Intestinal microbiota-specific Th17 cells possess regulatory properties and suppress effector T cells via c-MAF and IL-10.

Commensal microbes induce cytokine-producing effector tissue-resident CD4+ T cells, but the function of these T cells in mucosal homeostasis is not well understood. Here, we report that commensal-specific intestinal Th17 cells possess an anti-inflammatory phenotype marked by expression of interleukin (IL)-10 and co-inhibitory receptors. The anti-inflammatory phenotype of gut-resident commensal-specific Th17 cells was driven by the transcription factor c-MAF. IL-10-producing commensal-specific Th17 cells were heterogeneous and derived from a TCF1+ gut-resident progenitor Th17 cell population. Th17 cells acquired IL-10 expression and anti-inflammatory phenotype in the small-intestinal lamina propria. IL-10 production by CD4+ T cells and IL-10 signaling in intestinal macrophages drove IL-10 expression by commensal-specific Th17 cells. Intestinal commensal-specific Th17 cells possessed immunoregulatory functions and curbed effector T cell activity in vitro and in vivo in an IL-10-dependent and c-MAF-dependent manner. Our results suggest that tissue-resident commensal-specific Th17 cells perform regulatory functions in mucosal homeostasis.

A tRNA modifying enzyme as a tunable regulatory nexus for bacterial stress responses and virulence.

Post-transcriptional modifications can impact the stability and functionality of many different classes of RNA molecules and are an especially important aspect of tRNA regulation. It is hypothesized that cells can orchestrate rapid responses to changing environmental conditions by adjusting the specific types and levels of tRNA modifications. We uncovered strong evidence in support of this tRNA global regulation hypothesis by examining effects of the well-conserved tRNA modifying enzyme MiaA in extraintestinal pathogenic Escherichia coli (ExPEC), a major cause of urinary tract and bloodstream infections. MiaA mediates the prenylation of adenosine-37 within tRNAs that decode UNN codons, and we found it to be crucial to the fitness and virulence of ExPEC. MiaA levels shifted in response to stress via a post-transcriptional mechanism, resulting in marked changes in the amounts of fully modified MiaA substrates. Both ablation and forced overproduction of MiaA stimulated translational frameshifting and profoundly altered the ExPEC proteome, with variable effects attributable to UNN content, changes in the catalytic activity of MiaA, or availability of metabolic precursors. Cumulatively, these data indicate that balanced input from MiaA is critical for optimizing cellular responses, with MiaA acting much like a rheostat that can be used to realign global protein expression patterns.

Trends of alcohol-attributable deaths in Lithuania 2001-2021: epidemiology and policy conclusions.

BACKGROUND: Lithuania, a Baltic country in the European Union, can be characterized by high alcohol consumption and attributable burden. The aim of this contribution is to estimate the mortality burden due to alcohol use for the past two decades based on different relative risk functions, identify trends, and analyse the associations of alcohol-attributable burden with alcohol control policies and life expectancy. METHODS: The standard methodology used by the World Health Organization for estimating alcohol-attributable mortality was employed to generate mortality rates for alcohol-attributable mortality, standardized for Lithuania's 2021 population distribution. Joinpoint analysis, T-tests, correlations, and regression analyses including meta-regressions were used to describe trends and associations. RESULTS: Age-standardized alcohol-attributable mortality was high in Lithuania during the two decades between 2001 and 2021, irrespective of which relative risks were used for the estimates. Overall, there was a downward trend, mainly in males, which was associated with four years of intensive implementation of alcohol control policies in 2008, 2009, 2017, and 2018. For the remaining years, the rates of alcohol-attributable mortality were stagnant. Among males, the correlations between alcohol-attributable mortality and life expectancy were 0.90 and 0.76 for Russian and global relative risks respectively, and regression analyses indicated a significant association between changes in alcohol-attributable mortality and life expectancy, after controlling for gross domestic product. CONCLUSIONS: Male mortality and life expectancy in Lithuania were closely linked to alcohol-attributable mortality and markedly associated with strong alcohol control policies. Further implementation of such policies is predicted to lead to further improvements in life expectancy.

Impact of health spending on hospitalization rates in Baltic countries: a comparative analysis.

INTRODUCTION: This study examines the association between healthcare indicators and hospitalization rates in three high-income European countries, namely Estonia, Latvia, and Lithuania, from 2015 to 2020. METHOD: We used a sex-stratified generalized additive model (GAM) to investigate the impact of select healthcare indicators on hospitalization rates, adjusted by general economic status-i.e., gross domestic product (GDP) per capita. RESULTS: Our findings indicate a consistent decline in hospitalization rates over time for all three countries. The proportion of health expenditure spent on hospitals, the number of physicians and nurses, and hospital beds were not statistically significantly associated with hospitalization rates. However, changes in the number of employed medical doctors per 10,000 population were statistically significantly associated with changes of hospitalization rates in the same direction, with the effect being stronger for males. Additionally, higher GDP per capita was associated with increased hospitalization rates for both males and females in all three countries and in all models. CONCLUSIONS: The relationship between healthcare spending and declining hospitalization rates was not statistically significant, suggesting that the healthcare systems may be shifting towards primary care, outpatient care, and on prevention efforts.

Public awareness of the alcohol-cancer link in the EU and UK: a scoping review.

BACKGROUND: Alcohol increases cancer risk, but less is known about public awareness of this link. This scoping review summarizes recent findings on the public awareness of alcohol as a cancer risk factor in European Union and UK. METHODS: Four databases (Web of Science, MEDLINE, PsycInfo, CINAHL) were searched for papers containing data on awareness of alcohol as cancer risk factor in EU or UK published between January 2017 and December 2022, and complemented with grey literature searches. RESULTS: In total, 45 studies were included covering 18 EU countries (Austria, Belgium, Cyprus, Czechia, Denmark, Finland, France, Germany, Hungary, Ireland, Italy, Netherlands, Poland, Romania, Slovakia, Slovenia, Spain, Sweden) and UK, presenting data collected between 2009 and 2022. Studies covered general population (17 studied a nationally representative sample), women, health professionals, patients and young people. Awareness of alcohol causing cancer in general was higher and studied more often than awareness of alcohol's impact on specific cancers. Among the EU general population, awareness of the link between alcohol and breast cancer ranged between 10% and 20%, head and neck cancer 15-25%, colorectal and oesophagus cancer 15-45% and liver cancer 40%. Awareness was higher among young people and specialized health professions and lower among women (the latter specifically for the breast cancer). CONCLUSIONS: While awareness rates varied depending on the exact question wording, many studies showed low awareness of the alcohol-cancer link, especially for specific types such as breast and colon cancer. Public should be better informed about alcohol consumption-related cancer risk.

A mystery-shopping study to test enforcement of minimum legal purchasing age in Lithuania in 2022.

BACKGROUND: According to the Lithuanian law to prevent the sale of alcohol to customers below the legal minimum purchasing age of 20 years, young adults below 25 years must be asked to show an age-verification document when purchasing alcohol. The aim of this study was to assess whether off-premise outlets comply with the law. METHODS: In 2022, mystery-shopping study was carried out in three consecutive phases: (i) in a representative sample (n = 239) of off-premise alcohol outlets covering all Lithuanian district centres, (ii) after lifting the requirement to wear a mask and (iii) after warning the outlets that a mystery-shopping study was ongoing. Phases 2 and 3 were held in two cities. The mystery shopping involved attempts by young, but legally eligible customers to purchase alcohol. Across the three study phases, we compared compliance with the law by measuring overall success of purchase attempts and included situational characteristics (working day or weekend), time of day and number of customers in line as an additional predictor. RESULTS: Out of 239 attempts to purchase alcohol from off-premise outlets in the main phase of the study, 107 (or 44.8%) were considered to be successful (visits in which staff were willing to sell alcohol). There was a significantly higher chance of success to purchase alcohol with no ID request if a mystery shopper was the only customer in a queue and on weekends. CONCLUSIONS: The results indicate an insufficient level of age-verification control in Lithuania, and that additional action is needed to increase compliance.

Using Direct and Indirect Estimates for Alcohol-Attributable Mortality: A Modelling Study Using the Example of Lithuania.

INTRODUCTION: Comparative risk assessments (CRAs) for alcohol use are based on indirect estimates of attributable harm, and usually combine country-specific exposure estimates and global risk relations derived from meta-analyses. CRAs for Eastern European countries, such as Lithuania, base their risk relations not on global risk relations, but on a large Russian cohort study. The availability of a direct estimate of alcohol-attributable mortality following the 2017 implementation of a large increase in alcohol excise taxes in Lithuania has allowed a comparison of these indirect estimates with a country-specific gold standard. METHODS: A statistical modelling study compared direct (predictions based on a time-series methodology) and indirect (predictions based on an attributable-fraction methodology) estimates of alcohol-attributable mortality before and after a large increase in alcohol excise taxes in Lithuania. Specifically, Russia-specific versus global relative risks were compared against the gold standard of time-series based predictions. RESULTS: Compared to direct estimates, indirect estimates markedly underestimated the reduction of alcohol-attributable mortality 12 months post intervention by at least 63%. While both of the indirect estimates differed markedly from the direct estimates, the Russia-specific estimates were closer to the direct estimates, primarily due to higher estimates for alcohol-attributable cardiovascular mortality. DISCUSSION: As all indirect estimates were markedly lower than direct estimates, current overall relative risks and price elasticities should be re-evaluated. In particular, global estimates should be replaced by new regional estimates based on cohort studies.

Impact of alcohol control policy on hemorrhagic and ischemic stroke mortality rates in Lithuania: An interrupted time series analysis. / Impacto de políticas de control de alcohol en las tasas de mortalidad por ictus hemorrágico e isquémico en Lituania: Análisis de series temporales interrumpidas.

Given the causal impact of alcohol use on stroke, alcohol control policies should presumably reduce stroke mortality rates. This study aimed to test the impact of three major Lithuanian alcohol control policies implemented in 2008, 2017 and 2018 on sex- and stroke subtype-specific mortality rates, among individuals 15+ years-old. Joinpoint regression analyses were performed for each sex- and stroke subtype-specific group to identify timepoints corresponding with significant changes in mortality rate trends. To estimate the impact of each policy, interrupted time series analyses using a generalized additive mixed model were performed on monthly sex- and stroke subtype-specific age-standardized mortality rates from January 2001-December 2018. Significant average annual percent decreases were found for all sex- and stroke subtype-specific mortality rate trends. The alcohol control policies were most impactful on ischemic stroke mortality rates among women. The 2008 policy was followed by a positive level change of 4,498 ischemic stroke deaths per 100,000 women and a negative monthly slope change of -0.048 ischemic stroke deaths per 100,000 women. Both the 2017 and 2018 policy enactment timepoints coincided with a significant negative level change for ischemic stroke mortality rates among women, at -0.901 deaths and -1.431 deaths per 100,000 population, respectively. Hemorrhagic stroke mortality among men was not affected by any of the policies, and hemorrhagic stroke mortality among women and ischemic stroke mortality among men were only associated with the 2008 policy. Our study findings suggest that the impact of alcohol control policies on stroke mortality may vary by sex and subtype.

Dado el impacto del alcohol en los ictus, las políticas de control de alcohol deberían reducir las tasas de mortalidad. Nuestro objetivo fue demostrar el impacto de tres importantes políticas lituanas implementadas en 2008, 2017 y 2018 en las tasas de mortalidad específicas por subtipo de ictus y sexo, en mayores de 15 años. Se realizaron análisis de regresión «joinpoint¼ para identificar los cambios de tendencia. Para estimar el impacto, se realizaron análisis de series temporales interrumpidas utilizando un modelo mixto aditivo generalizado en las tasas mensuales estandarizadas por edad, desde enero 2001 hasta diciembre 2018. Se encontraron disminuciones porcentuales anuales promedio significativas en ambos subtipos de ictus y por sexo. Las políticas tuvieron un mayor impacto en las tasas de mortalidad por ictus isquémico en mujeres. Posterior a la política del 2008, ocurrió un cambio positivo de 4,498 muertes por ictus isquémico por 100 000 mujeres y un cambio de pendiente mensual negativo de -0,048 muertes por ictus isquémico por 100 000 mujeres. Posterior a las políticas de 2017 y 2018, hubo un cambio de tendencia negativo significativo para la mortalidad por ictus isquémico en mujeres, de -0.901 muertes y -1.431 muertes por 100 000 habitantes, respectivamente. La mortalidad por ictus hemorrágico en hombres no se vio afectada, y la mortalidad por ictus hemorrágico en mujeres y por ictus isquémico en hombres solo se vio afectada por la política del 2008. Nuestros hallazgos sugieren que el impacto de las políticas en la mortalidad por ictus puede variar según sexo y subtipo.

Can alcohol control policies reduce cirrhosis mortality? An interrupted time-series analysis in Lithuania.

BACKGROUND AND AIMS: The relationship between alcohol consumption and cirrhosis is well established. Policies that can influence population-level use of alcohol should, in turn, impact cirrhosis. We examined the effect of population-level alcohol control policies on cirrhosis mortality rates in Lithuania - a high-income European Union country with high levels of alcohol consumption. METHODS: Age-standardized, monthly liver mortality data (deaths per 100,000 adults, aged 15+) from Lithuania were analysed from 2001 to 2018 (n = 216 months) while controlling for economic confounders (gross domestic product and inflation). An interrupted time-series analysis was conducted to estimate the effect of three alcohol control policies implemented in 2008, 2017 and 2018 and the number of cirrhosis deaths averted. RESULTS: There was a significant effect of the 2008 (P < .0001) and 2017 (P = .0003) alcohol control policies but a null effect of the 2018 policy (P = .40). Following the 2008 policy, the cirrhosis mortality rate dropped from 4.93 to 3.41 (95% CI: 3.02-3.80) deaths per 100,000 adults, which equated to 493 deaths averted. Further, we found that following the 2017 policy, the mortality rate dropped from 2.85 to 2.01 (95% CI: 1.50-2.52) deaths per 100,000 adults, corresponding to 245 deaths averted. CONCLUSIONS: Our findings support the hypothesis that alcohol control policies can have a significant, immediate effect on cirrhosis mortality. These policy measures are cost-effective and aid in reducing the burden of liver disease.

Estimating effects of health policy interventions using interrupted time-series analyses: a simulation study.

BACKGROUND: A classic methodology used in evaluating the impact of health policy interventions is interrupted time-series (ITS) analysis, applying a quasi-experimental design that uses both pre- and post-policy data without randomization. In this paper, we took a simulation-based approach to estimating intervention effects under different assumptions. METHODS: Each of the simulated mortality rates contained a linear time trend, seasonality, autoregressive, and moving-average terms. The simulations of the policy effects involved three scenarios: 1) immediate-level change only, 2) immediate-level and slope change, and 3) lagged-level and slope change. The estimated effects and biases of these effects were examined via three matched generalized additive mixed models, each of which used two different approaches: 1) effects based on estimated coefficients (estimated approach), and 2) effects based on predictions from models (predicted approach). The robustness of these two approaches was further investigated assuming misspecification of the models. RESULTS: When one simulated dataset was analyzed with the matched model, the two analytical approaches produced similar estimates. However, when the models were misspecified, the number of deaths prevented, estimated using the predicted vs. estimated approaches, were very different, with the predicted approach yielding estimates closer to the real effect. The discrepancy was larger when the policy was applied early in the time-series. CONCLUSION: Even when the sample size appears to be large enough, one should still be cautious when conducting ITS analyses, since the power also depends on when in the series the intervention occurs. In addition, the intervention lagged effect needs to be fully considered at the study design stage (i.e., when developing the models).

Comparing gender-specific suicide mortality rate trends in the United States and Lithuania, 1990-2019: putting one of the "deaths of despair" into perspective.

INTRODUCTION: The increase in the suicide mortality rate among middle-aged adults in the United States (US) has been well documented. Aside from a few studies from the United Kingdom, it is unclear whether the suicide mortality rate trend in the US is also occurring in other developed countries. Accordingly, we aimed to compare the suicide mortality rate trends over the past 30 years in the US to a country in the European Union-Lithuania. METHODS: Joinpoint regression analyses were performed to identify secular trends in the gender-specific age-standardized suicide mortality rate among individuals 15 + years of age, as well as middle-aged adults (45-54 years of age), and suicide mortality rate ratio for men-to-women. RESULTS: Age-standardized suicide mortality rates among middle-aged adults in the US increased annually, on average, by 0.89% (95% CI: 0.66%, 1.12%) among men and 1.21% (95% CI: 0.75%, 1.66%) among women between 1990 and 2019. In contrast to the US, there was an overall downward trend in the suicide mortality rates among middle-aged adults in Lithuania across the study period. The average annual percent change in the suicide mortality rate ratio for men-to-women were not statistically significant for either country. CONCLUSION: The suicide mortality rate trend in the US does not appear to be an indicator of an upcoming global trend, but rather should be regarded as a cautionary example of what other countries should strive to avoid.

Predicting the Impact of Alcohol Taxation Increases on Mortality-A Comparison of Different Estimation Techniques.

AIMS: To examine how standard analytical approaches to model mortality outcomes of alcohol use compare to the true results using the impact of the March 2017 alcohol taxation increase in Lithuania on all-cause mortality as an example. METHODS: Four methodologies were used: two direct methodologies: (a) interrupted time-series on mortality and (b) comparing predictions based on time-series modeling with the real number of deaths for the year following the implementation of the tax increase; and two indirect methodologies: (c) combining a regression-based estimate for the impact of taxation on alcohol consumption with attributable-fraction methodology and (d) using price elasticities from meta-analyses to estimate the impact on alcohol consumption before applying attributable-fraction methodology. RESULTS AND CONCLUSIONS: While all methodologies estimated reductions in all-cause mortality, especially for men, there was substantial variability in the level of mortality reductions predicted. The indirect methodologies had lower predictions as the meta-analyses on elasticities and risk relations seem to underestimate the true values for Lithuania. Directly estimated effects of taxation based on the actual mortalities seem to best represent the true reductions in alcohol-attributable mortality. A significant increase in alcohol excise taxation had a marked impact on all-cause mortality in Lithuania.

The Impact of Increasing the Minimum Legal Drinking Age from 18 to 20 Years in Lithuania on All-Cause Mortality in Young Adults-An Interrupted Time-Series Analysis.

AIMS: To determine the effect of an alcohol policy change, which increased the minimum legal drinking age (MLDA) from 18 years of age to 20 years of age on all-cause mortality rates in young adults (18-19 years old) in Lithuania. METHODS: An interrupted time series analysis was conducted on a dataset from 2001 to 2019 (n = 228 months). The model tested the effects of the MLDA on all-cause mortality rates (deaths per 100,000 individuals) in three age categories (15-17 years old, 18-19 years old, 20-22 years old) in order to control for general mortality trends in young adults, and to isolate the effects of the MLDA from other alcohol control policies. Additional models that included GDP as a covariate and a taxation policy were tested as well. RESULTS: There was a significant effect of the MLDA on all-cause mortality rates in those 18-19 years old, when modelled alone. Additional analyses controlling for the mortality rate of other age groups showed similar findings. Inclusion of confounding factors (policies on alcohol taxation, GDP) eliminated the effects of MLDA. CONCLUSIONS: Although there was a notable decline in all-cause mortality rates among young adults in Lithuania, a direct causal impact of MLDA on all-cause mortality rates in young adults was not definitively found.

The temporal trend of cause-specific mortality: comparing Estonia and Lithuania, 2001 - 2019.

BACKGROUND: Despite being two Baltic countries with similar histories, Estonia and Lithuania have diverged in life expectancy trends in recent years. We investigated this divergence by comparing cause-specific mortality trends. METHODS: We obtained yearly mortality data for individuals 20 + years of age from 2001-2019 (19 years worth of data) through Statistics Lithuania, the Lithuanian Institute for Hygiene, and the National Institute for Health Development (Estonia). Using ICD-10 codes, we analyzed all-cause mortality rates and created eight major disease categories: ischemic heart disease, cerebrovascular disease, all other cardiovascular disease, cancers (neoplasms), digestive diseases, self-harm and interpersonal violence, unintentional injuries and related conditions, and other mortality (deaths per 100,000 population). We used joinpoint regression analysis, and analyzed the proportional contribution of each category to all-cause mortality. RESULTS: There was a steeper decline in all-cause mortality in Estonia (average annual percent change, AAPC = -2.55%, 95% CI: [-2.91%, -2.20%], P < .001) as compared to Lithuania (AAPC = -1.26%, 95% CI: [-2.18%, -0.57%], P = .001). For ischemic heart disease mortality Estonia exhibited a relatively larger decline over the 19-year period (AAPC = -6.61%, 95% CI: [-7.02%, -6.21%], P < .001) as compared to Lithuania (AAPC = -2.23%, 95% CI: [-3.40%, -1.04%], P < .001). CONCLUSION: Estonia and Lithuania showed distinct mortality trends and distributions of major disease categories. Our findings highlight the role of ischemic heart disease mortality. Differences in public health care, management and prevention of ischemic heart disease, alcohol control policies may explain these differences.

Gender-specific risk relationship between heavy alcohol use/alcohol use disorders and suicidal thoughts and behavior among adults in the United States over time.

PURPOSE: Suicidal thoughts and behaviors have been on the rise in the recent years in the US. There is a well-known link between heavy alcohol use/alcohol use disorders (AUDs) and suicidal thoughts and behaviors. An increase in the respective risk relationships is one way in which heavy alcohol use/AUDs may be driving the increase in the rate of suicidal thoughts and behaviors. The objective of the current study was to investigate whether the gender-specific risk relationships between heavy alcohol use/AUDs and past-year (1) suicidal thoughts and (2) attempted suicide have increased over time. METHODS: Individual-level annual data from the National Survey on Drug Use and Health for the past 12 years (2008-2019) were utilized. Year- and gender-specific multivariate binary logistic regression analyses were first conducted. Gender-stratified random-effects meta-regressions across study years were then conducted. RESULTS: Heavy alcohol use/AUDs were associated with elevated odds of past-year suicidal thoughts and attempted suicide for both men and women; however, a linear increase in the risk relationships over time was not found. CONCLUSION: Although a temporal increase in the risk relationships of interest was not found, until additional research in this area is conducted, heavy alcohol use/AUDs cannot be ruled out as being a driving force behind the increasing rate of suicidal thoughts and behaviors in the US.

Targeting the Maladaptive Effects of Binge Drinking on Circadian Gene Expression.

Previous studies (1) support a role of circadian genes in regulating alcohol intake, and (2) reveal that harmful alcohol use alters circadian rhythms. However, there is minimal knowledge of the effects of chronic alcohol processes on rhythmic circadian gene expression across brain regions important for circadian biology and alcohol intake. Therefore, the present study sought to test the effects of chronic binge-like drinking on diurnal circadian gene expression patterns in the master circadian pacemaker (SCN), the ventral tegmental area (VTA), and the nucleus accumbens (NAc) in High Drinking in the Dark-1 (HDID-1) mice, a unique genetic risk model for drinking to intoxication. Consistent with earlier findings, we found that 8 weeks of binge-like drinking reduced the amplitude of several core circadian clock genes in the NAc and SCN, but not the VTA. To better inform the use of circadian-relevant pharmacotherapies in reducing harmful drinking and ameliorating alcohol's effects on circadian gene expression, we tested whether the casein kinase-1 inhibitor, PF-67046, or the phosphodiesterase type-4 (an upstream regulator of circadian signalling) inhibitor, apremilast, would reduce binge-like intake and mitigate circadian gene suppression. PF-67046 did not reduce intake but did have circadian gene effects. In contrast, apremilast reduced drinking, but had no effect on circadian expression patterns.

Oxytocin and 'social hyperthermia': Interaction with ß3-adrenergic receptor-mediated thermogenesis and significance for the expression of social behavior in male and female mice.

Oxytocin (OT) is a critical regulator of multiple facets of energy homeostasis, including brown adipose tissue (BAT) thermogenesis. Nevertheless, it is unclear what, if any, consequence the thermoregulatory and metabolic effects of OT have for the display of social behavior in adult rodents. Here, we examine the contribution of the OT receptor (OTR) and ß3 adrenergic receptor (ß3AR) to the increase in body temperature that typically accompanies social interaction (i.e., social hyperthermia; SH) and whether SH relates to the expression of social behavior in adult mice. Specifically, we examined how OTR antagonism via peripheral injection of L-368,899 (10 mg/kg) affects the expression of social behavior in C57BL/6J mice, in the presence of active/agonized versus antagonized ß3AR, the receptor known to mediate stress-induced BAT thermogenesis. After drug treatment and a 30 min delay, mice were provided a 10 min social interaction test with an unfamiliar, same-sex conspecific. We hypothesized that OTR and ß3AR/BAT interact to influence behavior during social interaction, with at least some effects of OT on social behavior dependent upon OT's thermal effects via ß3AR/BAT. We found that OTR-mediated temperature elevation is largely responsible for SH during social interaction in mice-albeit not substantially via ß3AR-dependent BAT thermogenesis. Further, our results reveal a complex relationship between OTR, ß3AR, social hyperthermia and the display of specific social behaviors, with SH most closely associated with anxiety and/or vigilance-related behaviors-that is, behaviors that antagonize or interfere with the initiation of close, non-agonistic social behavior.

Determining the sex-specific distributions of average daily alcohol consumption using cluster analysis: is there a separate distribution for people with alcohol dependence?

BACKGROUND: It remains unclear whether alcohol use disorders (AUDs) can be characterized by specific levels of average daily alcohol consumption. The aim of the current study was to model the distributions of average daily alcohol consumption among those who consume alcohol and those with alcohol dependence, the most severe AUD, using various clustering techniques. METHODS: Data from Wave 1 and Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions were used in the current analyses. Clustering algorithms were applied in order to group a set of data points that represent the average daily amount of alcohol consumed. Gaussian Mixture Models (GMMs) were then used to estimate the likelihood of a data point belonging to one of the mixture distributions. Individuals were assigned to the clusters which had the highest posterior probabilities from the GMMs, and their treatment utilization rate was examined for each of the clusters. RESULTS: Modeling alcohol consumption via clustering techniques was feasible. The clusters identified did not point to alcohol dependence as a separate cluster characterized by a higher level of alcohol consumption. Among both females and males with alcohol dependence, daily alcohol consumption was relatively low. CONCLUSIONS: Overall, we found little evidence for clusters of people with the same drinking distribution, which could be characterized as clinically relevant for people with alcohol use disorders as currently defined.

Cardiovascular diseases mortality and alcohol control policy in Lithuania: exploring a possible link.

BACKGROUND: Lithuania possesses one of the highest alcohol per capita consumption and has previously implemented alcohol control policies to reduce the alcohol-attributable burden. The aim of this study was to investigate Lithuanian cardiovascular disease (CVD) mortality rate trends between 2001 and 2018 and to explore a possible link between CVD mortality rate and alcohol control policy implementation. METHODS: Lithuanian population mortality and alcohol consumption data for 2001-2018 were obtained from Statistics Lithuania and The State Register of Death Cases and Their Causes, Institute of Hygiene. Sex-specific CVD mortality rates were directly standardized to the European standard population by five-year age groups and categorized according to the ICD-10 codes for all CVDs (I00-I99), ischemic heart disease (IHD) (I20-I25), cerebrovascular diseases (I60-I69) and alcoholic cardiomyopathy (ACM) (I42.6). Joinpoint regression analyses were performed to identify points of inflection to explore their alignment with five selected alcohol policy enactments. RESULTS: Overall, the 2001-2018 yearly mortality rates for all CVDs significantly decreased on average by - 1.6% (95% CI -2.0, - 1.2%) among men and - 2.1% (95% CI -2.5, - 1.8%) among women. Yearly changes in all CVDs, IHD, cerebrovascular diseases and ACM mortality rates were insignificant prior to their respective critical year points in 2006, 2005, 2008 and 2007, but significantly decreased afterwards by an average of - 2.4% (95% CI -2.7, - 2.0%), - 1.6% (95% CI -2.1, - 1.1%), - 1.2% (95 CI -1.7, - 0.6%) and - 4.5% (95% CI -7.3, - 1.6%) among men, and by - 2.7% (95% CI -3.0, - 2.3%), - 2.0% (95% CI -2.6, - 1.4%), - 1.8% (95% CI 2.4, - 1.3%) and - 6.6% (95% CI -10.7, - 2.2%) among women, respectively. The changes in the mortality rate trends for all CVDs, IHD, cerebrovascular diseases and especially ACM coincided with alcohol policies enacted on the January 1, 2008, January 1, 2009, April 1, 2014 and March 1, 2017. CONCLUSIONS: Yearly mortality rates for all CVDs, IHD, cerebrovascular diseases and ACM have declined in Lithuania between 2001 and 2018, and declining trends were more prominent in women than in men. Among the ICD-10 CVD categories investigated, the points of inflection identified for the ACM mortality rate trend coincided best with the selected alcohol policy enactment dates.

Pseudo-Symmetric Assembly of Protodomains as a Common Denominator in the Evolution of Polytopic Helical Membrane Proteins.

The polytopic helical membrane proteome is dominated by proteins containing seven transmembrane helices (7TMHs). They cannot be grouped under a monolithic fold or superfold. However, a parallel structural analysis of folds around that magic number of seven in distinct protein superfamilies (SWEET, PnuC, TRIC, FocA, Aquaporin, GPCRs) reveals a common homology, not in their structural fold, but in their systematic pseudo-symmetric construction during their evolution. Our analysis leads to guiding principles of intragenic duplication and pseudo-symmetric assembly of ancestral transmembrane helical protodomains, consisting of 3 (or 4) helices. A parallel deconstruction and reconstruction of these domains provides a structural and mechanistic framework for their evolutionary paths. It highlights the conformational plasticity inherent to fold formation itself, the role of structural as well as functional constraints in shaping that fold, and the usefulness of protodomains as a tool to probe convergent vs divergent evolution. In the case of FocA vs. Aquaporin, this protodomain analysis sheds new light on their potential divergent evolution at the protodomain level followed by duplication and parallel evolution of the two folds. GPCR domains, whose function does not seem to require symmetry, nevertheless exhibit structural pseudo-symmetry. Their construction follows the same protodomain assembly as any other pseudo-symmetric protein suggesting their potential evolutionary origins. Interestingly, all the 6/7/8TMH pseudo-symmetric folds in this study also assemble as oligomeric forms in the membrane, emphasizing the role of symmetry in evolution, revealing self-assembly and co-evolution not only at the protodomain level but also at the domain level.