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Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of chronic kidney disease and the fourth leading cause of end-stage kidney disease, accounting for over 50% of prevalent cases requiring renal replacement therapy. There is a pressing need for improved therapy for ADPKD. Recent insights into the pathophysiology of ADPKD revealed that cyst cells undergo metabolic changes that up-regulate aerobic glycolysis in lieu of mitochondrial respiration for energy production, a process that ostensibly fuels their increased proliferation. The present work leverages this metabolic disruption as a way to selectively target cyst cells for apoptosis. This small-molecule therapeutic strategy utilizes 11beta-dichloro, a repurposed DNA-damaging anti-tumor agent that induces apoptosis by exacerbating mitochondrial oxidative stress. Here, we demonstrate that 11beta-dichloro is effective in delaying cyst growth and its associated inflammatory and fibrotic events, thus preserving kidney function in perinatal and adult mouse models of ADPKD. In both models, the cyst cells with homozygous inactivation of Pkd1 show enhanced oxidative stress following treatment with 11beta-dichloro and undergo apoptosis. Co-administration of the antioxidant vitamin E negated the therapeutic benefit of 11beta-dichloro in vivo, supporting the conclusion that oxidative stress is a key component of the mechanism of action. As a preclinical development primer, we also synthesized and tested an 11beta-dichloro derivative that cannot directly alkylate DNA, while retaining pro-oxidant features. This derivative nonetheless maintains excellent anti-cystic properties in vivo and emerges as the lead candidate for development., Competing Interests: Competing interests statement:The patent US9982009 was granted to B.I.F., R.G.C., J.M.E., S.V.F., and S.S., and assigned to Massachusetts Institute of Technology and Yale University. The patent covers the use of the 11beta-dipropyl and related compounds as therapeutics for polycystic kidney disease and polycystic liver disease. All other authors declare no competing interests.

Objectives: To assess the effectiveness of a brief alcohol intervention for improving awareness of alcohol as a breast cancer risk factor, improving alcohol literacy, and reducing alcohol consumption by women attending routine breast screening., Design: Single-site, double-blinded randomised controlled trial., Setting: Maroondah BreastScreen (Eastern Health, Melbourne), part of the national breast cancer screening program., Participants: Women aged 40 years or more, with or without a history of breast cancer and reporting any alcohol consumption, who attended the clinic for routine mammography during 5 February - 27 August 2021., Intervention: Active arm: animation including brief alcohol intervention (four minutes) and lifestyle health promotion (three minutes)., Control Arm: lifestyle health promotion only., Major Outcome Measure: Change in proportion of women who identified alcohol use as a clear risk factor for breast cancer (scaled response measure)., Results: The mean age of the 557 participants was 60.3 years (standard deviation, 7.7 years; range, 40-87 years); 455 had recently consumed alcohol (82%). The proportions of participants aware that alcohol use increased the risk of breast cancer were larger at four weeks than at baseline for both the active intervention (65% v 20%; odds ratio [OR], 41; 95% confidence interval [CI], 18-97) and control arms of the study (38% v 20%; OR, 4.9; 95% CI, 2.8-8.8), but the change over time was greater for the active intervention arm (arm × time: P < 0.001). Alcohol literacy also increased to a greater extent in the active than the control arm, but alcohol consumption did not significantly change in either arm., Conclusion: A tailored brief alcohol intervention for women attending breast screening was effective for improving awareness of the increased breast cancer risk associated with alcohol use and alcohol literacy more broadly. Such interventions are particularly important given the rising prevalence of risky drinking among middle-aged and older women and evidence that even very light alcohol consumption increases breast cancer risk., Registration: ClinicalTrials.gov, NCT04715516 (prospective; 20 January 2021)., (© 2023 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Background: Alcohol consumption is a major modifiable risk factor for female breast cancer, even in small amounts. However, awareness of this risk remains low. National breast screening programs are uniquely positioned to provide timely and targeted health information and behavior change strategies to improve alcohol literacy and reduce consumption. A breast screening service is a novel health care setting for brief alcohol intervention, with the potential for extensive reach., Objective: This study aimed to conduct a formative evaluation with breast screening service consumers to understand the need for, and acceptability of, brief alcohol intervention in the breast screening setting and collaboratively design a brief alcohol intervention (Health4Her); to test the effectiveness of Health4Her in improving knowledge of alcohol as a breast cancer risk factor (primary outcome), improving alcohol literacy, and reducing consumption among women attending a breast screening service; and to examine the implementation strategy through process evaluation., Methods: This was a hybrid type II effectiveness-implementation trial comprising a randomized controlled trial (RCT) alongside a mixed methods program evaluation guided by applicable elements of the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework and Consolidated Framework for Implementation Research. Formative evaluation comprised a retrospective analysis of alcohol consumption data (n=49,240), a web-based survey (n=391), and focus groups and interviews (n=31) with breast screening service consumers. Women attending routine mammography, drinking at any level, were recruited to the single-site, double-blind RCT (n=558), and completed a baseline assessment before randomization (1:1) to receive Health4Her (alcohol brief intervention + lifestyle information) or control (lifestyle information) via animation on an iPad. Follow-up assessments were performed 4 and 12 weeks after randomization. The process evaluation included evaluation of trial administrative data, participant quantitative (n=497) and qualitative feedback (n=30), and site staff qualitative feedback (n=11)., Results: This research was funded in March and May 2019. Data collection for the formative evaluation and trial recruitment occurred between January and April 2020 and February and August 2021, respectively, with finalization of follow-up data collection in December 2021. Quantitative process evaluation data were collected during trial implementation, and collection of participant and staff feedback was finalized in December 2021. Results of the retrospective analysis of alcohol consumption data from breast screening service consumers is anticipated to be published in March 2023 and the results of the RCT to be published in March 2023., Conclusions: This study is anticipated to generate new substantial knowledge on the alcohol consumption and literacy needs of women attending breast screening and the extent to which these can be addressed using a novel, tailored brief alcohol intervention. The study design permits the evaluation of the effectiveness and implementation of Health4Her to predict and facilitate uptake in breast screening services., Trial Registration: ClinicalTrials.gov NCT04715516; https://clinicaltrials.gov/ct2/show/NCT04715516., International Registered Report Identifier (irrid): RR1-10.2196/44867., (©Jasmin Grigg, Victoria Manning, Darren Lockie, Michelle Giles, Robin Bell, Peta Stragalinos, Chloe Bernard, Isabelle Volpe, Christopher J Greenwood, Liam Smith, Peter Bragge, Dan I Lubman. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 30.03.2023.)

Background: Alerts about changes in unregulated drug markets may be useful for supporting health and community workers to anticipate, prevent, and respond to unexpected adverse drug events. This study aimed to establish factors influencing the successful design and implementation of drug alerts for use in clinical and community service settings in Victoria, Australia., Methods: An iterative mixed methods design was used to co-produce drug alert prototypes with practitioners and managers working across various alcohol and other drug services and emergency medicine settings. A quantitative needs-analysis survey (n = 184) informed five qualitative co-design workshops (n = 31). Alert prototypes were drafted based on findings and tested for utility and acceptability. Applicable constructs from the Consolidated Framework for Implementation Research helped to conceptualise factors that impact successful alert system design., Results: Timely and reliable alerts about unexpected drug market changes were important to nearly all workers (98%) yet many reported insufficient access to this kind of information (64%). Workers considered themselves 'conduits' for information-sharing and valued alerts for increasing exposure to drug market intelligence; facilitating communication about potential threats and trends; and improving capacity for effective responding to drug-related harm. Alerts should be 'shareable' across a range of clinical and community settings and audiences. To maximise engagement and impact, alerts must command attention, be easily recognisable, be available on multiple platforms (electronic and printable formats) in varying levels of detail, and be disseminated via appropriate notification mechanisms to meet the needs of diverse stakeholder groups. Three drug alert prototypes (SMS prompt, summary flyer, and a detailed poster) were endorsed by workers as useful for supporting their work responding to unexpected drug-related harms., Discussion: Alerts informed by coordinated early warning networks that offer close to real-time detection of unexpected substances can provide rapid, evidence-based drug market intelligence to inform preventive and responsive action to drug-related harm. The success of alert systems requires adequate planning and resourcing to support design, implementation, and evaluation, which includes consultation with all relevant audiences to understand how to maximise engagement with information, recommendations, and advice. Our findings about factors impacting successful alert design have utility to inform the development of local early warning systems., (© 2023. The Author(s).)

Aims: Despite the magnitude of alcohol use problems globally, treatment uptake remains low. This study sought to determine the proportion of people presenting to telephone-delivered alcohol treatment who are first-time help-seekers, and explored perceived barriers to help-seeking to understand the barriers this format of treatment may help to address., Methods: Secondary analysis of baseline data from a randomized controlled trial of a telephone-delivered intervention for alcohol use problems. Latent class analysis (LCA) identified participant profiles according to self-reported barriers to alcohol treatment., Results: Participants' (344) mean age was 39.86 years (SD = 11.36, 18-73 years); 51.45% were male. Despite high alcohol problem severity (Alcohol Use Disorder Identification Test: mean = 21.54, SD = 6.30; 63.37% probable dependence), multiple barriers to accessing treatment were endorsed (mean = 5.64, SD = 2.41), and fewer than one-third (29.36%) had previously accessed treatment. LCA revealed a two-class model: a 'low problem recognition' class (43.32%) endorsed readiness-for-change and attitudinal barriers; a 'complex barriers' class (56.68%) endorsed stigma, structural, attitudinal and readiness-to-change barriers, with complex barrier class membership predicted by female sex (adjusted OR = 0.45, 95% CI 0.28, 0.72) and higher psychological distress (adjusted OR = 1.13, 95% CI 1.08, 1.18)., Conclusion: The majority of people accessing this telephone-delivered intervention were new to treatment, yet had high alcohol problem severity. Two distinct profiles emerged, for which telephone interventions may overcome barriers to care and tailored approaches should be explored (e.g. increasing problem awareness, reducing psychological distress). Public health strategies to address stigma, and raise awareness about the low levels of drinking that constitute problem alcohol use, are needed to increase help-seeking., (© The Author(s) 2022. Medical Council on Alcohol and Oxford University Press.)

Background: Drug alerts designed for health and community workforces have potential to avert acute harms associated with unpredictable illicit drug markets, by preparing workers to respond to unusual drug-related events, and distribute information to service users. However, the design of such alerts is complicated by diverse needs of individuals, and broader socio-political contexts. Here, we discuss the tensions that arose in the process of co-designing drug alert templates with health and community workers., Methods: We conducted five in-depth digital co-design workshops with 31 workers employed in alcohol and other drug and urgent care settings. Our approach to analysis was informed by Iterative Categorisation and reflexive thematic analysis methods., Results: We identified five key tensions. First, there is a need to provide comprehensive information to meet the information needs of a diverse group of workers with varying knowledge levels, while also designing alerts to be clear, concise, and relevant to the work of individuals. Second, it is important that alerts do not create 'information overload'; however, it is also important that information should be available to those who want it. Third, alert design and dissemination must be perceived to be credible, to avoid 'alert scepticism'; however, credibility is challenging to develop in a broader context of criminalisation, stigmatisation, and sensationalism. Fourth, alerts must be carefully designed to achieve 'intended effects' and avoid unintended effects, while acknowledging that it is impossible to control all potential effects. Finally, while alerts may be intended for an audience of health and community workers, people who use drugs are the end-users and must be kept front of mind in the design process., Conclusions: The co-design process revealed complexities in designing drug alerts, particularly in the context of stigmatised illicit drug use, workforce diversity, and dissemination strategies. This study has highlighted the value of developing these important risk communication tools with their target audiences to ensure that they are relevant, useful, and impactful. The findings have informed the development of our drug alert prototypes and provide local context to complement existing best-practice risk-communications literature., (© 2023. The Author(s).)

Importance: Despite the magnitude of alcohol use problems globally, treatment uptake remains low. Telephone-delivered interventions have potential to overcome many structural and individual barriers to help seeking, yet their effectiveness as a stand-alone treatment for problem alcohol use has not been established., Objective: To examine the effectiveness of the Ready2Change telephone-delivered intervention in reducing alcohol problem severity up to 3 months among a general population sample., Design, Setting, and Participants: This double-blind, randomized clinical trial recruited participants with an Alcohol Use Disorders Identification Test (AUDIT) score of greater than 6 (for female participants) and 7 (for male participants) from across Australia during the period of May 25, 2018, to October 2, 2019. Telephone assessments occurred at baseline and 3 months after baseline (84.9% retention). Data collection was finalized September 2020., Interventions: The telephone-based cognitive and behavioral intervention comprised 4 to 6 telephone sessions with a psychologist. The active control condition comprised four 5-minute telephone check-ins from a researcher and alcohol and stress management pamphlets., Main Outcomes and Measures: The primary outcome was change in alcohol problem severity, measured with the AUDIT total score. Drinking patterns were measured with the Timeline Followback (TLFB) instrument., Results: This study included a total of 344 participants (mean [SD] age, 39.9 [11.4] years; range, 18-73 years; 177 male participants [51.5%]); 173 participants (50.3%) composed the intervention group, and 171 participants (49.7%) composed the active control group. Less than one-third of participants (101 [29.4%]) had previously sought alcohol treatment, despite a high mean (SD) baseline AUDIT score of 21.5 (6.3) and 218 (63.4%) scoring in the probable dependence range. For the primary intention-to-treat analyses, there was a significant decrease in AUDIT total score from baseline to 3 months in both groups (intervention group decrease, 8.22; 95% CI, 7.11-9.32; P < .001; control group decrease, 7.13; 95% CI, 6.10-8.17; P < .001), but change over time was not different between groups (difference, 1.08; 95% CI, -0.43 to 2.59; P = .16). In secondary analyses, the intervention group showed a significantly greater reduction in the AUDIT hazardous use domain relative to the control group at 3 months (difference, 0.58; 95% CI, 0.02-1.14; P = .04). A greater reduction in AUDIT total score was observed for the intervention group relative to the control group when adjusting for exposure to 2 or more sessions (difference, 3.40; 95% CI, 0.36-6.44; P = .03) but not 1 or more sessions (per-protocol analysis)., Conclusions and Relevance: Based on the primary outcome, AUDIT total score, this randomized clinical trial did not find superior effectiveness of this telephone-based cognitive and behavioral intervention compared with active control. However, the intervention was effective in reducing hazardous alcohol use and reduced alcohol problem severity when 2 or more sessions were delivered. Trial outcomes demonstrate the potential benefits of this highly scalable and accessible model of alcohol treatment., Trial Registration: ANZCTR Identifier: ACTRN12618000828224.

Introduction: Telehealth has considerable potential to overcome many of the barriers to accessing care for substance use problems, thereby increasing the opportunity for earlier intervention. The Ready2Change program is a multiple-session outbound telephone-delivered cognitive and behavioural intervention for mild-to-moderate substance use disorders, embedded within a long-established 24/7 alcohol and drug helpline. We sought to analyse routinely collected program data in a preliminary study to examine the effectiveness of Ready2Change in reducing substance use problem severity and psychological distress., Methods: A retrospective analysis of program data from December 2013 to June 2018 was performed. Analysed cases were 249 clients living in Victoria, Australia with alcohol (n = 191), methamphetamine (n = 40) or cannabis (n = 18) as their primary drug of concern. A within-subjects design was used to examine pre- and post-intervention substance use problem severity and psychological distress., Results: For alcohol cases, there was a statistically significant decrease in alcohol problem severity [AUDIT, mean difference = -12.7, 95% confidence interval (CI) -14.0, -11.5]. Statistically significant reductions in drug problem severity (DUDIT) were observed for methamphetamine (mean difference = -17.3, 95% CI -20.9, -13.7) and cannabis (mean difference = -15.9, 95% CI -22.3, -9.6) cases. All groups showed reductions in problem severity for other substances used (P < 0.05) and psychological distress (P < 0.001)., Discussion and Conclusions: Results suggest Ready2Change benefits clients with alcohol, methamphetamine and cannabis use problems, with the potential to improve treatment access for health inequity groups including those living in remote areas. These findings warrant further investigation into the effectiveness of this program., (© 2021 Australasian Professional Society on Alcohol and other Drugs.)

Improvements in the survival and clinical outcomes of cystic fibrosis (CF) patients raised questions about their workforce participation and capacity to work. One hundred and ninety-six outpatients, attending the Adult CF Center of an Italian University Hospital, were enrolled between May 2020 and March 2021. The patients' personal and clinical characteristics, employment status, and profession were assessed. The Cystic Fibrosis Questionnaire-Revised and the work ability index (WAI) were employed to assess CF health-related quality of life and the employee's perception of their ability to work, respectively. Among the enrolled patients, 98 (50%) were employed. The non-working subjects were significantly younger (mean age ± standard deviation: 30 ± 10 vs. 37 ± 10 years) and were diagnosed with CF significantly earlier (9 ± 13 vs. 17 ± 18 years) than the employed subjects. The vast majority of CF workers (82.6%) were employed in tertiary professions. A general good work ability perception was determined in the employed population. Aging and being employed for >15 years could significantly predict a reduction in work ability, while a better quality of life was a positive predictor for its enhancement. Although further research is necessary, these results may introduce interdisciplinary CF healthcare management that includes a work function assessment, formal career counseling, and job guidance to support the personal, social and professional lives of CF patients.

Methamphetamine use disorder involves continued use of the drug despite negative consequences. Such 'compulsivity' can be measured by reversal learning tasks, which involve participants learning action-outcome task contingencies (acquisition-contingency) and then updating their behaviour when the contingencies change (reversal). Using these paradigms, animal models suggest that people with methamphetamine use disorder (PwMUD) may struggle to avoid repeating actions that were previously rewarded but are now punished (inflexibility). However, difficulties in learning task contingencies (reinforcement learning) may offer an alternative explanation, with meaningful treatment implications. We aimed to disentangle inflexibility and reinforcement learning deficits in 35 PwMUD and 32 controls with similar sociodemographic characteristics, using novel trial-by-trial analyses on a probabilistic reversal learning task. Inflexibility was defined as (a) weaker reversal phase performance, compared with the acquisition-contingency phases, and (b) persistence with the same choice despite repeated punishments. Conversely, reinforcement learning deficits were defined as (a) poor performance across both acquisition-contingency and reversal phases and (b) inconsistent postfeedback behaviour (i.e., switching after reward). Compared with controls, PwMUD exhibited weaker learning (odds ratio [OR] = 0.69, 95% confidence interval [CI] [0.63-0.77], p < .001), though no greater accuracy reduction during reversal. Furthermore, PwMUD were more likely to switch responses after one reward/punishment (OR = 0.83, 95% CI [0.77-0.89], p < .001; OR = 0.82, 95% CI [0.72-0.93], p = .002) but just as likely to switch after repeated punishments (OR = 1.03, 95% CI [0.73-1.45], p = .853). These results indicate that PwMUD's reversal learning deficits are driven by weaker reinforcement learning, not inflexibility., (© 2021 Society for the Study of Addiction.)

In light of the recent announcement from the Victorian (Australia) state government that they are moving to decriminalise public drunkenness and replace it with a 'health-based response', it is timely to reflect on a number of important considerations identified from the academic literature on this topic. We briefly review a number of models of health-care delivery that have been utilised in other jurisdictions, and suggest there are opportunities at a more principled level to respond more adequately to the decriminalisation of public drunkenness in Victoria (and elsewhere). First, embedding research and evaluation, particularly that draws on the needs, views and experiences of those who are deemed to be drunk in public, is essential from the outset, and must be ongoing to enable the continual refinement of models of care. Second, significant funding and intersectoral support are needed to ensure that the laws are not tokenistic and do not remain the responsibility of police. Third, there are opportunities to put policies and principles in place to ensure that police do not use more coercive powers to address concerns around public drunkenness. Most importantly, state-wide education and training efforts are needed alongside the repeal of the law to ensure that emergency services and health-care workers (as well as the community), have a good understanding of the contexts and needs of people who are considered drunk in public, and consequently treat them with care and respect., (© 2020 Australasian Professional Society on Alcohol and other Drugs.)

Background: Current population surveys suggest around 20% of Australians meet diagnostic criteria for an alcohol use disorder. However, only a minority seek professional help due to individual and structural barriers, such as low health literacy, stigma, geography, service operating hours and wait lists. Telephone-delivered interventions are readily accessible and ideally placed to overcome these barriers. We will conduct a randomised controlled trial (RCT) to examine the efficacy of a standalone, structured telephone-delivered intervention to reduce alcohol consumption, problem severity and related psychological distress among individuals with problem alcohol use., Methods/design: This is a single site, parallel group, two-arm superiority RCT. We will recruit 344 participants from across Australia with problem alcohol use. After completing a baseline assessment, participants will be randomly allocated to receive either the Ready2Change (R2C) intervention (n = 172, four to six sessions of structured telephone-delivered intervention, R2C self-help resource, guidelines for alcohol consumption and stress management pamphlets) or the control condition (n = 172, four phone check-ins < 5 min, guidelines for alcohol consumption and stress management pamphlets). Telephone follow-up assessments will occur at 4-6 weeks, 3 months, 6 months and 12 months post-baseline. The primary outcome is the Alcohol Use Disorders Identification Test (AUDIT) score administered at 3 months post-baseline. Secondary outcomes include change in AUDIT score (6 and 12 months post-baseline), change in number of past-month heavy drinking days, psychological distress, health and wellbeing, quality of life, client treatment evaluation and cost effectiveness., Discussion: This study will be one of the first RCTs conducted internationally to examine the impact of a standalone, structured telephone-delivered intervention to address problem alcohol use and associated psychological morbidity. The proposed intervention is expected to contribute to the health and wellbeing of individuals who are otherwise unlikely to seek treatment through mainstream service models, to reduce the burden on specialist services and primary care providers and to provide an accessible and proportionate response, with resulting cost savings for the health system and broader community., Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12618000828224 . Pre-registered on 16 May 2018.

Epigenetics are heritable changes in gene expression not coded in the DNA sequence, which stand at the interface between the genome, environmental exposure and development. From an occupational health perspective, epigenetic variants may link workplace exposures and health effects. Therefore, this review aimed to overview possible epigenetic effects induced by welding fumes on exposed workers and health implications. A systematic search was performed on Pubmed, Scopus, and ISI Web of Knowledge databases. DNA methylation changes have been reported in genes responsible for the cardiac autonomic function and coagulation, i.e., LINE-1, GPR133 and F2RL3, in mitochondrial-DNA-sequences involved in the regulation of energy-generation/redox-signaling, as well as in inflammatory activated genes, i.e., iNOS. However, the limited number of retrieved articles, their cross-sectional nature, the lack of a suitable qualitative-quantitative exposure assessment, and the heterogeneity of biological-outcomes investigated, prevent the extrapolation of a definite causal relationship between welding fumes and epigenetic phenomena. Future studies should clarify the function of such epigenetic alterations as possible markers of occupational exposure and early effect, dose-response relationships, and underlying molecular mechanisms. Overall, this may be helpful to guide suitable risk assessment and management strategies to protect the health of workers exposed to welding fumes.

We investigated an outbreak of Acinetobacter baumannii in the intensive care unit (ICU) of a hospital in Rome, Italy. The outbreak involved 14 patients whose isolates were most frequently recovered from bronchoalveolar lavage. All isolates were multidrug-resistant and showed diminished susceptibility or resistance to carbapenems. A. baumannii strains with a similar antibiotic susceptibility pattern were isolated from the environment. Pulsed-field gel electrophoresis identified a single clone from both the patients' and environmental isolates. Because of the lack of a single source of infection, the eradication of the epidemic required a broad approach, including contact isolation and cohorting, aggressive environmental disinfection, and close monitoring of the ward staff's performance. Infected patients were successfully treated with combined therapy. Although considered of low virulence, A. baumannii can be particularly aggressive and difficult to treat in ICU patients.