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We describe a novel device to mimic the metastasis of cancer cells from the colon into the liver in a human model. The colon mimic is connected to the liver model by a gravity-driven recirculating unidirectional flow of a blood surrogate and can mimic the five steps of the metastatic cascade: invasion in the colon, intravasation into the bloodstream, systemic transportation, extravasation into the liver, and colonization in the liver. The colon mimic uses established normal colon epithelial organoid cells (NL) and human umbilical vein endothelial cells (HUVEC) plated on opposite sides of a membrane. To better mimic the colon structure the NL side of the membrane is exposed to air to establish an air-liquid interface. The liver mimic consists of human liver sinusoidal endothelial cells (HHSEC) and epithelial hepatic cells (HepG2 C3A) plated in Matrigel on opposite sides of a membrane. Labeled colorectal cancer cells/clusters (CA) from organoids are introduced into an established normal colon epithelial cell (NL) layer from the same patient before assembly of the system or alternatively NL organoids and fluorescently labeled CA organoids from the same patient were prepared as a ratio of 10:1 NL:CA and established together before assembly of the system. Cell viability is greater than 85% in this system. We demonstrate that over 5 days of operation that the five steps of the metastatic cascade are replicated. This novel device allows an in vitro estimate of metastatic capability (as measured by using percentages of the labeled areas per device through ImageJ) in response to selected variables. In this study, the metastatic capability depends on the source of cancer cells (e.g., the patient), the clumping of cancer cells, glucose concentration, and oxygen levels (hypoxia). For the first time, this new in vitro system mimics all five steps of the metastatic cascade in a single device and provides a new device to probe and observe the process of metastasis in a human-based model in only 5 days. The rapid observation is due to the use of a high concentration of cancer cells in the colon (e.g. 10%) and the absence of the immune system. Our device makes it possible to probe aspects of each step of metastasis and interactions between steps., (© 2024 Wiley Periodicals LLC.)

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., (© 2024 The Author(s). Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

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 ages 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 photo identification at the time of delivery and whether deliveries were left unattended., Results: The average time from order to delivery for rapid deliveries was less than 1 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 that alcohol can be delivered to the home within 1 hour, and not all deliveries include an identification check at the 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.

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.

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., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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 (β = 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., Competing Interests: Declaration of competing interest The authors declare no conflict of interest. Ryan Baldwin is supported by Deakin University Research Services through an Australian Government Research Training Program Scholarship. Peter Miller receives funding from Australian Research Council and Australian National Health and Medical Research Council, grants from NSW Government, National Drug Law Enforcement Research Fund, Foundation for Alcohol Research and Education, Cancer Council Victoria, Queensland government, Northern Territory government, and Australian Drug Foundation, travel and related costs from Australasian Drug Strategy Conference. Kerri Coomber currently receives funding from Cancer Council Western Australia. Debbie Scott receives grant funding from Google.org, the Australian Institute of Health and Welfare, the Commonwealth Department of Health and the Victorian Department of Health and Human Services., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: N.F. declares that she has received fees for serving as an expert witness for the Government of Ireland in a challenge to pandemic-related restrictions on licensed premises. T.S. declares receipt of fees for serving as an expert witness on behalf of (i) the Ontario Public Service Employees Union in a challenge to 7/11′s applications for liquor licences in their many corner stores and gas stations; (ii) individuals seeking damages for injuries caused by accidents involving intoxicated people. He also declares receiving research funds, travel expenses and personal fees from government alcohol monopolies for research on alcohol and public health policy in Sweden, Finland and Canada. R.O., I.U., J.M., M.C., K.G., K.H., K.H., C.W., E.M., P.M., J.R., Z.Q. and C.A. declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Protein phosphatase, Mg 2+ /Mn 2+ 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.

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (© 2023 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

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 (β = -1.67) and a significant step increase in police recorded youth assault victimisation (β = 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., (© 2024 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

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., (© 2023 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that although Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer., (© 2023 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

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.

Somatic mutations accumulate in all cells with age and can confer a selective advantage, leading to clonal expansion over time. In hematopoietic cells, mutations in a subset of genes regulating DNA repair or epigenetics frequently lead to clonal hematopoiesis (CH). Here, we describe the context and mechanisms that lead to enrichment of hematopoietic stem cells (HSCs) with mutations in SRCAP, which encodes a chromatin remodeler that also influences DNA repair. We show that SRCAP mutations confer a selective advantage in human cells and in mice upon treatment with the anthracycline-class chemotherapeutic doxorubicin and bone marrow transplantation. Furthermore, Srcap mutations lead to a lymphoid-biased expansion, driven by loss of SRCAP-regulated H2A.Z deposition and increased DNA repair. Altogether, we demonstrate that SRCAP operates at the intersection of multiple pathways in stem and progenitor cells, offering a new perspective on the functional impact of genetic variants that promote stem cell competition in the hematopoietic system., Competing Interests: Declaration of interests A.S.S. receives consulting fees from Novartis and Roche. P.N. receives research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis; receives personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis; has scientific advisory board membership in Esperion Therapeutics, Preciseli, and TenSixteen Bio; is a scientific co-founder of TenSixteen Bio; has equity in Preciseli and TenSixteen Bio; and has spousal employment at Vertex Pharmaceuticals—all unrelated to the present work. EpiCypher is a commercial developer and supplier of reagents and platforms used in this study. S.P. is employed by (and owns shares in) New England Biolabs. B.J.V. and M.-C.K. are employed by (and own shares in) EpiCypher. M.-C.K. is a board member of EpiCypher., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The expansion of hematopoietic stem cells carrying recurrent somatic mutations, termed clonal hematopoiesis (CH), is common in elderly individuals and is associated with increased risk of myeloid malignancy and all-cause mortality. Though chemotherapy is a known risk factor for developing CH, how myelosuppressive therapies affect the short-term dynamics of CH remains incompletely understood. Most studies have been limited by retrospective design, heterogeneous patient populations, varied techniques to identifying CH, and analysis of single timepoints., Methods: We examined serial samples from 40 older women with triple-negative or hormone receptor-positive breast cancer treated on the prospective ADjuVANt Chemotherapy in the Elderly trial to evaluate the prevalence and dynamics of CH at baseline and throughout chemotherapy (6 and 12 weeks)., Results: CH was detected in 44% of patients at baseline and in 53% at any timepoint. Baseline patient characteristics were not associated with CH. Over the course of treatment, mutations exhibited a variety of dynamics, including emergence, expansion, contraction, and disappearance. All mutations in TP53 (n = 3) and PPM1D (n = 4), genes that regulate the DNA damage response, either became detectable or expanded over the course of treatment. Neutropenia was more common in patients with CH, particularly when the mutations became detectable during treatment, and CH was significantly associated with cyclophosphamide dose reductions and holds (P = .02)., Conclusions: Our study shows that CH is common, dynamic, and of potential clinical significance in this population. Our results should stimulate larger efforts to understand the biological and clinical importance of CH in solid tumor malignancies., Trial Registration: ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03858322). Clinical trial registration number: NCT03858322., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription., Competing Interests: Declaration of interests B.L.E. has received research funding from Celgene, Deerfield, Novartis, and Calico and consulting fees from GRAIL. He is a member of the Scientific Advisory Board and shareholder for Neomorph Inc., TenSixteen Bio, Skyhawk Therapeutics, and Exo Therapeutics. A.S.S. received consulting fees from Adaptive Technologies. N.H.T. receives funding from the Novartis Research Foundation and is a member of the Scientific Advisory Board of Monte Rosa Therapeutics. K.A.D. is a consultant to Kronos Bio and Neomorph Inc. E.S.F. is a founder, Scientific Advisory Board (SAB) member, and equity holder of Civetta Therapeutics, Lighthorse Therapeutics, Proximity Therapeutics, and Neomorph, Inc. (also board of directors). B.L.E. and M.S. have received research funding from Calico Life Sciences LLC. E.S.F. is an equity holder and SAB member for Avilar Therapeutics and Photys Therapeutics and a consultant to Odyssey, Novartis, Sanofi, EcoR1 Capital, Ajax Therapeutics, and Deerfield. The Fischer lab receives or has received research funding from Deerfield, Novartis, Ajax, Interline, and Astellas., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

There is an increasing focus on evaluating the effectiveness of Relationship Education (RE) programs on reducing relationship aggression. Nevertheless, there has been little by way of a systematic quantitative synthesis of research to date. The primary aim of this research was to conduct a meta-analysis into the effects of RE programs on relationship aggression and provide a comprehensive assessment as to the moderating effects of various methodological characteristics of studies. A secondary aim was to determine whether RE programs reduce negative aspects of relationship functioning that are known to exacerbate relationship aggression. Thirty-one studies (n = 25,527) were included comprising of pre-post comparison studies and control trials. Overall, RE programs were significantly associated with reductions in relationship aggression (d = 0.11, p = .001). Pre-post studies yielded a significantly larger effect size (d = 0.28, p < .001) than RCT studies (d = 0.05, p = .10). Subgroup analysis revealed that participants who reported moderate to severe relationship aggression upon RE program entry demonstrated large reductions in physical (d = 0.66, p = .01) and psychological (d = 0.85, p < .001) aggression compared to those who reported minimal to low relationship aggression on entry (physical aggression d = 0.07, p = .009; psychological aggression d = -0.04; p = .17). Amongst participants who reported moderate to severe relationship aggression, RE programs were also found to reduce controlling behavior (d = 0.20, p < .01) and conflict behavior (d = 0.40, p < .001). Findings demonstrate the emerging efficacy of RE programs for reducing relationship aggression and conflict behavior, particularly in those with a history of moderate to severe levels of relationship aggression., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Young women treated for breast cancer with cytotoxic therapies are at risk for clonal hematopoiesis of indeterminate potential (CHIP), a condition in which blood cells carrying a somatic mutation associated with hematologic malignancy comprise at least 4% of the total blood system. CHIP has primarily been studied in older patient cohorts with limited clinical phenotyping., Experimental Design: We performed targeted sequencing on longitudinal blood samples to characterize the clonal hematopoietic landscape of 878 women treated for breast cancer enrolled in the prospective Young Women's Breast Cancer Study., Results: We identified somatic driver mutations in 252 study subjects (28.7%), but only 24 (2.7%) had clones large enough to meet criteria for CHIP. The most commonly mutated genes were DNMT3A and TET2, similar to mutations observed in noncancer cohorts. At 9-year median follow-up, we found no association between the presence of a somatic blood mutation (regardless of clone size) and adverse breast cancer (distant relapse-free survival) or non-breast cancer-related outcomes in this cohort. A subset of paired blood samples obtained over 4 years showed no evidence of mutant clonal expansion, regardless of genotype. Finally, we identified a subset of patients with likely germline mutations in genes known to contribute to inherited cancer risk, such as TP53 and ATM., Conclusions: Our data show that for young women with early-stage breast cancer, CHIP is uncommon after cytotoxic exposure, is unlikely to contribute to adverse outcomes over the decade-long follow-up and may not require additional monitoring if discovered incidentally., (©2023 American Association for Cancer Research.)

Background: Acute alcohol intoxication impairs cognitive and psychomotor abilities leading to various public health hazards such as road traffic accidents and alcohol-related violence. Intoxicated individuals are usually identified by measuring their blood alcohol concentration (BAC) using breathalyzers that are expensive and labor intensive. In this paper, we developed the Audio-based Deep Learning Algorithm to Identify Alcohol Inebriation (ADLAIA) that can instantly predict an individual's intoxication status based on a 12-s recording of their speech., Methods: ADLAIA was trained on a publicly available German Alcohol Language Corpus that comprises a total of 12,360 audio clips of inebriated and sober speakers (total of 162, aged 21-64, 47.7% female). ADLAIA's performance was determined by computing the unweighted average recall (UAR) and accuracy of inebriation prediction., Results: ADLAIA was able to identify inebriated speakers - with a BAC of 0.05% or higher - with an UAR of 68.09% and accuracy of 67.67%. ADLAIA had a higher performance (UAR of 75.7%) in identifying intoxicated speakers (BAC > 0.12%)., Conclusion: Being able to identify intoxicated individuals solely based on their speech, ADLAIA could be integrated into mobile applications and used in environments (such as bars, sports stadiums) to get instantaneous results about inebriation status of individuals., Competing Interests: Declaration of competing interest No conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Individuals who engage in problematic behaviours within Australian night-time entertainment precincts can be banned from entering certain locations. Bans are expected to deter recipients, and prospective recipients, from further inappropriate behaviours. The collective effect is intended to reduce crime and increase community safety within entertainment precincts. This article explores key informant perspectives regarding the enforcement of two patron banning mechanisms (police barring notices and prohibition orders) used across Western Australia., Methods: Interviews were conducted with 54 participants, including licensees, venue staff, WA Police officers, ID scanner representatives, and Registered Training Organisations., Results: Few participants opposed patron banning in principle, but most identified limitations within the current operation of both provisions. Concerns were expressed about the effectiveness of enforcement, linked to questions about the way in which banned patron information is currently shared and the practicalities of identifying recipients of bans. Suggestions included improved data-sharing protocols and the wider use of ID scanners., Discussion/conclusion: With improvements to operational processes-particularly more effective sharing of banned patron data, and consideration of networked ID scanners-there is clear potential to improve the enforcement and increase the effectiveness of police barring notices and prohibition orders. This study is part of a wider project which has examined the use and effects of patron banning in WA. Additional findings are presented in further papers., (© 2023 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Introduction: To explore whether receipt of either of two patron banning provisions currently used in Western Australia-in response to alcohol-related disorderly and anti-social behaviour-is associated with changes to subsequent offending., Method: Western Australia Police de-identified the offender records and associated data for 3440 individuals who had received one or more police-imposed barring notice/s between 2011 and 2020, and 319 individuals who had received one or more prohibition orders between 2013 and 2020. The number of offences recorded for each recipient before and after the first notice/order were examined to understand the potential effect of both provisions upon subsequent offending., Results: The low number of repeat barring notices (5% of the total) and prohibition orders (1% of the total) points to their general success. Analysis of offending records before and after receipt/expiry of either provision indicates that both have a generally positive effect on subsequent behaviours. For all barring notice recipients, 52% recorded no further offences and for all prohibition order recipients, 58% recorded no further offences. There was a less positive effect for the sub-set of multiple ban recipients and prolific offenders., Discussion and Conclusions: Barring notices and prohibition orders appear to have a generally positive effect on subsequent behaviours for the majority of recipients. More targeted interventions are recommended for repeat offenders, for whom patron banning provisions have a more limited effect., (© 2023 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Alcohol harms are often determined using a proxy measure based on temporal patterns during the week when harms are most likely to occur. This study utilised coded Australian ambulance data from the Victorian arm of the National Ambulance Surveillance System (NASS) to investigate temporal patterns across the week for alcohol-related ambulance attendances in 2019. These patterns were examined by season, regionality, gender, and age group. We found clear temporal peaks: from Friday 6:00 p.m. to Saturday 3:59 a.m. for both alcohol-involved and alcohol-intoxication-related attendance, from Saturday 6:00 p.m. to Sunday 4:59 a.m. for alcohol-involved attendances, and from Saturday 5:00 p.m. to Sunday 4:49 a.m. for alcohol-intoxication-related attendances. However, these temporal trends varied across age groups. Additionally, hours during Thursday and Sunday evenings also demonstrated peaks in attendances. There were no substantive differences between genders. Younger age groups (18-24 and 25-29 years) had a peak of alcohol-related attendances from 7:00 p.m. to 7:59 a.m. on Friday and Saturday nights, whereas the peak in attendances for 50-59 and 60+ years was from 5:00 p.m. to 2:59 a.m. on Friday and Saturday nights. These findings further the understanding of the impacts of alcohol during different times throughout the week, which can guide targeted policy responses regarding alcohol use and health service capacity planning.

Introduction: Alcohol-related harms place a significant burden on the Australian economy and health-care system. The current study aims to: (i) explore the relationship between blood alcohol concentration (BAC) and self-estimated blood alcohol concentration (EBAC); and (ii) determine whether BAC underestimation is related to an increased risk of experiencing physical aggression, verbal aggression, drink driving, ejection from a venue or refusal of service., Methods: Patron street surveys were conducted in four night-time entertainment precincts (NEP) across Queensland, Australia, between June 2016 and November 2018. Participants (N = 2144) reported on their EBAC and recent negative or harmful experiences in NEPs. BAC was measured via a breathalyser. Paired samples t tests were conducted to determine if patrons' BAC and EBAC were significantly different. Logistic regressions were conducted to examine whether BAC underestimation is a significant predictor of harm and negative outcomes., Results: Analyses identified a small, significant difference between patron's BAC and EBAC. Patrons with a low BAC were more likely to overestimate their BAC, while patrons with higher BACs were more likely to underestimate their BAC. Moderately intoxicated patrons had the most precise BAC estimations. Patrons with a high BAC and who underestimated their intoxication level were more likely to have been recently ejected from licensed venues, compared to accurate estimators or over-estimators., Discussion and Conclusions: Overall, patrons are poor evaluators of their own intoxication level, which may have implications for their experiences in NEPs. The findings highlight the need for improved BAC education for patrons., (© 2022 Australasian Professional Society on Alcohol and other Drugs.)

Introduction: Older adults with breast cancer receiving neo/adjuvant chemotherapy are at high risk for poor outcomes and are underrepresented in clinical trials. The ADVANCE (ADjuVANt Chemotherapy in the Elderly) trial evaluated the feasibility of two neo/adjuvant chemotherapy regimens in parallel-enrolling cohorts of older patients with human epidermal growth factor receptor 2-negative breast cancer: cohort 1-triple-negative; cohort 2-hormone receptor-positive., Materials and Methods: Adults age ≥ 70 years with stage I-III breast cancer warranting neo/adjuvant chemotherapy were enrolled. Cohort 1 received weekly carboplatin (area under the curve 2) and weekly paclitaxel 80 mg/m 2 for twelve weeks; cohort 2 received weekly paclitaxel 80 mg/m 2 plus every-three-weekly cyclophosphamide 600 mg/m 2 over twelve weeks. The primary study endpoint was feasibility, defined as ≥80% of patients receiving ≥80% of intended weeks/doses of therapy. All dose modifications were applied per clinician discretion., Results: Forty women (n = 20 per cohort) were enrolled from March 25, 2019 through August 3, 2020 from three centers; 45% and 35% of patients in cohorts 1 and 2 were age > 75, respectively. Neither cohort achieved targeted thresholds for feasibility. In cohort 1, eight (40.0%) met feasibility (95% confidence interval [CI] = 19.1-63.9%), while ten (50.0%) met feasibility in cohort 2 (95% CI = 27.2-72.8). Neutropenia was the most common grade 3-4 toxicity (cohort 1-65%, cohort 2-55%). In cohort 1, 80% and 85% required ≥1 dose holds of carboplatin and/or paclitaxel, respectively. In cohort 2, 10% required dose hold(s) for cyclophosphamide and/or 65% for paclitaxel., Discussion: In this pragmatic pilot examining chemotherapy regimens in older adults with breast cancer, neither regimen met target goals for feasibility. Developing efficacious and tolerable regimens for older patients with breast cancer who need chemotherapy remains an important goal., Clinicaltrials: gov Identifier: NCT03858322., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: The objective of this study was to explore key informant attitudes towards the 'Last Drinks at 3am' legislation in Safe Night Precincts in Queensland, Australia., Method: Sixty-six interviews were conducted with a range of stakeholders including licensees, law enforcement and frontline health professionals. Interviews were semi-structured and analysed using thematic analysis. Key informants responded to questions regarding their experiences of, and opinions about, the last drinks legislation., Results: Key informants reported a range of experiences around the impact of last drinks restrictions, including reduced staffing costs and patron-related problems within licensed venues. While some venues reported that their businesses lost money, others reported no change in income or that they changed their business model to compensate. Law enforcement and health professionals reported a range of benefits including reduced alcohol-related anti-social behaviour, drunkenness and injury., Conclusions: The majority of key informants reported that the last drinks legislation reduced harm, while having minimal detrimental impact on business., (© 2022 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Clonal hematopoiesis of indeterminate potential (CHIP), an emerging biomarker for personalized risk-directed interventions, is increased in cancer survivors. However, little is known about patient preferences for CHIP testing. We surveyed participants in a prospective cohort study of young women with breast cancer (BC). The emailed survey included an introduction to CHIP and a vignette eliciting participants' preferences for CHIP testing, considering sequentially: population-based 10-year risk of BC recurrence, hematologic malignancy, and heart disease; increased CHIP-associated risks; current CHIP management; dedicated CHIP clinic; and hypothetical CHIP treatment. Preference changes were evaluated using the McNemar test. The survey response rate was 82.2% (528/642). Median age at time of survey was 46 years and median time from diagnosis was 108 months. Only 5.9% had prior knowledge of CHIP. After vignette presentation, most survivors (87.1%) recommended CHIP testing for the vignette patient. Presented next with CHIP-independent, population-based risks, 11.1% shifted their preference from testing to not testing. After receiving information about CHIP-associated risks, an additional 10.1% shifted their preference to testing. Preference for testing increased if vignette patient was offered a CHIP clinic or hypothetical CHIP treatment, with 7.2% and 14.1% switching preferences toward testing, respectively. Finally, 75.8% of participants desired CHIP testing for themselves. Among participants, 28.2% reported that learning about CHIP caused at least moderate anxiety. Most young survivors favored CHIP testing, with preferences influenced by risk presentation and potential management strategies. Our findings highlight the importance of risk communication and psychosocial support when considering biomarkers for future risk in cancer survivors. This trial has been registered at www.clinicaltrials.gov as #NCT01468246., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Experiences of unwanted sexual attention (UWSA) are commonplace within nightlife environments. While typically associated with aggression perpetration, literature has suggested that a history of childhood corporal punishment (CCP) may also be related to experiences of victimisation in nightlife environments. The current exploratory study aims to examine the associations between experiences of UWSA victimisation and a history of CCP, trait aggression, and conformity to masculine norms (Playboy and Winning), for males and females separately., Method: Street intercept interviews in the Brisbane inner-city entertainment precincts were used to measure demographic details and participants' breath alcohol concentration. Online follow-up surveys were used to record participants' experiences of UWSA on the night of interview, history of CCP, and self-reported rates of trait aggression and conformity to masculine norms. The final sample consisted of 288 females, as there were not sufficient male UWSA experiences for analysis., Results: Approximately 20% of female nightlife patrons experienced some form of UWSA victimisation. Logistic regression analyses identified that after controlling for age and intoxication, a history of CCP, trait aggression and masculine norm conformity were unrelated to experiences of UWSA for female respondents., Conclusions: The current study found that individual factors were unrelated to experiences of UWSA, indicating that simply being in the nightlife environment, especially as a female, increases the risk of UWSA victimisation. Understanding and exploring social and environmental risk factors, rather than individual factors, is needed to prevent victimisation in nightlife environments.

There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Gout is a common inflammatory arthritis caused by precipitation of monosodium urate (MSU) crystals in individuals with hyperuricemia. Acute flares are accompanied by secretion of proinflammatory cytokines, including interleukin-1β (IL-1β). Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition predisposing to hematologic cancers and cardiovascular disease. CHIP is associated with elevated IL-1β, thus we investigated CHIP as a risk factor for gout. To test the clinical association between CHIP and gout, we analyzed whole exome sequencing data from 177 824 individuals in the MGB Biobank (MGBB) and UK Biobank (UKB). In both cohorts, the frequency of gout was higher among individuals with CHIP than without CHIP (MGBB, CHIP with variant allele fraction [VAF] ≥2%: odds ratio [OR], 1.69; 95% CI, 1.09-2.61; P = .0189; UKB, CHIP with VAF ≥10%: OR, 1.25; 95% CI, 1.05-1.50; P = .0133). Moreover, individuals with CHIP and a VAF ≥10% had an increased risk of incident gout (UKB: hazard ratio [HR], 1.28; 95% CI, 1.06-1.55; P = .0107). In murine models of gout pathogenesis, animals with Tet2 knockout hematopoietic cells had exaggerated IL-1β secretion and paw edema upon administration of MSU crystals. Tet2 knockout macrophages elaborated higher levels of IL-1β in response to MSU crystals in vitro, which was ameliorated through genetic and pharmacologic Nlrp3 inflammasome inhibition. These studies show that TET2-mutant CHIP is associated with an increased risk of gout in humans and that MSU crystals lead to elevated IL-1β levels in Tet2 knockout murine models. We identify CHIP as an amplifier of NLRP3-dependent inflammatory responses to MSU crystals in patients with gout., (© 2022 by The American Society of Hematology.)

Introduction: Illicit drug use has been found to increase the risks of male barroom aggression (MBA). Personality traits such as dispositional aggressiveness have been associated with illicit substance use and aggressive behaviour, along with social normative masculinity factors. The present study assessed the relationships between illicit drug use, key personality (trait aggression, impulsivity, narcissism) and masculinity (conformity to masculine norms, male honour) variables with physical MBA perpetration and victimisation among male Australian construction workers., Methods: A purposive, high-risk sample of male construction workers aged 18-69 years (n = 476, M age  = 25.90 years, SD age  = 9.44) completed interviews at their place of work or training., Results: Participants reported high rates of both physical MBA perpetration (21%; n = 100) and victimisation (31.1%; n = 148) as well as any illicit drug use (33.61%; n = 160). Logistic regressions revealed the use of amphetamine-type stimulants (methamphetamine, ecstasy) was associated with violence perpetration, even after accounting for high-intensity drinking (HID) which was the strongest predictor of MBA involvement. Trait variables (Trait Physical aggressiveness, narcissism) and the masculine norm CMNI Violence were also risk factors for MBA perpetration while CMNI Playboy was protective against MBA., Discussion and Conclusions: The use of amphetamine-type stimulants is a risk-factor for MBA perpetration, as are key personality traits such as aggressiveness and narcissism. Most aspects of masculinity, including male honour, were either unrelated to or protective against involvement in physical violence in bars, clubs or pubs., (© 2022 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early-phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR/Cas9 screens implicated decreased translation initiation as protective following GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to the effects of GSPT1 degradation. We defined 2 Crbn amino acids that prevent Gspt1 degradation in mice, generated a knockin mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant acute myeloid leukemia.

There is substantial evidence supporting the association between alcohol license density and violent crime. However, the impact of different types of alcohol licenses on intimate partner and family violence is sparse. We explored the associations between access to alcohol outlets, and family and intimate partner violence using paramedic clinical records, given this service is often the first to respond to acute crises. Coded ambulance attendance data from 694 postcodes in Victoria, Australia, from July 1, 2016 to June 30, 2018 where alcohol or another drug, mental health or self-harm associated with family or intimate partner violence was indicated were examined. A hybrid model of spatial autoregressive and negative binomial zero-inflated Poisson-based count regression models was used to examine associations with alcohol outlet density and socioeconomic factors. We found that access to a liquor license outlet was significantly associated with family violence-related attendances across all types of outlets, including on-premise (late night) licenses ( β = 1.73, SE: 0.18), restaurant licenses ( β = 0.83, SE: 0.28), and packaged liquor licenses ( β = 0.62, SE: 0.06). Our results demonstrate a significant relationship between alcohol-related harms in the context of family violence and provides evidence of the relationship between alcohol-related family violence in both victims and perpetrators. The findings of this study highlight the need for public health interventions such as licensing policy and town planning changes to reduce these harms by restricting alcohol availability.

PPM1D encodes a serine/threonine phosphatase that regulates numerous pathways including the DNA damage response and p53. Activating mutations and amplification of PPM1D are found across numerous cancer types. GSK2830371 is a potent and selective allosteric inhibitor of PPM1D, but its mechanism of binding and inhibition of catalytic activity are unknown. Here we use computational, biochemical and functional genetic studies to elucidate the molecular basis of GSK2830371 activity. These data confirm that GSK2830371 binds an allosteric site of PPM1D with high affinity. By further incorporating data from hydrogen deuterium exchange mass spectrometry and sedimentation velocity analytical ultracentrifugation, we demonstrate that PPM1D exists in an equilibrium between two conformations that are defined by the movement of the flap domain, which is required for substrate recognition. A hinge region was identified that is critical for switching between the two conformations and was directly implicated in the high-affinity binding of GSK2830371 to PPM1D. We propose that the two conformations represent active and inactive forms of the protein reflected by the position of the flap, and that binding of GSK2830371 shifts the equilibrium to the inactive form. Finally, we found that C-terminal truncating mutations proximal to residue 400 result in destabilization of the protein via loss of a stabilizing N- and C-terminal interaction, consistent with the observation from human genetic data that nearly all PPM1D mutations in cancer are truncating and occur distal to residue 400. Taken together, our findings elucidate the mechanism by which binding of a small molecule to an allosteric site of PPM1D inhibits its activity and provides insights into the biology of PPM1D., (© 2022. The Author(s).)

Introduction: Pre-drinking behaviour has grown in prevalence and generates harm for pre-drinkers and others. In this article, we answer three research questions: (i) Where and when do pre-drinkers obtain their alcohol?; (ii) What is the difference in the level of intoxication of pre-drinkers versus non-pre-drinkers, and how does this difference vary over the course of a night?; and (iii) Is the level of intoxication of pre-drinkers related to where and when they obtain their alcohol?, Methods: We obtained data from 469 respondents using a street-intercept survey conducted in Hamilton, New Zealand in 2019. Data were analysed by cross-tabulation, linear regression and plotting the average intoxication level in the night-time economy over time., Results: The majority of pre-drinkers purchase their alcohol for pre-drinking on the day of consumption. Half of the same-day purchasers purchase before 6 pm. The average level of intoxication increases over the course of the night, and is unambiguously higher for pre-drinkers than non-pre-drinkers. The level of intoxication does not differ based on the source or timing of pre-drinking purchases. The main motivation for pre-drinking was price, especially among women., Discussion and Conclusions: Pre-drinking is a contributor to intoxication in the night-time economy, but most drinkers purchase their alcohol for pre-drinking before 7 pm. Further research is required to understand whether trading hours restrictions for off-premises alcohol suppliers will affect the most harmful drinking patterns. Price interventions to reduce the price differential between on-licenced and off-licence alcohol outlets offer the greatest potential to reduce pre-drinking and associated harm., (© 2022 Australasian Professional Society on Alcohol and other Drugs.)

Background: Children are often exposed to increased rates of secondary harm such as physical harm, motor vehicle incidents, maltreatment, and neglect because of others' or their own alcohol consumption. Alcohol supply reduction, or alcohol control policies, are often enacted to mitigate alcohol harms within the community. The current systematic narrative review aims to synthesise recent literature that examines how alcohol supply reduction policies impact the physical health, mental health, and offending behaviour of children and adolescents., Methods: Eight databases and grey literature sources were systematically searched, and results were synthesised by policy under evaluation. Twenty-one peer reviewed articles and ten grey literature articles were included after screening of 7,135 original articles. Included articles examined the alcohol control policies of the minimum legal drinking age, price control, and trading restrictions, with the most common outcomes under evaluation being related to the physical health or offending behaviour of adolescents., Results: Overall, the current review identified that the impact of alcohol policy on children and adolescents varied depending on the policy type, policy environment and assessed outcome. Common limitations within the literature include inability to control for covariates, use of alcohol related outcomes unsuitable to children and adolescents, and use of cross-sectional data and regression-discontinuity analysis in lieu of actual policy changes., Conclusions: The current review highlights the need to further evaluate the impact of actual alcohol-related policy changes on children and adolescents., Competing Interests: Declarations of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004-defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0-6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation., (© 2022 by The American Society of Hematology.)

The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition., (© 2022. The Author(s).)

Chronic obstructive pulmonary disease (COPD) is associated with age and smoking, but other determinants of the disease are incompletely understood. Clonal hematopoiesis of indeterminate potential (CHIP) is a common, age-related state in which somatic mutations in clonal blood populations induce aberrant inflammatory responses. Patients with CHIP have an elevated risk for cardiovascular disease, but the association of CHIP with COPD remains unclear. We analyzed whole-genome sequencing and whole-exome sequencing data to detect CHIP in 48 835 patients, of whom 8444 had moderate to very severe COPD, from four separate cohorts with COPD phenotyping and smoking history. We measured emphysema in murine models in which Tet2 was deleted in hematopoietic cells. In the COPDGene cohort, individuals with CHIP had risks of moderate-to-severe, severe, or very severe COPD that were 1.6 (adjusted 95% confidence interval [CI], 1.1-2.2) and 2.2 (adjusted 95% CI, 1.5-3.2) times greater than those for noncarriers. These findings were consistently observed in three additional cohorts and meta-analyses of all patients. CHIP was also associated with decreased FEV1% predicted in the COPDGene cohort (mean between-group differences, -5.7%; adjusted 95% CI, -8.8% to -2.6%), a finding replicated in additional cohorts. Smoke exposure was associated with a small but significant increased risk of having CHIP (odds ratio, 1.03 per 10 pack-years; 95% CI, 1.01-1.05 per 10 pack-years) in the meta-analysis of all patients. Inactivation of Tet2 in mouse hematopoietic cells exacerbated the development of emphysema and inflammation in models of cigarette smoke exposure. Somatic mutations in blood cells are associated with the development and severity of COPD, independent of age and cumulative smoke exposure., (© 2022 by The American Society of Hematology.)