When the Going Gets Tough: Multimorbidity and Heavy and Binge Drinking Among Adults.

INTRODUCTION: Multimorbidity, the presence of two or more long-term health conditions in the same individual, is an emerging epidemic associated with increased morbidity and mortality. Continued drinking concurrent with alcohol-related chronic conditions, particularly with multimorbidity, is likely to further elevate health risk. This study aimed to examine the associations of multimorbidity among diabetes, hypertension, heart disease, and cancer with drinking, and moderation of these associations by age. METHODS: Logistic regression modeling was performed in 2023 using a nationally representative sample of U.S. adults from the 2015-19 National Survey on Drug Use and Health. Multimorbidity was assessed using (1) a count of these conditions and (2) disease-specific categories. The outcomes were past month heavy drinking (7+/14+ drinks weekly) and binge drinking (4+/5+ drinks per occasion) for women and men. RESULTS: A pattern of reduced odds for drinking outcomes associated with a greater degree of multimorbidity was found. This pattern was more apparent in models using the continuous measure of multimorbidity than in those using the categorical measure, and more consistent for binge drinking than for heavy drinking and for women than for men. Significant age interactions were found: the log odds of heavy drinking and binge drinking for both men and women decreased as the number of conditions increased, and more steeply for those ages 50+ than the younger. The log odds of heavy drinking varied little among men under age 50 regardless of multimorbidity. CONCLUSIONS: Alcohol interventions to reduce drinking with multimorbidity, particularly among heavy-drinking men under age 50, are warranted.

Drinking contexts, coping motive, simultaneous cannabis use, and high-intensity drinking among adults in the United States.

AIMS: High-intensity drinking (HID), extreme drinking considerably above the level of heavy episodic drinking (HED), is associated with long-term health and social consequences. There is limited understanding of HID beyond young adulthood. This study aims to identify concurrent risk factors for HID, comparing age differences among all adults. METHODS: Multinomial logistic and linear regression modeling was performed using a nationally-representative sample of adults (analytic n = 7956) from the 2015 and 2020 National Alcohol Surveys. The outcomes were any HID of 8-11 drinks and 12+ drinks for men, and 8+ drinks for women, and corresponding frequencies. Concurrent risk factors included coping motive, sensation seeking, simultaneous use of alcohol and cannabis (SAC), and drinking at a bar or party. Analyses were stratified by age (18-29 vs. older) and sex. RESULTS: For younger men, sensation-seeking was significantly associated with HID (vs. no HED) at both levels and frequency of HID 8-11 drinks, while drinking to cope was only significant for 12+ drinks. For older men, drinking to cope was a consistent predictor for both HID level and its frequency, but sensation-seeking was not significant. Both coping and sensation-seeking were significantly associated with any HID for all women, while coping was significant for HID frequency for younger women. Frequent drinking at bars and parties were associated with greater odds of HID for all adults. With HED as referent, similar patterns of (though fewer significant) associations were observed. CONCLUSIONS: Younger and older adults share similar risk factors for HID, with coping more consistent for older men.

Long-term trends in beverage-specific drinking in the National Alcohol Surveys: Differences by sex, age, and race and ethnicity.

BACKGROUND: Despite substantial declines in underage drinking and binge drinking, alcohol consumption has increased in the past 30 years. This study examined how beverage-specific drinking patterns varied by sex, age, and race and ethnicity from 1979 to 2020. METHODS: Secondary data analysis was conducted on pooled data from the National Alcohol Survey series from 1979 to 2020 of a sample of U.S. adults ages 18 years or older. Total and beverage-specific volume were calculated from graduated frequency questions on reported beverage type, which included beer, wine, and spirits. Sex-stratified analyses focused on descriptive trends of each alcohol measure over time and by age and race and ethnicity. Time-varying effect models were also conducted to identify subgroups at higher risk for increased consumption over time. RESULTS: Women's drinking increased, with alcohol volume rising substantially from 2000 to 2020; the largest increase was among women 30 and older. Men's alcohol volume also rose over this period but remained below the levels of 1979 and 1984, with older adults increasing their consumption those 18-29 decreased their drinking. Beverage-specific trends showed some similarities by gender: in 2020, wine volume was at its highest level for both women and men, while spirits volume also was at its highest level for men and in women was tied with the 1979 peak in spirits consumption. Increases were also found among Black men and women and Latina women from 2000 to 2020. CONCLUSIONS: Given the increases in alcohol volume, particularly among women and older age groups, alcohol policy, interventions, and education should consider ways to reduce harms associated with alcohol use among these groups. Continued monitoring of beverage-specific drinking patterns is needed to track policy-relevant changes.

Comparative effectiveness of sotrovimab versus no treatment in non-hospitalised high-risk COVID-19 patients in north west London: a retrospective cohort study.

BACKGROUND: We assessed the effectiveness of sotrovimab vs no early COVID-19 treatment in highest-risk COVID-19 patients during Omicron predominance. METHODS: Retrospective cohort study using the Discover dataset in North West London. Included patients were non-hospitalised, aged ≥12 years and met ≥1 National Health Service highest-risk criterion for sotrovimab treatment. We used Cox proportional hazards models to compare HRs of 28-day COVID-19-related hospitalisation/death between highest-risk sotrovimab-treated and untreated patients. Age, renal disease and Omicron subvariant subgroup analyses were performed. RESULTS: We included 599 sotrovimab-treated patients and 5191 untreated patients. Compared with untreated patients, the risk of COVID-19 hospitalisation/death (HR 0.50, 95% CI 0.24, 1.06; p=0.07) and the risk of COVID-19 hospitalisation (HR 0.43, 95% CI 0.18, 1.00; p=0.051) were both lower in the sotrovimab-treated group; however, statistical significance was not reached. In the ≥65 years and renal disease subgroups, sotrovimab was associated with a significantly reduced risk of COVID-19 hospitalisation, by 89% (HR 0.11, 95% CI 0.02, 0.82; p=0.03) and 82% (HR 0.18, 95% CI 0.05, 0.62; p=0.007), respectively. CONCLUSIONS: Risk of COVID-19 hospitalisation in sotrovimab-treated patients aged ≥65 years and with renal disease was significantly lower compared with untreated patients. Overall, risk of hospitalisation was also lower for sotrovimab-treated patients, but statistical significance was not reached.

SHIP inhibition mediates select TREM2-induced microglial functions.

Microglia play a pivotal role in the pathology of Alzheimer's Disease (AD), with the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) central to their neuroprotective functions. The R47H variant of TREM2 has emerged as a significant genetic risk factor for AD, leading to a loss-of-function phenotype in mouse AD models. This study elucidates the roles of TREM2 in human microglia-like HMC3 cells and the regulation of these functions by SH2-containing inositol-5'-phosphatase 1 (SHIP1). Using stable cell lines expressing wild-type TREM2, the R47H variant, and TREM2-deficient lines, we found that functional TREM2 is essential for the phagocytosis of Aß, lysosomal capacity, and mitochondrial activity. Notably, the R47H variant displayed increased phagocytic activity towards apoptotic neurons. Introducing SHIP1, known to modulate TREM2 signaling in other cells, revealed its role as a negative regulator of these TREM2-mediated functions. Moreover, pharmacological inhibition of both SHIP1 and its isoform SHIP2 amplified Aß phagocytosis and lysosomal capacity, independently of TREM2 or SHIP1 expression, suggesting a potential regulatory role for SHIP2 in these functions. The absence of TREM2, combined with the presence of both SHIP isoforms, suppressed mitochondrial activity. However, pan-SHIP1/2 inhibition enhanced mitochondrial function in these cells. In summary, our findings offer a deeper understanding of the relationship between TREM2 variants and SHIP1 in microglial functions, and emphasize the therapeutic potential of targeting the TREM2 and SHIP1 pathways in microglia for neurodegenerative diseases.

Secondhand harms from cannabis use: Findings from Washington State, United States.

OBJECTIVE: There are few studies on harms attributed to others' cannabis use. We assessed individual- and contextual-level correlates of secondhand harms from cannabis use and considered whether cannabis legalization support, along with cannabis user status, predicted such harms. METHOD: Data were from five repeated cross-sectional, state-representative telephone surveys of Washington State residents ages 18 and over, years 2014-2016. For four surveys, outcome variables were past 12-month reports of experiencing any of five harms (family, traffic-related, vandalism, physical or financial), and in 2016 only, three harm types separately: 1) harassment, 2) safety-related (traffic, vandalism, physical), 3) family or financial, attributed to another's cannabis use. All models included a three-category typology comprised of participants' own cannabis use and whether they supported cannabis use legalization (user supporter, non-user non-supporter, non-user supporter). We estimated logistic regression models for the full sample and by gender, adjusting for individual- and Census tract-level covariates. RESULTS: Compared to non-cannabis-users supporting legalization, nonusers who did not support legalization reported significantly greater odds of perceiving secondhand cannabis harms. Cannabis users supporting legalization did not differ from nonuser supporters. Predictors of reported harms also differed by gender. While current drinkers had lower odds of reporting any harm from others' cannabis use overall, heavy drinking women but not men reported greater odds of any cannabis secondhand harm. CONCLUSIONS: Augmenting research on individual harms associated with cannabis use by including secondhand impacts such as social and family problems, along with safety risks, provides a more comprehensive picture of the effects of cannabis use.

Associations between alcohol taxes and varied health outcomes among women of reproductive age and infants.

OBJECTIVE: No studies have examined whether alcohol taxes may be relevant for reducing harms related to pregnant people's drinking. METHOD: We examined how beverage-specific ad valorem, volume-based, and sales taxes are associated with outcomes across three data sets. Drinking outcomes came from women of reproductive age in the 1990-2020 US National Alcohol Surveys (N = 11 659 women $\le$ 44 years); treatment admissions data came from the 1992-2019 Treatment Episode Data Set: Admissions (N = 1331 state-years; 582 436 pregnant women admitted to treatment); and infant and maternal outcomes came from the 2005-19 Merative Marketscan® database (1 432 979 birthing person-infant dyads). Adjusted analyses for all data sets included year fixed effects, state-year unemployment and poverty, and accounted for clustering by state. RESULTS: Models yield no robust significant associations between taxes and drinking. Increased spirits ad valorem taxes were robustly associated with lower rates of treatment admissions [adjusted IRR = 0.95, 95% CI: 0.91, 0.99]. Increased wine and spirits volume-based taxes were both robustly associated with lower odds of infant morbidities [wine aOR = 0.98, 95% CI: 0.96, 0.99; spirits aOR = 0.99, 95% CI: 0.98, 1.00] and lower odds of severe maternal morbidities [wine aOR = 0.91, 95% CI: 0.86, 0.97; spirits aOR = 0.95, 95% CI: 0.92, 0.97]. Having an off-premise spirits sales tax was also robustly related to lower odds of severe maternal morbidities [aOR = 0.78, 95% CI: 0.64, 0.96]. CONCLUSIONS: Results show protective associations between increased wine and spirits volume-based and sales taxes with infant and maternal morbidities. Policies that index tax rates to inflation might yield more public health benefits, including for pregnant people and infants.

Alcoholic beverage types consumed by population subgroups in the United States: Implications for alcohol policy to address health disparities.

INTRODUCTION: We aimed to identify alcoholic beverage types more likely to be consumed by demographic subgroups with greater alcohol-related health risk than others, mainly individuals with low socio-economic status, racial/ethnic minority status and high drinking levels. METHODS: Fractional logit modelling was performed using a nationally representative sample of US adult drinkers (analytic N = 37,657) from the National Epidemiologic Survey on Alcohol and Related Conditions Waves 2 (2004-2005) and 3 (2012-2013). The outcomes were the proportions of pure alcohol consumed as beer, wine, liquor and coolers (defined as wine-/malt-/liquor-based coolers, hard lemonade, hard cider and any prepackaged cocktails of alcohol and mixer). RESULTS: Adults with lower education and low or medium income were more likely to drink beer, liquor and coolers, while those with a 4-year college/advanced degree and those with high income preferred wine. Excepting Asian adults, racial/ethnic minority adults were more likely to drink beer (Hispanics) and liquor (Blacks), compared with White adults. High- or very-high-level drinkers were more likely to consume liquor and beer and less likely to consume wine (and coolers), compared with low-level drinkers. High-level and very-high-level drinkers, who were less than 10% of all drinkers, consumed over half of the total volume of beer, liquor and coolers consumed by all adults. DISCUSSION AND CONCLUSIONS: Individuals with low socio-economic status, racial/ethnic minority status or high drinking level prefer liquor and beer. As alcohol taxes, sales and marketing practices all are beverage-specific, targeted approaches to reduce consumption of these beverages, particularly among individuals with these profiles, are warranted.

Differential Associations of Alcohol Use With Ischemic Heart Disease Mortality by Socioeconomic Status in the US, 1997-2018.

Importance: People with low socioeconomic status (SES) experience greater burden from alcohol-attributable health conditions and mortality at equal levels of alcohol consumption compared with those with high SES. A U-shaped association has been established between alcohol use and ischemic heart disease (IHD), but no study has explored how such an association differs by SES in the US. Objective: To investigate how the association of alcohol use with ischemic heart disease mortality differs by SES in the general US population. Design, Setting, and Participants: This cohort study used record-linked, cross-sectional National Health Interview Survey data for US adults aged 25 years and older, covering 1997 to 2018 with mortality follow-up until 2019. Data analysis was performed from March to June 2023. Exposures: SES (operationalized using education attainment) and alcohol consumption were obtained from self-reported questionnaires. Main Outcomes and Measures: The outcome was time to IHD mortality or last presumed alive by December 31, 2019. Cox proportional hazard models were applied to evaluate the interaction of SES and alcohol use on IHD mortality, with age as the time scale. Sex-stratified analyses were performed, adjusting for race and ethnicity, marital status, smoking, body mass index, physical activity, and survey year. Fine-Gray subdistribution models were applied to account for competing risks. Results: This cohort study of 524 035 participants (mean [SD] age at baseline, 50.3 [16.2] years; 290 492 women [51.5%]) found a statistically significantly greater protective association of drinking less than 20 g per day (vs lifetime abstinence) with IHD mortality in the high-SES group compared with the low-SES group (interaction term hazard ratio [HR], 1.22 [95% CI, 1.02-1.45] in men; HR, 1.35 [95% CI, 1.09-1.67] in women). In addition, the differential associations of drinking less than 20 g per day with IHD mortality by SES were observed only among people with less than monthly heavy episodic drinking (HED) (interaction term, HR, 1.20 [95% CI, 1.01-1.43] in men; HR, 1.34 [95% CI, 1.08-1.67] in women); no difference was found in people with at least monthly HED. Among women there was a greater protective association of drinking less than 20 g per day with IHD mortality in the high-SES group than the middle-SES group (interaction term, HR, 1.35 [95% CI, 1.06-1.72]). Among men, the harmful association of drinking more than 60 g per day with IHD mortality in the low-SES group was largely explained by other behavioral risk factors (ie, smoking, body mass index, and physical activity). Conclusions and Relevance: This cohort study found a greater protective association between drinking less than 20 g per day with less than monthly HED and IHD mortality in the high-SES group compared with the low-SES group, in both sexes even after adjusting for key covariables and behavioral risk factors. The findings suggest that public health interventions on alcohol use should account for different socioeconomic backgrounds when assessing the level of risk related to alcohol exposure, bearing in mind that levels of consumption deemed safe regarding a specific outcome such as IHD may indeed be less safe or not safe across all sociodemographic groups.

Associations between simultaneous use of alcohol and cannabis and cannabis-related problems in 2014-2016: evidence from the Washington panel survey.

BACKGROUND: To address the research question of how simultaneous users of alcohol and cannabis differ from concurrent users in risk of cannabis use problems after the recreational marijuana legalization in Washington State. METHODS: We used generalized estimating equations with a Poisson distribution to analyze the association between simultaneous use of alcohol and marijuana (SAM) and cannabis-related problems compared to concurrent use. The data is a longitudinal sample of drinkers and cannabis users (n = 257, 47% female) aged 18 years and older from Washington State in 2014-2016. We adjusted for survey weights to account for differential probability of selection and response rates. The primary outcome is the past-six-month CUDIT problem subscale (ranging from 0 to 28), which is the total score for seven CUDIT problem items, after excluding the three items that covered marijuana use frequency. Covariates include marijuana use frequency (daily/near daily use, regular use, or infrequent use), marijuana daily quantity, alcohol daily volume, panel survey cycle, medical marijuana recommendation, driving time to nearest marijuana outlet, age of marijuana use onset, and other demographics. RESULTS: After adjusting for covariates, we found that compared to concurrent use, SAM was significantly positively associated with CUDIT problem subscale (IRR = 1.68, 95% CI: 1.25-2.27, p < 0.001); daily/near daily use of marijuana was strongly significantly associated with CUDIT problem subscale compared with infrequent use (IRR = 5.1, 2.71-9.57, p < 0.001) or regular use (IRR = 3.05, 1.91-4.85, p < 0.001). Secondary analyses using CUDIT total score as the outcome also showed a significant positive association with SAM compared to concurrent use (IRR = 1.17, 1.02-1.34, p < 0.05). CONCLUSIONS: This study highlighted the importance of SAM, in addition to cannabis use frequency for predicting cannabis-related problems.

Relationships Between Alcohol Policies and Infant Morbidities and Injuries.

INTRODUCTION: Previous research has found that policies specifically focused on pregnant people's alcohol use are largely ineffective. Therefore, the purpose of this study is to analyze the relationships between general population policies regulating alcohol physical availability and outcomes related to pregnant people's alcohol use, specifically infant morbidities and injuries. METHODS: Outcome data were obtained from Merative MarketScan, a longitudinal commercial insurance claims data set. Policy data were obtained from the National Institute on Alcohol Abuse and Alcoholism's Alcohol Policy Information System, the National Alcohol Beverage Control Association, and Liquor Handbooks and merged using policies in effect during the estimated year of conception. Relationships between state-level policies regulating sites, days/hours, and government monopoly of liquor sales and infant morbidities and injuries were examined. Analyses used logistic regression with individual controls, fixed effects for state and year, state-specific time trends, and SEs clustered by state. The study analysis was conducted from 2021 to 2023. RESULTS: The analytic sample included 1,432,979 infant-birthing person pairs, specifically people aged 25-50 years who gave birth to a singleton between 2006 and 2019. A total of 3.1% of infants had a morbidity and 2.1% of infants had an injury. State government monopoly on liquor sales was associated with reduced odds of infant morbidities and injuries, whereas gas station liquor sales were associated with increased odds of infant morbidities and injuries. Allowing liquor sales after 10PM was associated with increased odds for infant injuries. No effect was found for allowing liquor sales in grocery stores or on Sundays. CONCLUSIONS: Findings suggest that limiting alcohol availability for the general population may help reduce adverse infant outcomes related to pregnant people's alcohol use.

The Scottish Medical Imaging Archive: 57.3 Million Radiology Studies Linked to Their Medical Records.

Keywords: MRI, Imaging Sequences, Ultrasound, Mammography, CT, Angiography, Conventional Radiography Published under a CC BY 4.0 license. See also the commentary by Whitman and Vining in this issue.

Life-course Accumulated Cannabis Use and Recent Cannabis-related Problems in the Washington Panel Survey.

BACKGROUND: Previous studies have only investigated the short-term association of recent cannabis use with cannabis-related problems, without accounting for the onset, duration, and variations in frequency of use in the life-course. METHODS: We obtained data from the Washington panel survey during 2014-2016. We constructed accumulated lifetime exposure to cannabis use, heavy drinking (5+ drinks on one occasion), and cigarette pack-years from age of onset based on a series of decades-based questions on cannabis use and heavy drinking, and tobacco use history. We used Generalized Estimating Equation with Poisson distribution to investigate the association between accumulated cannabis use and the past-6-month CUDIT score. We adjusted for accumulated heavy drinking and cigarette pack-years, substance co-use variables, demographics, and applied survey weights. RESULTS: We found strong and statistically significant correlations for the lifetime measures across the four panel surveys, indicating that the life-course measures of cannabis use and heavy drinking were largely reliable. We found a statistically significant relationship between the lifetime accumulated exposure to cannabis and CUDIT. The results were robust to the inconsistencies in reported frequencies and onset age across panel surveys. CONCLUSIONS: This study established the relationship between lifetime exposure to cannabis and cannabis-related problems in a representative sample of drinkers and marijuana users in Washington state. We have also provided test-retest validity and question details for the decades-based cannabis and heavy drinking measures to facilitate their use in future studies of cannabis and alcohol-related outcomes.

Copper-Mediated N-Trifluoromethylation of O-Benzoylhydroxylamines.

The use of trifluoromethyl containing compounds is well established within medicinal chemistry, with a range of approved drugs containing C-CF3 and O-CF3 moieties. However, the utilisation of the N-CF3 functional group remains relatively unexplored. This may be attributed to the challenging synthesis of this unit, with many current methods employing harsh conditions or less accessible reagents. A robust methodology for the N-trifluoromethylation of secondary amines has been developed, which employs an umpolung strategy in the form of a copper-catalysed electrophilic amination. The method is operationally simple, uses mild, inexpensive reagents, and has been used to synthesise a range of novel, structurally complex N-CF3 containing compounds.

Associations between state-level general population alcohol policies and drinking outcomes among women of reproductive age: Results from 1984 to 2020 National Alcohol Surveys.

BACKGROUND: Policies specific to alcohol use during pregnancy have not been found to reduce risks related to alcohol use during pregnancy. In contrast, general population alcohol policies are protective for the general population. Here, we assessed whether US state-level general population alcohol policies are related to drinking outcomes among women of reproductive age. METHODS: We conducted secondary analyses of 1984-2020 National Alcohol Survey data (N = 13,555 women ≤44 years old). State-level policy exposures were government control of liquor retail sales, heavy beer at gas stations, heavy beer at grocery stores, liquor at grocery stores, Sunday off-premise liquor sales, and blood alcohol concentration (BAC) driving limits (no law, 0.10 limit, 0.05-0.08 limit). Outcomes were past 12-month number of drinks, ≥5 drink days, ≥8 drink days, and any DSM-IV alcohol abuse/dependence symptoms. Regressions adjusted for individual and state-level controls, clustering by state, and included fixed effects for survey month and year. RESULTS: Allowing Sunday off-premise liquor sales versus not was related to having 1.20 times as many drinks (95% CI: 1.01, 1.42), 1.41 times as many ≥5 drink days (95% CI: 1.08, 1.85), and 1.91 times as many ≥8 drink days (95% CI: 1.28, 2.83). BAC limits of 0.05-0.08 for driving versus no BAC limit was related to 0.51 times fewer drinks (95% CI: 0.27, 0.96), 0.28 times fewer days with ≥5 drinks (95% CI: 0.10, 0.75), and 0.20 times fewer days with ≥8 drinks (95% CI: 0.08, 0.47). CONCLUSIONS: US state-level policies prohibiting Sunday off-premise liquor sales and BAC limits of 0.05-0.08 for driving are related to less past 12-month overall and heavy drinking among women 18-44 years old.

Structure-Activity Studies on Bis-Sulfonamide SHIP1 Activators.

The SH2-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) enzyme opposes the activity of PI3K and therefore is of interest in the treatment of inflammatory disorders. Recent results also indicate that SHIP1 promotes phagolysosomal degradation of lipids by microglia, suggesting that the enzyme may be a target for the treatment of Alzheimer's disease. Therefore, small molecules that increase SHIP1 activity may have benefits in these areas. Recently we discovered a bis-sulfonamide that increases the enzymatic activity of SHIP1. A series of similar SHIP1 activators have been synthesized and evaluated to determine structure-activity relationships and improve in vivo stability. Some new analogs have now been found with improved potency. In addition, both the thiophene and the thiomorpholine in the parent structure can be replaced by groups without a low valent sulfur atom, which provides a way to access activators that are less prone to oxidative degradation.

Structure-Guided Design of a Domain-Selective Bromodomain and Extra Terminal N-Terminal Bromodomain Chemical Probe.

Small-molecule-mediated disruption of the protein-protein interactions between acetylated histone tails and the tandem bromodomains of the bromodomain and extra-terminal (BET) family of proteins is an important mechanism of action for the potential modulation of immuno-inflammatory and oncology disease. High-quality chemical probes have proven invaluable in elucidating profound BET bromodomain biology, with seminal publications of both pan- and domain-selective BET family bromodomain inhibitors enabling academic and industrial research. To enrich the toolbox of structurally differentiated N-terminal bromodomain (BD1) BET family chemical probes, this work describes an analysis of the GSK BRD4 bromodomain data set through a lipophilic efficiency lens, which enabled identification of a BD1 domain-biased benzimidazole series. Structure-guided growth targeting a key Asp/His BD1/BD2 switch enabled delivery of GSK023, a high-quality chemical probe with 300-1000-fold BET BD1 domain selectivity and a phenotypic cellular fingerprint consistent with BET bromodomain inhibition.

Higher Concentration of Marijuana Dispensaries in Neighborhoods with More Disadvantage Following Legalization in Washington.

Washington is one of 21 states that have legalized recreational marijuana resulting in neighborhoods that have experienced a change in physical environment with the emergence of dispensaries. This study examines the selection of dispensaries into disadvantage area, incorporating local policies and neighborhood characteristics. Marijuana and alcohol sales data were from the Washington State Liquor and Cannabis Board; and neighborhood characteristics were drawn from the American Community Survey 2010-2016 5-year estimates. Using factor analysis we created a neighborhood disadvantage index where census tracts were stratified into disadvantaged tertiles; and counties were stratified by urban/rural status. We examined the association between dispensaries, neighborhood characteristics, and local marijuana policies using Negative Binomial Regression with a natural log of land area as an offset, separately for 2014-2016. Dispensaries opened in high-disadvantaged CTs in 2014 and then dispersed across the state while retaining higher concentrations in disadvantaged urban CTs. Marijuana-specific policies (allotted dispensaries and retail cap) were found to be predictors of marijuana dispensary density. This study provides evidence that marijuana dispensaries were disproportionately located in areas with greater disadvantage. State and local marijuana policies emerged as important predictors, underscoring the importance of designing thoughtful and equitable license allocation procedures and policies.

Robust and General Late-Stage Methylation of Aryl Chlorides: Application to Isotopic Labeling of Drug-like Scaffolds.

The preparation of isotopically labeled compounds for drug discovery and development presents a unique challenge. Both stable and radioactive isotopes must be incorporated into complex bioactive molecules as efficiently as possible, using precious, and often expensive, isotopically enriched reagents. Due to the ubiquity and importance of methyl groups in drug molecules, there is a requirement for a general, late-stage methylation that allows for the incorporation of both carbon and hydrogen isotopes. Herein, we report a highly efficient, robust palladium-catalyzed approach, optimized via high-throughput experimentation, for the methylation of aryl chlorides using potassium methyltrifluoroborate. A practically straightforward route to isotopically labeled methylating agents has also been developed, and the methodology applied to isotopologue synthesis, including the installation of isotopic labels in a range of drug-like scaffolds.

SHIP1 inhibition via 3-alpha-amino-cholestane enhances protection against Leishmania infection.

Leishmania major and L. donovani cause cutaneous leishmaniasis and visceral leishmaniasis, respectively. Available chemotherapies suffer from toxicity, drug-resistance or high cost of production prompting the need for the discovery of new anti-leishmanials. Here, we test a novel aminosteriodal compound- 3-alpha-amino-cholestane [3AC] - that shows selective inhibition of SHIP1, an inositol-5'-phosphate-specific phosphatase with potent effects on the immune system. We report that 3AC-sensitive SHIP1 expression increases in Leishmania-infected macrophages. Treatment of BALB/c mice, a Leishmania-susceptible host, with 3AC increased anti-leishmanial, but reduced pro-leishmanial, cytokines' production and reduced the parasite load in both L. major and L. donovani infections. These findings implicate SHIPi as a potential novel immunostimulant with anti-leishmanial function.