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Abstract As the part of a study to develop buparvaquone (BPQ) formulations for the treatment of cutaneous leishmaniasis, the topical delivery of BPQ and one of its prodrugs from a range of formulations was evaluated. In previous studies, BPQ and its prodrugs were shown to be potent antileishmanials in-vitro, with ED50 values in the nanomolar range. 3-Phosphono-oxymethyl-buparvaquone (3-POM-BPQ) was the most potent antileishmanial and was chosen, together with the parent drug, for further investigation. The ability of the parent and prodrug formulations to cross human and murine skin was tested in-vitro using the Franz diffusion cells. Formulations intended for topical application containing either BPQ or 3-POM-BPQ were developed using excipients that were either acceptable for topical use (GRAS or FDA inactive ingredients) or currently going through the regulatory process. BPQ was shown to penetrate both human epidermal membranes and full thickness BALB/c skin from a range of formulations (gels, emulsions). Similarly, 3-POM-BPQ penetrated full-thickness BALB/c skin from several gel formulations. In-vitro binding studies showed that BPQ bound melanin in a dose-dependent manner and preferably bound to delipidized skin over untreated BALB/c skin (on a weight to weight basis). The results confirm that BPQ and its prodrug 3-POM-BPQ can penetrate the skin from several formulations, making them potentially interesting candidates for further investigation of topical formulations using in-vivo models of cutaneous leishmaniasis.

Anaphylactic reactions to ethanol are rare with only seven cases reported in the literature. All previous cases have occurred following ingestion of alcoholic beverages or food to which an alcoholic beverage has been added. To date there are no cases in the literature of ethanol-induced anaphylaxis caused by the accumulation of endogenous ethanol in overripe fruit.We report a patient with ethanol-induced anaphylaxis who developed anaphylaxis following ingestion of overripe, but not fresh rock melon (Cucumis melo). The patient is a 24-year-old, previously well woman who experienced five episodes of acute anaphylaxis following ingestion of various alcoholic beverages and, on one occasion, following ingestion of overripe rock melon to which no ethanol was added. Ethanol-induced anaphylaxis was confirmed on blinded challenge; however, challenge with freshly prepared rock melon was negative. The patient declined further challenges.Ingestion of overripe fruits may cause anaphylaxis in patients with ethanol-induced anaphylaxis. These patients should therefore, be advised to avoid ingestion of overripe fruits.

Neuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is known about the relation between GM volume abnormalities and polysubstance use.In this study we assessed the relation between GM volume, and the use of alcohol, tobacco, cocaine and cannabis as well as the total number of substances used, in a sample of 169 males: 15 non-substance users, 89 moderate drinkers, 27 moderate drinkers who also smoke tobacco, 13 moderate drinkers who also smoke tobacco and use cocaine, 10 heavy drinkers who smoke tobacco and use cocaine and 15 heavy drinkers who smoke tobacco, cannabis and use cocaine.Regression analyses showed that there was a negative relation between the number of substances used and volume of the dorsal medial prefrontal cortex (mPFC) and the ventral mPFC. Without controlling for the use of other substances, the volume of the dorsal mPFC was negatively associated with the use of alcohol, tobacco, and cocaine. After controlling for the use of other substances, a negative relation was found between tobacco and cocaine and volume of the thalami and ventrolateral PFC, respectively.These findings indicate that mPFC alterations may not be substance-specific, but rather related to the number of substances used, whereas, thalamic and ventrolateral PFC pathology is specifically associated with tobacco and cocaine use, respectively. These findings are important, as the differential alterations in GM volume may underlie different cognitive deficits associated with substance use disorders.

Failure to successfully implement and sustain change over the long term continues to be a major problem in health and social care. Translating evidence into routine clinical practice is notoriously complex, and it is recognised that to implement new evidence-based interventions and sustain them over time, professional behaviour needs to change accordingly. A number of theories and frameworks have been developed to support behaviour change among health and social care professionals, and models of sustainability are emerging, but few have translated into valid and reliable interventions. The long-term success of healthcare professional behavioural change interventions is variable, and the characteristics of successful interventions unclear. Previous reviews have synthesised the evidence for behaviour change, but none have focused on sustainability. In addition, multiple overlapping reviews have reported inconsistent results, which do not aid translation of evidence into practice. Overviews of reviews can provide accessible succinct summaries of evidence and address barriers to evidence-based practice. We aim to compile an overview of reviews, identifying, appraising and synthesising evidence relating to sustained social and healthcare professional behaviour change.We will conduct a systematic review of Cochrane reviews (an Overview). We plan to systematically search the Cochrane Database of Systematic Reviews. We will include all systematic reviews of randomised controlled trials comparing a healthcare professional targeted behaviour change intervention to a standard care or no intervention control group. Two reviewers will independently assess the eligibility of the reviews and the methodological quality of included reviews using the ROBIS tool. The quality of evidence within each comparison in each review will be judged based on the GRADE criteria. Disagreements will be resolved through discussion. Effects of interventions will be systematically tabulated and the quality of evidence used to determine implications for clinical practice and make recommendations for future research.This overview will bring together the best available evidence relating to the sustainability of health professional behaviour change, thus supporting policy makers with decision-making in this field.

The effect of extreme temperature has become an increasing public health concern. Evaluating the impact of ambient temperature on morbidity has received less attention than its impact on mortality.We performed a systematic literature review and extracted quantitative estimates of the effects of hot temperatures on cardiorespiratory morbidity. There were too few studies on effects of cold temperatures to warrant a summary. Pooled estimates of effects of heat were calculated using a Bayesian hierarchical approach that allowed multiple results to be included from the same study, particularly results at different latitudes and with varying lagged effects.Twenty-one studies were included in the final meta-analysis. The pooled results suggest an increase of 3.2% (95% posterior interval = -3.2% to 10.1%) in respiratory morbidity with 1°C increase on hot days. No apparent association was observed for cardiovascular morbidity (-0.5% [-3.0% to 2.1%]). The length of lags had inconsistent effects on the risk of respiratory and cardiovascular morbidity, whereas latitude had little effect on either.The effects of temperature on cardiorespiratory morbidity seemed to be smaller and more variable than previous findings related to mortality.

Many countries are developing or reviewing national adaptation policy for climate change but the extent to which these meet the health needs of vulnerable groups has not been assessed. This study examines the adequacy of such policies for nine known climate-vulnerable groups: people with mental health conditions, Aboriginal people, culturally and linguistically diverse groups, aged people, people with disabilities, rural communities, children, women, and socioeconomically disadvantaged people.The study analyses an exhaustive sample of national adaptation policy documents from Annex 1 ('developed') countries of the United Nations Framework Convention on Climate Change: 20 documents from 12 countries. A 'critical computational linguistics' method was used involving novel software-driven quantitative mapping and traditional critical discourse analysis.The study finds that references to vulnerable groups are relatively little present or non-existent, as well as poorly connected to language about practical strategies and socio-economic contexts, both also little present.The conclusions offer strategies for developing policy that is better informed by a 'social determinants of health' definition of climate vulnerability, consistent with best practice in the literature and global policy prescriptions.

Few studies on population-specific health effects of extreme temperature on cardiovascular diseases (CVDs) deaths have been conducted in the subtropical and tropical climates of China. We examined the association between extreme temperature and CVD across four cities in China. We performed a two-stage analysis; we generated city-specific estimates using a distributed lag non-linear model (DLNM) and estimated the overall effects by conducting a meta-analysis. Heat thresholds of 29 °C, 29 °C, 29 °C, and 30 °C and cold thresholds of 6 °C, 10 °C, 14 °C, and 15 °C were observed in Hefei, Changsha, Nanning, and Haikou, respectively. The lag periods for heat-related CVD mortality were observed only for 0–2 days, while those of cold-related CVD mortality were observed for 10–15 days. The meta-analysis showed that a 1 °C increase above the city-specific heat threshold was associated with average overall CVD mortality increases of 4.6% (3.0%–6.2%), 6.4% (3.4%–9.4%), and 0.2% (−4.8%–5.2%) for all ages, ≥65 years, and <65 years over a lag period of 0–2 days, respectively. Similarly, a 1 °C decrease below the city-specific cold threshold was associated with average overall CVD mortality increases of 4.2% (3.0%–5.4%), 4.9% (3.5%–6.3%), and 3.1% (1.7%–4.5%), for all ages, ≥65 years, and <65 years over a lag period of 0–15 days, respectively. This work will help to take appropriate measures to reduce temperature-mortality risk in different populations in the subtropical and tropical climates of China.