Impact of nocturnal hypoxia on glycaemic control, appetite, gut microbiota and inflammation in adults with type 2 diabetes mellitus: A single-blind cross-over trial.

High altitude residents have a lower incidence of type 2 diabetes mellitus (T2DM). Therefore, we examined the effect of repeated overnight normobaric hypoxic exposure on glycaemic control, appetite, gut microbiota and inflammation in adults with T2DM. Thirteen adults with T2DM [glycated haemoglobin (HbA1c): 61.1 ± 14.1 mmol mol-1; aged 64.2 ± 9.4 years; four female] completed a single-blind, randomised, sham-controlled, cross-over study for 10 nights, sleeping when exposed to hypoxia (fractional inspired O2 [ F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ] = 0.155; ∼2500 m simulated altitude) or normoxic conditions ( F I O 2 ${{F}_{{\mathrm{I}}{{{\mathrm{O}}}_{\mathrm{2}}}}}$  = 0.209) in a randomised order. Outcome measures included: fasted plasma [glucose]; [hypoxia inducible factor-1α]; [interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]; [heat shock protein 70]; [butyric acid]; peak plasma [glucose] and insulin sensitivity following a 2 h oral glucose tolerance test; body composition; appetite indices ([leptin], [acyl ghrelin], [peptide YY], [glucagon-like peptide-1]); and gut microbiota diversity and abundance [16S rRNA amplicon sequencing]. During intervention periods, accelerometers measured physical activity, sleep duration and efficiency, whereas continuous glucose monitors were used to assess estimated HbA1c and glucose management indicator and time in target range. Overnight hypoxia was not associated with changes in any outcome measure (P > 0.05 with small effect sizes) except fasting insulin sensitivity and gut microbiota alpha diversity, which exhibited trends (P = 0.10; P = 0.08 respectively) for a medium beneficial effect (d = 0.49; d = 0.59 respectively). Ten nights of overnight moderate hypoxic exposure did not significantly affect glycaemic control, gut microbiome, appetite, or inflammation in adults with T2DM. However, the intervention was well tolerated and a medium effect-size for improved insulin sensitivity and reduced alpha diversity warrants further investigation. KEY POINTS: Living at altitude lowers the incidence of type 2 diabetes mellitus (T2DM). Animal studies suggest that exposure to hypoxia may lead to weight loss and suppressed appetite. In a single-blind, randomised sham-controlled, cross-over trial, we assessed the effects of 10 nights of hypoxia (fractional inspired O2 ∼0.155) on glucose homeostasis, appetite, gut microbiota, inflammatory stress ([interleukin-6]; [tumour necrosis factor-α]; [interleukin-10]) and hypoxic stress ([hypoxia inducible factor 1α]; heat shock protein 70]) in 13 adults with T2DM. Appetite and inflammatory markers were unchanged following hypoxic exposure, but an increased insulin sensitivity and reduced gut microbiota alpha diversity were associated with a medium effect-size and statistical trends, which warrant further investigation using a definitive large randomised controlled trial. Hypoxic exposure may represent a viable therapeutic intervention in people with T2DM and particularly those unable or unwilling to exercise because barriers to uptake and adherence may be lower than for other lifestyle interventions (e.g. diet and exercise).

Evaluating trends in cigarette and HTP use in Japan and measurement issues in the National Health and Nutrition Survey.

INTRODUTION: Studies have reported that the rapid rise in heated tobacco product (HTP) sales in Japan accompanied an accelerated decline in cigarette sales. However, these studies do not distinguish whether those who previously smoked cigarettes became dual users with HTPs (smoking fewer cigarettes) or instead switched completely to HTPs. If HTPs present lower health risks than cigarettes, replacing cigarettes with HTPs is more likely to improve public health than cigarette users continuing as dual users. METHODS: To evaluate the role of HTP introduction relative to smoking prevalence, we examine trends in cigarette prevalence as related to trends in HTP use using Japan's National Health and Nutrition Survey (NHNS) from 2011 to 2019. We develop measures of relative changes in smoking prevalence use by age and gender in the pre-HTP and post-HTP periods. We then analyse prevalence data by year using joinpoint regression to statistically distinguish changes in trend. RESULTS: Compared with the pre-HTP 2011-2014 period, cigarette prevalence decreased more rapidly during the post-HTP 2014-2017 period, particularly among younger age groups. However, the changing format of NHNS questions limits our ability to determine the impact on smoking prevalence, particularly after 2017. CONCLUSIONS: While suggesting that HTPs helped some people who smoke to quit smoking, this study also shows the difficulties in eliciting accurate survey responses about product use and distinguishing the impact of a potentially harm-reducing product in an environment subject to rapidly evolving patterns of use.

Support for banning sale of smoked tobacco products among adults who smoke: findings from the International Tobacco Control Four Country Smoking and Vaping Surveys (2018-2022).

BACKGROUND: Many people continue to smoke despite strong policies to deter use, thus stronger regulatory measures may be required. In four high-income countries, we examined whether people who smoke would support a total ban on smoked tobacco products under two differing policy scenarios. METHODS: Data were from 14 363 adults (≥18) who smoked cigarettes (≥monthly) and participated in at least one of the 2018, 2020 or 2022 International Tobacco Control Four Country Smoking and Vaping Surveys in Australia, Canada, England and the USA. In 2018, respondents were asked whether they would support a law that totally bans smoked tobacco if the government provides smoking cessation assistance (Cessation Assistance scenario). In 2020 and 2022, respondents were asked a slightly different question as to whether they would support a law that totally bans smoked tobacco if the government encourages people who smoke to use alternative nicotine products like vaping products and nicotine replacement products instead (substitution scenario). Responses (support vs oppose/don't know) were estimated on weighted data. RESULTS: Support was greater for the cessation assistance scenario (2018, 36.6%) than the nicotine substitution scenario (2020, 26.9%; 2022, 26.3%, both p<0.0001). In the longitudinal analysis, there was a significant scenario by country interaction effect with lower support in Canada, the USA and Australia under the substitution scenario than in the cessation scenario, but equivalent levels in England under both scenarios. The strongest correlates of support under both scenarios were planning to quit smoking within 6 months, wanting to quit smoking 'a lot' and recent use of nicotine replacement therapy. CONCLUSIONS: Opposition to banning smoked tobacco predominates among people who smoke, but less with a cessation assistance scenario than one encouraging nicotine substitution. Wanting to quit a lot was the strongest indicator of support.

The effect of repeated hot water immersion on insulin sensitivity, heat shock protein 70, and inflammation in individuals with type 2 diabetes mellitus.

Repeated hot water immersion (HWI) can improve glycemic control in healthy individuals but data are limited for individuals with type 2 diabetes mellitus (T2DM). The present study investigated whether repeated HWI improves insulin sensitivity and inflammatory status and reduces plasma ([extracellular heat shock protein 70]) [eHSP70] and resting metabolic rate (RMR). Fourteen individuals with T2DM participated in this pre- versus postintervention study, with outcome measures assessed in fasted (≥12 h) and postprandial (2-h post-75 g glucose ingestion) states. HWI consisted of 1 h in 40°C water (target rectal temperature 38.5°C-39°C) repeated 8-10 times within a 14-day period. Outcome measures included insulin sensitivity, plasma [glucose], [insulin], [eHSP70], inflammatory markers, RMR, and substrate utilization. The HWI intervention increased fasted insulin sensitivity (QUICKI; P = 0.03) and lowered fasted plasma [insulin] (P = 0.04), but fasting plasma [glucose] (P = 0.83), [eHSP70] (P = 0.08), [IL-6] (P = 0.55), [IL-10] (P = 0.59), postprandial insulin sensitivity (P = 0.19), plasma [glucose] (P = 0.40), and [insulin] (P = 0.47) were not different. RMR was reduced by 6.63% (P < 0.05), although carbohydrate (P = 0.43) and fat oxidation (P = 0.99) rates were unchanged. This study shows that 8-10 HWIs within a 14-day period improved fasting insulin sensitivity and plasma [insulin] in individuals with T2DM, but not when glucose tolerance is challenged. HWI also improves metabolic efficiency (i.e., reduced RMR). Together these results could be clinically important and have implications for metabolic health outcomes and well-being in individuals with T2DM.NEW & NOTEWORTHY This is the first study to investigate repeated HWI to raise deep body temperature on insulin sensitivity, inflammation, eHSP70, and substrate utilization in individuals with T2DM. The principal novel findings were improvements in fasting insulin sensitivity and fasting plasma [insulin] but no change in fasting plasma [glucose], postprandial insulin sensitivity, plasma [insulin], or [glucose]. There was also no change in eHSP70, inflammatory status, or substrate utilization but there were reductions in RMR and oxygen consumption.

Follow the money: a closer look at US tobacco industry marketing expenditures.

INTRODUCTION: While much of the concern with tobacco industry marketing has focused on direct media advertising, a less explored form of marketing strategy is to discount prices. Price discounting is important because it keeps the purchase price low and can undermine the impact of tax increases. METHODS: We examine annual US marketing expenditures from 1975 to 2019 by the largest cigarette and smokeless tobacco companies as reported to the Federal Trade Commission. We consider three categories: direct advertising, promotional allowances and price discounting. In addition to considering trends in these expenditures, we examine how price discounting expenditures relate to changes in product prices and excise taxes. RESULTS: US direct advertising expenditures for cigarettes fell from 80% of total industry marketing expenditures in 1975 to less than 3% in 2019, while falling from 39% in 1985 to 6% in 2019 for smokeless tobacco. Price discounting expenditures for cigarettes became prominent after the Master Settlement Agreement and related tax increases in 2002. By 2019, 87% of cigarette marketing expenditures were for price discounts and 7% for promotional allowances. Smokeless marketing expenditures were similar: 72% for price promotions and 13% for promotional allowances. Price discounting increased with prices and taxes until reaching their currently high levels. CONCLUSIONS: Between 1975 and 2019, direct advertising dramatically fell while price discounting and promotional expenditures increased. Local, state and federal policies are needed that apply non-tax mechanisms to increase tobacco prices and restrict industry contracts to offset industry marketing strategies. Further study is needed to better understand industry decisions about marketing expenditures.

Characterisation of vaping liquids used in vaping devices across four countries: results from an analysis of selected vaping liquids reported by users in the 2016 ITC Four Country Smoking and Vaping Survey.

OBJECTIVES: This study presents an analysis of vaping products (VPs) purchased in the USA, Canada, England and Australia and assesses whether differences in regulations were associated with differences in the chemical composition of the VPs. METHODS: April-September 2017, a total of 234 VP refill liquids and prefilled cartridges were purchased in convenience samples of retail locations in each country. Products were chosen from brands and styles most commonly reported by current VP users in the 2016 ITC Four Country Smoking and Vaping Survey. All products were tested for nicotine, tobacco-specific nitrosamines (TSNAs), minor tobacco alkaloids, organic acids and flavouring chemicals. RESULTS: Consistent with the laws in Canada and Australia at the time of product purchase, nicotine was not detected in any of the VPs (n=10 in Canada; n=15 in Australia). US liquids (n=54) had a mean nicotine concentration of 16.2 mg/mL, (range=0.0-58.6) and English liquids (n=166) had a mean concentration of 11.9 mg/mL ((range=0.0-31.2) F(3244)=12.32, p<0.001). About 5% of English samples exceeded the UK's 20 mg/mL nicotine limit. Substantial country differences were observed in levels ofTSNAs, with the USA being higher than elsewhere. Of all products tested, 18.8% contained at least one organic acid. Liquids purchased in England contained far more identifiable flavouring chemicals than those in the other countries. CONCLUSIONS: VP composition, particularly with respect to nicotine and flavouring, varies by country, likely reflecting both marketplace preferences and country-specific regulations. There are differences between nicotine levels claimed on the package and actual levels, particularly in England.

Switching to cigarette brand variants with different filter ventilation levels: a descriptive analysis.

BACKGROUND: Regulation of filter ventilation (FV) has been proposed to reduce misperceptions that ventilation reduces the health risks of smoking. We describe smoking behaviour and exposure after switching to a cigarette brand variant (CBV) with a different FV level. METHODS: Wave 1 (2013-2014) of the Population Assessment of Tobacco Use and Health Study was merged with FV levels of participants' CBV and restricted to adults with a usual CBV, smoked daily and included in wave 4 (2016-2017; n=371). Generalised estimation equations method modelled changes in FV and cigarettes per day (CPD), quit interest, total nicotine equivalents (TNE) and total NNAL (biomarker of a tobacco-specific carcinogen). FV change was defined as a change in CBV resulting in a ≥20% increase or decrease in FV. Secondary analyses used FV change based on an increase from <5% to >10% or a decrease from >10% to <5%. RESULTS: A non-significant pattern indicating an increase of 0.97 and 0.49 CPD was observed among those who switched to a CBV and increased FV by ≥20% and from <5% to >10%, respectively. A non-significant pattern indicating a decrease of 1.31 and 1.97 CPD was observed among those who decreased FV by ≥20% and from >10% to <5%, respectively. Changes in quit interest and biomarkers were also non-significant with one exception: greater reduction in TNE among those who decreased from >10% to <5% FV versus no change (-8.51 vs -0.25 nmol/mg creatinine; p=0.0447). CONCLUSIONS: Switching to CBV with lower FV does not appear to increase exposure and may even reduce exposure for some. Additional investigations are recommended to confirm these descriptive findings.

Development and validation of a case definition for problematic menopause in primary care electronic medical records.

BACKGROUND: Menopause is a normal transition in a woman's life. For some women, it is a stage without significant difficulties; for others, menopause symptoms can severely affect their quality of life. This study developed and validated a case definition for problematic menopause using Canadian primary care electronic medical records, which is an essential step in examining the condition and improving quality of care. METHODS: We used data from the Canadian Primary Care Sentinel Surveillance Network including billing and diagnostic codes, diagnostic free-text, problem list entries, medications, and referrals. These data formed the basis of an expert-reviewed reference standard data set and contained the features that were used to train a machine learning model based on classification and regression trees. An ad hoc feature importance measure coupled with recursive feature elimination and clustering were applied to reduce our initial 86,000 element feature set to a few tens of the most relevant features in the data, while class balancing was accomplished with random under- and over-sampling. The final case definition was generated from the tree-based machine learning model output combined with a feature importance algorithm. Two independent samples were used: one for training / testing the machine learning algorithm and the other for case definition validation. RESULTS: We randomly selected 2,776 women aged 45-60 for this analysis and created a case definition, consisting of two occurrences within 24 months of International Classification of Diseases, Ninth Revision, Clinical Modification code 627 (or any sub-codes) OR one occurrence of Anatomical Therapeutic Chemical classification code G03CA (or any sub-codes) within the patient chart, that was highly effective at detecting problematic menopause cases. This definition produced a sensitivity of 81.5% (95% CI: 76.3-85.9%), specificity of 93.5% (91.9-94.8%), positive predictive value of 73.8% (68.3-78.6%), and negative predictive value of 95.7% (94.4-96.8%). CONCLUSION: Our case definition for problematic menopause demonstrated high validity metrics and so is expected to be useful for epidemiological study and surveillance. This case definition will enable future studies exploring the management of menopause in primary care settings.

Influence of air mapping errors on the dosimetric accuracy of prostate CBCT-guided online adaptive radiation therapy.

PURPOSE: CBCT-guided online adaptive radiotherapy (oART) plans presently utilize daily synthetic CTs (sCT) that are automatically generated using deformable registration algorithms. These algorithms may have poor performance at reproducing variable volumes of gas present during treatment. Therefore, we have analyzed the air mapping error between the daily CBCTs and the corresponding sCT and explored its dosimetric effect on oART plan calculation. METHODS: Abdominopelvic air volume was contoured on both the daily CBCT images and the corresponding synthetic images for 207 online adaptive pelvic treatments. Air mapping errors were tracked over all fractions. For two case studies representing worst case scenarios, dosimetric effects of air mapping errors were corrected in the sCT images using the daily CBCT air contours, then recalculating dose. Dose volume histogram statistics and 3D gamma passing rates were used to compare the original and air-corrected sCT-based dose calculations. RESULTS: All analyzed patients showed observable air pocket contour differences between the sCT and the CBCT images. The largest air volume difference observed in daily CBCT images for a given patient was 276.3 cc, a difference of more than 386% compared to the sCT. For the two case studies, the largest observed change in DVH metrics was a 2.6% reduction in minimum PTV dose, with all other metrics varying by less than 1.5%. 3D gamma passing rates using 1%/1 mm criteria were above 90% when comparing the uncorrected and corrected dose distributions. CONCLUSION: Current CBCT-based oART workflow can lead to inaccuracies in the mapping of abdominopelvic air pockets from daily CBCT to the sCT images used for the optimization and calculation of the adaptive plan. Despite the large observed mapping errors, the dosimetric effects of such differences on the accuracy of the adapted plan dose calculation are unlikely to cause differences greater than 3% for prostate treatments.

A critical assessment of gene catalogs for metagenomic analysis.

MOTIVATION: Microbial gene catalogs are data structures that organize genes found in microbial communities, providing a reference for standardized analysis of the microbes across samples and studies. Although gene catalogs are commonly used, they have not been critically evaluated for their effectiveness as a basis for metagenomic analyses. RESULTS: As a case study, we investigate one such catalog, the Integrated Gene Catalog (IGC), however, our observations apply broadly to most gene catalogs constructed to date. We focus on both the approach used to construct this catalog and on its effectiveness when used as a reference for microbiome studies. Our results highlight important limitations of the approach used to construct the IGC and call into question the broad usefulness of gene catalogs more generally. We also recommend best practices for the construction and use of gene catalogs in microbiome studies and highlight opportunities for future research. AVAILABILITY AND IMPLEMENTATION: All supporting scripts for our analyses can be found on GitHub: https://github.com/SethCommichaux/IGC.git. The supporting data can be downloaded from: https://obj.umiacs.umd.edu/igc-analysis/IGC_analysis_data.tar.gz. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Changes in responses to nicotine vaping product warnings and leaflets in England compared with Canada, the US and Australia: findings from the 2016-2018 ITC Four Country Smoking and Vaping Surveys.

BACKGROUND AND AIMS: In May 2017, black-and-white text nicotine addiction warning labels ('warnings') and health and safety leaflets ('leaflets') became mandatory for nicotine vaping products (NVPs) in England, in accordance with the European Union's Tobacco Products Directive. We compared changes over time in noticing warnings and leaflets, recall of warnings about nicotine and concerns about using NVP due to noticing warnings in England, compared with Canada, the US and Australia, where no warnings and leaflets were mandated. DESIGN: 19 005 adult (aged 18+) NVP users, smokers and quitters of cigarettes and NVP from the 2016 and 2018 International Tobacco Control Four Country Smoking and Vaping Surveys in England, Canada, the US and Australia, recruited via probability and non-probability sampling. FINDINGS: Noticing warnings increased in England from 4.9% (2016) to 9.4% (2018) (adjusted OR/AOR=1.64, 95% CI=1.15-2.36); this change was larger than changes in Canada (AOR=2.51, 95% CI=1.71-3.69) and the US (AOR=2.22, 95% CI=1.45-3.39). Recall of a nicotine warning increased in England from 86% (2016) to 94.9% (2018) (AOR=5.50, 95% CI=1.57-19.27) but not significantly elsewhere. Noticing leaflets increased in England from 14.6% (2016) to 19.1% (2018) (AOR=1.42, 95% CI=1.15-1.74); this change was larger than in Canada (AOR=1.42, 95% CI=1.12-1.79), the US (AOR=1.55, 95% CI=1.17-2.06) and Australia (AOR=1.51, 95% CI=1.02-2.22). Among those noticing warnings, concern about NVP use did not change significantly between 2016 and 2018 (all countries p>0.081). CONCLUSIONS: Introduction of mandatory NVP warnings and leaflets in England was associated with small increases in noticing them but not with changes in concerns about NVP use.

A randomised placebo controlled trial of VSL#3® probiotic on biomarkers of cardiovascular risk and liver injury in non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with increased cardiovascular risk irrespective of conventional risk factors. The role of gut-liver interaction is implicated in its development. We investigated the effects of VSL#3® probiotic supplementation on biomarkers of cardiovascular risk and liver injury in patients with NAFLD. METHODS: A randomised, double-blinded, placebo-controlled, proof-of-concept study was undertaken. Patients with NAFLD were randomly allocated to take 2 sachets VSL#3® probiotic or placebo twice daily for 10 weeks. Measurements of endothelial function (digital photoplethysmography, sVCAM-1 and cGMP), oxidative stress (glutathione ratio and LHP), inflammation (hsCRP), insulin resistance (HOMA-IR) and liver injury [transaminases, fibrosis risk score and acoustic structure quantification (ASQ)] were undertaken before and after intervention. Difference in baseline characteristics between the treatment groups was analysed using independent t-test or Mann Whitney U test for non-parametric data. Independent t-test was used to compare the outcomes at the end of the study between the two treatment groups. Wilcoxon Signed Rank test was used to determine the difference in fibrosis risk scores before and after treatment. Spearman's correlation was used to determine any association between cardiovascular and hepatic markers at baseline. RESULTS: Thirty-five patients completed the study (28 males and 7 females) with a mean age of 57 ± 8 years, body mass index of 32.6 ± 5.0 kg/m2 and a relatively short duration of NAFLD (median duration 0.3 IQR 2.0 years). No significant difference was observed in biomarkers of cardiovascular risk and liver injury following VSL#3® supplementation. Significant correlations were noted between sVCAM-1 and hsCRP (rho = 0.392, p = 0.01), and HOMA-IR and AST (rho = 0.489, p < 0.01) at baseline. CONCLUSIONS: This is the first study to evaluate the effect of VSL#3® on ASQ in patients with NAFLD. VSL#3® did not significantly improve markers of cardiovascular risk and liver injury in patients with NAFLD. However, the study supports an association between endothelial dysfunction and inflammation in patients with NAFLD and suggests that NAFLD is linked with insulin resistance. TRIAL REGISTRATION: ISRCTN05474560 ( https://doi.org/10.1186/ISRCTN05474560 ) Registered 9 August 2012 (retrospectively registered).

Smokers' awareness of filter ventilation, and how they believe it affects them: findings from the ITC Four Country Survey.

BACKGROUND: Filter ventilation creates sensations of 'lightness' or 'smoothness' and is also highly effective for controlling machine-tested yields of tar, nicotine and carbon monoxide. Nearly all factory-made cigarettes (FMC) now have filter ventilation in countries such as Australia, Canada, the UK and the USA. Research conducted before 'light' and 'mild' labelling was banned found low smoker awareness of filter ventilation and its effects. This study explores current levels of awareness of filter ventilation and current understanding of its effects in these four countries. METHODS: We used data from the 2018 wave of the ITC Four Country Smoking and Vaping Survey with samples from USA, England, Canada and Australia. Analyses were conducted initially on a weighted sample of 11 844, and subsequently on 7541 daily FMC smokers. FINDINGS: Only 40.3% of all respondents reported being aware of filter ventilation. Among daily FMC smokers, only 9.4% believed their cigarettes had filter ventilation. Believing that their usual cigarettes are smoother was positively associated with believing they are also less harmful. Both these beliefs independently predict believing their cigarettes are ventilated (smoother OR=1.97 (95% CI 1.50 to 2.59) and less harmful OR=2.41 (95% CI 1.66 to 3.49) in relation to those believing each characteristic is average. INTERPRETATION: Awareness of filter ventilation is currently low, despite decades of public 'education efforts around the misleading nature of 'light' and 'mild" descriptors. Few smokers realise that their cigarettes almost certainly are vented. Smokers who believed their cigarettes have filter ventilation were more likely to believe they were both smoother and less harmful. Awareness of the technology appears to be insufficient to prevent smokers being deceived by it. Filter ventilation is inherently misleading to smokers and it is time to ban it.

BEAGLE 3: Improved Performance, Scaling, and Usability for a High-Performance Computing Library for Statistical Phylogenetics.

BEAGLE is a high-performance likelihood-calculation library for phylogenetic inference. The BEAGLE library defines a simple, but flexible, application programming interface (API), and includes a collection of efficient implementations for calculation under a variety of evolutionary models on different hardware devices. The library has been integrated into recent versions of popular phylogenetics software packages including BEAST and MrBayes and has been widely used across a diverse range of evolutionary studies. Here, we present BEAGLE 3 with new parallel implementations, increased performance for challenging data sets, improved scalability, and better usability. We have added new OpenCL and central processing unit-threaded implementations to the library, allowing the effective utilization of a wider range of modern hardware. Further, we have extended the API and library to support concurrent computation of independent partial likelihood arrays, for increased performance of nucleotide-model analyses with greater flexibility of data partitioning. For better scalability and usability, we have improved how phylogenetic software packages use BEAGLE in multi-GPU (graphics processing unit) and cluster environments, and introduced an automated method to select the fastest device given the data set, evolutionary model, and hardware. For application developers who wish to integrate the library, we also have developed an online tutorial. To evaluate the effect of the improvements, we ran a variety of benchmarks on state-of-the-art hardware. For a partitioned exemplar analysis, we observe run-time performance improvements as high as 5.9-fold over our previous GPU implementation. BEAGLE 3 is free, open-source software licensed under the Lesser GPL and available at https://beagle-dev.github.io.

Dopamine antagonist antipsychotics in diverted forensic populations.

In community settings, negative symptoms and cognitive deficits are the primary barriers to independent living, stable relationships, and employment for individuals suffering from schizophrenia-spectrum disorders. In contrast, however, positive psychotic symptoms (e.g., command hallucinations and persecutory delusions) often drive behavior which serves as the gateway to arrest and criminalization. Historically, the keystone of treatment for positive psychotic symptoms has been antagonism of dopamine D2 receptors in the mesolimbic tract. In this article, we review and explore the principles underlying dopamine antagonism for the treatment of psychosis; optimization of dopamine antagonists in treating positive psychotic symptoms; the advantages of depot dopamine antagonist antipsychotics in forensic settings; the concepts of pharmacokinetic and pharmacodynamic treatment failures; and the role of medication plasma concentrations in optimizing and managing treatment.

The Cal-DSH diversion guidelines.

The Cal-DSH Diversion Guidelines provide 10 general guidelines that jurisdictions should consider when developing diversion programs for individuals with a serious mental illness (SMI) who become involved in the criminal justice system. Screening for SMI in a jail setting is reviewed. In addition, important treatment interventions for SMI and substance use disorders are highlighted with the need to address criminogenic risk factors highlighted.

Cross-country comparison of cigarette and vaping product marketing exposure and use: findings from 2016 ITC Four Country Smoking and Vaping Survey.

OBJECTIVE: To compare exposure to and use of certain cigarette and vaping product marketing among adult smokers and vapers in four countries with contrasting regulations-Australia (AU), Canada, England and the USA. DATA SOURCES: Adult smokers and vapers (n=12 294) from the 2016 International Tobacco Control (ITC) Four Country Smoking and Vaping Survey (4CV1). ANALYSIS: Self-reported exposure to cigarette and vaping product advertising through point-of-sale, websites/social media, emails/texts, as well as exposure to and use of price offers were assessed for country differences using logistic regression models adjusted for multiple covariates. RESULTS: Reported exposure to cigarette advertising exposure at point-of-sale was higher in the USA (52.1%) than in AU, Canada and England (10.5%-18.5%). Exposure to cigarette advertising on websites/social media and emails/texts was low overall (1.5%-10.4%). Reported exposure to vaping ads at point-of-sale was higher in England (49.3%) and USA (45.9%) than in Canada (32.5%), but vaping ad exposure on websites/social media in Canada (15.1%) was similar with England (18.4%) and the USA (12.1%). Exposure to vaping ads via emails/texts was low overall (3.1%-9.9%). Exposure to, and use of, cigarette price offers was highest in the USA (34.0 % and 17.8 %, respectively), but the use rate among those exposed was highest in AU (64.9%). Exposure to, and use of, price offers for vaping products was higher in the USA (42.3 % and 21.7 %) than in AU, Canada and England (25.9%-31.5 % and 7.4%-10.3 %). CONCLUSIONS: Patterns of cigarette and vaping product marketing exposure generally reflected country-specific policies, except for online vaping ads. Implications for research and policy are discussed.

Methods to improve the quality of smoking records in a primary care EMR database: exploring multiple imputation and pattern-matching algorithms.

BACKGROUND: Primary care electronic medical record (EMR) data are emerging as a useful source for secondary uses, such as disease surveillance, health outcomes research, and practice improvement. These data capture clinical details about patients' health status, as well as behavioural risk factors, such as smoking. While the importance of documenting smoking status in a healthcare setting is recognized, the quality of smoking data captured in EMRs is variable. This study was designed to test methods aimed at improving the quality of patient smoking information in a primary care EMR database. METHODS: EMR data from community primary care settings extracted by two regional practice-based research networks in Alberta, Canada were used. Patients with at least one encounter in the previous 2 years (2016-2018) and having hypertension according to a validated definition were included (n = 48,377). Multiple imputation was tested under two different assumptions for missing data (smoking status is missing at random and missing not-at-random). A third method tested a novel pattern matching algorithm developed to augment smoking information in the primary care EMR database. External validity was examined by comparing the proportions of smoking categories generated in each method with a general population survey. RESULTS: Among those with hypertension, 40.8% (n = 19,743) had either no smoking information recorded or it was not interpretable and considered missing. Those with missing smoking data differed statistically by demographics, clinical features, and type of EMR system used in the clinic. Both multiple imputation methods produced fully complete smoking status information, with the proportion of current smokers estimated at 25.3% (data missing at random) and 12.5% (data missing not-at-random). The pattern-matching algorithm classified 18.2% of patients as current smokers, similar to the population-based survey (18.9%), but still resulted in missing smoking information for 23.6% of patients. The algorithm was estimated to be 93.8% accurate overall, but varied by smoking status category. CONCLUSION: Multiple imputation and algorithmic pattern-matching can be used to improve EMR data post-extraction but the recommended method depends on the purpose of secondary use (e.g. practice improvement or epidemiological analyses).

Comparative morphology and evolution of the cnidosac in Cladobranchia (Gastropoda: Heterobranchia: Nudibranchia).

BACKGROUND: A number of shelled and shell-less gastropods are known to use multiple defensive mechanisms, including internally generated or externally obtained biochemically active compounds and structures. Within Nudipleura, nudibranchs within Cladobranchia possess such a special defense: the ability to sequester cnidarian nematocysts - small capsules that can inject venom into the tissues of other organisms. This ability is distributed across roughly 600 species within Cladobranchia, and many questions still remain in regard to the comparative morphology and evolution of the cnidosac - the structure that houses sequestered nematocysts (called kleptocnides). In this paper, we describe cnidosac morphology across the main groups of Cladobranchia in which it occurs, and place variation in its structure in a phylogenetic context to better understand the evolution of nematocyst sequestration. RESULTS: Overall, we find that the length, size and structure of the entrance to the cnidosac varies more than expected based on previous work, as does the structure of the exit, the musculature surrounding the cnidosac, and the position and orientation of the kleptocnides. The sequestration of nematocysts has originated at least twice within Cladobranchia based on the phylogeny presented here using 94 taxa and 409 genes. CONCLUSIONS: The cnidosac is not homologous to cnidosac-like structures found in Hancockiidae. Additionally, the presence of a sac at the distal end of the digestive gland may have originated prior to the sequestration of nematocysts. This study provides a more complete picture of variation in, and evolution of, morphological characters associated with nematocyst sequestration in Cladobranchia.