RASA2 ablation in T cells boosts antigen sensitivity and long-term function.

The efficacy of adoptive T cell therapies for cancer treatment can be limited by suppressive signals from both extrinsic factors and intrinsic inhibitory checkpoints1,2. Targeted gene editing has the potential to overcome these limitations and enhance T cell therapeutic function3-10. Here we performed multiple genome-wide CRISPR knock-out screens under different immunosuppressive conditions to identify genes that can be targeted to prevent T cell dysfunction. These screens converged on RASA2, a RAS GTPase-activating protein (RasGAP) that we identify as a signalling checkpoint in human T cells, which is downregulated upon acute T cell receptor stimulation and can increase gradually with chronic antigen exposure. RASA2 ablation enhanced MAPK signalling and chimeric antigen receptor (CAR) T cell cytolytic activity in response to target antigen. Repeated tumour antigen stimulations in vitro revealed that RASA2-deficient T cells show increased activation, cytokine production and metabolic activity compared with control cells, and show a marked advantage in persistent cancer cell killing. RASA2-knockout CAR T cells had a competitive fitness advantage over control cells in the bone marrow in a mouse model of leukaemia. Ablation of RASA2 in multiple preclinical models of T cell receptor and CAR T cell therapies prolonged survival in mice xenografted with either liquid or solid tumours. Together, our findings highlight RASA2 as a promising target to enhance both persistence and effector function in T cell therapies for cancer treatment.

Cutting Edge: l-Arginine Transfer from Antigen-Presenting Cells Sustains CD4+ T Cell Viability and Proliferation.

Metabolomics analyses suggest changes in amino acid abundance, particularly l-arginine (L-ARG), occur in patients with tuberculosis. Immune cells require L-ARG to fuel effector functions following infection. We have previously described an L-ARG synthesis pathway in immune cells; however, its role in APCs has yet to be uncovered. Using a coculture system with mycobacterial-specific CD4+ T cells, we show APC L-ARG synthesis supported T cell viability and proliferation, and activated T cells contained APC-derived L-ARG. We hypothesize that APCs supply L-ARG to support T cell activation under nutrient-limiting conditions. This work expands the current model of APC-T cell interactions and provides insight into the effects of nutrient availability in immune cells.

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.

The prevalence of alcohol-related deaths in autopsies performed in Lithuania between 2017 and 2020: a cross-sectional study.

BACKGROUND: Consumption of alcohol is a risk factor for non-communicable and infectious diseases, mental health problems, and can lead injuries and violence. The aim of this study was to evaluate the prevalence of alcohol-involved deaths among decedents who died of external causes and underwent autopsy in Lithuania. METHODS: Study includes age persons of any age (from 0 to 110 years) who died and were autopsied in Lithuania from 1 January 2017 to 31 December 2020. Data were obtained from the Lithuanian State Register of Deaths and Their Causes. RESULTS: Among external causes of death, the presence of alcohol was detected in 55.0% of cases. Male decedents had a significantly higher number of positive BAC level recorded, at 46.6%, compared with female decedents (32.1%; P < 0.001). The highest incidence of deaths where the alcohol was detected in the deceased's blood was found when the decedent was listed as being in the victims of assault group (71.5%, 95% CI 65.4-77.2). However, the highest median BAC score was found for those in the accidents group (59.7%, 95% CI: 58.2-61.2, BAC 2.42 ‰, IQR 1.86). CONCLUSIONS: The findings of this study suggest that alcohol use may be a contributing factor in a wide range of fatal incidents, including accidents, injuries, and cases of violent intent. Inequalities between males and females were identified, with a higher proportion of males with alcohol detected in blood at the time of death.

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.

Feasibility and effectiveness of extended-release buprenorphine (XR-BUP) among correctional populations: a systematic review.

Background: Medications for opioid use disorder (MOUD) reduce risks for overdose among correctional populations. Among other barriers, daily dosing requirements hinder treatment continuity post-release. Extended-release buprenorphine (XR-BUP) may therefore be beneficial. However, limited evidence exists.Objectives: To conduct a systematic review examining the feasibility and effectiveness of XR-BUP among correctional populations.Methods: Searches were carried out in Pubmed, Embase, and PsychINFO in October 2023. Ten studies reporting on feasibility or effectiveness of XR-BUP were included, representing n = 819 total individuals (81.6% male). Data were extracted and narratively reported under the following main outcomes: 1) Feasibility; 2) Effectiveness; and 3) Barriers and Facilitators.Results: Studies were heterogeneous. Correctional populations were two times readier to try XR-BUP compared to non-correctional populations. XR-BUP was feasible and safe, with no diversion, overdoses, or deaths; several negative side effects were reported. Compared to other MOUD, XR-BUP significantly reduced drug use, resulted in similar or higher treatment retention rates, fewer re-incarcerations, and was cost-beneficial, with a lower overall monthly/yearly cost. Barriers to XR-BUP, such as side effects and a fear of needles, as well as facilitators, such as a lowered risk of opioid relapse, were also identified.Conclusion: XR-BUP appears to be a feasible and potentially effective alternative treatment option for correctional populations with OUD. XR-BUP may reduce community release-related risks, such as opioid use and overdose risk, as well as barriers to treatment retention. Efforts to expand access to and uptake of XR-BUP among correctional populations are warranted.

A comparative analysis of solitary suicides, suicides following homicide, and suicide pacts using the National Violent Death Reporting System.

BACKGROUND: Incidents of suicide can be categorized into three main types: solitary suicides, suicides following homicide, and suicide pacts. Although these three suicide incidents vary by definition, no studies to-date have simultaneously examined and compared them for potential differences. The objective of the current study was to empirically and descriptively compare solitary suicides, suicides following homicide, and suicide pacts in the United States. METHODS: Restricted-access data from the National Violent Death Report System for 2003-2019 for 262,679 solitary suicides, 4,352 suicides following homicide, and 450 suicide pacts were used. Pairwise comparisons of the three suicide incident types were made for demographic factors, method of suicide, preceding circumstances, mental health status, and toxicology findings. RESULTS: Solitary suicides, suicides following homicide, and suicide pacts have distinct profiles, with statistically significant (p < 0.05) differences across all pairwise comparisons of sex, race, ethnicity, marital status, education, method of suicide, financial problems, interpersonal relationship problems, physical health problems, mental health problems, mood disorders, suicide attempt history, and opiate use at the time of death. CONCLUSION: Despite sharing a few commonalities, solitary suicides, suicides following homicide, and suicide pacts represent distinct phenomena. Each of these suicide incident types likely have their own unique prevention pathways.

Unrecorded alcohol consumption in Lithuania: a modelling study for 2000-2021.

The aim of the study was to estimate unrecorded alcohol consumption in Lithuania for the period 2000-2021 using an indirect method for modelling consumption based on official consumption data and indicators of alcohol-related harm. Methodology employed for estimating the unrecorded alcohol consumption was proposed by Norström and was based on the country's 2019 European Health Interview Survey and indicators of fully alcohol-attributable mortality. The proportion of unrecorded alcohol consumption was estimated as 8.30% (95% CI 7.7-8.9%) for 2019 in Lithuania. The estimated total (recorded and unrecorded) alcohol per capita consumption among individuals 15 years of age and older in 2019 was 12.2 L of pure alcohol, 1.01 (95% CI 0.94-1.09%) L of which is likely unrecorded. The lowest unrecorded alcohol level was estimated for 2009 and 2014, while 2018 had the highest level (i.e. 9.33% of total alcohol per capita consumption). Unrecorded alcohol consumption in Lithuania is likely to be modest when compared to recorded alcohol consumption, the latter of which still remains a major challenge to public health.

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.

Opioid agonist treatment take-home doses ('carries'): Are current guidelines resulting in low treatment coverage among high-risk populations in Canada and the USA?

Opioid agonist treatment (OAT) is the primary intervention for opioid use disorder (OUD) in Canada and the USA. Yet, a number of barriers contribute to sub-optimal treatment uptake and retention, including daily-supervised medication administration. Thus, clients are eventually granted access to take-home OAT doses (i.e., 'carries') to reduce this burden. However, this decision is based on physician discretion and whether patients can demonstrate stability in various life domains, many of which are inextricably linked to the social determinants of health (SDOH). Current Canadian and USA OAT carry guidance documents are not standardized and do not take the SDOH into consideration, resulting in the potential for inequitable access to OAT carries, which may be the case particularly among marginalized populations such as individuals with OUD who have been released from custody. This perspective article posits that current OAT guidelines contribute to inequities in access to OAT carries, and that these inequities likely result in disproportionately low coverage for OUD treatment among some high-risk groups, including individuals on release from incarceration in particular. Relevant impacts of COVID-19 and related policy changes are considered, and suggestions and recommendations to amend current OAT guidance documents are provided.

The dose-response relationship between socioeconomic deprivation and alcohol-attributable mortality risk-a systematic review and meta-analysis.

BACKGROUND: Individuals with low socioeconomic status (SES) experience a higher risk of mortality, in general, and alcohol-attributable mortality in particular. However, a knowledge gap exists concerning the dose-response relationships between the level of socioeconomic deprivation and the alcohol-attributable mortality risk. METHODS: We conducted a systematic literature search in August of 2020 to update a previous systematic review that included studies published up until February of 2013. Quantitative studies reporting on socioeconomic inequality in alcohol-attributable mortality among the general adult population were included. We used random-effects dose-response meta-analyses to investigate the relationship between the level of socioeconomic deprivation and the relative alcohol-attributable risk (RR), by sex and indicator of SES (education, income, and occupation). RESULTS: We identified 25 eligible studies, comprising about 241 million women and 230 million men, among whom there were about 75,200 and 308,400 alcohol-attributable deaths, respectively. A dose-response relationship between the level of socioeconomic deprivation and the RR was found for all indicators of SES. The sharpest and non-linear increase in the RR of dying from an alcohol-attributable cause of death with increasing levels of socioeconomic deprivation was observed for education, where, compared to the most educated individuals, individuals at percentiles with decreasing education had the following RR of dying: women: 25th: 2.09 [95% CI 1.70-2.59], 50th: 3.43 [2.67-4.49], 75th: 4.43 [3.62-5.50], 100th: 4.50 [3.26-6.40]; men: 25th: 2.34 [1.98-2.76], 50th: 4.22 [3.38-5.24], 75th: 5.87 [4.75-7.10], 100th: 6.28 [4.89-8.07]. CONCLUSIONS: The findings of this study show that individuals along the entire continuum of SES are exposed to increased alcohol-attributable mortality risk. Differences in the dose-response relationship can guide priorities in targeting public health initiatives.