Childhood maltreatment and adult aggression: The moderating role of neurocognitive ability and substance use.

BACKGROUND: Achieving positive intervention outcomes for aggressive behaviour in adulthood is challenging. This difficulty is enhanced by the complex presentations of those engaging in such behaviours and the impact this has on their engagement with interventions. OBJECTIVE: This study assessed the cumulative impact of childhood maltreatment, substance use, and neurocognitive ability (working memory, cognitive flexibility, decision making, response inhibition, and cognitive control) on aggressive behaviour in adulthood. PARTICIPANTS AND SETTING: Adult participants (N = 179; 69 % female) recruited from the community, and clinical and forensic services, aged 18 to 81 (M = 40.5, SD = 15.9). METHODS: Participants completed an online Qualtrics survey and remote neurocognitive testing via Inquisit. RESULTS: We implemented an a priori approach, assessing three-way interactions between childhood maltreatment, substance use, neurocognitive ability, and aggression. No three-way interactions were significant. We then utilised a data-driven modelling approach, using automatic linear forward stepwise modelling to identify the most important variables for predicting aggression. Four were significant: physical maltreatment (b = 0.053, p < .001), drug use risk level (b = 0.015, p < .001), poorer response inhibition (b = 0.001, p = .016), and the interaction between poorer response inhibition and physical maltreatment (b = 0.205, p = .017). CONCLUSIONS: Physical maltreatment in childhood, drug use risk level, and response inhibition impact significantly on adult aggression, indicating a need for early intervention for children who have experienced maltreatment. Consideration should be given to how maltreatment in childhood may impact on ability to engage with interventions as an adult, particularly response inhibition difficulties that may hinder skill implementation.

Cryptosporidium lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy.

Cryptosporidiosis is a diarrheal disease caused by infection with Cryptosporidium spp. parasites and is a leading cause of death in malnourished children worldwide. The only approved treatment, nitazoxanide, has limited efficacy in this at-risk patient population. Additional safe therapeutics are urgently required to tackle this unmet medical need. However, the development of anti-cryptosporidial drugs is hindered by a lack of understanding of the optimal compound properties required to treat this gastrointestinal infection. To address this knowledge gap, a diverse set of potent lysyl-tRNA synthetase inhibitors was profiled to identify optimal physicochemical and pharmacokinetic properties required for efficacy in a chronic mouse model of infection. The results from this comprehensive study illustrated the importance of balancing solubility and permeability to achieve efficacy in vivo. Our results establish in vitro criteria for solubility and permeability that are predictive of compound efficacy in vivo to guide the optimization of anti-cryptosporidial drugs. Two compounds from chemically distinct series (DDD489 and DDD508) were identified as demonstrating superior efficacy and prioritized for further evaluation. Both compounds achieved marked parasite reduction in immunocompromised mouse models and a disease-relevant calf model of infection. On the basis of these promising data, these compounds have been selected for progression to preclinical safety studies, expanding the portfolio of potential treatments for this neglected infectious disease.

Red Blood Cell Transfusion in Critically Ill Adults: An American College of Chest Physicians Clinical Practice Guideline.

BACKGROUND: Blood products frequently are administered to critically ill patients. Considering recent trials and practice variability, a comprehensive review of current evidence was deemed essential to offer pertinent guidance to critical care practitioners. This American College of Chest Physicians (CHEST) guidelines panel examined the literature on RBC transfusions among critically ill patients overall and specific subgroups, including patients with gastrointestinal bleeding, acute coronary syndrome (ACS), cardiac surgery, isolated troponin elevation, and septic shock, to provide evidence-based recommendations. STUDY DESIGN AND METHODS: A panel of experts developed 6 Population, Intervention, Comparator, and Outcome questions addressing RBC transfusions in critically ill patients and performed a comprehensive evidence review. The panel applied the Grading of Recommendations, Assessment, Development, and Evaluations approach to assess the certainty of evidence and to formulate and grade recommendations. A modified Delphi technique was used to reach consensus on the recommendations. RESULTS: The initial search identified a total of 3,082 studies, and after the initial screening, 38 articles were reviewed. Among them, 23 studies met inclusion criteria, comprising 22 randomized controlled trials and 1 cohort study. Based on the analysis of these studies, the panel formulated 2 strong and 4 conditional recommendations. The overall quality of evidence for recommendations ranged from very low to moderate. CONCLUSIONS: In most critically ill patients, a restrictive strategy was preferable to a permissive approach because it does not increase the risk of death or complications, but does decrease RBC use significantly. Data from critically ill subpopulations also supported a restrictive approach, except in patients with ACS, for whom favoring a restrictive approach could increase adverse outcomes.

Identification of potent and orally efficacious phosphodiesterase inhibitors in Cryptosporidium parvum-infected immunocompromised male mice.

Cryptosporidium parvum and C. hominis are parasites that cause life-threatening diarrhea in children and immunocompromised people. There is only one approved treatment that is modestly effective for children and ineffective for AIDS patients. Here, screening 278 compounds from the Merck KGaA, Darmstadt, Germany collection and accelerated follow-up enabled by prior investigation of the compounds identifies a series of pyrazolopyrimidine human phosphodiesterase (PDE)-V (hPDE-V) inhibitors with potent anticryptosporidial activity and efficacy following oral administration in C. parvum-infected male mice. The lead compounds affect parasite host cell egress, inhibit both C. parvum and C. hominis, work rapidly, and have minimal off-target effects in a safety screening panel. Interestingly, the hPDE-V inhibitors sildenafil and the 4-aminoquinoline compound 7a do not affect Cryptosporidium. C. parvum expresses one PDE (CpPDE1) continuously during asexual growth, the inhibited life stage. According to homology modeling and docking, the lead compounds interact with CpPDE1. Bulkier amino acids (Val900 and His884) in the CpPDE1 active site replace alanines in hPDE-V and block sildenafil binding. Supporting this, sildenafil kills a CRISPR-engineered Cryptosporidium CpPDE1 V900A mutant. The CpPDE1 mutation also alters parasite susceptibility to pyrazolopyrimidines. CpPDE1 is therefore a validated pyrazolopyrimidine molecular target to exploit for target-based optimization for improved anticryptosporidial development.

Long-term persistent exposure to cigarette smoke induces AhR driven corneal endothelial dysfunction in mice.

Epidemiological studies show cigarette smoking enhances corneal endothelial dysfunction, but mechanisms remain unclear. Our study reveals that prolonged smoke exposure activates the aryl hydrocarbon receptor (AhR), increasing CYP1B1 expression and accelerating senescence and fibrosis in corneal endothelium, potentially reflecting adaptive responses to maintain corneal resilience. Although these molecular modifications indicate early endothelial dysfunction, no pathological changes were observed. The findings indicate that while chronic cigarette smoke exposure triggers initial molecular alterations and endothelial dysfunction, the progression to Fuchs endothelial corneal dystrophy likely requires additional environmental or genetic factors beyond smoke exposure alone.

Police-issued barring notices in Western Australia: An analysis of the type, seriousness and trajectory of associated offences.

INTRODUCTION: Police-issued barring notices are currently used in Western Australia in response to alcohol-related disorderly and anti-social behaviour. This paper examines the type, severity and trajectory of the offending behaviours associated with served barring notices. METHOD: WA Police Force de-identified the data for 3815 individuals who had received one or more police-imposed barring notice/s between 2011 and 2020. The offence category associated with each barring notice was examined to explore the overall breakdown and whether/how offending categories change for recipients of subsequent barring notices. RESULTS: For single and multiple barring notice recipients, the most common offence categories were fighting/physical violence and public order offences. Within a subset of the data, non-anti-social offences also spiked. Aggressive behaviours predominate for recipients in metropolitan areas, compared with public order offences in regional locations. DISCUSSION AND CONCLUSIONS: For recipients of multiple barring notices, behaviours do not become more serious but neither do they moderate to any notable extent. The low number of repeat barring notices (5%) may suggest an overall beneficial effect on recipient behaviours but more analysis is needed to examine the potential confounding effects of factors, such as fly-in/fly-out workers, policing and locational differences.

Evaluating social rehabilitation of aggression for persons with Acquired Brain Injury: a systematic review.

PURPOSE: Social rehabilitation of aggression following an Acquired Brain Injury (ABI) is critically important for persons with ABI due to increased vulnerability of criminal behaviour related to post-injury changes in functioning. This review presents findings from studies that evaluated aggression interventions in both community and forensic populations of people with ABI. METHODS: We searched PsycINFO, EMBASE, SocINDEX, CINAHL and Medline databases for studies published between 1st January 2000 and 15th October 2023. RESULTS: There were 15 studies (14 community-based, one forensic) that met inclusion criteria. Pharmacological management (6) was largely ineffective and anger management interventions (6) presented with inconsistent effectiveness. Emotion regulation (1) may be effective for externalised aggression. Both mindfulness and transcranial direct current stimulation (1) were effective, and the results of a forensic peer group approach (1) were not tested for statistical significance. There was variability in the measurement of aggression, injury severity, and cognitive impairment. CONCLUSIONS: Whilst community interventions for aggression in persons with ABI are prevalent, findings for effectiveness have been mixed and there is a paucity of evaluated interventions in forensic samples. Further research is needed to unravel the complex interplay of factors contributing to aggression and develop effective social rehabilitation for persons with ABI.

Social rehabilitation is critical following an Acquired Brain Injury (ABI) due to increased risk of displaying challenging behaviours, such as aggression, that may significantly reduce an individual's quality of life.The current review highlights a lack of suitable interventions targeting aggression for individuals with ABI that account for injury-related impairments which impact capacity to engage in intervention.Findings emphasise the need to develop appropriate and relevant social rehabilitation interventions for aggression in ABI populations, particularly forensic populations, to prevent negative outcomes.

Trends in child and adolescent assault and maltreatment following the re-introduction of the Banned Drinker Register in the Northern Territory, Australia.

OBJECTIVE: In 2017 the Northern Territory (NT) government re-introduced the Banned Drinker Register (BDR) to address the high rates of alcohol related harm. This paper aims to evaluate whether trends in assault, maltreatment and sentinel injuries in children and adolescents were associated with the re-introduction of the BDR, in the context of other local interventions such as police officers stationed in bottle shops being partially removed, Police Auxiliary Liquor Inspectors, and the introduction of a minimum unit price of alcohol. METHOD: Interrupted time series analysis was used to assess monthly trends in emergency department presentations and inpatient hospital admissions for assault, maltreatment and sentinel injuries between January 2014 and December 2019 in the regions of Greater Darwin, Alice Springs, and Katherine. RESULTS: A significant step increase after the introduction of the BDR in emergency department presentations for assault and maltreatment was present when examining the three regions combined (ß = 7.65, 95 % CI = 2.15, 13.16). However, this was not present at the individual community level. Results across a range of other models pointed towards null effects of the BDR introduction. CONCLUSIONS: The current study found that the re-introduction of the BDR had minimal impact on rates of assault, maltreatment, or sentinel injuries in children and adolescents. To ensure long-term harm mitigation from alcohol use, a combination of evidence informed alcohol policies that address the price and availability of alcohol in a comprehensive framework, along with measures which address the underlying social determinants of unregulated drinking and health more broadly will assist in reducing alcohol related harm in both children and adults.

Identification of Small Molecule Inhibitors of PPM1D Using a Novel Drug Discovery Platform.

Protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D), is a serine/threonine phosphatase that is recurrently activated in cancer, regulates the DNA damage response (DDR), and suppresses the activation of p53. Consistent with its oncogenic properties, genetic loss or pharmacologic inhibition of PPM1D impairs tumor growth and sensitizes cancer cells to cytotoxic therapies in a wide range of preclinical models. Given the therapeutic potential of targeting PPM1D specifically and the DDR and p53 pathway more generally, we sought to deepen our biological understanding of PPM1D as a drug target and determine how PPM1D inhibition differs from other therapeutic approaches to activate the DDR. We performed a high throughput screen to identify new allosteric inhibitors of PPM1D, then generated and optimized a suite of enzymatic, cell-based, and in vivo pharmacokinetic and pharmacodynamic assays to drive medicinal chemistry efforts and to further interrogate the biology of PPM1D. Importantly, this drug discovery platform can be readily adapted to broadly study the DDR and p53. We identified compounds distinct from previously reported allosteric inhibitors and showed in vivo on-target activity. Our data suggest that the biological effects of inhibiting PPM1D are distinct from inhibitors of the MDM2-p53 interaction and standard cytotoxic chemotherapies. These differences also highlight the potential therapeutic contexts in which targeting PPM1D would be most valuable. Therefore, our studies have identified a series of new PPM1D inhibitors, generated a suite of in vitro and in vivo assays that can be broadly used to interrogate the DDR, and provided important new insights into PPM1D as a drug target.

Reducing alcohol harms whilst minimising impact on hospitality businesses: 'Sweetspot' policy options.

BACKGROUND: During COVID-19, hospitality businesses (e.g. bars, restaurants) were closed/restricted whilst off-sales of alcohol increased, with health consequences. Post-covid, governments face lobbying to support such businesses, but many health services remain under pressure. We appraised 'sweetspot' policy options: those with potential to benefit public services and health, whilst avoiding or minimising negative impact on the hospitality sector. METHODS: We conducted rapid non-systematic evidence reviews using index papers, citation searches and team knowledge to summarise the literature relating to four possible 'sweetspot' policy areas: pricing interventions (9 systematic reviews (SR); 14 papers/reports); regulation of online sales (1 SR; 1 paper); place-shaping (2 SRs; 18 papers/reports); and violence reduction initiatives (9 SRs; 24 papers/reports); and led two expert workshops (n = 11). RESULTS: Interventions that raise the price of cheaper shop-bought alcohol appear promising as 'sweetspot' policies; any impact on hospitality is likely small and potentially positive. Restrictions on online sales such as speed or timing of delivery may reduce harm and diversion of consumption from on-trade to home settings. Place-shaping is not well-supported by evidence and experts were sceptical. Reduced late-night trading hours likely reduce violence; evidence of impact on hospitality is scant. Other violence reduction initiatives may modestly reduce harms whilst supporting hospitality, but require resources to deliver multiple measures simultaneously in partnership. CONCLUSIONS: Available evidence and expert views point to regulation of pricing and online sales as having greatest potential as 'sweetspot' alcohol policies, reducing alcohol harm whilst minimising negative impact on hospitality businesses.

High-risk subgroups were not identified to benefit from thromboprophylaxis after hospitalization for COVID-19.

Background: The Accelerating COVID-19 Therapeutic Interventions and Vaccines-4c (ACTIV-4c) trial investigated prophylactic apixaban for 30 days following hospitalization for COVID-19. The overall incidence of early postdischarge death or thromboembolism was low, and the trial was closed early. Objectives: To identify a high-risk patient population who might benefit from postdischarge thromboprophylaxis through subgroup analyses stratified by age, race/ethnicity, obesity, D-dimer elevation, World Health Organization score, and modified International Medical Prevention Registry on Venous Thromboembolism score on 30-day composite outcome of all-cause death, arterial thromboembolism (ATE), and venous thromboembolism (VTE). Methods: Cumulative incidences of all-cause death, ATE, and VTE within 30 days were described for each subgroup. Time to death, ATE, or VTE by 30 days was analyzed using Cox proportional hazard models with interaction testing for each subgroup. Results: Among 1217 patients randomized to apixaban or placebo group, 32% were >60 years old. Modified International Medical Prevention Registry on Venous Thromboembolism score was ≥4 in 2% and 2 or 3 with an elevated D-dimer in an additional 9% of participants. The overall incidence of the primary endpoint was 2.13% in the apixaban group and 2.31% in the placebo group. At day 30, similar rates of the primary endpoint occurred within subgroups, except for participants aged >60 years. No benefit of thromboprophylaxis was seen in any subgroup. Conclusion: The combined incidence of 30-day death, ATE, and VTE was low in patients who survived COVID-19 hospitalization, except in patients over age 60 years. Due to the limited number of events, the findings remain inconclusive; nonetheless, the study did not identify a high-risk subgroup that would derive benefits from extended thromboprophylaxis.

Preventing Sexual Harm in Nightlife Settings: A Scoping Review.

Sexual harm within nightlife settings is a pervasive global concern; however, little is known about the nature of available interventions. The current study aims to review the literature on the nature and effectiveness of nightlife-related sexual harm interventions. A systematic literature search of six databases was conducted to identify records that were published between 1970 and June 2023 and reported approaches that aimed to reduce or prevent nightlife-related sexual harm. Records were included if they theorized, discussed, or evaluated an intervention, prevention or response strategy; however, individual safety strategies were excluded. Results were categorized according to intervention type. Thirty-five peer-reviewed journal articles and 16 gray literature records were identified. The most common nightlife-related sexual harm intervention strategies covered by the literature included targeted policies, laws, and regulations, bystander interventions, and awareness-raising campaigns. Literature in the area is increasing, with the majority of the articles (77.1%) being published in the previous six years; however, there are very few interventions that have been critically evaluated (22.9%). Promising areas for intervention include targeted alcohol regulations (e.g., lockout policies), venue-level policies, and environmental interventions. However, an increase in rigorous evaluative practices is urgently required to ensure future interventions are based on sound theoretical work and empirical evidence.

Test purchasing of same day and rapid online alcohol home delivery in two Australian jurisdictions.

OBJECTIVE: With same day online alcohol sales increasing, there is a need to study their regulation. Test purchasing of alcohol home delivery was conducted to measure compliance with regulations for identification checks and unattended deliveries in two Australian jurisdictions (Perth, Western Australia and Geelong, Victoria), which have differing regulations. METHOD: Alcohol orders for same day or rapid (<2 hours) delivery on Friday and Saturday nights were made by research assistants aged 18-24 years in Perth (n=34) and Geelong (n=29). An observation checklist was used to record the delivery interaction, with a specific focus on checking of photo identification at time of delivery and whether deliveries were left unattended. RESULTS: Average time from order to delivery for rapid deliveries was less than one hour in both sites (Perth = 50 minutes; Geelong = 36 minutes). More than 20% of deliveries were made without an identification check in both sites (Perth = 24%; Geelong = 21%). CONCLUSIONS: This pilot study showed alcohol can be delivered to the home within one hour, and not all deliveries include an identification check at point of delivery. These findings indicate a need for policies that empower regulators and police to undertake 'mystery shopper' monitoring to reduce potential harms and improve compliance with alcohol delivery policy.

What are the impacts of alcohol supply reduction measures on police-recorded adult domestic and family violence in the Northern Territory of Australia?

BACKGROUND: During 2017-18, the Northern Territory (NT) introduced a Banned Drinker Register (BDR) and Minimum Unit Price (MUP) NT-wide; Police Auxiliary Liquor Inspectors (PALIs) in three regional towns; and restrictions on daily purchases/opening hours (DPOH) in one regional town. The BDR is an individual-level alcohol ban; MUP is a pricing policy; and PALIs enforce bans on restricted areas at takeaway outlets. This study examines the impact of these policies on adult domestic and family violence (DFV). METHODS: We examined DFV assaults and breaches of violence orders from January 2014 - February 2020 using interrupted time series models for NT, Greater Darwin, Katherine, Tennant Creek, and Alice Springs. To account for increasing numbers of individuals on the BDR we tested two timepoints (Sept 2017, March 2018). FINDINGS: Following DPOH, assaults (78 %) and alcohol-involved assaults (92 %) decreased in Tennant Creek. After PALIs, assaults (79 %) in Tennant Creek, and breaches (39 %) and alcohol-involved breaches (58 %) in Katherine decreased. After MUP, assaults (11 %), alcohol-involved assaults (21 %) and alcohol-involved breaches (21%) decreased NT wide. After MUP/PALIs in Alice Springs, alcohol-involved assaults (33 %), breaches (42 %), and alcohol-involved breaches (57 %) decreased. BDR (Sept 2017) found increases in assaults (44 %) and alcohol-involved assaults (39 %) in Katherine and assaults (10%) and alcohol-involved assaults NT-wide (17 %). There were increases of 21 %-45 % in breaches NT-wide, in Darwin, Katherine, and Alice Springs. Following March 2018 found increases in assaults (33 %) and alcohol-involved assaults (48 %) in Katherine. There were increases - from 20 % to 56 % - in breaches in NT-wide, Katherine, and Alice Springs. CONCLUSION: PALIs and DPOH were associated with some reductions in DFV; the BDR was associated with some increases. The upward trend commences prior to the BDR, so it is also plausible that the BDR had no effect on DFV outcomes. Although MUP was associated with reductions in the NT-wide model, there were no changes in sites without cooccurring PALIs.

Prevalence, Dynamics, and Prognostic Role of Clonal Hematopoiesis of Indeterminate Potential in Patients With Breast Cancer.

PURPOSE: Clonal hematopoiesis of indeterminate potential (CHIP) is frequent in patients with solid tumors. Prospective data about CHIP prevalence at breast cancer diagnosis and its dynamic evolution under treatment selective pressure are limited. PATIENTS AND METHODS: We performed targeted error-corrected sequencing on 614 samples from 380 patients with breast cancer. We investigated the dynamics of CHIP on prospectively collected paired samples from patients with early breast cancer (eBC) receiving chemotherapy (CT) or endocrine therapy (ET). We assessed the correlation of CHIP with survival in patients with metastatic triple-negative breast cancer (mTNBC). We estimated the risk of progression to treatment-related myeloid neoplasms (t-MN) according to the clonal hematopoiesis risk score (CHRS). In exploratory analyses, we considered clonal hematopoiesis (CH) with variant allele fraction (VAF) ≥0.005. RESULTS: CHIP was identified in 15% of patients before treatment. Few CHIP emerged after treatment, and the risk of developing new mutations was similar for patients receiving CT versus ET (odds ratio [OR], 1.16; P = .820). However, CT increased the risk of developing new CH with VAF ≥0.005 (OR, 3.45; P = .002). Five TP53-mutant CH with VAF ≥0.005 emerged among patients receiving CT. Most patients had low risk of t-MN according to the CHRS score. CHIP did not correlate with survival in mTNBC. CONCLUSION: CHIP is frequent in patients with breast cancer. In this study, CT did not lead to emergence of new CHIP, and most patients had low risk of developing t-MN. This finding is reassuring, given long life expectancy of patients with eBC and the association of CHIP with morbidity and mortality. However, TP53-mutant CH with VAF ≥0.005 emerged with CT, which carries high risk of t-MN. Evolution of these small clones and their clinical significance warrant further investigation.

Impacts of Northern Territory banned drinker register on police recorded youth assault.

INTRODUCTION: In September 2017 the Northern Territory Government of Australia introduced a banned drinker register (BDR) to mitigate the high levels of alcohol-related harm within the Northern Territory. The current study aimed to examine the impact of the Northern Territory BDR on youth (aged <18 years) using police recorded assault data. METHODS: Interrupted time-series models were used to assess monthly trends in assaults and alcohol-related assaults perpetration and victimisation in the regions of Greater Darwin, Alice Springs and Katherine between January 2014 and December 2019. RESULTS: Examining the three regions combined, after the re-introduction of the BDR a significant step decrease in police recorded youth assault perpetration (ß = -1.67) and a significant step increase in police recorded youth assault victimisation (ß = 1.40) was identified. However, no significant effects were identified at the individual region level. DISCUSSION AND CONCLUSIONS: Findings suggest that restricting alcohol consumption in high-risk adults through the BDR had a limited immediate effect in police recorded youth assaults. Individual level or contextual factors may have influenced both immediate and long-term impacts of the BDR, and as such, future policy design needs to support and empower community leaders across the policy development and implementation process. A wider evaluation of the BDR currently underway may provide additional understanding behind the mechanisms that underpin alcohol-related harm in the Northern Territory.

Police-recorded adult sexual assault in the Northern Territory, Australia: Alcohol involvement and alcohol policy effects.

INTRODUCTION: Between 2017 and 2018 three major alcohol policy changes were introduced in the Northern Territory (NT): the Banned Drinker Register, an individual-level ban enforced via ID scanners at takeaway outlets; a Minimum Unit Price on alcohol; and Police Auxiliary Liquor Inspectors, who monitor takeaway outlets to prevent purchase by people who do not have a legal place to consume alcohol. We aimed to: (i) describe alcohol-involved adult sexual assault in the NT; and (ii) estimate the impacts of these alcohol policies on police-recorded adult sexual assault. METHODS: We used victim records for sexual assault where victims were aged 15 years and over. We undertook descriptive analyses for the NT from 2014 to 2020 and used interrupted time series analysis to assess policy impacts across the NT and in Greater Darwin. RESULTS: In 2020, the NT adult victimisation rate was 105 per 100,000. A large minority (40%) of adult sexual assaults involved alcohol. Interrupted time series analyses showed no effect of the Banned Drinker Register or Minimum Unit Price on sexual assault across the NT or in Greater Darwin. DISCUSSION AND CONCLUSIONS: The rate of adult sexual assaults in the NT is extremely high and many involve alcohol. Neither the Banned Drinker Register or Minimum Unit Price were associated with changes in police-recorded adult sexual assault in Greater Darwin or across the NT. Due to small counts, we were unable to assess policy impacts in three of the four main towns, highlighting the challenges of assessing impacts of policies on sexual assault in small population areas.

Characteristics of high- and low-risk drinkers who use online alcohol home delivery in Western Australia.

INTRODUCTION: Variation in alcohol availability is an important driver of levels of consumption and harm, with recent increases in online alcohol home delivery use expanding availability. There is limited research on the impacts of these changes and the characteristics of consumers who use alcohol home delivery. METHODS: This study presents findings from an online survey (n = 465) of Western Australian adults who had purchased alcohol for home delivery within the past 6 months. Analyses compared high-risk and low-risk drinkers on use of, and exposure to, alcohol home delivery. RESULTS: Compared to low-risk drinkers, high-risk drinkers were significantly more likely to make more frequent online purchases (odds ratio 5.42), utilise same day delivery (odds ratio 2.91) and purchase through specialised online-only retailers (odds ratio 2.69). High-risk drinkers also reported receiving deliveries while intoxicated more often (odds ratio 11.62), and ordering alcohol for delivery to continue a current drinking session (odds ratio 7.47). High-risk drinkers also received advertising for alcohol home delivery more frequently (odds ratio 1.60) than low-risk drinkers. High-risk drinkers also ordered larger quantities of alcohol than low-risk drinkers (M = 49 vs. 32 standard drinks). DISCUSSION AND CONCLUSIONS: Findings from this study indicate that these services are popular with high-risk drinkers and potentially undermine other policy efforts to reduce drinking. Within Australia, stronger legislation (such as mandatory delay between order and delivery) and monitoring (e.g., test purchasing for compliance) are recommended.

Clonal Somatic Mutations in Chronic Lung Diseases Are Associated with Reduced Lung Function.

Rationale: Constantly exposed to the external environment and mutagens such as tobacco smoke, human lungs have one of the highest somatic mutation rates among all human organs. However, the relationship of these mutations to lung disease and function is not known. Objectives: To identify the prevalence and significance of clonal somatic mutations in chronic lung diseases. Methods: We analyzed the clonal somatic mutations from 1,251 samples of normal and diseased noncancerous lung tissue RNA sequencing with paired whole-genome sequencing from the Lung Tissue Research Consortium. We examined the associations of somatic mutations with lung function, disease status, and computationally deconvoluted cell types in two of the most common diseases represented in our dataset, chronic obstructive pulmonary disease (COPD; 29%) and idiopathic pulmonary fibrosis (IPF; 13%). Measurements and Main Results: Clonal somatic mutational burden was associated with reduced lung function in both COPD and IPF. We identified an increased prevalence of clonal somatic mutations in individuals with IPF compared with normal control subjects and individuals with COPD independent of age and smoking status. IPF clonal somatic mutations were enriched in disease-related and airway epithelial-expressed genes such as MUC5B in IPF. Patients who were MUC5B risk variant carriers had increased odds of developing somatic mutations of MUC5B that were explained by increased expression of MUC5B. Conclusions: Our identification of an increased prevalence of clonal somatic mutation in diseased lung that correlates with airway epithelial gene expression and disease severity highlights for the first time the role of somatic mutational processes in lung disease genetics.