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Access to healthcare is a requirement for human well-being that is constrained, in part, by the allocation of healthcare resources relative to the geographically dispersed human population1-3. Quantifying access to care globally is challenging due to the absence of a comprehensive database of healthcare facilities. We harness major data collection efforts underway by OpenStreetMap, Google Maps and academic researchers to compile the most complete collection of facility locations to date. Leveraging the geographically variable strengths of our facility datasets, we use an established methodology4 to characterize travel time to healthcare facilities in unprecedented detail. We produce maps of travel time with and without access to motorized transport, thus characterizing travel time to healthcare for populations distributed across the wealth spectrum. We find that just 8.9% of the global population (646 million people) cannot reach healthcare within one hour if they have access to motorized transport, and that 43.3% (3.16 billion people) cannot reach a healthcare facility by foot within one hour. Our maps highlight an additional vulnerability faced by poorer individuals in remote areas and can help to estimate whether individuals will seek healthcare when it is needed, as well as providing an evidence base for efficiently distributing limited healthcare and transportation resources to underserved populations both now and in the future.

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[This corrects the article on p. 5 in vol. 11, PMID: 31695854.].

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Laparoscopy is widely utilised to diagnose and treat acute and chronic, gynaecological and general surgical conditions. It has only been in recent years that laparoscopy has become an acceptable surgical alternative to open surgery in pregnancy. To date there is little clinical guidance pertaining to laparoscopic surgery in pregnancy. This is why the BSGE commissioned this guideline. MEDLINE, EMBASE, CINAHL and the Cochrane library were searched up to February 2017 and evidence was collated and graded following the NICE-approved process. The conditions included in this guideline are laparoscopic management of acute appendicitis, acute gall bladder disease and symptomatic benign adnexal tumours in pregnancy. The intended audience for this guideline is obstetricians and gynaecologists in secondary and tertiary care, general surgeons and anaesthetists. However, only laparoscopists who have adequate laparoscopic skills and who perform complex laparoscopic surgery regularly should undertake laparoscopy in pregnant women, since much of the evidence stems from specialised centres.

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Convergent-margin basins (CMBs) are commonly associated with active arcs, and hence are rich in detrital zircon (DZ) whose ages closely reflect the timing of deposition. Consequently, maximum depositional ages (MDA) from DZ geochronology can be employed to resolve the stratigraphy and evolution of CMBs. Herein, we use DZ to revise the internal architecture of the lower Nanaimo Group, which partially comprises the fill of the (forearc) Georgia (or Nanaimo) Basin. Maximum depositional ages and multi-dimensional scaling of DZ age distributions are employed to determine chronologic equivalency of strata and assess sediment provenance variability within the pre-existing lithostratigraphic framework. The results are compared to a recently developed sequence stratigraphic framework for the lower Nanaimo Group. The basal lithostratigraphic unit of the Nanaimo Group, the Comox Formation (Fm), comprises strata that are neither time correlative nor genetically related. The three lithostratigraphic units directly overlying the Comox Fm (Haslam, Extension, and Protection formations) comprise strata with similar genetic affinities and MDAs that indicate deposition of these units was not always sequential and locally was contemporaneous. Through this work, we provide an example of how MDAs from DZ geochronology in CMBs can resolve basin-scale stratigraphic relations, and identify chronological changes in sediment provenance.

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The economic and man-made resources that sustain human wellbeing are not distributed evenly across the world, but are instead heavily concentrated in cities. Poor access to opportunities and services offered by urban centres (a function of distance, transport infrastructure, and the spatial distribution of cities) is a major barrier to improved livelihoods and overall development. Advancing accessibility worldwide underpins the equity agenda of 'leaving no one behind' established by the Sustainable Development Goals of the United Nations. This has renewed international efforts to accurately measure accessibility and generate a metric that can inform the design and implementation of development policies. The only previous attempt to reliably map accessibility worldwide, which was published nearly a decade ago, predated the baseline for the Sustainable Development Goals and excluded the recent expansion in infrastructure networks, particularly in lower-resource settings. In parallel, new data sources provided by Open Street Map and Google now capture transportation networks with unprecedented detail and precision. Here we develop and validate a map that quantifies travel time to cities for 2015 at a spatial resolution of approximately one by one kilometre by integrating ten global-scale surfaces that characterize factors affecting human movement rates and 13,840 high-density urban centres within an established geospatial-modelling framework. Our results highlight disparities in accessibility relative to wealth as 50.9% of individuals living in low-income settings (concentrated in sub-Saharan Africa) reside within an hour of a city compared to 90.7% of individuals in high-income settings. By further triangulating this map against socioeconomic datasets, we demonstrate how access to urban centres stratifies the economic, educational, and health status of humanity.

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BACKGROUND: Prenatal exposure to traffic pollution has been associated with faster infant weight gain, but implications for cardiometabolic health in later childhood are unknown. METHODS: Among 1418 children in Project Viva, a Boston-area pre-birth cohort, we assessed anthropometric and biochemical parameters of cardiometabolic health in early (median age 3.3 years) and mid- (median age 7.7 years) childhood. We used spatiotemporal models to estimate prenatal and early life residential PM2.5 and black carbon exposure as well as traffic density and roadway proximity. We performed linear regression analyses adjusted for sociodemographics. RESULTS: Children whose mothers lived close to a major roadway at the time of delivery had higher markers of adverse cardiometabolic risk in early and mid-childhood. For example, total fat mass was 2.1 kg (95%CI: 0.8, 3.5) higher in mid-childhood for children of mothers who lived <50 m vs. ≥200 m from a major roadway. Black carbon exposure and traffic density were generally not associated with cardiometabolic parameters, and PM2.5 exposure during the year prior was paradoxically associated with improved cardiometabolic profile. CONCLUSIONS: Infants whose mothers lived close to a major roadway at the time of delivery may be at later risk for adverse cardiometabolic health.

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An iterative alternate projection-based algorithm is developed to design structured surface reflectors to operate as beam splitters at GHz and THz frequencies. To validate the method, a surface profile is determined to achieve a reflector at 610 GHz that generates four equal-intensity beams towards desired directions of ±12.6° with respect to the specular reflection axis. A prototype is fabricated and the beam splitter behavior is experimentally demonstrated. Measurements confirm a good agreement (within 1%) with computer simulations using Feko, validating the method. The beam splitter at 610 GHz has a measured efficiency of 78% under oblique incidence illumination that ensures a similar intensity between the four reflected beams (variation of about 1%).

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AIMS: To evaluate a standard aerosolization method for uniformly depositing threat-representative spores onto surfaces. METHODS AND RESULTS: Lyophilized Bacillus anthracis ΔSterne spores, coated in silica, were aerosolized into a containment chamber and deposited onto nine surface types by two independent laboratories. Laboratory A produced a mean loading concentration of 1·78 × 10(5) CFU cm(-2) ; coefficient of variation (CV) was <40% for 96% of samples. Laboratory B produced a mean loading concentration of 7·82 × 10(6) CFU cm(-2) ; 68% of samples demonstrated CV <40%. CONCLUSIONS: This method has been shown to meet the goal of loading threat-representative spores onto surfaces with low variability at concentrations relevant to the Department of Defense. SIGNIFICANCE AND IMPACT OF THE STUDY: As demonstrated in 2001, a biological attack using anthrax disseminated as a dry powder is a credible threat. This method will provide a means to load spores onto surfaces that mimic a 'real-world' scenario of an aerosolized anthrax attack. The method has utility for evaluating sporicidal technologies and for nondecontamination studies, for example fate and transport or reaerosolization.

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Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a costimulatory molecule that negatively regulates T-cell activation. Originally identified in murine CD8(+) T cells, it has been found to be rapidly induced on human T cells. Furthermore, CTLA-4 is expressed on regulatory T cells. Clinically, targeting CTLA-4 has clinical utility in the treatment of melanoma. Whether the expression of CTLA-4 is differentially regulated in CD8(+) vs CD4(+) human T cells is unclear. Here, we analyzed CTLA-4 in normal human CD4(+) and CD8(+) T-cell subsets and show for the first time that CTLA-4 is expressed significantly higher in the CD4(+) T cells than in CD8(+) T cells. CTLA-4 is higher at the protein and the transcriptional levels in CD4(+) T cells. This increase is due to the activation of the CTLA-4 promoter, which undergoes acetylation at the proximal promoter. Furthermore, we show that blocking CTLA-4 on CD4(+) T cells permits greater proliferation in CD4(+) vs CD8(+) cells. These findings demonstrate a differential regulation of CTLA-4 on CD4(+) and CD8(+) T-cell subsets, which is likely important to the clinical efficacy for anti-CTLA-4 therapies. The findings hint to strategies to modulate CTLA-4 expression by targeting epigenetic transcription to alter the immune response.

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BACKGROUND: Living in a damp or mouldy home reportedly damages children's respiratory health, yet mould appears not to be a prominent risk factor in the public's perception. Analyses of data on over 58,000 children from the Pollution and the Young (PATY) study are presented. In this collaboration, researchers from 12 cross-sectional studies pooled their data to assess the effects of air quality on a spectrum of children's respiratory disorders. METHOD: Original studies were conducted in Russia, North America and 10 countries in Eastern and Western Europe. Pooled analyses were restricted to children aged 6-12 years. Associations between visible mould reported in the household and a spectrum of eight respiratory and allergic symptoms were estimated within each study. Logistic regressions were used, controlling for individual risk factors and for study area. Heterogeneity between study-specific results and mean effects (allowing for heterogeneity) were estimated using meta-analysis. RESULTS: Visible mould was reported by 13.9% of respondents in Russia, increasing to 39.1% in North America. Positive associations between exposure to mould and children's respiratory health were seen with considerable consistency across studies and across outcomes. Confounder-adjusted combined ORs ranged from 1.30 (95% CI 1.22 to 1.39) for "nocturnal cough" to 1.50 (1.31 to 1.73) for "morning cough". Evidence of stronger effects in more crowded households was statistically significant for only asthma and sensitivity to inhaled allergens. No consistent interactions between mould and age, sex or parental smoking were found. CONCLUSION: Indoor mould exposure was consistently associated with adverse respiratory health outcomes in children living in these diverse countries.

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AIMS: Investigate the effect of detergent treatment on susceptibility of attached Escherichia coli and Listeria monocytogenes to subsequent disinfectant treatment. METHODS AND RESULTS: Plate counts show that E. coli attached to stainless steel surfaces became significantly more susceptible to benzalkonium chloride (BAC) after treatment with sodium alkyl sulfate (SAS) and fatty alcohol ethoxylate (FAE). No change in susceptibility was observed with Sodium dodecyl sulfate (SDS). L. monocytogenes became significantly less susceptible to BAC after treatment with SAS and SDS yet no change in susceptibility was observed with FAE. Flow cytometry using the fluoresceine propidium iodide revealed significant increases in cell membrane permeability of both organisms by SAS and FAE, although the effect was much greater in E. coli. No change was observed with SDS. Hydrophobic interaction chromatography showed that both organisms became less hydrophobic following treatment with SAS and SDS but FAE had no effect. CONCLUSIONS: In E. coli, detergents that increase susceptibility to BAC increase membrane permeability. In L. monocytogenes, detergents that reduce susceptibility to BAC lower cell surface hydrophobicity. SIGNIFICANCE AND IMPACT OF THE STUDY: Detergents can influence the sensitivity of pathogenic food borne micro-organisms to BAC.

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AIMS: To determine the effectiveness of premilking teat-cleaning regimes in reducing the teat microbial load and effect on milk quality. METHODS AND RESULTS: The effectiveness of several premilking teat-cleaning regimes in reducing teat microbial load was assessed using 40 cows on each of the four commercial UK dairy farms with herringbone parlours during two sampling periods. In the first experiment, all the treatments reduced teat total viable count (TVC), but there was no significant difference between the hypochlorite wash and dry wipe, iodine dip and dry and alcohol-medicated wipe or dry wipe alone. In the second experiment, the chlorine wash and dry wipe was significantly more effective in reducing teat TVC than a water wash and dry, chlorine dip and dry or a dry wipe. There was no relationship between cleaning regime and milk TVC, Enterobacteriaceae or Escherichia coli levels. CONCLUSIONS: All of the cleaning techniques studied reduced teat microbial load, however, the chlorine wash and dry was the most effective. SIGNIFICANCE AND IMPACT OF THE STUDY: The premilking teat-cleaning techniques studied reduced the teat microbial load and therefore reduced the potential for milk contamination; however, a wash including an effective disinfectant followed by a dry wipe was the most effective.

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Linearly sloped or "ramp" potentials belong to a class of core-softened models which possess a liquid-liquid critical point (LLCP) in addition to the usual liquid-gas critical point. Furthermore, they exhibit thermodynamic anomalies in their density and compressibility, the nature of which may be akin to those occurring in water. Previous simulation studies of ramp potentials have focused on just one functional form, for which the LLCP is thermodynamically stable. In this work we construct a series of ramp potentials, which interpolate between this previously studied form and a ramp-based approximation to the Lennard-Jones (LJ) potential. By means of Monte Carlo simulation, we locate the LLCP, the first order high density liquid (HDL)-low density liquid (LDL) coexistence line, and the line of density maxima for a selection of potentials in the series. We observe that as the LJ limit is approached, the LLCP becomes metastable with respect to freezing into a hexagonal close packed crystalline solid. The qualitative nature of the phase behavior in this regime shows a remarkable resemblance to that seen in simulation studies of accurate water models. Specifically, the density of the liquid phase exceeds that of the solid; the gradient of the metastable LDL-HDL line is negative in the pressure (p)-temperature (T) plane; while the line of density maxima in the p-T plane has a shape similar to that seen in water and extends into the stable liquid region of the phase diagram. As such, our results lend weight to the "second critical point" hypothesis as an explanation for the anomalous behavior of water.

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Inequalities in health between socio-economic groups are a major public health concern. The current authors studied associations between parental socio-economic status (SES) and children's respiratory and allergic symptoms in 13 diverse countries, including the Russian Federation, North America (Canada and the USA), and countries across Eastern and Western Europe. Data of 57,000 children aged 6-12 yrs, originating from eight cross-sectional studies, were analysed. SES was defined by parental education. Respiratory and allergic symptoms were defined by parental questionnaire reports. Multiple logistic regressions showed that low parental education was associated with a decreased risk of inhalant allergy and itchy rash in school children. Furthermore, low parental education was associated with an increased prevalence of wheeze and nocturnal dry cough. No clear association was found between parental education and prevalence of doctor-diagnosed asthma and bronchitis. Part of the difference between socio-economic groups with regard to their children's symptoms was explained by established risk factors, such as parental allergy, smoking during pregnancy, pet ownership, crowding, mould/moisture in the home, use of gas for cooking, and air pollution (particulate matter with a diameter of <10 microm). However, differences remained after adjusting for these variables. Children's health was associated with parental education. The association could not fully be explained by established risk factors.

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Growth and survival of a nontoxigenic strain of Escherichia coli O157:H7 (ATCC 43888) was determined in traditionally fermented pasteurized milk. Preheated milk was inoculated with 1% (v/v) of a mixed culture of Lactobacillus delbrueckii ssp. bulgaricus (NCIMB 11778) and Streptococcus salivarius ssp. thermophilus (NCIMB 110368) and incubated at 25, 30, 37 or 43 degrees C for 24 h. E. coli O157:H7 (10(5) CFU/ml) were introduced into the milk pre- and post-fermentation. Fermented milk samples were subsequently stored at either 4 degrees C (refrigerator temperature) or 25 degrees C (to mimic African ambient temperature) for 5 days. After 24 h of fermentation, the pH of the samples fermented at the higher temperatures of 37-43 degrees C decreased from 6.8 to 4.4-4.0 ( +/- 0.2) whereas at the lower temperature of 25 degrees C, the pH decreased to pH 5.0 +/- 0.1. During this period, viable counts for E. coli O157:H7 increased from 10(5) to 10(8) - 10(9) CFU/ml except in milk fermented at 43 degrees C wherein viability declined to 10(4) CFU/ml. In fermented (25-30 degrees C) milk stored at 4 degrees C for 5 days, E. coli O157:H7 viability decreased from 10(8-9) to 10(6-7) CFU/ml whereas milk fermented at 43 degrees C resulted in loss of detectable cells. In contrast, storage of fermented milk samples at 25 degrees C for 5 days eventually resulted in complete loss of viability irrespective of fermentation temperature. Stationary phase E. coli O157:H7 inoculated post-fermentation (25 and 43 degrees C) survived during 4 degrees C storage, but not 25 degrees C storage. Fermentation temperature and subsequent storage temperature are critical to the growth and survival of E. coli O157:H7 in traditional fermented products involving yoghurt starter cultures.

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The chemokine SDF-1 alpha (CXC12) and its receptor CXCR4 have been shown to play a role in the development of normal cerebellar cytoarchitecture. We report here that SDF-1 alpha both induces chemotactic responses in granule precursor cells and enhances granule cell proliferative responses to Sonic hedgehog. Chemotactic and proliferative responses to SDF-1 alpha are greater in granule cells obtained from cerebella of animals in the first postnatal week, coinciding with the observed in vivo peak in cerebellar CXCR4 expression. SDF-1 alpha activation of neuronal CXCR4 differs from activation of CXCR4 in leukocytes in that SDF-1 alpha-induced calcium flux is activity dependent, requiring predepolarization with KCl or pretreatment with glutamate. However, as is the case in leukocytes, neuronal responses to SDF-1 alpha are all abolished by pretreatment of granule cells with pertussis toxin, suggesting they occur through G(alpha i) activation. In conclusion, SDF-1 alpha plays a role in two important processes of granule cell maturation - proliferation and migration - assisting in the achievement of appropriate cell number and position in the cerebellar cortex.

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