Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1.

Hematopoietic progenitor kinase 1 (HPK1) serves a key immunosuppressive role as a negative regulator of T-cell receptor (TCR) signaling. HPK1 loss-of-function is associated with augmentation of immune function and has demonstrated synergy with immune checkpoint inhibitors in syngeneic mouse cancer models. These data offer compelling evidence for the use of selective small molecule inhibitors of HPK1 in cancer immunotherapy. We identified a novel series of isoquinoline HPK1 inhibitors through fragment-based screening that displayed promising levels of biochemical potency and activity in functional cell-based assays. We used structure-based drug design to introduce key selectivity elements while simultaneously addressing pharmacokinetic liabilities. These efforts culminated in a molecule demonstrating subnanomolar biochemical inhibition of HPK1 and strong in vitro augmentation of TCR signaling in primary human T-cells. Further profiling of this molecule revealed excellent kinase selectivity (347/356 kinases <50% inhibition @ 0.1 µM), a favorable in vitro safety profile, and good projected human pharmacokinetics.

Birth outcomes and survival by sex among newborns and children under 2 in the Birhan Cohort: a prospective cohort study in the Amhara Region of Ethiopia.

INTRODUCTION: Despite the progress in reducing child mortality, the rate remains high, particularly in sub-Saharan African countries. Limited data exist on child survival and other birth outcomes by sex. This study compared survival rates and birth outcomes by sex among neonates and children under 2 in Ethiopia. METHODS: Women who gave birth after 28 weeks of gestation and their newborns were included in the analysis. Survival probabilities were estimated for males and females in the neonatal period as well as the 2-year period following birth using Kaplan-Meier curves. HRs and 95% CIs were compared between males and females under 2. Descriptive statistics and χ2 tests were used to determine the sex-disaggregated variation in the birth outcomes of preterm birth, low birth weight (LBW), stillbirth, small for gestational age (SGA) and large for gestational age (LGA). RESULTS: The study included a total of 3904 women and child pairs. The neonatal mortality rate for males (3.4%, 95% CI 2.6% to 4.2%) was higher compared with females (1.7%, 95% CI 1.1% to 2.3%). The hazard of death during the first 28 days of life was approximately two times higher for males compared with females (HR 1.99, 95% CI 1.30 to 3.06) but was not significantly different after this period. While there was a non-significant difference between males and females in the proportion of preterm, LBW and LGA births, we found a significantly higher proportion of stillbirth (2.7% vs 1.3%, p=0.003) and SGA (20.5% vs 15.6%, p<0.001) for males compared with females. CONCLUSIONS: This study identified a significant sex difference in mortality and birth outcomes. We recommend focusing future research on the mechanisms of these sex differences in order to better design intervention programmes to reduce disparities and improve outcomes for neonates.

Estimates and determinants of health facility delivery in the Birhan cohort in Ethiopia.

Health facility delivery is one of the critical indicators to monitor progress towards the provision of skilled delivery care and reduction in perinatal mortality. In Ethiopia, utilization of health facilities for skilled delivery care has been increasing but varies greatly by region and among specific socio-demography groups. We aimed to measure the prevalence and determinants of health facility delivery in the Amhara region in Ethiopia. From December 2018 to November 2020, we conducted a longitudinal study from a cohort of 2801 pregnant women and described the location of delivery and the association with determinants. We interviewed a subset of women who delivered in the community and analyzed responses using the three delays model to understand reasons for not using health facility services. A multivariable poisson regression model with robust error variance was used to estimate the presence and magnitude of association between location of delivery and the determinants. Of the 2,482 pregnant women followed through to birth, 73.6% (n = 1,826) gave birth in health facilities, 24.3% (n = 604) gave birth at home and 2.1% (n = 52) delivered on the way to a health facility. Determinants associated with increased likelihood of delivery at a health facility included formal maternal education, shorter travel times to health facilities, primiparity, higher wealth index and having attended at least one ANC visit. Most common reasons mothers gave for not delivering in a health facility were delays in individual/family decision to seek care. The proportion of deliveries occurring in health facilities is increasing but falls below targets. Interventions that focus on the identified social-demographic determinants and delays are warranted.

MicroRNAs as Bile-based biomarkers in pancreaticobiliary cancers (MIRABILE): a cohort study.

BACKGROUND: Biliary obstruction can be due to both malignant and benign pancreaticobiliary disease. Currently, there are no biomarkers that can accurately help make this distinction. MicroRNAs (miRNAs) are stable molecules in tissue and biofluids that are commonly deregulated in cancer. The MIRABILE study aimed to identify miRNAs in bile that can differentiate malignant from benign pancreaticobiliary disease. MATERIALS AND METHODS: There were 111 patients recruited prospectively at endoscopic retrograde cholangiopancreatography (ERCP) or percutaneous transhepatic cholangiography (PTC) for obstructive jaundice, and bile was aspirated for cell-free RNA (cfRNA) extraction and analysis. In a discovery cohort of 78 patients (27 with pancreatic ductal adenocarcinoma (PDAC), 14 cholangiocarcinoma (CCA), 37 benign disease), cfRNA was subjected to small-RNA sequencing. LASSO regression was used to define bile miRNA signatures, and NormFinder to identify endogenous controls. In a second cohort of 87 patients (34 PDAC, 14 CCA, 39 benign disease), RT-qPCR was used for validation. RESULTS: LASSO regression identified 14 differentially-expressed bile miRNAs of which 6 were selected for validation. When comparing malignant and benign pancreaticobiliary disease, bile miR-340 and miR-182 were validated and significantly differentially expressed (P<0.05 and P<0.001, respectively). This generated an AUC of 0.79 (95%CI 0.70-0.88, sensitivity 65%; specificity 82%) in predicting malignant disease. CONCLUSION: Bile collected during biliary drainage contains miRNAs able to differentiate benign from malignant pancreaticobiliary diseases in patients with obstructive jaundice. These bile miRNAs have the potential to increase diagnostic accuracy.

Computer-assisted patient identification tool in inborn errors of metabolism - potential for rare disease patient registry and big data analysis.

BACKGROUND: Patient registries are crucial for rare disease management. However, manual registry construction is labor-intensive and often not user-friendly. Our goal is to establish Hong Kong's first computer-assisted patient identification tool for rare diseases, starting with inborn errors of metabolism (IEM). METHODS: Patient data from 2010 to 2019 was retrieved from electronic databases. Through big data analytics, patient data were filtered based on specific IEM-related biochemical and genetic tests. Clinical notes were analyzed using a rule-based natural language processing technique called regular expression. The algorithm classified each extracted paragraph as "IEM-related" or "not IEM-related." Pathologists reviewed the paragraphs for curation, and the algorithm's performance was evaluated. RESULTS: Out of 46,419 patients with IEM-related tests, the algorithm identified 100 as "IEM-related." After pathologists' validation, 96 cases were confirmed as true IEM, with 1 uncertain case and 3 false positives. A secondary ascertainment yielded a sensitivity of 92.3% compared to our previously published IEM cohort. CONCLUSIONS: Our artificial intelligence approach provides a novel method to identify IEM patients, facilitating the creation of a centralized, computer-assisted rare disease patient registry at the local and national levels. This data can potentially be accessed by multiple stakeholders for collaborative research and to enhance healthcare management for rare diseases.

Alcohol milestones and internalizing, externalizing, and executive function: longitudinal and polygenic score associations.

BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

Carriage of antimicrobial-resistant Enterobacterales among pregnant women and newborns in Amhara, Ethiopia.

OBJECTIVES: Infections are one of the most common causes of neonatal mortality, and maternal colonization has been associated with neonatal infection. In this study, we sought to quantify carriage prevalence of extended-spectrum-beta-lactamase (ESBL) -producing and carbapenem-resistant Enterobacterales (CRE) among pregnant women and their neonates and to characterize risk factors for carriage in rural Amhara, Ethiopia. METHODS: We conducted a prospective cohort study nested in the Birhan field site. We collected rectal and vaginal samples from 211 pregnant women in their third trimester and/or during labor/delivery and perirectal or stool samples from 159 of their neonates in the first week of life. RESULTS: We found that carriage of ESBL-producing organisms was fairly common (women: 22.3%, 95% CI: 16.8-28.5; neonates: 24.5%, 95% CI: 18.1-32.0), while carriage of CRE (women: 0.9%, 95% CI: 0.1-3.4; neonates: 2.5%, 95% CI: 0.7-6.3) was rare. Neonates whose mothers tested positive for ESBL-producing organisms were nearly twice as likely to also test positive for ESBL-producing organisms (38.7% vs 21.1%, P-value = 0.06). Carriage of ESBL-producing organisms was also associated with Woreda (district) of sample collection and recent antibiotic use. CONCLUSION: Understanding carriage patterns of potential pathogens and antibiotic susceptibility among pregnant women and newborns will inform local, data-driven recommendations to prevent and treat neonatal infections.

Colonisation of hospital surfaces from low- and middle-income countries by extended spectrum ß-lactamase- and carbapenemase-producing bacteria.

Hospital surfaces can harbour bacterial pathogens, which may disseminate and cause nosocomial infections, contributing towards mortality in low- and middle-income countries (LMICs). During the BARNARDS study, hospital surfaces from neonatal wards were sampled to assess the degree of environmental surface and patient care equipment colonisation by Gram-negative bacteria (GNB) carrying antibiotic resistance genes (ARGs). Here, we perform PCR screening for extended-spectrum ß-lactamases (blaCTX-M-15) and carbapenemases (blaNDM, blaOXA-48-like and blaKPC), MALDI-TOF MS identification of GNB carrying ARGs, and further analysis by whole genome sequencing of bacterial isolates. We determine presence of consistently dominant clones and their relatedness to strains causing neonatal sepsis. Higher prevalence of carbapenemases is observed in Pakistan, Bangladesh, and Ethiopia, compared to other countries, and are mostly found in surfaces near the sink drain. Klebsiella pneumoniae, Enterobacter hormaechei, Acinetobacter baumannii, Serratia marcescens and Leclercia adecarboxylata are dominant; ST15 K. pneumoniae is identified from the same ward on multiple occasions suggesting clonal persistence within the same environment, and is found to be identical to isolates causing neonatal sepsis in Pakistan over similar time periods. Our data suggests persistence of dominant clones across multiple time points, highlighting the need for assessment of Infection Prevention and Control guidelines.

Clinical, genomic, and neurophysiological correlates of lifetime suicide attempts among individuals with alcohol dependence.

Research has identified clinical, genomic, and neurophysiological markers associated with suicide attempts (SA) among individuals with psychiatric illness. However, there is limited research among those with an alcohol use disorder (AUD), despite their disproportionately higher rates of SA. We examined lifetime SA in 4,068 individuals with DSM-IV alcohol dependence from the Collaborative Study on the Genetics of Alcoholism (23% lifetime suicide attempt; 53% female; 17% Admixed African American ancestries; mean age: 38). We 1) conducted a genome-wide association study (GWAS) of SA and performed downstream analyses to determine whether we could identify specific biological pathways of risk, and 2) explored risk in aggregate across other clinical conditions, polygenic scores (PGS) for comorbid psychiatric problems, and neurocognitive functioning between those with AD who have and have not reported a lifetime suicide attempt. The GWAS and downstream analyses did not produce any significant associations. Participants with an AUD who had attempted suicide had greater rates of trauma exposure, major depressive disorder, post-traumatic stress disorder, and other substance use disorders compared to those who had not attempted suicide. Polygenic scores for suicide attempt, depression, and PTSD were associated with reporting a suicide attempt (ORs = 1.22-1.44). Participants who reported a SA also had decreased right hemispheric frontal-parietal theta and decreased interhemispheric temporal-parietal alpha electroencephalogram resting-state coherences relative to those who did not, but differences were small. Overall, individuals with alcohol dependence who report SA appear to experience a variety of severe comorbidities and elevated polygenic risk for SA. Our results demonstrate the need to further investigate suicide attempts in the presence of substance use disorders.

Perspectives and gaps in the management of food allergy and anaphylaxis in the Asia-Pacific Region.

Background: Food allergy (FA), which is a condition that has no effective cure and can result in severe life-threatening allergic reactions, remains a global public health concern; however, little is known about how FAs are currently managed in the Asia-Pacific region. Objective: The main objective of this survey was to evaluate the epidemiology of FA, as well as the availability of resources and practices for management of FA and anaphylaxis by health care providers across Asia. Methods: From June 2022 to September 2022, a questionnaire-based survey comprising 66 questions was electronically sent to member societies of the Asia Pacific Association of Allergy Asthma and Clinical Immunology by using Survey Monkey. Results: A total of 20 responses were received from 15 member countries and territories. Compared with the pediatric data, there was a lack of prevalence data for FA in adults. Except for Australia and Japan, most regions had between 0.1 and 0.5 allergists per 100,000 population and some had fewer than 0.1 allergists per 100,000 population. The perceived rate of FA in regions with a short supply of allergists was high. Although specific IgE tests and oral food challenges were available in all regions, the median wait time for oral food challenges at government facilities was 37 days (interquartile range = 10.5-60 days). Seven regions still relied on prescriptions of ampules and syringes of injectable adrenaline, and adrenaline autoinjectors were not accessible in 4 regions. Oral immunotherapy as FA treatment was available in half of the surveyed countries and territories. Conclusions: Our study offers a cross-sectional evaluation of the management practices for FA in each Asia Pacific Association of Allergy Asthma and Clinical Immunology member country or territory. Urgent actions are required to enhance allergy services, improve the accessibility and affordability of adrenaline autoinjectors, and conduct robust epidemiologic studies.

Prevalence, Incidence, and Reversal Pattern of Childhood Stunting From Birth to Age 2 Years in Ethiopia.

Importance: Although there has been a reduction in stunting (low-height-for-age and low-length-for-age), a proxy of malnutrition, the prevalence of malnutrition in Ethiopia is still high. Child growth patterns and estimates of stunting are needed to increase awareness and resources to improve the potential for recovery. Objective: To estimate the prevalence, incidence, and reversal of stunting among children aged 0 to 24 months. Design, Setting, and Participants: This population-based cohort study of the Birhan Maternal and Child Health cohort in North Shewa Zone, Amhara, Ethiopia, was conducted between December 2018 and November 2020. Eligible participants included children aged 0 to 24 months who were enrolled during the study period and had their length measured at least once. Data analysis occurred from Month Year to Month Year. Main Outcomes and Measures: The primary outcome of this study was stunting, defined as length-for-age z score (LAZ) at least 2 SDs below the mean. Z scores were also used to determine the prevalence, incidence, and reversal of stunting at each key time point. Growth velocity was determined in centimeters per month between key time points and compared with global World Health Organization (WHO) standards for the same time periods. Heterogeneity was addressed by excluding outliers in sensitivity analyses using modeled growth trajectories for each child. Results: A total of 4354 children were enrolled, out of which 3674 (84.4%; 1786 [48.7%] female) had their length measured at least once and were included in this study. The median population-level length was consistently below WHO growth standards from birth to 2 years of age. The observed prevalence of stunting was highest by 2 years of age at 57.4% (95% CI, 54.8%-9 60.0%). Incidence of stunting increased over time and reached 51.0% (95% CI, 45.3%-56.6%) between ages 12 and 24 months. Reversal was 63.5% (95% CI, 54.8%-71.4%) by age 6 months and 45.2% (95% CI, 36.0%-54.8%) by age 2 years. Growth velocity point estimate differences were slowest compared with WHO standards during the neonatal period (-1.4 cm/month for girls and -1.6 cm/month for boys). There was substantial heterogeneity in anthropometric measurements. Conclusions and Relevance: The evidence from this cohort study highlights a chronically malnourished population with much of the burden associated with growth faltering during the neonatal periods as well as after 6 months of age. To end all forms of malnutrition, growth faltering in populations such as that in young children in Amhara, Ethiopia, needs to be addressed.

Examining associations between genetic and neural risk for externalizing behaviors in adolescence and early adulthood.

BACKGROUND: Researchers have identified genetic and neural risk factors for externalizing behaviors. However, it has not yet been determined if genetic liability is conferred in part through associations with more proximal neurophysiological risk markers. METHODS: Participants from the Collaborative Study on the Genetics of Alcoholism, a large, family-based study of alcohol use disorders were genotyped and polygenic scores for externalizing (EXT PGS) were calculated. Associations with target P3 amplitude from a visual oddball task (P3) and broad endorsement of externalizing behaviors (indexed via self-report of alcohol and cannabis use, and antisocial behavior) were assessed in participants of European (EA; N = 2851) and African ancestry (AA; N = 1402). Analyses were also stratified by age (adolescents, age 12-17 and young adults, age 18-32). RESULTS: The EXT PGS was significantly associated with higher levels of externalizing behaviors among EA adolescents and young adults as well as AA young adults. P3 was inversely associated with externalizing behaviors among EA young adults. EXT PGS was not significantly associated with P3 amplitude and therefore, there was no evidence that P3 amplitude indirectly accounted for the association between EXT PGS and externalizing behaviors. CONCLUSIONS: Both the EXT PGS and P3 amplitude were significantly associated with externalizing behaviors among EA young adults. However, these associations with externalizing behaviors appear to be independent of each other, suggesting that they may index different facets of externalizing.

A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency.

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction.

Pediatric Primary Cutaneous Marginal Zone Lymphoma Treated With Doxycycline.

Primary cutaneous marginal zone lymphoma (PCMZL) is a cutaneous B-cell lymphoma that rarely occurs in children. We present a 13-year-old boy with multiple asymptomatic erythematous papules and nodules on the trunk and arms that were confirmed on biopsy to be PCMZL. He was treated with doxycycline and intralesional triamcinolone with improvement of lesions. This case supports the use of doxycycline for the treatment of pediatric PCMZL in patients with widespread involvement despite negative Borrelia serology. Multiple low-risk treatment modalities may be used in conjunction to clear disease in pediatric patients.

Polygenic Contributions to Suicidal Thoughts and Behaviors in a Sample Ascertained for Alcohol Use Disorders.

Introduction: Suicidal thoughts and behaviors have partially distinct genetic etiologies. Methods: We used PRS-CS to create polygenic risk scores (PRSs) from GWAS of non-suicidal self-injury, broad-sense self-harm ideation, nonfatal suicide attempt, death by suicide, and depression. Using mixed-effect models, we estimated whether these PRSs were associated with a range of suicidal thoughts and behaviors in the Collaborative Study on the Genetics of Alcoholism (N = 7,526). Results: All PRSs were significantly associated with suicidal ideation and suicide attempt (betas = 0.08-0.44, false discovery rate [FDR] <0.023). All PRSs except non-suicidal self-injury PRS were associated with active suicidal ideation (betas = 0.14-0.22, FDR <0.003). Several associations remained significant in models where all significant PRSs were included as simultaneous predictors, and when all PRSs predicted suicide attempt, the PRS together explained 6.2% of the variance in suicide attempt. Significant associations were also observed between some PRSs and persistent suicidal ideation, non-suicidal self-injury, compounded suicide attempt, and desire to die. Conclusion: Our findings suggest that PRS for depression does not explain the entirety of the variance in suicidal thoughts and behaviors, with PRS specifically for suicidal thoughts and behaviors making additional and sometimes unique contributions.

Antenatal care coverage in a low-resource setting: Estimations from the Birhan Cohort.

Antenatal care (ANC) coverage estimates commonly rely on self-reported data, which may carry biases. Leveraging prospectively collected longitudinal data from the Birhan field site and its pregnancy and birth cohort, the Birhan Cohort, this study aimed to estimate the coverage of ANC, minimizing assumptions and biases due to self-reported information and describing retention patterns in ANC in rural Amhara, Ethiopia. The study population were women enrolled and followed during pregnancy between December 2018 and April 2020. ANC visits were measured by prospective facility chart abstraction and self-report at enrollment. The primary study outcomes were the total number of ANC visits attended during pregnancy and the coverage of at least one, four, or eight ANC visits. Additionally, we estimated ANC retention patterns. We included 2069 women, of which 150 (7.2%) women enrolled <13 weeks of gestation with complete prospective facility reporting. Among these 150 women, ANC coverage of at least one visit was 97.3%, whereas coverage of four visits or more was 34.0%. Among all women, coverage of one ANC visit was 92.3%, while coverage of four or more visits was 28.8%. No women were found to have attended eight or more ANC visits. On retention in care, 70.3% of participants who had an ANC visit between weeks 28 and <36 of gestation did not return for a subsequent visit. Despite the high proportion of pregnant women who accessed ANC at least once in our study area, the coverage of four visits remains low. Further efforts are needed to enhance access to more ANC visits, retain women in care, and adhere to the most recent Ethiopian National ANC guideline of at least eight ANC visits. It is essential to identify the factors that lead a large proportion of women to discontinue ANC follow-up.

Alcohol use polygenic risk score, social support, and alcohol use among European American and African American adults.

Alcohol use is influenced by genetic and environmental factors. We examined the interactive effects between genome-wide polygenic risk scores for alcohol use (alc-PRS) and social support in relation to alcohol use among European American (EA) and African American (AA) adults across sex and developmental stages (emerging adulthood, young adulthood, and middle adulthood). Data were drawn from 4,011 EA and 1,274 AA adults from the Collaborative Study on the Genetics of Alcoholism who were between ages 18-65 and had ever used alcohol. Participants completed the Semi-Structured Assessment for the Genetics of Alcoholism and provided saliva or blood samples for genotyping. Results indicated that social support from friends, but not family, moderated the association between alc-PRS and alcohol use among EAs and AAs (only in middle adulthood for AAs); alc-PRS was associated with higher levels of alcohol use when friend support was low, but not when friend support was high. Associations were similar across sex but differed across developmental stages. Findings support the important role of social support from friends in buffering genetic risk for alcohol use among EA and AA adults and highlight the need to consider developmental changes in the role of social support in relation to alcohol use.