conjugations

A mosaic of cross-phylum chemical interactions occurs between all metazoans and their microbiomes. A number of molecular families that are known to be produced by the microbiome have a marked effect on the balance between health and disease. Considering the diversity of the human microbiome (which numbers over 40,000 operational taxonomic units), the effect of the microbiome on the chemistry of an entire animal remains underexplored. Here we use mass spectrometry informatics and data visualization approaches to provide an assessment of the effects of the microbiome on the chemistry of an entire mammal by comparing metabolomics data from germ-free and specific-pathogen-free mice. We found that the microbiota affects the chemistry of all organs. This included the amino acid conjugations of host bile acids that were used to produce phenylalanocholic acid, tyrosocholic acid and leucocholic acid, which have not previously been characterized despite extensive research on bile-acid chemistry. These bile-acid conjugates were also found in humans, and were enriched in patients with inflammatory bowel disease or cystic fibrosis. These compounds agonized the farnesoid X receptor in vitro, and mice gavaged with the compounds showed reduced expression of bile-acid synthesis genes in vivo. Further studies are required to confirm whether these compounds have a physiological role in the host, and whether they contribute to gut diseases that are associated with microbiome dysbiosis