The epidemiology of acute pancreatitis in Tasmania over a 12-year period: Is this a disease of disadvantage?

BACKGROUND: The global incidence of acute pancreatitis (AP) is increasing, but little information exists about trends in Australia. This study aimed to describe incidence trends, along with clinical and socio-demographic associations, in the state of Tasmania over a recent 12-year period. METHODS: The study cohort was obtained by linking clinical and administrative datasets encompassing the whole Tasmanian population between 2007 and 2018, inclusive. Pancreatitis case definition was based on relevant ICD-10 hospitalization codes, or elevated serum lipase or amylase in pathology data. Age-standardised incidence rates were estimated, overall and stratified by sex, aetiology, and Index of Relative Socio-economic Disadvantage (IRSD). RESULTS: In the study period, 4905 public hospital AP episodes were identified in 3503 people. The age-standardised person-based incidence rate across the entire period was 54 per 100,000 per year. Incidence was inversely related to IRSD score; 71 per 100,000 per year in the most disadvantaged quartile compared to 32 in the least disadvantaged. Biliary AP incidence was higher than that of alcohol-related AP, although the greatest incidence was in "unspecified" cases. There was an increase in incidence for the whole cohort (average annual percent change 3.23 %), largely driven by the two most disadvantaged IRSD quartiles; the least disadvantaged quartile saw a slight overall decrease. CONCLUSION: This is the first Australian study providing robust evidence that AP incidence is increasing and is at the upper limit of population-based studies worldwide. This increased incidence is greatest in socio-economically disadvantaged areas, meriting further research to develop targeted, holistic management strategies.

Being precise with anticoagulation to reduce adverse drug reactions: are we there yet?

Anticoagulants are potent therapeutics widely used in medical and surgical settings, and the amount spent on anticoagulation is rising. Although warfarin remains a widely prescribed oral anticoagulant, prescriptions of direct oral anticoagulants (DOACs) have increased rapidly. Heparin-based parenteral anticoagulants include both unfractionated and low molecular weight heparins (LMWHs). In clinical practice, anticoagulants are generally well tolerated, although interindividual variability in response is apparent. This variability in anticoagulant response can lead to serious incident thrombosis, haemorrhage and off-target adverse reactions such as heparin-induced thrombocytopaenia (HIT). This review seeks to highlight the genetic, environmental and clinical factors associated with variability in anticoagulant response, and review the current evidence base for tailoring the drug, dose, and/or monitoring decisions to identified patient subgroups to improve anticoagulant safety. Areas that would benefit from further research are also identified. Validated variants in VKORC1, CYP2C9 and CYP4F2 constitute biomarkers for differential warfarin response and genotype-informed warfarin dosing has been shown to reduce adverse clinical events. Polymorphisms in CES1 appear relevant to dabigatran exposure but the genetic studies focusing on clinical outcomes such as bleeding are sparse. The influence of body weight on LMWH response merits further attention, as does the relationship between anti-Xa levels and clinical outcomes. Ultimately, safe and effective anticoagulation requires both a deeper parsing of factors contributing to variable response, and further prospective studies to determine optimal therapeutic strategies in identified higher risk subgroups.

Using artificial intelligence to predict choledocholithiasis: can machine learning models abate the use of MRCP in patients with biliary dysfunction?

BACKGROUND: Prompt diagnosis of choledocholithiasis is crucial for reducing disease severity, preventing complications and minimizing length of stay. Magnetic resonance cholangiopancreatography (MRCP) is commonly used to evaluate patients with suspected choledocholithiasis but is expensive and may delay definitive intervention. To optimize patient care and resource utilization, we have developed five machine learning models that predict a patients' risk of choledocholithiasis based on clinical presentation and pre-MRCP investigation results. METHODS: Inpatients admitted to the Royal Hobart Hospital from 2018 to 2023 with a suspicion of choledocholithiasis were included. Exclusion criteria included prior hepatobiliary surgery, known hepatobiliary disease, or incomplete records. Variables related to clinical presentation, laboratory testing, and sonographic or CT imaging were collected. Four machine learning techniques were employed: logistic regression, XGBoost, random forest, and K-nearest neighbours. The three best performing models were combined to create an ensemble model. Model performance was compared against the American Society for Gastrointestinal Endoscopy (ASGE) choledocholithiasis risk stratification guidelines. RESULTS: Of the 222 patients included, 113 (50.9%) had choledocholithiasis. The most successful models were the random forest (accuracy: 0.79, AUROC: 0.83) and ensemble (accuracy and AUROC: 0.81). Every model outperformed the ASGE guidelines. Key variables influencing the models' predictions included common bile duct diameter, lipase, imaging evidence of cholelithiasis, and liver function tests. CONCLUSION: Machine learning models can accurately assess a patient's risk of choledocholithiasis and could assist in identifying patients who could forgo an MRCP and proceed directly to intervention. Ongoing validation on prospective data is necessary to refine their accuracy and clinical utility.

Cough in chronic lung disease: a state of the art review.

Chronic cough (CC; ≥8 weeks in duration) is a common and burdensome feature of respiratory diseases. The understanding of cough has progressed significantly in recent years, albeit largely in refractory (unexplained) chronic cough (RCC) in the absence of other respiratory conditions. The prevalence of CC in respiratory diseases is poorly described, but estimates have been reported: asthma (8-58%), chronic obstructive pulmonary disease (COPD; 10-74%), bronchiectasis (82-98%), interstitial lung disease (ILD; 50-89%) and sarcoidosis (3-64%). CC in respiratory conditions generally predicts impaired health status and more severe disease. It is associated with increased symptom burden and disease severity in asthma, COPD, bronchiectasis and ILD, higher exacerbation frequency in asthma and bronchiectasis, and increased mortality and lung transplantation in idiopathic pulmonary fibrosis (IPF). Physiologically, heightened cough reflex sensitivity (CRS) has been reported and postulated to be mechanistic in isolated RCC. Cough reflex hypersensitivity (CRH) has also been reported in asthma, COPD, bronchiectasis, ILD and sarcoidosis. Unlike recent advances in isolated RCC, there are limited studies and understanding of central cough neuropathways in other respiratory conditions. Of note, dysfunctional central voluntary cough suppression neuropathways and physiology were observed in isolation in RCC; cough suppression is preserved in COPD. Understanding in the mechanism of RCC cannot be simply extrapolated to other respiratory conditions. The restricted understanding of cough mechanisms in these conditions has limited cough-specific therapeutic options in this context. There is currently an unmet need to expand our understanding of cough in chronic respiratory conditions, both in order to improve the quality of life of patients, and to improve knowledge of cough in general. This review aims to describe the prevalence, impact, pathophysiology and management of CC in asthma, COPD, bronchiectasis, ILD and sarcoidosis.

Enhanced harvest performance predictability through advanced multivariate data analysis of mammalian cell culture particle size distribution.

The industry's pursuit for higher antibody production has led to increased cell density cultures that impact the performance of subsequent product recovery steps. This increase in cell concentration has highlighted the critical role of solids concentration in centrifugation yield, while recent product degradation cases have shed light on the impact of cell lysis on product quality. Current methods for measuring solids concentration and cell lysis are not suited for early-stage high-throughput experimentation, which means that these cell culture outputs are not well characterized in early process development. This article describes a novel approach that leveraged the data from a widely-used automated cell counter (Vi-CELL™ XR) to accurately predict solids concentration and a common cell lysis indicator represented as lactate dehydrogenase (LDH) release. For this purpose, partial least squares (PLS) models were derived with k-fold cross-validation from the particle size distribution data generated by the cell counter. The PLS models showed good predictive potential for both LDH release and solids concentration. This novel approach reduced the time required for evaluating the solids concentration and LDH for a typical high-throughput cell culture system (with 48 bioreactors in parallel) from around 7 h down to a few minutes.

Chronic Cough as a Genetic Neurological Disorder? Insights from Cerebellar Ataxia with Neuropathy and Vestibular Areflexia Syndrome (CANVAS).

Chronic cough is common, and in many cases unexplained or refractory to otherwise effective treatment of associated medical conditions. Cough hypersensitivity has developed as a paradigm that helps to explain clinical and research observations that frequently point towards chronic cough as a neuropathic disorder. Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recently described neurological condition whose clinical features include gait ataxia, unsteadiness, peripheral neuropathy, and autonomic dysfunction. Chronic cough is also a common feature of the syndrome, with features of hypersensitivity, often preceding core neurological symptoms by up to 30 years or more. The genetic basis in a majority of cases of CANVAS appears to be biallelic variable repeat intron expansion sequences within RFC1, a gene normally involved in the regulation of DNA replication and repair. The same polymorphism has now been identified at an increased frequency in patients with unexplained or refractory chronic cough in the absence of defining clinical features of CANVAS. This review expands on these points, aiming to increase the awareness of CANVAS amongst clinicians and researchers working with chronic cough. We discuss the implications of a link between RFC1 disease and cough. Improved understanding of CANVAS may lead to an enhanced grasp of the pathophysiology of chronic cough, and new approaches to antitussive treatments.

Patient Global Impression of Severity Scale in Chronic Cough: Validation and Formulation of Symptom Severity Categories.

BACKGROUND: The Patient Global Impression of Severity (PGI-S) scale is a self-reported, single-item categorical scale that is increasingly used when assessing chronic cough (CC). OBJECTIVE: This study aimed to establish validity, repeatability, and responsiveness of the PGI-S scale in CC and use the scale to define discrete categories of severity when measured with other commonly used patient-reported outcome (PRO) tools. METHODS: Consecutive patients with CC completed the PGI-S scale, cough severity and urge to cough visual analog scales (VAS), and cough-specific health status Leicester Cough Questionnaire (LCQ) at a clinic visit. Validity, repeatability, and responsiveness were assessed, and threshold scores for PRO severity categories determined. RESULTS: A total of 482 participants completed the assessments; the median (interquartile range [IQR]) age was 57 (46-67) years, 71% were female, and the median (IQR) duration of cough was 48 (24-120) months. They reported a median (IQR) PGI-S score of 3 (3-4; moderate severity), cough severity VAS of 57 (31-75) mm, urge to cough VAS of 62 (40-81) mm, and LCQ of 11.5 (8.7-14.4). There were strong associations between PGI-S scores and cough severity VAS (ρ = 0.81), urge to cough VAS (ρ = 0.73), and LCQ (ρ = -0.73) (all P < .001). Repeatability of the PGI-S scale was high (n = 77); the intraclass correlation coefficient (95% confidence interval) was 0.85 (0.77-0.91) (P < .001). The PGI-S scale was responsive in participants with a treatment response (P < .001). The suggested PRO thresholds to define severe cough are ≥61 mm (cough severity VAS), ≥71 mm (urge to cough VAS), and ≤10 (LCQ). CONCLUSION: The PGI-S scale is a simple and valid tool that characterizes cough severity and is repeatable and responsive in CC. The proposed categorical severity thresholds for VAS and LCQ can provide intuitive meaning for patients and clinicians.

Next-generation cell line selection methodology leveraging data lakes, natural language generation and advanced data analytics.

Cell line development is an essential stage in biopharmaceutical development that often lies on the critical path. Failure to fully characterise the lead clone during initial screening can lead to lengthy project delays during scale-up, which can potentially compromise commercial manufacturing success. In this study, we propose a novel cell line development methodology, referenced as CLD 4, which involves four steps enabling autonomous data-driven selection of the lead clone. The first step involves the digitalisation of the process and storage of all available information within a structured data lake. The second step calculates a new metric referenced as the cell line manufacturability index (MI CL) quantifying the performance of each clone by considering the selection criteria relevant to productivity, growth and product quality. The third step implements machine learning (ML) to identify any potential risks associated with process operation and relevant critical quality attributes (CQAs). The final step of CLD 4 takes into account the available metadata and summaries all relevant statistics generated in steps 1-3 in an automated report utilising a natural language generation (NLG) algorithm. The CLD 4 methodology was implemented to select the lead clone of a recombinant Chinese hamster ovary (CHO) cell line producing high levels of an antibody-peptide fusion with a known product quality issue related to end-point trisulfide bond (TSB) concentration. CLD 4 identified sub-optimal process conditions leading to increased levels of trisulfide bond that would not be identified through conventional cell line development methodologies. CLD 4 embodies the core principles of Industry 4.0 and demonstrates the benefits of increased digitalisation, data lake integration, predictive analytics and autonomous report generation to enable more informed decision making.

Measuring cough: what really matters?

The clinical and research discipline of cough has grown substantially over the last two decades as methods to measure cough have developed and evolved. Cough can be thought of both as a symptom and an objectively observable pathophysiological phenomenon, two aspects whose interrelationship is complicated. The following review explores the varied methods to measuring cough, both subjective, patient-reported measures and objective approaches. Specifically, symptom scores, questionnaires of cough-related quality of life, and associated mental health impacts of chronic cough are addressed, as are developments in measuring cough frequency, cough intensity, cough reflex sensitivity, and cough suppressibility. Measuring patient reported cough-severity with a simple visual analogue scale increasingly appears to be justified, but has limitations. The Leicester Cough Questionnaire has been widely used for twenty years, within varied settings and diseases, in research and routine clinical practice, and captures cough-related quality of life. Objective cough frequency has become the primary outcome measure for clinical trials of antitussives, and technology is now enabling the wider application of cough counting. Inhaled tussive challenge testing still has a role, including in the assessment of cough hypersensitivity, and in the identification of failure to supress cough. Ultimately, many measures have a contributory and complementary role, with differing merits in quantifying the multiple facets of cough, the complexity of which is being increasingly recognised.

Wellbeing while waiting evaluating social prescribing in CAMHS: study protocol for a hybrid type II implementation-effectiveness study.

BACKGROUND: Social prescribing is a mechanism of connecting patients with non-medical forms of support within the community and has been shown to improve mental health and wellbeing in adult populations. In the last few years, it has been used in child and youth settings with promising results. Currently, pathways are being developed for social prescribing in Child and Adolescent Mental Health Services (CAMHS) to support children and young people on treatment waiting lists. The Wellbeing While Waiting study will evaluate whether social prescribing benefits the mental health and wellbeing of children and young people. METHODS: This study utilises an observational, hybrid type II implementation-effectiveness design. Up to ten CAMHS who are developing social prescribing pathways as part of a programme run across England with support from the Social Prescribing Youth Network will participate. Outcomes for children and young people receiving social prescribing whilst on CAMHS waiting lists will be compared to a control group recruited prior to the pathway roll-out. Questionnaire data will be collected at baseline, 3 months and 6 months. Primary outcomes for children and young people are mental health symptoms (including anxiety, depression, stress, emotional and behavioural difficulties). Secondary outcomes include: loneliness, resilience, happiness, whether life is worthwhile, life satisfaction, and service use. An implementation strand using questionnaires and interviews will explore the acceptability, feasibility, and suitability of the pathway, potential mechanisms of action and their moderating effects on the outcomes of interest, as well as the perceived impact of social prescribing. Questionnaire data will be analysed mainly using difference-in-differences or controlled interrupted time series analysis. Interview data will be analysed using reflexive thematic analysis. DISCUSSION: The Wellbeing While Waiting study will provide the first rigorous evidence of the impact of social prescribing for children and young people on waiting lists for mental health treatment. Findings will help inform the prioritisation, commissioning, and running of social prescribing in other CAMHS. To maximise impact, findings will be available on the study website ( https://sbbresearch.org ) and disseminated via national and international networks. TRIAL REGISTRATION: N/A.

Process economics evaluation and optimization of adeno-associated virus downstream processing.

Adeno-associated virus (AAV) manufacturing has traditionally focused upon lab-scale techniques to culture and purify vector products, leading to limitations in production capacity. The tool presented in this paper assesses the feasibility of using non-scalable technologies at high AAV demands and identifies optimal flowsheets at large-scale that meet both cost and purity targets. The decisional tool comprises (a) a detailed process economics model with the relevant mass balance, sizing, and costing equations for AAV upstream and downstream technologies, (b) a built-in Monte Carlo simulation to assess uncertainties, and (c) a brute-force optimization algorithm for rapid investigation into the optimal purification combinations. The results overall highlighted that switching to more scalable upstream and downstream processing alternatives is economically advantageous. The base case analysis showed the cost and robustness advantages of utilizing suspension cell culture over adherent, as well as a fully chromatographic purification platform over batch ultracentrifugation. Expanding the set of purification options available gave insights into the optimal combination to satisfy both cost and purity targets. As the purity target increased, the optimal polishing solution moved from the non-capsid purifying multimodal chromatography to anion-exchange chromatography or continuous ultracentrifugation.

A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study.

BACKGROUND: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. METHODS: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. FINDINGS: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001). INTERPRETATION: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. FUNDING: European Union Horizon 2020.

Comprehensive studies on building a scalable downstream process for mRNAs to enable mRNA therapeutics.

In recent years, mRNA-based therapeutics have been a fast-growing new class of biologics that can, in principle, encode any protein(s) directly in patients to treat various diseases. mRNA vaccines have been proven to work efficiently, have high potency, and can be rapidly developed and deployed, which is critical for a quick responses in the case of a pandemic. Such agile development is enabled by rapid synthesis of RNA in vitro using recombinant enzymes rather than relying on lengthy and complex cell culture processes. mRNA exhibits physical and chemical properties differing from protein-based therapeutics. It is highly negatively charged and the hydroxyl group makes mRNA less stable and more susceptible to hydrolysis and nucleophilic cleavage. This novel work shares comprehensive studies carried out to compare the performance of various mRNA purification strategies by considering its scalability and critical quality attributes. In addition, the paper provides insights on how to establish a scalable mRNA purification process that consists of ultrafiltration/diafiltration and chromatography steps with good recoveries. Alternative Oligo(dT) based columns were further explored aiming to improve total process recovery. With Oligo(dT) as a capture step, overall recoveries of 70% can be achieved for mRNAs studied here that encode anti-influenza immunoglobulin G monoclonal antibodies.

Atrial flutter and fibrillation in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension in the ASPIRE registry: Comparison of rate versus rhythm control approaches.

BACKGROUND: The development of atrial flutter and fibrillation (AFL/AF) in patients with pre-capillary pulmonary hypertension has been associated with an increased risk of morbidity and mortality. Rate and rhythm control strategies have not been directly compared. METHODS: Eighty-four patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) with new-onset AFL/AF were identified in the ASPIRE registry. First, baseline characteristics and rates of sinus rhythm (SR) restoration of 3 arrhythmia management strategies (rate control, medical rhythm control and DC cardioversion, DCCV) in an early (2009-13) and later (2014-19) cohort were compared. Longer-term outcomes in patients who achieved SR versus those who did not were then explored. RESULTS: Sixty (71%) patients had AFL and 24 (29%) AF. Eighteen (22%) patients underwent rate control, 22 (26%) medical rhythm control and 44 (52%) DCCV. SR was restored in 33% treated by rate control, 59% medical rhythm control and 95% DCCV (p < 0.001). Restoration of SR was associated with greater improvement in functional class (FC) and Incremental Shuttle Walk Distance (p both <0.05). It also independently predicted superior survival (3-year survival 62% vs 23% in those remaining in AFL/AF, p < 0.0001). In addition, FC III/IV independently predicted higher mortality (HR 2.86, p = 0.007). Right atrial area independently predicted AFL/AF recurrence (OR 1.08, p = 0.01). DCCV was generally well tolerated with no immediate major complications. CONCLUSIONS: Restoration of SR is associated with superior functional improvement and survival in PAH/CTEPH compared with rate control. DCCV is generally safe and is more effective than medical therapy at achieving SR.

Chronic cough: is the end nigh?

Chronic cough (lasting more than 8 weeks) is a common condition with substantial psychosocial impact. Despite huge efforts following robust guidelines, chronic cough in many patients remains refractory or unexplained (RU-CC). Recent insights support a significant role for cough hypersensitivity in RU-CC, including neuropathophysiological evidence from inhalational cough challenge testing, functional magnetic resonance imaging, and airway nerve biopsy. Along with improved approaches to measuring cough, this knowledge has developed in tandem with repurposing neuromodulator medications, including gabapentin, and evidence for non-pharmacological treatments. Most significantly, there is now a pipeline for novel classes of drugs specifically for chronic cough. The P2X3 receptor antagonist gefapixant is the first such drug to be approved in Europe. However, challenges persist. The field of chronic cough needs more robust epidemiological data, enhanced diagnostic tools, further well-designed clinical trials accounting for the effects of placebo, and treatments with minimal side-effects. Addressing these challenges are novel chronic cough registries, improved International Classification of Diseases (10th revision) coding, genetic testing options and further mechanistic studies. This Viewpoint article discusses these facets and considers how, whilst the end of chronic cough may not be imminent for all patients, the evolving landscape looks increasingly optimistic.

Adapting the ADVANCE group program for digitally-supported delivery to reduce intimate partner violence by men in substance use treatment: a feasibility study.

Introduction: COVID-19 restrictions created barriers to "business as usual" in healthcare but also opened the door to innovation driven by necessity. This manuscript (1) describes how ADVANCE, an in-person group perpetrator program to reduce intimate partner violence (IPV) against female (ex)partners by men in substance use treatment, was adapted for digitally-supported delivery (ADVANCE-D), and (2) explores the feasibility and acceptability of delivering ADVANCE-D to men receiving substance use treatment. Methods: Firstly, the person-based approach and mHealth development framework were used to iteratively adapt ADVANCE for digitally-supported delivery including conceptualization, formative research, and pre-testing. Then, a non-randomized feasibility study was conducted to assess male participants' eligibility, recruitment, and attendance rates and uptake of support offered to their (ex)partners. Exploratory analyses on reductions in IPV perpetration (assessed using the Abusive Behavior Inventory; ABI) and victimization (using the revised ABI; ABI-R) at the end of the program were performed. Longitudinal qualitative interviews with participants, their (ex)partners, and staff provided an understanding of the program's implementation, acceptability, and outcomes. Results: The adapted ADVANCE-D program includes one goal-setting session, seven online groups, 12 self-directed website sessions, and 12 coaching calls. ADVANCE-D includes enhanced risk management and support for (ex)partners. Forty-five participants who had perpetrated IPV in the past 12 months were recruited, forty of whom were offered ADVANCE-D, attending 11.4 (SD 9.1) sessions on average. Twenty-one (ex)partners were recruited, 13 of whom accepted specialist support. Reductions in some IPV perpetration and victimization outcome measures were reported by the 25 participants and 11 (ex)partners interviewed pre and post-program, respectively. Twenty-two participants, 11 (ex)partners, 12 facilitators, and 7 integrated support service workers were interviewed at least once about their experiences of participation. Overall, the program content was well-received. Some participants and facilitators believed digital sessions offered increased accessibility. Conclusion: The digitally-supported delivery of ADVANCE-D was feasible and acceptable. Remote delivery has applicability post-pandemic, providing greater flexibility and access. Given the small sample size and study design, we do not know if reductions in IPV were due to ADVANCE-D, time, participant factors, or chance. More research is needed before conclusions can be made about the efficacy of ADVANCE-D.