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Abstract Axillary hyperhidrosis and osmidrosis are challenging to treat, and neither topical nor systemic drugs have provided optimal treatment outcomes. In the past decades, treatment with botulinum toxin (BTX) has gained status as the gold standard, but it has its limitations both in regard to duration as well as indication for osmidrosis, specifically. A variety of local interventions have been explored in both the surgical field and within energy‐based devices (EBDs) for alternative in‐office treatments, but a collective overview is lacking. This study sought to investigate and assess the evidence on and effect of current local procedures for axillary hyperhidrosis and osmidrosis. A systematic search for prospective and controlled clinical trials in the databases PubMed, Embase and Cochrane Library until 31 December 2023 was executed. Relevant literature was identified independently by two authors according to predefined inclusion and exclusion criteria. Fifty‐nine studies met the criteria for final inclusion, of which 46 studies were randomized controlled trials and 13 were nonrandomized trials. The included studies were classified by procedure type. Individually, a total of 28 studies investigated BTXs, 11 studies explored EBDs, while six studies reported on surgical interventions. Additionally, 14 studies evaluated alternative procedures or investigated combinations and side‐by‐side comparisons of the different procedure types. The dominant evidence on efficacy and safety was of BTX A. EBDs are increasingly being investigated with microwave thermolysis appearing to be the singular most established and scientifically well‐founded method. In the surgical field, less‐invasive methods are gaining ground. To meet the increasing demand for individualized treatment, additional high‐quality comparative studies are required for the establishment of a future variety of standard treatments.

Agonists of the secretin receptor have potential applications for diseases of the cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists of this receptor have yet been developed. In the current work, we have identified a new small molecule lead compound with this pharmacological profile. We have prepared and characterized a systematic structure-activity series around this thiadiazole scaffold to better understand the molecular determinants of its activity. We were able to enhance the in vitro activity and to maintain the specificity of the parent compound. We found the most active candidate to be quite stable in plasma, although it was metabolized by hepatic microsomes. This chemical probe should be useful for in vitro studies and needs to be tested for in vivo pharmacological activity. This could be an important lead toward the development of a first-in-class orally active agonist of the secretin receptor, which could be useful for multiple disease states.

Introduction Acute undifferentiated febrile illnesses (AUFIs) impose a large burden in the tropics. Understanding of AUFI’s epidemiology is limited. Insufficient diagnostic capacity hinders the detection of outbreaks. The lack of interconnection in healthcare systems hinders timely response. We describe a protocol to study the epidemiology and aetiologies of AUFI and pathogen discovery in strategic areas of Latin America (LA).Methods and analysis Global Infectious Diseases Network investigators comprising institutions in Colombia, Dominican Republic, México, Perú and the USA, developed a common cohort study protocol. The primary objective is to determine the aetiologies of AUFI at healthcare facilities in high-risk areas. Data collection and laboratory testing for viral, bacterial and parasitic agents are performed in rural and urban healthcare facilities and partner laboratories. Centralised laboratory and data management cores deploy diagnostic tests and data management tools. Subjects >6 years with fever for

Summary: Background: More than 3 billion people do not have access to clean energy and primarily use solid fuels to cook. Use of solid fuels generates household air pollution, which was associated with more than 2 million deaths in 2019. Although local patterns in cooking vary systematically, subnational trends in use of solid fuels have yet to be comprehensively analysed. We estimated the prevalence of solid-fuel use with high spatial resolution to explore subnational inequalities, assess local progress, and assess the effects on health in low-income and middle-income countries (LMICs) without universal access to clean fuels. Methods: We did a geospatial modelling study to map the prevalence of solid-fuel use for cooking at a 5 km × 5 km resolution in 98 LMICs based on 2·1 million household observations of the primary cooking fuel used from 663 population-based household surveys over the years 2000 to 2018. We use observed temporal patterns to forecast household air pollution in 2030 and to assess the probability of attaining the Sustainable Development Goal (SDG) target indicator for clean cooking. We aligned our estimates of household air pollution to geospatial estimates of ambient air pollution to establish the risk transition occurring in LMICs. Finally, we quantified the effect of residual primary solid-fuel use for cooking on child health by doing a counterfactual risk assessment to estimate the proportion of deaths from lower respiratory tract infections in children younger than 5 years that could be associated with household air pollution. Findings: Although primary reliance on solid-fuel use for cooking has declined globally, it remains widespread. 593 million people live in districts where the prevalence of solid-fuel use for cooking exceeds 95%. 66% of people in LMICs live in districts that are not on track to meet the SDG target for universal access to clean energy by 2030. Household air pollution continues to be a major contributor to particulate exposure in LMICs, and rising ambient air pollution is undermining potential gains from reductions in the prevalence of solid-fuel use for cooking in many countries. We estimated that, in 2018, 205 000 (95% uncertainty interval 147 000–257 000) children younger than 5 years died from lower respiratory tract infections that could be attributed to household air pollution. Interpretation: Efforts to accelerate the adoption of clean cooking fuels need to be substantially increased and recalibrated to account for subnational inequalities, because there are substantial opportunities to improve air quality and avert child mortality associated with household air pollution. Funding: Bill & Melinda Gates Foundation.

ABSTRACT The rate of visual field progression is an essential factor in determining risk of visual disability or blindness in glaucoma patients. Knowledge of the rate of progression of a particular patient, in combination with an estimation of their longevity and other clinical factors, allows clinicians to optimize management by providing appropriately aggressive treatment. Despite decades of research on the treatment of glaucoma, the natural history of glaucomatous visual field progression in untreated and treated patients remains unclear. The purpose of this review is to provide a comprehensive summary of the literature surrounding the rate of visual field progression in glaucoma. Most of the available data pertains to primary open angle glaucoma, but we will also review progression rates in other subtypes of open angle glaucoma, such as pseudoexfoliative glaucoma and normal tension glaucoma, as well as in primary angle closure glaucoma. Specifically, we will cover methods to identify rates of progression, rates of progression in treated versus untreated patients, factors that may influence progression, and lastly, suggest some parameters that might help clinicians in determining acceptable rates of visual field deterioration in patients with glaucoma.

Abstract Background Oral rehydration solution (ORS) is a simple intervention that can prevent childhood deaths from severe diarrhea and dehydration. In a previous study, we mapped the use of ORS treatment subnationally and found that ORS coverage increased over time, while the use of home-made alternatives or recommended home fluids (RHF) decreased, in many countries. These patterns were particularly striking within Senegal, Mali, and Sierra Leone. It was unclear, however, whether ORS replaced RHF in these locations or if children were left untreated, and if these patterns were associated with health policy changes. Methods We used a Bayesian geostatistical model and data from household surveys to map the percentage of children with diarrhea that received (1) any ORS, (2) only RHF, or (3) no oral rehydration treatment between 2000 and 2018. This approach allowed examination of whether RHF was replaced with ORS before and after interventions, policies, and external events that may have impacted healthcare access. Results We found that RHF was replaced with ORS in most Sierra Leone districts, except those most impacted by the Ebola outbreak. In addition, RHF was replaced in northern but not in southern Mali, and RHF was not replaced anywhere in Senegal. In Senegal, there was no statistical evidence that a national policy promoting ORS use was associated with increases in coverage. In Sierra Leone, ORS coverage increased following a national policy change that abolished health costs for children. Conclusions Children in parts of Mali and Senegal have been left behind during ORS scale-up. Improved messaging on effective diarrhea treatment and/or increased ORS access such as through reducing treatment costs may be needed to prevent child deaths in these areas.

Abstract Background Primary cutaneous signet-ring cell/histiocytoid carcinoma of the eyelid is an extremely rare but aggressive neoplasm diagnosed primarily in elderly men. Until now there are 32 published cases of signet-ring cell carcinoma or histiocytoid carcinoma of the eyelid. We report the clinical, radiographic and histological features of the 33rd reported case of PCSRCC in the eyelid of a 73-year-old male, and review diagnostic and treatment challenges of this rare entity. Case presentation Our case highlights a 73-year-old male who was referred for surgical correction of right eye ptosis that was present for 2 years. Upon assessment, he was noted to have an upper lateral orbital rim mass. Computed tomography (CT) noted ill-defined soft tissue thickening anterior to the right globe, predominantly pre-septal but with slight post-septal extension. The pathology revealed diffusely and deeply infiltrating tumour cells extending through the dermis, subcutis, orbicularis muscle bundles and nerve fibers; the tumour cells were noted to have a monotonous histiocytoid appearance with foamy granular eosinophilic cytoplasm. At high magnification, intracytoplasmic vacuoles and occasional intermixed signet ring cells were identified. Immunohistochemical staining revealed the tumour cells to be AE1/AE3, CK7, GCDFP-15, E-cadherin, androgen receptor stain and GATA3 positive. Final pathology report confirmed the diagnosis of primary cutaneous signet-ring cell/histiocytoid carcinoma. Further imaging failed to identify a distant primary malignancy or metastatic disease. The decision was made to attempt surgical excision of the tumor. After the bulk of the grossly apparent tumor was removed, intraoperative frozen sections were sent. Superficial biopsies of the right periorbital region were performed, which revealed extension significantly further than the gross disease. Thereafter, the patient underwent a wide orbital exenteration with reconstruction using a temporary split-thickness skin graft. Due to positive margins on final permanent sections, the patient underwent further wide resection with free muscle-skin flap reconstruction followed by adjuvant radiation treatment. Conclusion Our case represents the 33rd case of primary signet-ring cell/histiocytoid carcinoma of the eyelid in a 73-year-old male, the first documented case with GATA3 positivity and the second documented case with androgen receptor stain positivity.

Abstract Background Climate change creates opportune conditions that favour the spread of pests and diseases outside their known active range. Modelling climate change scenarios is oftentimes useful tool to assess the climate analogues to unveil the potential risk of spreading suitability conditions for pests and diseases and hence allows development of appropriate responses to address the impending challenge. In the current study, we modelled the impact of climate change on the distribution of Varroa destructor, a parasitic mite that attacks all life forms of honey bees and remains a significant threat to their survival and productivity of bee products in Tanzania and elsewhere. Methods The data about the presence of V. destructor were collected in eight regions of Tanzania selected in consideration of several factors including potentials for beekeeping activities, elevation (highlands vs. lowlands) and differences in climatic conditions. A total of 19 bioclimatic datasets covering the entire country were used for developing climate scenarios of mid-century 2055 and late-century 2085 for both rcp4.5 and rcp8.5. We thereafter modelled the current and future risk distribution of V. destructor using MaxEnt. Results The results indicated a model performance of AUC = 0.85, with mean diurnal range in temperature (Bio2, 43.9%), mean temperature (Bio1, 20.6%) and mean annual rainfall (Bio12, 11.7%) as the important variables. Future risk projections indicated mixed responses of the potential risk of spreads of V. destructor, exhibiting both decrease and increases in the mid-century 2055 and late-century 2085 on different sites. Overall, there is a general decline of highly suitable areas of V. destructor in mid- and late-century across all scenarios (rcp4.5 and rcp8.5). The moderately suitable areas indicated a mixed response in mid-century with decline (under rcp4.5) and increase (under rcp8.5) and consistent increase in late century. The marginally suitable areas show a decline in mid-century and increase in late-century. Our results suggest that the climate change will continue to significantly affect the distribution and risks spread of V. destructor in Tanzania. The suitability range of V. destructor will shift where highly suitable areas will be diminishing to the advantage of the honey bees’ populations, but increase of moderately suitable sites indicates an expansion to new areas. The late century projections show the increased risks due to surge in the moderate and marginal suitability which means expansion in the areas where V. destructor will operate. Conclusion The current and predicted areas of habitat suitability for V. destructor’s host provides information useful for beekeeping stakeholders in Tanzania to consider the impending risks and allow adequate interventions to address challenges facing honey bees and the beekeeping industry. We recommend further studies on understanding the severity of V. destructor in health and stability of the honey bees in Tanzania. This will provide a better picture on how the country will need to monitor and reduce the risks associated with the increase of V. destructor activities as triggered by climate change. The loss of honey bees’ colonies and its subsequent impact in bees’ products production and pollination effect have both ecological and economic implications that need to have prioritization by the stakeholders in the country to address the challenge of spreading V. destructor.

P92 steel is used as a piping material in ultra super critical power plants that can be operated at steam temperatures up to 650°C. The changes in the martensitic microstructure of P92 steel must be evaluated thoroughly before it is put into actual service. In this study, indigenously developed P92 steel was used. The steel was subjected to normalizing and tempering heat treatments in the range of 1,040–1,060°C and 740–780°C. The changes in the microstructure were evaluated and creep-rupture properties were studied at test temperatures of 600 and 650°C. Although normalizing temperatures influenced the microstructure and creep strength marginally, the change in tempering temperatures led to significant changes. The creep rupture strength at 600°C was influenced largely by the changes in the dislocation substructure, while the precipitation of Laves phases was a significant observation made for 650°C test temperature. Proposed mechanisms for the microstructural evolution and its consequences on the rupture life are discussed in this study.

Until recently, 10% of hepatocellular adenomas (HCAs) remained unclassified (UHCA). Among the UHCAs, the sonic hedgehog HCA (shHCA) was defined by focal deletions that fuse the promoter of Inhibin beta E chain with GLI1. Prostaglandin D2 synthase was proposed as immunomarker. In parallel, our previous work using proteomic analysis showed that most UHCAs constitute a homogeneous subtype associated with overexpression of argininosuccinate synthase (ASS1). To clarify the use of ASS1 in the HCA classification and avoid misinterpretations of the immunohistochemical staining, the aims of this work were to study (1) the link between shHCA and ASS1 overexpression and (2) the clinical relevance of ASS1 overexpression for diagnosis. Molecular, proteomic, and immunohistochemical analyses were performed in UHCA cases of the Bordeaux series. The clinico‐pathological features, including ASS1 immunohistochemical labeling, were analyzed on a large international series of 67 cases. ASS1 overexpression and the shHCA subgroup were superimposed in 15 cases studied by molecular analysis, establishing ASS1 overexpression as a hallmark of shHCA. Moreover, the ASS1 immunomarker was better than prostaglandin D2 synthase and only found positive in 7 of 22 shHCAs. Of the 67 UHCA cases, 58 (85.3%) overexpressed ASS1, four cases were ASS1 negative, and in five cases ASS1 was noncontributory. Proteomic analysis performed in the case of doubtful interpretation of ASS1 overexpression, especially on biopsies, can be a support to interpret such cases. ASS1 overexpression is a specific hallmark of shHCA known to be at high risk of bleeding. Therefore, ASS1 is an additional tool for HCA classification and clinical diagnosis.

There is continued interest in the occurrence and monitoring of emerging contaminants (ECs) in wastewater treatment plants (WWTPs) to assess their potential impact when released into the environment. The objective of this study was to determine the occurrence of pharmaceutical and personal care products (PPCPs) in WWTP influents and effluents and receiving river waters in Pretoria, South Africa. Targeted screening and identification of PPCPs in the samples was done using liquid chromatography (LC) coupled with high resolution mass spectrometry (HRMS) Orbitrap™ HRMS, after clean-up and preconcentration with Waters Oasis® hydrophilic-lipophilic-balanced (HLB) solid phase extraction (SPE) cartridges. Of the 156 target analytes screened in the study, 120 could be satisfactorily determined under the study conditions, with 71 and 73 compounds being detected and quantified in the influent and effluent samples, respectively. Concentrations in the influents ranged from < ILOQ-14.2 μg L−1 and those in the effluent from < ILOQ - 2.45 μg L−1. It was found that 84% of the quantified compounds belonged to various classes of pharmaceuticals. Ibuprofen, caffeine, paracetamol and estradiol were the major individual contaminants in influent samples with average concentrations of 14.2, 8.68, 4.79 and 1.02 μg L−1, respectively. In the effluent samples, the highest concentrations were recorded for estradiol (2.45 μg L−1), ibuprofen (1.03 μg L−1) and efavirenz (0.58 μg L−1). The highest mean concentrations (above 0.5 μg L−1) recorded in the river water samples were for ibuprofen, (4.14 μg L−1downstream; 3.19 μg L−1 upstream), caffeine (2.98 μg L−1 downstream; 1.42 μg L−1 upstream), paraxanthine (1.22 μg L−1 downstream; 0.798 μg L−1 upstream). Analysis of river water samples also revealed that PPCP contamination in the river system cannot be solely attributed to the WWTP effluents. Twenty-four compounds presented in this study are reported for the first time in South African surface waters.

Abstract This study aims to compare iso-rank vitrinite-rich and inertinite-rich coal samples to understand the impact of coal-forming processes on pyrolysis chemistry. A medium rank C bituminous coal was density-fractionated to create a vitrinite-rich and an inertinite-rich sub-sample. The vitrinite-rich sample has 83 vol% total vitrinite (mineral-matter-free basis), whereas the inertinite-rich counterpart has 66 vol% total inertinite. The vitrinite-rich sample is dominated by collotelinite and collodetrinite. Fusinite, semifusinite, and inertodetrinite are the main macerals of the inertinite-rich sample. Molecular chemistry was assessed using a pyrolysis gas chromatograph (py-GC) equipped with a thermal desorption unit coupled to a time of flight mass spectrometer (MS) (py-GC/MS) and solid-state nuclear magnetic resonance (13C CP-MAS SS NMR). The pyrolysis products of the coal samples are generally similar, comprised of low and high molecular weight alkanes, alkylbenzenes, alkylphenols, and alkyl-subtituted polycyclic aromatic hydrocarbons, although the vitrinite-rich sample is chemically more diverse. The lack of diversity exhibited by the inertinite-rich sample upon pyrolysis may be interpreted to suggest that major components were heated in their geologic history. Based on the 13C CP-MAS SS NMR analysis, the inertinite-rich sample has a greater fraction of phenolics, reflected in the py-GC/MS results as substituted and unsubstituted derivatives. The greater abundance of phenolics for the inertinite-rich sample may suggest a fire-related origin for the dominant macerals of this sample. The C2-alkylbenzene isomers (p-xylene and o-xylene) were detected in the pyrolysis products for the vitrinite-rich and inertinite-rich samples, though more abundant in the former. The presence of these in both samples likely reflects common source vegetation for the dominant vitrinite and inertinite macerals.

Domesticated maize and some varieties of wild teosinte grow in close proximity in parts of Mexico but rarely cross-fertilize. Here the authors show that a pistil-expressed pectin methylesterase, encoded by a gene within the Teosinte crossing barrier1-s haplotype, prevents fertilization of these teosintes by incompatible pollen.

Summary: Background: Universal access to safe drinking water and sanitation facilities is an essential human right, recognised in the Sustainable Development Goals as crucial for preventing disease and improving human wellbeing. Comprehensive, high-resolution estimates are important to inform progress towards achieving this goal. We aimed to produce high-resolution geospatial estimates of access to drinking water and sanitation facilities. Methods: We used a Bayesian geostatistical model and data from 600 sources across more than 88 low-income and middle-income countries (LMICs) to estimate access to drinking water and sanitation facilities on continuous continent-wide surfaces from 2000 to 2017, and aggregated results to policy-relevant administrative units. We estimated mutually exclusive and collectively exhaustive subcategories of facilities for drinking water (piped water on or off premises, other improved facilities, unimproved, and surface water) and sanitation facilities (septic or sewer sanitation, other improved, unimproved, and open defecation) with use of ordinal regression. We also estimated the number of diarrhoeal deaths in children younger than 5 years attributed to unsafe facilities and estimated deaths that were averted by increased access to safe facilities in 2017, and analysed geographical inequality in access within LMICs. Findings: Across LMICs, access to both piped water and improved water overall increased between 2000 and 2017, with progress varying spatially. For piped water, the safest water facility type, access increased from 40·0% (95% uncertainty interval [UI] 39·4–40·7) to 50·3% (50·0–50·5), but was lowest in sub-Saharan Africa, where access to piped water was mostly concentrated in urban centres. Access to both sewer or septic sanitation and improved sanitation overall also increased across all LMICs during the study period. For sewer or septic sanitation, access was 46·3% (95% UI 46·1–46·5) in 2017, compared with 28·7% (28·5–29·0) in 2000. Although some units improved access to the safest drinking water or sanitation facilities since 2000, a large absolute number of people continued to not have access in several units with high access to such facilities (>80%) in 2017. More than 253 000 people did not have access to sewer or septic sanitation facilities in the city of Harare, Zimbabwe, despite 88·6% (95% UI 87·2–89·7) access overall. Many units were able to transition from the least safe facilities in 2000 to safe facilities by 2017; for units in which populations primarily practised open defecation in 2000, 686 (95% UI 664–711) of the 1830 (1797–1863) units transitioned to the use of improved sanitation. Geographical disparities in access to improved water across units decreased in 76·1% (95% UI 71·6–80·7) of countries from 2000 to 2017, and in 53·9% (50·6–59·6) of countries for access to improved sanitation, but remained evident subnationally in most countries in 2017. Interpretation: Our estimates, combined with geospatial trends in diarrhoeal burden, identify where efforts to increase access to safe drinking water and sanitation facilities are most needed. By highlighting areas with successful approaches or in need of targeted interventions, our estimates can enable precision public health to effectively progress towards universal access to safe water and sanitation. Funding: Bill & Melinda Gates Foundation.

Summary: Background: Lymphatic filariasis is a neglected tropical disease that can cause permanent disability through disruption of the lymphatic system. This disease is caused by parasitic filarial worms that are transmitted by mosquitos. Mass drug administration (MDA) of antihelmintics is recommended by WHO to eliminate lymphatic filariasis as a public health problem. This study aims to produce the first geospatial estimates of the global prevalence of lymphatic filariasis infection over time, to quantify progress towards elimination, and to identify geographical variation in distribution of infection. Methods: A global dataset of georeferenced surveyed locations was used to model annual 2000–18 lymphatic filariasis prevalence for 73 current or previously endemic countries. We applied Bayesian model-based geostatistics and time series methods to generate spatially continuous estimates of global all-age 2000–18 prevalence of lymphatic filariasis infection mapped at a resolution of 5 km2 and aggregated to estimate total number of individuals infected. Findings: We used 14 927 datapoints to fit the geospatial models. An estimated 199 million total individuals (95% uncertainty interval 174–234 million) worldwide were infected with lymphatic filariasis in 2000, with totals for WHO regions ranging from 3·1 million (1·6–5·7 million) in the region of the Americas to 107 million (91–134 million) in the South-East Asia region. By 2018, an estimated 51 million individuals (43–63 million) were infected. Broad declines in prevalence are observed globally, but focal areas in Africa and southeast Asia remain less likely to have attained infection prevalence thresholds proposed to achieve local elimination. Interpretation: Although the prevalence of lymphatic filariasis infection has declined since 2000, MDA is still necessary across large populations in Africa and Asia. Our mapped estimates can be used to identify areas where the probability of meeting infection thresholds is low, and when coupled with large uncertainty in the predictions, indicate additional data collection or intervention might be warranted before MDA programmes cease. Funding: Bill & Melinda Gates Foundation.

Summary: Background: Oral rehydration solution (ORS) is a form of oral rehydration therapy (ORT) for diarrhoea that has the potential to drastically reduce child mortality; yet, according to UNICEF estimates, less than half of children younger than 5 years with diarrhoea in low-income and middle-income countries (LMICs) received ORS in 2016. A variety of recommended home fluids (RHF) exist as alternative forms of ORT; however, it is unclear whether RHF prevent child mortality. Previous studies have shown considerable variation between countries in ORS and RHF use, but subnational variation is unknown. This study aims to produce high-resolution geospatial estimates of relative and absolute coverage of ORS, RHF, and ORT (use of either ORS or RHF) in LMICs. Methods: We used a Bayesian geostatistical model including 15 spatial covariates and data from 385 household surveys across 94 LMICs to estimate annual proportions of children younger than 5 years of age with diarrhoea who received ORS or RHF (or both) on continuous continent-wide surfaces in 2000–17, and aggregated results to policy-relevant administrative units. Additionally, we analysed geographical inequality in coverage across administrative units and estimated the number of diarrhoeal deaths averted by increased coverage over the study period. Uncertainty in the mean coverage estimates was calculated by taking 250 draws from the posterior joint distribution of the model and creating uncertainty intervals (UIs) with the 2·5th and 97·5th percentiles of those 250 draws. Findings: While ORS use among children with diarrhoea increased in some countries from 2000 to 2017, coverage remained below 50% in the majority (62·6%; 12 417 of 19 823) of second administrative-level units and an estimated 6 519 000 children (95% UI 5 254 000–7 733 000) with diarrhoea were not treated with any form of ORT in 2017. Increases in ORS use corresponded with declines in RHF in many locations, resulting in relatively constant overall ORT coverage from 2000 to 2017. Although ORS was uniformly distributed subnationally in some countries, within-country geographical inequalities persisted in others; 11 countries had at least a 50% difference in one of their units compared with the country mean. Increases in ORS use over time were correlated with declines in RHF use and in diarrhoeal mortality in many locations, and an estimated 52 230 diarrhoeal deaths (36 910–68 860) were averted by scaling up of ORS coverage between 2000 and 2017. Finally, we identified key subnational areas in Colombia, Nigeria, and Sudan as examples of where diarrhoeal mortality remains higher than average, while ORS coverage remains lower than average. Interpretation: To our knowledge, this study is the first to produce and map subnational estimates of ORS, RHF, and ORT coverage and attributable child diarrhoeal deaths across LMICs from 2000 to 2017, allowing for tracking progress over time. Our novel results, combined with detailed subnational estimates of diarrhoeal morbidity and mortality, can support subnational needs assessments aimed at furthering policy makers' understanding of within-country disparities. Over 50 years after the discovery that led to this simple, cheap, and life-saving therapy, large gains in reducing mortality could still be made by reducing geographical inequalities in ORS coverage. Funding: Bill & Melinda Gates Foundation.

We measured food availability and diet composition of juvenile salmonids over multiple years and seasons before and during the world's largest dam removal on the Elwha River, Washington State. We conducted these measurements over three sediment-impacted sections (the estuary and two sections of the river downstream of each dam) and compared these to data collected from mainstem tributaries not directly affected by the massive amount of sediment released from the reservoirs. We found that sediment impacts from dam removal significantly reduced invertebrate prey availability, but juvenile salmon adjusted their foraging so that the amount of energy in diets was similar before and during dam removal. This general pattern was seen in both river and estuary habitats, although the mechanisms driving the change and the response differed between habitats. In the estuary, the dietary shifts were related to changes in invertebrate assemblages following a hydrological transition from brackish to freshwater caused by sediment deposition at the river's mouth. The loss of brackish invertebrate species caused fish to increase piscivory and rely on new prey sources such as plankton. In the river, energy provided to fish by Ephemeroptera, Plecoptera, and Trichoptera taxa before dam removal was replaced first by terrestrial invertebrates, and then by sediment-tolerant taxa such as Chironomidae. The results of our study are consistent with many others that have shown sharp declines in invertebrate density during dam removal. Our study further shows how those changes can move through the food web and affect fish diet composition, selectivity, and energy availability. As we move further along the dam removal response trajectory, we hypothesize that food web complexity will continue to increase as annual sediment load now approaches natural background levels, anadromous fish have recolonized the majority of the watershed between and above the former dams, and revegetation and microhabitats continue to develop in the estuary.

Algorithms for separation of heart sounds from background lung sound noises are vital for accurate diagnosis of heart diseases. In this paper, an improved adaptive noise cancellation technique based on the Least Mean Square (LMS) algorithm is used to separate heart sounds from lung sounds. The step size parameter in the LMS algorithm is optimally chosen using a hybrid Nelder-Mead (H-NM) optimization algorithm. The NM algorithm is initialized with a good initial solution by using computationally cheap random search to compute a rough estimate of the global minimum. Initialization of the NM algorithm with a good initial guess avoided convergence to shallow local minima and improved the quality of the final solution. The effects of using two state-of-the-arts biologically inspired heuristic optimization algorithms instead of the H-NM algorithm and three variants of the standard LMS algorithm are investigated. The correlation coefficient between the ideal and filtered heart sound signal and running time-complexity of different algorithms are taken as the metric for comparison of different heart sound separation approaches. Simulation results indicate that the approach presented in this paper performs significantly better than a variety of alternate approaches on heart sound separation problems.

Synthetic biology holds great promise to deliver transformative technologies to the world in the coming years. However, several challenges still remain to be addressed before it can deliver on its promises. One of the most important issues to address is the lack of reproducibility within research of the life sciences. This problem is beginning to be recognised by the community and solutions are being developed to tackle the problem. The recent emergence of automated facilities that are open for use by researchers (such as biofoundries and cloud labs) may be one of the ways that synthetic biologists can improve the quality and reproducibility of their work. In this perspective article, we outline these and some of the other technologies that are currently being developed which we believe may help to transform how synthetic biologists approach their research activities.

Limited studies have been done on silk fibroins of wild silkworm species owing to their relative insolubility in many solvents. In this study, the solubility of Argema mimosae wild silk fibroin in different salts (LiBr, LiCl, Ca(NO3)2, and CaCl2) dissolved in formic acid under varying temperatures was investigated. The dissolution conditions under which the solubility was optimum were optimized using a central composite design approach. The optimum range for solvation of the fibroin were visualized using contour plots. The influence of temperature and salt concentration were found to significantly influence the solvation of the fibroin. Following the successful dissolution of the fibroin, the regenerated silk fibroin solutions were cast to obtain water insoluble films which were used in investigating optimum electrospinning conditions. Average nanofiber diameters in the 110–141 nm range were obtained under optimum electrospinning conditions. The silk forms were characterized using the FTIR, TGA, XRD, and SEM to understand their properties. The investigations revealed that formic acid—salt solvents were effective in the solvation of the wild silk fibroin. Some of the dissolution conditions induced mild effects on the silk fibroin while others were harsh. Furthermore, processing to nanofibers resulted in the degradation of the β-sheets producing nanofibers rich in α-helices. However, post-treatment using methanol and water vapor were effective in restoring β-sheet crystallinity.

The activation status of the insulin‐like growth factor‐1 receptor (IGF‐1R) regulates the cellular response of keratinocytes to ultraviolet B (UVB) exposure, both in vitro and in vivo. Geriatric skin is deficient in IGF‐1 expression resulting in an aberrant IGF‐1R‐dependent UVB response which contributes to the development of aging‐associated squamous cell carcinoma. Furthermore, our lab and others have reported that geriatric keratinocytes repair UVB‐induced DNA damage less efficiently than young adult keratinocytes. Here, we show that IGF‐1R activation influences DNA damage repair in UVB‐irradiated keratinocytes. Specifically, in the absence of IGF‐1R activation, the rate of DNA damage repair following UVB‐irradiation was significantly slowed (using immortalized human keratinocytes) or inhibited (using primary human keratinocytes). Furthermore, inhibition of IGF‐1R activity in human skin, using either ex vivo explant cultures or in vivo xenograft models, suppressed DNA damage repair. Primary keratinocytes with an inactivated IGF‐1R also exhibited lower steady‐state levels of nucleotide excision repair mRNAs. These results suggest that deficient UVB‐induced DNA repair in geriatric keratinocytes is due in part to silenced IGF‐1R activation in geriatric skin and provide a mechanism for how the IGF‐1 pathway plays a role in the initiation of squamous cell carcinoma in geriatric patients.

Type 316L(N) stainless steel (SS) containing 0.02–0.03 wt% carbon and 0.06–0.08 wt% nitrogen is used as the major structural material for the components of fast reactors. Research is underway to improve the high-temperature mechanical properties of 316LN SS by increasing the nitrogen content in the steel above the level of 0.08 wt%. In this investigation, ball indentation (BI) technique was used to evaluate the effect of nitrogen content on the tensile properties of 316LN SS. BI tests were conducted on four different heats of 316LN SS containing 0.07, 0.11, 0.14 and 0.22 wt% nitrogen in the temperature range 300–923 K. The tensile properties such as yield strength and ultimate tensile strength increased with increase in nitrogen content at all the investigated temperatures. These results were consistent with the corresponding uniaxial tensile test results. These studies showed that BI technique can be used to optimize the chemical composition during alloy development by evaluating tensile properties with minimum volume of material.

A near global dataset of homogenized clear-sky 6.5-μm brightness temperatures (BTs) from international geostationary (GEO) weather satellites has recently been generated and validated. In this study, these radiance measurements are used to construct the diurnal variation of upper tropospheric humidity (UTH) and to evaluate these diurnal variations simulated by five reanalysis datasets over the 45° N–45° S region. The features of the diurnal variation described by the new dataset are comparable with previous observational studies that a land–sea contrast in the diurnal variation of UTH is exhibited. Distinct diurnal variations are observed over the deep convective regions where high UTH exists. The evaluation of reanalysis datasets indicates that reanalysis systems still have considerable difficulties in capturing the observed features of the diurnal variation of UTH. All five reanalysis datasets present the largest wet biases in the afternoon when the observed UTH experiences a diurnal minimum. Reanalysis can roughly reproduce the day–night contrast of UTH but with much weaker amplitudes and later peak time over both land and ocean. Comparison of the geographical distribution of the diurnal variation shows that both ERA5 and MERRA-2 could capture the larger diurnal variations over convective regions. However, the diurnal amplitudes are widely underestimated, especially over convective land regions, while the phase biases are relatively larger over open oceans. These results suggest that some deficiencies may exist in convection and cloud parameterization schemes in reanalysis models.

No abstract available. Article truncated at 150 words. A 43 year-old female with a past medical history of right-sided hemiparesis secondary to motor vehicle accident 17 years prior presented a two week history of cough, fever and right-sided pleuritic chest pain. Her baseline status included using a wheelchair, living alone at home and working as a teacher. On admission she had a temperature of 39.6º C, was tachycardia and hypotensive requiring vasopressors. Labs were remarkable for a white count of 25,000 cells/mcL. Chest x-ray showed right-sided infiltrate and pleural effusion (Figure 1). Bronchoscopy and thoracentesis was performed upon admission. The pleural fluid was exudative with a glucose of 78 and no suggestion of loculations on chest x-ray or ultrasound. The patient was started on therapy for community-acquired pneumonia. On day 4 after admission, the patient had increasing sinus tachycardia, hypotension and was worsening despite being on antimicrobial therapy. A CT angiogram of the chest was performed (Figure 2). ...

A new species of the jumping spider genus Stenaelurillus Simon, 1886, S. albus sp. n., is described from the Western Ghats of India, one of the biodiversity hotspots of the world. Detailed morphological descriptions, diagnostic features and illustrations of copulatory organs of both sexes are given. Detailed redescription, diagnosis and illustration of S. lesserti Reimoser, 1934 are provided. The occurrence of a mating plug in the genus is reported.

Background: Prosthetic reconstruction of partial maxillectomy defects is a challenging procedure that requires multidisciplinary expertise to achieve an acceptable function, speech and esthetics. This procedure improves the quality of life for the patient as a normal individual. Obturation of the defect depends on its volume and position of remaining hard and soft tissues which determine the retention, stability and support for the prosthesis. The prosthesis should be simple to handle, easy to maintain, biocompatible, light in weight and convenient for future adjustments. This case report describes a clinical case of partial maxillectomy which was successfully rehabilitated with a definitive closed hollow bulb obturator and cast metal denture base.

Converting the hyperspectral infrared (IR) sounder radiance spectrum to broadband is a common approach for intercomparison/calibration. Usually the convolution is performed in wavenumber space. However, numerical experiments presented here indicate that there are brightness temperature (BT) differences between wavelength and wavenumber spaces in convolving hyperspectral IR sounder spectrum to broadband. The magnitudes of differences are related to the spectral region and the width of the spectral response functions (SRFs). In addition, the central wavelength and central wavenumber should be determined separately in wavelength and wavenumber spaces, respectively; they cannot be converted to each other directly for broadband BT calculations. There exist BT differences (BTDs) between interpolating the resolution of SRF to hyperspectral IR sounder spectrum, and vice versa, for convolution. This study provides clarity on convolution, central wavelength/wavenumber determination, and spectral resolution matching between broadband SRFs and hyperspectral IR sounder radiances for intercomparison/calibration.

No abstract available. Article truncated after first 150 words. History of Present Illness A 30 year old Hispanic man presented to the emergency department (ED) after being involved in a motor vehicle accident. He was a restrained passenger and his car was hit from behind by another vehicle. His initial presenting complaints were chest and back pain. PMH, SH, FH The patient was originally born in Sonora, Mexico but moved to the Phoenix area in 1998. However, he traveled to Mexico frequently. He has no allergies and no significant past medical or surgical history. His social habits include occasional alcohol consumption and a remote minimal smoking history. He denied illicit drug abuse. He was married and has 5 healthy children. He was working as a fork lift operator in a warehouse and was not taking any medications. A tuberculosis skin test and a human immunodeficiency virus (HIV) were negative 3 years ago when he applied for US Citizenship. His …

No abstract available. Article truncated at 150 words. The debate continues over the Patient Protection and Affordable Care Act (ACA, Obamacare) (1). One the one hand the White House and their Democratic supporters say the law will: 1. Expand coverage to the poor; 2. Control costs; and 3. Improve care. On the other hand, opponents say the law is a job killer. Employers will be forced to eliminate positions, or reduce staffers to part-time hours to save costs. A recent article stated that Obamacare is certain to create a number of new positions but that seemed to be only part of the story (2). Below we offer our short lists of who will benefit and who will lose under Obamacare. Who Will Benefit 1.Uninsured patients. Many patients who are uninsured or underinsured will benefit because their lack of health insurance results in delays in diagnosis and treatment. Uninsured patients often seek care in the hospital emergency department…

With the growing emphasis being placed upon situated learning theory, designs increasingly implement problem-based learning (PBL) in various educational contexts. However, some of the difficulties instructional designers face include interweaving elements such as breadth, depth, and situated knowledge in a contextualized learning task. This design case details how the 3C3R method was systematically employed to design a PBL learning environment that highlights the effects of environmental toxins on human fertility. We also discuss how a case library learning environment (CLLE) was implemented and designed to support the decision-making process. This design case examines the challenges involved, such as misunderstandings between the SMEs and instructional designer as we contextualized complex issues related to human biology. A discussion of how we designed for multiple solution paths is also included. Lastly, we discuss the challenges of interweaving the ill-structured problem with multiple narratives found in a case library.

Disability Adjusted Life Years (DALY) is a widely used measure to quantify the burden of diseases or illness. DALYs for a disease is calculated as the sum of the Years of Life Lost (YLL) due to premature mortality in the population and the equivalent healthy Years Lost due to Disability (YLD). The only difference from the YLD and Days Lost due to Disability (DLD) calculation is that instead of considering the duration of Adverse Drug Reaction (ADR) in years, it is calculated in days. Objective: DLD was measured for diclofenac tablets to prepare the ADR profile.Methods: The study was done on the patients (18-65 years old) attending the community pharmacy at Kasaragod district, South India, with prescription of diclofenac tablets. Patients reported ADRs on their next visit to the pharmacy or they had called to the provided phone number and reported it. Disability Weight (DW) was calculated in an analogue scale from 0-1. Zero represent complete health and 1 represent death or equivalent condition. DW was multiplied with occurrence and duration of ADRs in days.Results: About 943 patients received diclofenac tablets in 1000 prescriptions were successfully followed up for possible, probable and definite ADRs. A total of 561 reactions reported in 2010 for diclofenac tablet in the study population. There were 34 different types of ADRs under 12 physiological systems/organs. Most common reactions were on gastrointestinal (GI) system (48%), followed by skin (14%), Central Nervous System (10%), renal (7%), and cardiovascular (7%). Abdominal pain, cramps or flatulence was the highest occurring GI ADR (107), followed by 43 rashes, 42 nausea/vomiting, 37 indigestion, 34 peptic ulcers, 31 edema etc. DLD for peptic ulcer was considerably high (0.078) per 1000 of the study population on diclofenac. The most damaging ADR were peptic ulcer with or without perforation, followed by rash 0.036 DLD and edema 0.027 DLD. There was considerable DLD by acute renal failure (0.012) Steven-Johnson syndrom (0.013) even though few cases were reported.Conclusion: Diclofenac has a complex adverse drug profile. Around 34 types of reactions were reported. Diclofenac was widely prescribed because of the experiential belief of comparative safety with other NSAIDs. The study shows the importance of pharmacovigilance even on the most prescribed medicine. Most disabling ADR for the study population was peptic ulcer with or without perforation. YLD or DLD are useful measures of calculating disability caused by ADRs. Future studies could focus on improving the usefulness & precision of DLD.

A titanium-modified 14Cr-15Ni-2Mo austenitic stainless steel, known as alloy D9, has been chosen as the material for the fuel cladding and hexagonal wrapper of the Prototype Fast Breeder Reactor presently under construction at Kalpakkam. The alloy is generally produced by double vacuum melting process consisting of Vacuum Induction Melting (VIM) followed by Vacuum Arc Remelting (VAR). An alternate route consisting of vacuum induction melting followed by electro slag refining (ESR) has been employed to produce the alloy with lower inclusion content Tensile studies were carried out at various temperatures between ambient and 1023 K at an interval of 50 K and strain rate of 1.2 × 10–3 s–1 on the steels in 20% coldworked condition. Tensile properties of both VAR grade and ESR grade material were found to be similar. The influence of the secondary processing routes on the mechanical properties of alloy D9 is studied.

Palatal myoclonus is a rare movement disorder characterized by brief, rhythmic involuntary movements of the soft palate. Palatal myoclonus is further subdivided into “essential palatal tremor” (EPT) and “symptomatic palatal tremor” (SPT). EPT is characterized by involvement of the tensor veli palatini, myoclonus that might persist during sleep, as well as ear clicks, usually the patient’s presenting complaint. The MRI and neurological exam are normal in EPT. SPT is characterized by involvement of the levator veli palatini and myoclonus which consistently perseveres during sleep. The MRI shows olivary hypertrophy and clinical features may include ataxia, dysarthria and nystagmus, depending on the size of the lesion1. Glossopharyngeal breathing is a technique used by deep-sea divers to increase lung vital capacity, which is also useful in patients with ventilator dependence from poliomyelitis and Duchenne muscular dystrophy. To date there have been no reported cases of palatal myoclonus and glossopharyngeal breathing occurring simultaneously. We present the case of a 29 year-old female with palatal myoclonus and glossopharyngeal breathing after scuba-diving.

CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Previously, we demonstrated the efficacy of CMX001 in protecting New Zealand White rabbits from mortality following intradermal infection with rabbitpox virus as a model for smallpox, monkeypox and for treatment of adverse reactions to smallpox vaccination. Here we extend these studies by exploring different dosing regimens and performing randomized, blinded, placebo-controlled studies. In addition, because rabbitpox virus can be transmitted via naturally generated aerosols (animal to animal transmission), we report on studies to test the efficacy of CMX001 in protecting rabbits from lethal rabbitpox virus disease when infection occurs by animal to animal transmission. In all cases, CMX001 treatment was initiated at the onset of observable lesions in the ears to model the use of CMX001 as a treatment for symptomatic smallpox. The results demonstrate that CMX001 is an effective treatment for symptomatic rabbitpox virus infection. The rabbitpox model has key similarities to human smallpox including an incubation period, generalized systemic disease, the occurrence of lesions which may be used as a trigger for initiating therapy, and natural animal to animal spread, making it an appropriate model.

CMX001, a lipophilic nucleotide analog formed by covalently linking 3‑(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox virus, a zoonotic disease of Africa, and adverse reactions to smallpox virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the rabbitpox virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination.

No abstract available. Article truncated after 150 words. This month's journal club reviewed the role of macrolide antibiotics in chronic respiratory disease. Macrolide usage was suggested from observational studies in Japan in diffuse panbroncholitis, a disorder associated with chronic respiratory infection, usually Pseudomonas aeruginosa (1). Clinical improvement was noted despite doses of antibiotics well below the minimal inhibitory concentration (MIC) of the antibiotic. This suggested the antibiotic was likely working by an anti-inflammatory effect. These observations were extended to cystic fibrosis (CF) where prophylactic macrolide therapy in CF patients infected with Pseudomonas has become standard therapy (2). More recently, low dose macrolide therapy has been applied to non-CF lung diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis and asthma. Time did not permit a review of all studies so a representative sample was discussed. In patients with COPD, the four randomized, placebo-controlled trials reviewed all suggested that chronic therapy with macrolide antibiotics reduced COPD exacerbations (3-5). This ...

No abstract available. Article truncated at 150 words. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-82. Nintedanib is a tyrosine kinase inhibitor that has been shown to decrease the decline of FVC in phase 2 trials of idiopathic pulmonary fibrosis (IPF). This study was a phase 3 trial in which 2 replicate trials comparing nintedanib 150 mg twice daily to placebo. The trials were randomized double blind placebo controlled performed over 205 sites in 24 countries. Inclusion criteria were an age > 40, FVC > 50% and DLCO 30-79%. Patients were excluded if on prednisone > 15 mg/day or any other ...

Birds of the order Anseriformes, commonly referred to as waterfowl, are frequently infected by Haemosporidia of the genera Haemoproteus, Plasmodium, and Leucocytozoon via dipteran vectors. We analyzed nucleotide sequences of the Cytochrome b (Cytb) gene from parasites of these genera detected in six species of ducks from Alaska and California, USA to characterize the genetic diversity of Haemosporidia infecting waterfowl at two ends of the Pacific Americas Flyway. In addition, parasite Cytb sequences were compared to those available on a public database to investigate specificity of genetic lineages to hosts of the order Anseriformes. Haplotype and nucleotide diversity of Haemoproteus Cytb sequences was lower than was detected for Plasmodium and Leucocytozoon parasites. Although waterfowl are presumed to be infected by only a single species of Leucocytozoon, L. simondi, diversity indices were highest for haplotypes from this genus and sequences formed five distinct clades separated by genetic distances of 4.9%-7.6%, suggesting potential cryptic speciation. All Haemoproteus and Leucocytozoon haplotypes derived from waterfowl samples formed monophyletic clades in phylogenetic analyses and were unique to the order Anseriformes with few exceptions. In contrast, waterfowl-origin Plasmodium haplotypes were identical or closely related to lineages found in other avian orders. Our results suggest a more generalist strategy for Plasmodium parasites infecting North American waterfowl as compared to those of the genera Haemoproteus and Leucocytozoon.

We determine Green's function for a third-order three-point boundary-value problem of focal type and determine conditions on the coefficients and boundary points to ensure its positivity. We then apply this in the determination of the existence of positive solutions to a related higher-order functional differential equation.

We report a 52 year old male with a history splenic infarction, abdominal pain and shortness of breath. CT scanning revealed a splenic abcess and empyema. Cultures from both sites grew Streptococcus anginosus. These resolved with drainage and antibiotics. Physicians should consider Streptococcus species when confronted with a patient with splenic infarction.