Purpose To develop a deep learning model for segmenting pectoralis muscle volume (PMV) at CT and evaluate the reproducibility, group differences, and associations of pectoralis muscle area (PMA) and PMV with chronic obstructive pulmonary disease (COPD)-related outcomes. Materials and Methods This study was a secondary analysis of the prospective Canadian Cohort Obstructive Lung Disease study (CanCOLD, data collected from November 2009 to July 2015). Randomly sampled CT scans from CanCOLD were used for model training, validation, and internal testing (n = 96, 16, and 32, respectively) and an external dataset for external testing (n = 32). A U-Net model was trained for PMV segmentation, and performance was assessed using the Dice similarity coefficient (DSC). PMA and PMV values were extracted from paired inspiration and expiration scans to assess segmentation reproducibility. Differences between individuals with or without COPD and associations with forced expiratory volume in 1 second (FEV1), diffusing capacity of the lungs for carbon monoxide (Dlco), and peak oxygen uptake during exercise (VO2) were reported. Results Individuals included those with (n = 634; mean age, 67.3 years ± 10.1 [SD]; 394 male participants) and without (n = 601; mean age, 65.8 years ± 9.6; 327 male participants) COPD. The model yielded DSCs of 0.94 ± 0.04, 0.93 ± 0.03, and 0.92 ± 0.04 in the training and validation, internal testing, and external testing datasets, respectively. Contrary to PMV (bias, 0.1 cm3; P = .77), PMA showed bias between inspiration and expiration (bias, -2.7 cm2; P < .001). Both PMA and PMV were reduced in patients with COPD (P < .05), but PMV was more strongly associated with FEV1 (adjusted R2 [Radj2], 0.609/0.598), Dlco (Radj2, 0.645/0.627), and VO2 (Radj2, 0.680/0.666). Conclusion An accurate and generalizable CT-based deep learning model for pectoralis muscle segmentation was developed. Compared with PMA, PMV showed better reproducibility and stronger associations with COPD outcomes. Keywords: CT, Thorax, Lung, Volume Analysis, Chronic Obstructive Pulmonary Disease, Segmentation ClinicalTrials.gov identifier no. NCT00920348 © RSNA, 2026 Supplemental material is available for this article.

Neck-specific exercises are commonly used in the management of temporomandibular disorders (TMD); however, the additional role of aerobic training remains unclear. Given the involvement of central pain mechanisms in TMD and the effects of aerobic exercise on pain modulation, its potential adjunctive value warrants further investigation. To evaluate the additional effects of aerobic training to neck exercises on pain intensity, neck disability, and related outcomes in women with chronic TMD. Randomized controlled trial. Fifty-eight women with chronic TMD were randomized into: (1) neck exercises (CG; n=30); or (2) neck exercises plus aerobic training (EG; n=28). Primary outcomes were orofacial pain intensity (VAS) and neck disability (NDI). Secondary outcomes were pressure pain thresholds (PPTs), jaw function (MFIQ), self-efficacy (CPSS), and oral health-related quality of life (OHIP-14). Repeated-measures ANOVA and multilevel mixed modelling (MLM) were used for analysis. Both groups improved over time in pain intensity, neck disability, and secondary outcomes, with no statistically significant differences between groups. Within-group effect sizes for pain intensity were large in the EG (g=1.43) and in the CG (g=1.08) after treatment. The MLM models indicated that NDI, CPSS and OHIP-14 explained part of the variation in pain intensity, and central sensitization, OHIP-14, and CPSS explained part of the variation for neck disability. Moderate-intensity aerobic exercise did not yield statistically significant additional benefits compared with performing neck exercises alone. However, it remains important to explore other types of aerobic exercise for managing TMD.

Substance use disorder (SUD) is a polygenic psychiatric condition characterized by persistent drug use despite negative consequences. Several studies support that higher cognitive performance and educational attainment (EA) are associated with a reduced risk for SUD. Here, we aimed to understand better the genetic relationship between EA and SUD, using a general addiction risk-factor (addiction) as a proxy of SUD. We used GWAS summary statistics on EA (n = 766 345) and addiction (n = 647 703) and applied a multistep approach to: (i) examinate the genetic overlap between EA and addiction; (ii) test the polygenic contribution of addiction and EA on SUD diagnosis and its clinical heterogeneity in an independent in-house clinical sample (1427 individuals with SUD and 2309 controls); and (iii) dissect the genetic liability of addiction according to its role in EA and assessing its genetic overlap with SUD-related traits, other mental disorders and behavioral traits. We confirmed a negative genetic correlation between addiction and EA [rg = -0.33, standard error (SE) =0.02, P = 1.14e-57]. When we dissected the genetic liability of addiction by its relationship with EA we found that the discordant overlapping variation between addiction and EA, highly enriched for the genetic background of addiction (h2 SNP=2.42%, P = 6.37e-21), showed the strongest effect on SUD (OR =1.66, 95% confidence interval =1.54-1.79, P = 2.01e-40) and was associated with worse sociodemographic, health and SUD-related outcomes in individuals with SUD compared with the other genomic partitions studied. Our results provide new evidence on the shared genetic basis between addiction and educational attainment. By separating the genetic liability of addiction according to its relationship with educational attainment, we were able to clarify its polygenic effects on substance use disorder diagnosis and related outcomes, providing novel insights into the shared genetic signatures between addiction and other comorbid traits.

Core beliefs about you and me: Schema structures, relationship quality, and depressive severity in romantic couples.

Serum PCBs, OCPs, PBDEs and PCAs: Associations with metabolic syndrome risk factors in the Flemish Gut Flora Project cohort.

Skeletal muscle is a vital part of human physiology and is responsible for numerous essential functions. Not surprisingly, the loss of skeletal muscle mass and function is common in several pathologies including atrophy and sarcopenia, which profoundly impact quality of life of those afflicted. Thus, numerous investigations of potential therapies for mitigating or reversing such pathologies are available. Within these studies, experimental cell culture models such as the murine C2C12 myoblasts are commonly used. Over 100 publications have utilized dexamethasone-treated C2C12 myotubes to investigate various aspects of muscle atrophy. The purpose of this systematic review is to describe the experimental conditions common to these experiments, as well as phenotypical myotube presentation, and gene and protein expression of targets that regulate muscle mass, function, and metabolism. A systematic review of literature was conducted until 3 January 2025 using PUBMED. Articles were included if (1) C2C12 myotubes were used, (2) the article included a dexamethasone-only group along with appropriate vehicle or true control and (3) the article assessed at least one of the related phenotypical or molecular outcomes of importance to the scope of the review. A total of 182 articles were included after screening for relevance and inclusion criteria, which were assessed for outcomes (raw data reported when available or using ratio-metric estimates of relative differences between dexamethasone treatment and control). In 24 of 26 unique experiments that utilized 10 μM dexamethasone and 37 of 39 unique experiments that utilized 100 μM dexamethasone, a decrease in myotube diameter was reported (pooled experimental average estimates from 24-h time points 69.8% ± 7.5% and 66.9% ± 14.7% for 10 and 100 μM, respectively, vs. control). All six studies that utilized 10 μM dexamethasone and all nine that treated myotubes with 100 μM dexamethasone reported reduced fusion index (pooled experimental average estimates from 24-h time points: 67.6% ± 5.3% and 68.4% ± 8.4% for 10 and 100 μM, respectively, vs. control). Dexamethasone-treated myotubes also consistently expressed increased atrophic-related molecular targets including Atrogin-1 and muscle atrophy X box1 (MuRF1), as well as reductions in anabolic signalling (specifically, mTORC and Akt activation) and mitochondrial function. The striking consistency of these findings suggests dexamethasone treatment of C2C12 myotubes is a reliable method of mimicking many features common to skeletal muscle pathology. This review provides insight into the use and expected outcomes of the dexamethasone-mediated model of atrophy in C2C12 myotubes and may serve as a helpful reference for future experiments utilizing this model.

Sex differences in impact of daily and chronic psychological stressors on diurnal cortisol level.

Sarcopenia and malnutrition have detrimental health related outcomes not limited to falls, weakness, fractures, increased hospital length of stay, increased risk of infections, morbidity and mortality. Ultrasound is an establishing imaging modality that can be utilized at point-of care to measure muscle mass and quality. It is cheaper, less invasive, and more accessible than other gold-standard measurements of muscle mass. It is proposed that dietitians can utilize this measurement in clinical practice to support both diagnosis and monitoring of malnutrition and sarcopenia, however current evidence has not been synthesized. The search was completed in May 2024. MEDLINE, EMBASE, PubMed and Cochrane databases were searched. Search terms and search procedures were transposed across different databases based on known Booleen operators. Due to paucity of evidence in the area, a broad search strategy was employed. Simply the combination of synonyms of ultrasound and dietitian within any field was used to ensure any kind of ultrasound measured by a dietitian was captured. The initial search identified 946 titles for review from which 228 duplicates were removed, leaving 718 for screening. After screening, 55 papers remained for full-text review. Ten papers were included for appraisal. All peer-reviewed papers were observational, 441 participants in total were included (both healthy participants and patient cohorts). Study quality was low, with study design, documentation of training, timing of measurement and blinding poorly defined. The reference standard (if any) was inconsistent. All studies were basic research, none were translated into clinical practice. Quad muscle thickness was the most common measurement. Reliability of dietitians was reported in most, with intra-rater ICC ranges from 0.63 to 0.95 between dietitians and 'experts' (intensivists, trained clinicians or sonographers). Training undertaken was reported in half the papers reviewed but details were limited. Emerging evidence suggests dietitians have potential to develop skills in measuring muscles with ultrasound. Overall, there remains a paucity of publications in the area, particularly when considering dietitian training and reliability in various ultrasound measurements. There should be progress in Further studies with regard to verifying necessary training for dietitians to ensure accurate readings as an advanced scope of practice for dietitians.

Irritable bowel syndrome (IBS) is a common functional bowel disorder characterized by abdominal pain and altered bowel habits, with types classified based on stool patterns: (1) Diarrhea-predominant IBS (IBS-D); (2) IBS with constipation (IBS-C); and (3) Mixed IBS. This condition affects approximately 10% of adults globally and is challenging to treat due to the lack of definitive structural or biochemical markers. Treatment options include dietary, pharmacological, and psychological therapies, yet patients often struggle with refractory symptoms impacting quality of life (QoL). To review existing literature to evaluate Mirtazapine's effectiveness in treating IBS, particularly in older patients. This review as registered in the PROSPERO database (CRD420251022721) and followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic review was conducted between February 2024 and March 2024, searching PubMed, EMBASE, and BMJ Case Reports from database inception to present. We included English-language randomized controlled trials (RCTs), prospective clinical studies, and case reports of adult IBS-D or IBS-C patients treated with Mirtazapine, reporting on symptom resolution, abdominal pain, insomnia, or related outcomes. Data extraction covered study design, sample size, dosage, duration, and outcomes. No meta-analysis was performed due to heterogeneity. Of 77 identified references, five publications met inclusion criteria: (1) Three case reports; (2) One double-blind RCT (n = 67; Mirtazapine vs placebo); and (3) One prospective study (n = 116 with comorbid depression, 50 on Mirtazapine). The RCT demonstrated significant reductions in IBS symptoms severity score, diary-based symptoms (abdominal pain, urgency, frequency; all significant except bloating), and improved QoL and anxiety scores. Case reports (patients aged 35-66 years) reported normalization of stool frequency, weight gain, and relief of anxiety/depressive symptoms. The prospective study found baseline sleep disturbance correlated with improvements in pain and diarrhea. Although evidence is limited, current data indicate Mirtazapine improves IBS-related symptoms and associated mental health issues, with rapid onset and good tolerability. The small number of studies and absence of large-scale RCTs warrant cautious interpretation. Further RCTs are essential to confirm Mirtazapine's role in IBS treatment and define optimal patient profiles.

Purpose Upper limb dysfunctions are common in breast cancer patients, requiring valid range of motion (ROM) assessment methods. This cross-sectional study evaluates the convergent validity of an Inertial Measurement Unit set-up (IMUs) and three clinical tools: analogue goniometry, analogue inclinometry, and digital goniometry. Secondly, it examines agreement between these clinical tools. Materials and methods Humerothoracic and scapulothoracic upward rotation ROM were assessed during six movement tasks. Correlation analyses studied convergent validity. Agreement and interchangeability were assessed using interclass correlation coefficients (ICCs), Bland-Altman plots, and limits of agreement. Results Thirty participants were included (median age 52.50 [45.75–59.00] years). For humerothoracic ROM, clinical tools measured similar constructs (r = 0.609–0.949), and the IMUs show no or related outcomes (r = 0.078–0.809). The clinical tools showed good agreement (ICC = 0.816–0.985); however, systematic biases and outliers were present. For scapulothoracic ROM, results indicated that clinical tools mostly measured similar constructs (r = 0.205–0.888), while the IMUs measured unrelated constructs (r = −0.316–0.511). Moderate to excellent relative agreement was presented (ICC = 0.502–0.936), but with wide variability (up to 27.5°). Conclusions Clinical tools evaluate similar constructs for humerothoracic and scapulothoracic ROM, but vary for the IMUs. Results suggest not using the tools interchangeably for scapulothoracic ROM due to clinically significant differences.

People may often attempt to support a loved one by changing how that loved one interprets a stressful situation (i.e., other-focused cognitive reappraisal). However, there are many specific ways in which a situation can be reframed, and while some reappraisal tactics may be effective, other tactics may be inert or possibly backfire-even when used with good intentions. We propose that it is useful to distinguish between decommitment tactics that involve decommitting from a previously held perspective (e.g., reducing severity: "It is not as bad as it seems"; situational acceptance: "It is out of your hands") and commitment tactics that involve committing to an alternative perspective (e.g., finding benefits: "This will help you grow"; enhancing controllability: "You can handle this"). Across a pilot study (N = 963, collected in 2022), a longitudinal study (N = 261, collected in 2021), and a round-robin study (N = 344, collected in 2024), we investigated how regulators' use of different tactics to manage loved ones' (i.e., recipients') emotions predicted recipient and relationship outcomes in diverse samples. Across studies, people commonly used each tactic to regulate recipients' emotions. However, only the commitment tactics (enhancing controllability and finding benefits) consistently predicted better outcomes across three studies-improved recipient emotional experience and feelings of being supported and, in turn, better recipient well-being and relationship quality-while both decommitment tactics (reducing severity and situational acceptance) were inert and sometimes linked to worse interpersonal outcomes. These findings highlight the complex implications of managing loved ones' emotions using reappraisal. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Abstract Return on investment (ROI) analysis, when rooted in a theology of stewardship, can help Christian relief, development, and advocacy (CRDA) organizations steward the resources entrusted to them by God toward lasting transformation. Biblical teachings affirm the value of wise stewardship, tangible outcomes, and the just use of resources, while cautioning against treating wealth as an end in itself (e.g., Matthew 25:14–30; Proverbs 21:5; Matthew 6:19–21). Especially when combined with impact evaluation, ROI can enhance strategic decision-making, promote accountability, and align financial stewardship with kingdom values. Yet, it also raises important questions in faith-based development: Can market-based metrics capture relational, spiritual, and justice-oriented outcomes? Who defines “value” in this framework? And is monetizing outcomes always appropriate? This article explores these questions through a case study of Zoe Empowers, a faith-rooted, three-year empowerment program for orphaned and vulnerable youth. Operating in 12 countries, Zoe equips youth through micro grants, vocational training, life skills development, and spiritual formation—helping over 230,000 participants, with more than 95% achieving self-sufficiency by graduation, at a cost of just $9 per month per youth. Using both income gain modeling and the Harvard Human Flourishing Index (HHFI), the study demonstrates the potential of integrating economic and holistic outcome measures. Findings show that under conservative assumptions, Zoe delivers a financial ROI exceeding 3:1, and under standard assumptions, a 10.7:1 return per participant in the final year of implementation. HHFI results reveal that graduates are 21 times more likely than their peers to achieve ideal flourishing scores, with significant gains in happiness and life satisfaction, physical and mental health, character and virtue, and close social relationships. Together, these results suggest that ROI, when framed holistically and anchored in biblical principles, can serve as both a rigorous accountability tool and a faithful expression of love, justice, and transformation in CRDA practice.

Inequities in the division of household labor between spouses are well-established, particularly among heterosexual couples. However, while quantification of physical labor (e.g., doing dishes, folding laundry) is straightforward, the measurement of the cognitive and emotional labor that goes into running a home (e.g., planning, organizing, delegating) is not. The present study, therefore, aimed to develop a comprehensive measure of this mental labor, the Mental Load Scale (MLS), for use among cohabitating couples and to determine the mental health and relationship consequences of mental load. To this end, an online questionnaire was developed and administered to 569 adults (56% women) who were currently in a cohabitating romantic relationship. Results of exploratory and confirmatory factor analyses indicated that the MLS has three distinct subscales: invisible burden, logistical responsibility, and emotional labor. Further, an examination of the relationship consequences of mental load indicated that women endorsed higher levels of all three facets of mental load, and that women reported poorer relationship and mental health outcomes when mental load was high. The MLS is an important tool for researchers and clinicians who wish to measure this “invisible” construct among individuals and couples and mental load, as well as its negative effects, falls disproportionately to women.

Background/Objectives: Positive Psychotherapy (PPT) is an empirically supported treatment that directly targets positive resources and personal strengths as its primary logic. PPT is effective in amplifying happiness and well-being as an additional way to enhance positive mental health while also ameliorating symptoms of negative affect, especially in depression, anxiety disorders, and stress disorders. However, few studies have been conducted to investigate these effects in the long run. This study extends our previously published findings on the short-term efficacy of PPT by extending the follow-up period to 18 months and comparing its long-term effects with those of Cognitive Behavioral Therapy (CBT) within the same randomized controlled trial. Methods: Forty-nine out-patient participants with a DSM-IV diagnosis for depressive disorder (MDD, Dysthymia) were treated with 14 sessions of manualized PPT (n = 23) or CBT (n = 26) group therapy. In a randomized controlled two-center-study, questionnaires on depressive symptoms (BDI-II, MADRS, DHS), psychological distress (BSI), and well-being related outcomes (FS, PPTI, SWLS) were administered at baseline and 18-month follow-up. Results: Analyses using linear mixed models indicated significant differences in long-term treatment outcome for depressive symptoms (BDI-II, DHS, MADRS) and satisfaction with life (SWLS), depicting better outcomes for the PPT group. Between group effect sizes at 18-month follow-up were primarily in the middle range for all outcome measures, in favor of PPT. Conclusions: This study provides support for the long-term efficacy of PPT in the treatment of depression and improvement of positive resources.

ABSTRACT Background Individuals with chronic obstructive pulmonary disease (COPD) face increased risk of severe respiratory syncytial virus (RSV)-related outcomes. We assessed the uptake of adjuvanted-RSVPreF3 and its effectiveness against RSV hospitalization in such individuals. Research design and methods We assembled a Danish nationwide cohort of individuals aged ≥ 60 years with COPD during the 2024/25 RSV season. Vaccinated and unvaccinated individuals were matched using exact and propensity score matching resulting in balanced groups. Individuals were followed from 21 days post-vaccination until the earliest of event, end of data availability, migration, RSV vaccination, or death. Vaccine effectiveness was estimated as (1 – incidence rate ratio [IRR]) x 100, where IRRs were calculated using observed event counts and accumulated person-time. Confidence intervals (CIs) were based on Poisson distributions. Results Among 126,249 eligible individuals, 7,448 (5.9%) received adjuvanted-RSVPreF3. RSV hospitalization rates per 100,000 person-years were 0.0 (95% CI: 0.0—58.0) for vaccinated individuals and 200.6 (165.6 – 240.8) for unvaccinated individuals, yielding an effectiveness of 100.0% (71.1—100.0). Incidences of other RSV-related outcomes were lower among vaccinated individuals. Conclusions Adjuvanted-RSVPreF3 is highly effective in preventing RSV hospitalization in individuals aged ≥60 years with COPD. Disease outcomes could be improved by incorporating RSV vaccination into routine COPD management.

In daily social interactions, joint decision making is not just about the outcomes we reach but also about how partners experience reaching those decisions together. Across three studies, we examine how perceived co-creation - the subjective sense of building understanding together, rather than simply agreeing - shapes interpersonal relationships. Compared to low co-creation and pre-existing agreement, high co-creation consistently enhanced trust, rapport, and willingness to collaborate, whether participants envisioned, remembered, or directly engaged in a joint decision. In Study 3, high co-creation dyads were nearly twice as likely to leave the laboratory together, suggesting effects that extend beyond self-report to observable behavior. Mediation analyses revealed that generalized shared reality - the sense that partners see the world similarly across domains - partially explained these relational benefits. These findings highlight the relational importance of how agreement is formed: the process of building shared understanding together may be as valuable as the agreement itself.

Sexuality and relationship education is an effective approach to supporting positive relationship outcomes. However, the extent to which emerging adults engage with internet-based sources for developing knowledge and skills related to sexual and relationship health remains unclear. This study explores the content on sex and relationships that emerging adults learn through internet-based sources and how they apply the content in their own lives. Qualitative interview data were collected from 31 emerging adults. Data were analyzed using qualitative inductive content analysis techniques. Findings reveal internet-based sources support emerging adults in: 1) Navigating Relationship Stages; 2) Enhancing Connection with a Partner; 3) Navigating Sexual Health with Partners; 4) Avoiding Unhealthy Relationships; 5) Enhancing Personal & Partner Sexual Satisfaction; and 6) Seeking Representation and a Sense of Belonging. Some emerging adults apply their internet-based learnings directly with a partner or by sharing with friends, while others report minimal application due to confidence challenges and communication barriers. Findings suggest implications for expanding learning opportunities through internet-based sources around sexual and relationship health.

Impact of early life exposure to active play and movement on health and wellbeing across the lifespan: A narrative review of RCTs from 2020-2025.

The da Vinci single-port reduced-port robotic distal gastrectomy (spRRDG) approach shows promise in enhancing surgical recovery while maintaining oncologic safety, but robust multicenter comparative data across diverse robotic platforms are lacking. We aimed to compare clinical outcomes between spRRDG and conventional RRDG (cRRDG) using Korean Laparoendoscopic Gastrointestinal Surgery Study-13 data. Clinicopathologic variables and perioperative outcomes concerning 820 patients who underwent curative RRDG with D1+ or D2 lymph node dissection (LND) (da Vinci spRRDG, n = 86; cRRDG, n = 734) were analyzed. We compared continuous variables using Student's t- or Wilcoxon rank-sum tests, as appropriate, and categorical variables using χ2 or Fisher's exact tests. Subgroup analyses were performed according to the extent of LND (D1+ vs. D2). Statistical significance was defined as p < 0.05. spRRDG involved a longer operative time than cRRDG (227.06 ± 6.19 vs. 183.58 ± 2.18 min, p < 0.0001) and fewer retrieved LNs (rLNs) (36.38 ± 1.53 vs. 46.52 ± 0.66, p < 0.0001), but showed superior enhanced recovery after surgery (ERAS)-related outcomes, including shorter hospital stay (4.06 ± 0.23 vs. 5.95 ± 0.13 days), and earlier gas passage (postoperative day [POD] 2.24 ± 0.10 vs. 3.08 ± 0.04) and soft diet initiation (POD 1.59 ± 0.14 vs. 2.89 ± 0.07; all p < 0.0001). In subgroup analyses, the number of rLNs was lower in D1+ spRRDG (34.09 ± 1.58 vs. 44.36 ± 0.72, p < 0.0001), but remained above the oncologic threshold (≥16 LNs). In D2 dissections, no significant difference was observed (45.71 ± 3.69 vs. 53.30 ± 1.39, p = 0.1030). Faster postoperative recovery in spRRDG persisted after adjustment. spRRDG exhibited lower rLNs than cRRDG but remained within an oncologically acceptable range. Comparable complication rates and significantly improved ERAS outcomes suggest spRRDG is safe and feasible; however, its clinical application should remain limited to early gastric cancer until robust evidence from prospective studies emerges.

To investigate whether initiation of glucagon-like peptide-1 (GLP-1) receptor agonists is associated with both reduced risks of incident alcohol, cannabis, cocaine, nicotine, opioid, and other substance use disorders (SUDs) in people with no history of SUDs (protocol 1) and with reduced risk of SUD related adverse clinical outcomes among people with a pre-existing SUD (protocol 2). Emulation of eight parallel, new user, active comparator target trials using electronic health records: seven trials for each incident SUD outcome (protocol 1) and one trial for adverse outcomes in people with pre-existing SUD (protocol 2). US Department of Veterans Affairs. From a base population of 606 434 US veterans with type 2 diabetes, participants were assigned to one of the two protocols and followed for up to three years. Trial 1 (primary trial) of protocol 1 included 524 817 initiators of GLP-1 receptor agonists (n=124 001) or sodium-glucose cotransporter-2 (SGLT-2) inhibitors (n=400 816). Protocol 2 included 81 617 initiators of GLP-1 receptor agonists (n=16 768) and SGLT-2 inhibitors (n=64 849). Incident outcomes were alcohol, cannabis, cocaine, nicotine, opioid, other SUDs, and a composite of these outcomes. Adverse outcomes among participants with pre-existing SUDs included SUD related emergency department visits, SUD related hospital admissions, and SUD related mortality, and drug overdose and suicidal ideation or attempt. Hazard ratios and net three year risk difference (NRD) per 1000 people were reported based on inverse probability weighted (standardised mortality ratio weighted) cause specific Cox survival models. Compared with initiation of SGLT-2 inhibitors, initiation of GLP-1 receptor agonists was associated with reduced risk of disorders related to alcohol use (hazard ratio 0.82 (95% confidence interval (CI) 0.78 to 0.85); NRD per 1000 people -5.57 (-6.61 to -4.53)), cannabis use (0.86 (0.81 to 0.90), NRD -2.25 (-3.00 to -1.50)), cocaine use (0.80 (0.72 to 0.88), NRD -0.97 (-1.37 to -0.57)), nicotine use (0.80 (0.74 to 0.87), NRD -1.64 (-2.19 to -1.09)), and opioid use (0.75 (0.67 to 0.85), NRD -0.86 (-1.19 to -0.52)), and other SUDs (0.87 (0.81 to 0.94), NRD -1.12 (-1.68 to -0.55)) and composite outcome of all incident SUDs (0.86 (0.83 to 0.88), NRD -6.61 (-7.95 to -5.26)). Among people with pre-existing SUDs, initiation of GLP-1 receptor agonists was associated with reduced risk of SUD related emergency department visits (0.69 (0.61 to 0.78), NRD -8.92 (-11.59 to -6.25)), SUD related hospital admissions (0.74 (0.65 to 0.85), NRD -6.23 (-8.73 to -3.74)), and SUD related mortality (0.50 (0.32 to 0.79), NRD -1.52 (-2.32 to -0.72)), and drug overdose (0.61 (0.42 to 0.88), NRD -1.49 (-2.43 to -0.55)) and suicidal ideation or attempt (0.75 (0.67 to 0.83), NRD -9.95 (-13.14 to -6.77)). Analyses of treatment adherence showed directionally consistent results with analyses of treatment initiation for both incident SUDs and adverse outcomes among participants with pre-existing SUDs. Use of GLP-1 receptor agonists was consistently associated with reduced risks of developing various incident SUDs, suggesting a broad preventive effect across multiple substance types. Use was also associated with reduced risks of adverse clinical outcomes in people with pre-existing SUDs. These observational data suggest a potential role for GLP-1 receptor agonists in both the prevention and the treatment of various SUDs, warranting further evaluation.