We review recent evidence on the effectiveness of non-antimicrobial adjunctive interventions on the recovery of adults diagnosed with community-acquired pneumonia (CAP). Respiratory physiotherapy, early mobilization or tailored exercises may decrease length of stay (LoS), dyspnoea and readmissions, but there is little evidence of an effect on mortality. Nutritional interventions may decrease readmissions and improve 30-day mortality, but there are few studies on the effect of individual micronutrient supplementation. Strategies to improve discharge communications and patient education may decrease readmission rates, improve treatment compliance and patient satisfaction, whereas the implementation of guidelines and care bundles may decrease 30-day mortality but does not appear to affect length of stay or 30-day readmissions. For adjunctive therapeutic interventions, there is evidence that for severe CAP, corticosteroids probably decrease short-term mortality and possibly longer term mortality and LoS. Antiplatelet agents and statins may decrease short-term mortality. A wide range of adjunctive interventions have been trialled aiming to improve patient outcomes with variable results and considerable heterogeneity between studies and populations. Future studies should involve engagement with patient groups to identify uncertainties and outcomes they consider important, utilize a core set of outcome measures, and assess long-term outcomes.

Tonic motor activation (TOMAC) is a non-pharmacological treatment for moderate-to-severe medication-refractory Restless Legs Syndrome (RLS). This bilateral wearable device applies high-frequency electrical stimulation to the peroneal nerve, engaging the therapeutic mechanism while minimizing sleep discomfort. A recent meta-analysis evaluated TOMAC in RLS using aggregate data, which precluded subgroup analyses. The aim of our systematic review and meta-analysis was to extract individual participant data to enable the evaluation of TOMAC as adjunctive treatment and monotherapy in RLS. This study was registered on PROSPERO (CRD420251005571). Web of Science, Scopus, and PubMed were searched, from inception to March 31, 2025, to identify studies evaluating TOMAC for RLS. Risk of bias (Cochrane Risk of Bias Tool and Downs and Black checklist) and quality of evidence (Oxford Centre for Evidence-Based Medicine 2011 guidelines) of eligible studies were assessed. Primary outcomes were changes in International RLS Study Group Rating Scale (IRLS) score for efficacy and in Medical Outcomes Study Sleep Problem Index II (MOS-II) score for sleep improvement. Main safety outcome was the incidence of device-related adverse events. Subgroup analyses evaluated TOMAC as adjunctive therapy and as monotherapy, as well as by age, RLS age-of-onset, sex, RLS severity, and stimulation amplitude. Five studies from the United States were extracted including three randomized-controlled-trials with 252 participants for analyses (69 monotherapy/183 adjunctive TOMAC therapy). Relative to sham, TOMAC significantly reduced IRLS score both as adjunctive therapy (MD: 3.39, p=0.0001) and monotherapy (mean difference [MD]: 3.80, p=0.0047), and significantly reduced MOS-II score both as adjunctive therapy (MD: 8.23, p=0.0006) and monotherapy (MD: 9.65, p=0.0236). There were no significant differences in IRLS MD based on age, age of RLS onset, sex, RLS severity, and stimulation amplitude. Mild discomfort was the only adverse event with higher prevalence for TOMAC than sham. These results suggest that TOMAC is a tolerable non-pharmacological treatment that reduces RLS symptoms and improves sleep, both as adjunctive therapy and as monotherapy.

Type 1 diabetes (T1D) arises from T cell-mediated destruction of pancreatic β-cells. However, genetic susceptibility alone cannot account for the increasing incidence and earlier onset of T1D, suggesting a substantial contribution from environmental factors, particularly the gut microbiota. This review synthesises recent human, multiomics and experimental evidence linking gut microbiota dysbiosis and microbial metabolites to β-cell autoimmunity. We focus on two converging mechanisms: (1) metabolite-driven disruption of intestinal barrier integrity and immune regulation, and (2) molecular mimicry between microbial peptides and islet autoantigens that activate autoreactive T cells. Across human cohorts and animal models, T1D-associated dysbiosis features reduced short-chain fatty acid (SCFA)-producing bacteria (e.g., Faecalibacterium, Roseburia) and increased pro-inflammatory taxa (e.g., Bacteroides, Streptococcus spp.). SCFA deficiency compromises Treg induction and gut barrier stability, facilitating antigen translocation. Several gut-derived peptides, such as the Parabacteroides distasonis hprt4-18 peptide, share sequence homology with insulin and other islet antigens, activate insulin-reactive T cells and accelerate diabetes in NOD mice, supporting a role for molecular mimicry. Interventional approaches including FMT, probiotics and prebiotics show promise but remain heterogeneous; their efficacy is highly strain-, timing- and context-dependent and translation from animal studies to humans is still limited. Therapeutically targeting the gut-islet axis, through modulation of microbiota, microbial metabolites or cross-reactive antigens, offers potential for disease prevention or adjunctive treatment. We highlight emerging biomarkers, including MAIT-cell phenotypes, antimicrobial peptide reactivity and microbiome-derived functional signatures, and emphasise the need for stratified clinical trial designs based on age, genotype and baseline microbiota composition to address current variability. The microbiota-metabolite-molecular mimicry axis provides a coherent mechanistic framework linking gut dysbiosis to T1D pathogenesis. Advancing these insights into clinical application will require rigorous, genotype-stratified human studies and standardised, transparent methodological approaches.

Evaluating probiotic monotherapy in Helicobacter pylori infection: A meta-analysis of randomized controlled trials with trial sequential analysis.

Yinhuapinggan granules enhance cefotaxime efficacy and alleviate inflammation in extended-spectrum beta-lactamase-producing Escherichia fergusonii infections.

Debilitating Symptom Complexes Attributed to Ticks (DSCATT) is a chronic, debilitating illness associated with tick bites in Australia. DSCATT is of unknown aetiology, can impact emotional well-being and has no recognised treatments. The development and piloting of a novel psychotherapeutic adjunctive intervention for DSCATT that aimed to increase daily functioning, improve quality of life and reduce the impact of symptoms in people with DSCATT. This is a single-site, intervention development and acceptability study. The intervention was developed iteratively according to a Human-Centred Design (HCD) approach and manualised across four phases, with input from end users at each phase: qualitative interviews, development of the intervention, piloting, and revising and refining the intervention. Acceptability of the prototype intervention was evaluated through thematic template analysis of exit interviews. Self-report measures were completed before and after intervention delivery. Following qualitative interviews with 13 participants (11 females and 2 males; aged 35-70 years), the intervention was informed by an Acceptance and Commitment Therapy (ACT) model interwoven with cognitive and behavioural strategies that targeted DSCATT-specific difficulties. The manualised intervention consisted of 12 1-h weekly individual sessions, delivered by psychologists via Telehealth (video call or telephone). Modules addressed the six core psychological processes of ACT, alongside DSCATT-specific modules addressing cognitive function, sleep and social relationships. Pilot testing and follow-up interviews were conducted in a separate sample of six individuals with DSCATT (all females; aged 46-71 years). All participants reported that the approach benefited their emotional well-being and overall health and would recommend it to others with DSCATT. This is a novel and theoretically driven psychotherapeutic intervention for DSCATT, co-produced with patient involvement across four phases. Pilot testing suggested the manualised intervention was feasible and acceptable, supporting future evaluation of feasibility and treatment outcomes with randomised controlled trials. This study involved the engagement and participation of individuals with DSCATT across four stages of the project, according to an HCD approach-the choice of the intervention; the development of the intervention; the piloting of the intervention, and the assessment of the intervention. The pilot study component of this project was prospectively registered on the Australian and New Zealand Clinical Trial Registry (ANZCTR); trial ID: ACTRN12621001032842.

Background: Cerebral palsy is caused mainly by upper motor neuron injury and is characterized by spasticity, muscle weakness, reduced selective motor control, and secondary musculoskeletal impairments. Functional electrical stimulation has been proposed to improve lower-limb strength and functional outcomes in children with cerebral palsy. Objective: To evaluate the impact of functional electrical stimulation on lower limb strength in children with cerebral palsy. Methodology: A narrative review was conducted using a custom search strategy in Google Scholar for studies published between 2020 and 2025. Randomized controlled trials and crossover studies examining functional electrical stimulation as an independent intervention or adjunct to conventional therapy were included. Eligible studies involved children with cerebral palsy who received lower limb functional electrical stimulation and reported outcomes on muscle strength, gait, postural stability, and gross motor function. Due to heterogeneity in study designs, outcome measures, and intervention protocols, a quantitative meta-analysis was not conducted. Study characteristics, including Gross Motor Function Classification System level, cerebral palsy subtype, stimulation parameters, and comparisons with orthoses or therapeutic garments, were extracted. Results: Functional electrical stimulation may improve lower-limb strength and functional performance, particularly when combined with conventional therapy. Gains in muscle strength, range of motion, Gross Motor Function Measure scores, and reduced energy expenditure were reported. Improvements in gait and postural stability were seen, especially in hemiplegic and diplegic cerebral palsy. Results varied across studies, and functional electrical stimulation did not consistently outperform conventional orthotic interventions. Evidence on sustained benefits after discontinuation remains limited. Conclusion: Functional electrical stimulation is a promising adjunct intervention for lower-limb weakness and functional limitations in children with cerebral palsy. Variability in protocols and outcomes highlights the need for further high-quality research to determine optimal application strategies and long-term benefits.

The abnormal dilatation of the spermatic veins, or varicocele, affects 14%-20% of teenagers, a proportion similar to that of adults, which peaks in late adolescence (15-19 years old). It is more common in metropolitan and developed areas, possibly due to increased access to medical attention and diagnostic resources. Treatment myths and beliefs about adolescent varicocele (AV) persist, making it a highly disputable condition to address. Concerns include whether surgical intervention is necessary for teenage varicocele and whether it enhances seminal parameters after varicocelectomy. Inadequate or delayed management may contribute to future infertility, imposing a significant public health and economic burden due to the costs associated with assisted reproductive technologies and psychosocial impacts. This minireview addresses common misconceptions about teenage varicocele and clarifies the clinical assessment, treatment, and long-term effects of varicocele in adolescents. This minireview examines and provides information on essential topics, including etiopathogenesis, evaluation, and groups of patients at risk of infertility, emphasizing the importance of testicular volume asymmetry (greater than 20%) and semen parameters in predicting future subfertility. Principles of management, indications, and choice of intervention (follow-up, surgical, and adjunctive treatment) are explored, along with treatment outcomes, to address this challenging situation. A balance between intervention and cautious follow-up is emphasized in the evidence-based suggestions for treatment strategies, which depend on the clinical examination, scrotal Doppler, and semen parameter findings. Based on testicular asymmetry, semen parameters, and symptomatology, management strategies range from conservative surveillance to surgical varicocelectomy and minimally invasive procedures like embolization. AV is a complex condition. If untreated, it can cause oligospermia, infertility, and irreparable testicular damage. Timely intervention, such as subinguinal microsurgical varicocelectomy, is essential after an early diagnosis is made by clinical examination supported by Doppler ultrasound and semen analysis for symptomatic, bilateral palpable, or asymptomatic unilateral varicoceles with testicular asymmetry greater than 20% and abnormal semen parameters in Tanner V boys. Long-term data indicate that patients who have had surgery have better testicular growth and semen characteristics; nevertheless, the effect on future fertility is still being studied, indicating the need for individualized treatment plans. Testicular health, with preserved reproductive potential, is maintained through proactive evaluation and care. AV can affect quality of life in addition to causing physical discomfort; worries about fertility, body image, and social stigma call for comprehensive, patient-centered care.

BACKGROUND Schizophrenia presents complex challenges in older patients due to cognitive and social decline. Existing drug treatments offer limited benefits and pose risks, while aerobic exercise shows promise as a noninvasive intervention whose impact remains underexplored. AIM To investigate the effects of aerobic exercise on cognitive and social function in older patients with schizophrenia. METHODS A retrospective study was conducted in 158 older patients with schizophrenia treated at The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College (June 2023 and December 2024). The patients were divided into an observation group (n = 86), which received 3 months of aerobic rehabilitation alongside routine treatment, and a control group (n = 72), which received routine treatment alone. Cognitive function was assessed using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery, social function using the Inpatient Psychiatric Rehabilitation Outcome Scale (IPROS), and psychotic symptoms using the Positive and Negative Syndrome Scale. RESULTS Post-treatment, Positive and Negative Syndrome Scale total scores were lower in the observation group than in the controls (P < 0.001), with significant improvements in positive, negative, and general symptoms. Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery domain scores were improved in processing speed, working memory, verbal/visual learning, and executive function (all P < 0.05). IPROS total scores were decreased (P < 0.001), indicating better social functioning. Longer exercise duration correlated with greater cognitive gains and lower social function deficits. Body mass index declined (P < 0.001), and adverse events were mild and transient (9.3%). Multivariate linear regression confirmed that aerobic exercise was independently associated with a significant reduction in IPROS scores (Adjusted β = -4.57, 95% confidence intervals: -6.08 to -3.05, P < 0.001). CONCLUSION Aerobic exercise effectively improves cognitive function, social function, and psychotic symptoms in older patients with schizophrenia, is safe, and serves as a valuable adjunctive intervention.

Photodynamic therapy (PDT) is an interesting approach for the treatment of various otorhinolaryngological diseases, primarily when conventional therapeutic options are restricted by antibiotic resistance, biofilms, or high relapse rates. This systematic review critically analyzes 20 open-access clinical, microbiological, and experimental studies with PDT reported between 1992 and 2025. Initial clinical pilot data suggested a well-tolerated agent that improved symptoms and disrupted biofilm. In chronic and recurrent tonsillitis, existing evidence also indicates a decrease in microbial load, clinical improvement, and (in some cases) reduced infection over time. Case-based studies provide additional evidence for PDT as a non-invasive therapeutic option in pharyngotonsillitis. PDT decreases lesion size and delays recurrence in recurrent respiratory papillomatosis when applied adjunctively to surgery. These indicate potential utility for persistent viral conditions, including HPV-related diseases. Further studies on PDT indicate the reduction of SARS-CoV-2 colonization during the COVID-19 pandemic. PDT nasal application decreases viral shedding. New technologies, such as better photosensitizers, nanoparticle carrier delivery systems and improved light-delivery devices, have broadened the application of PDT in anatomically complex areas relating to ears, nose and throat (ENT). The above have improved treatment selectivity, reduced photo toxicity and increased the antimicrobial effect. Despite these promising results, the available evidence is restricted by small sample size, heterogeneity of the protocols and inconsistency of outcome measures. Larger, uniform clinical trials are required to define the optimal treatment features and their therapeutic value. Due to its antiviral, antimicrobial, and antibiofilm potential in otorhinolaryngology, there may well be opportunities to further develop PDT field as a beneficial adjunctive treatment.

Hydroxychloroquine (HCQ) has been identified as an interesting treatment option in adult IgA nephropathy. HCQ targets the active toll-like receptors in IgA nephropathy. The purpose of this study was to explore the effects and potential benefits of HCQ for childhood-onset IgA nephropathy (cIgAN). We conducted a retrospective multicenter cohort study including 16 children with biopsy-proven cIgAN treated with HCQ in tertiary pediatric nephrology centers in Canada and France. HCQ was prescribed as an adjunctive therapy for persistent proteinuria despite standard-of-care treatment and/or with a steroid-sparing intent. Clinical and histological data were collected at baseline, and urine protein-to-creatinine ratios (UPCR) and estimated glomerular filtration rates (eGFR) were documented at HCQ initiation, 3, 6, 9, and 12months of follow-up. Iterative biopsies before and after the introduction of HCQ (n = 8) were compared. Steroid exposure was assessed in both groups, and safety monitoring data for HCQ therapy were documented. Median age was 12.74 [11.33-14.07] years, with 37.5% male participants. Most (15/16, 93.8%) participants received steroid therapy, and all (16/16, 100%) were treated with renin-angiotensin-aldosterone system blockers. HCQ was initiated within a median time of 519 [249-1016.5] days from initial diagnosis. UPCR at 3, 6, 9, and 12months after HCQ initiation significantly decreased, both in absolute and relative metrics. A decrease of 50% was noted at 12months of follow-up. eGFR remained stable over the follow-up period. Follow-up biopsies in the HCQ-treated group showed stability or improvement of the Oxford score. No complications of HCQ were documented. In this first pediatric cohort reporting on real-life experience with HCQ, HCQ use was associated with a sustained reduction in proteinuria and stable kidney function in children with difficult-to-control cIgAN, with an excellent safety profile. Although causality cannot be inferred due to the observational design and concomitant therapies, these findings support further prospective evaluation of HCQ as a safe adjunctive treatment in selected cases of cIgAN.

ABSTRACT Introduction The aim of this study was to obtain the views of oral surgeons (OS) and oral and maxillofacial surgeons (OMFS) in the United Kingdom on labial frenectomies regarding their indication, timing and preferred surgical techniques. Materials and Methods This was a cross‐sectional, questionnaire‐based study. A 20‐item online questionnaire was sent to both OS and OMFS by distribution through the British Association of Oral Surgeons (BAOS) and British Association of Oral and Maxillofacial Surgeons (BAOMS). It included demographics of respondents, diagnostic methods for aberrant labial frenums as well as their preferred timing, surgical techniques, and instruments for labial frenectomies. Descriptive statistics were used to summarise the study sample characteristics and questionnaire responses. Results One hundred and thirty‐nine OS and 41 OMFS responded to the questionnaire with a response rate of 18.3% and 3.4% respectively. 84.4% of OS and 68.3% of OMFS believed that a low and hypertrophic frenum can be an important aetiological factor in the development of a median diastema. If a labial frenectomy was to be carried out as part of orthodontic treatment, the preferred timing among OS was just before closure of the median diastema (37.0%) while the majority of OMFS felt that timing did not matter (31.7%). More than half (55.7%) of the respondents used the Archer and Kruger classical technique exclusively for frenectomies, and a large majority (94.3%) preferred the use of a scalpel over electrosurgery or lasers. Conclusions Considerable variation was found in the diagnostic approach to aberrant frenums and preferred timing of frenectomies among OS and OMFS; however, some consensus was noted in their choice of surgical technique and instrument. Further studies are required to provide more insight on the appropriate indication and timing for labial frenectomies as well as the need for adjunctive orthodontic treatment for the closure of median diastemas following frenectomy procedures.

To explore and compare veteran and clinicians perspectives on veterans' strengths and ways strengths are used in care to promote engagement and recovery. We recruited veteran-clinician dyads from a rural Veterans Affairs Medical Center for qualitative interviews with veterans (n = 15) who had initiated a trauma-focused evidence-based psychotherapy (TF-EBP) with the dyad clinician (n = 8; some were interviewed about two veterans). They were interviewed about four types of veterans' strengths: coping skills, external supports, internal assets, and values/sources of meaning. We summarized and compared within-dyad responses. Both veterans and clinicians reported discussing strengths at least once, but they were often underutilized. Psychotherapy coping skills, internal assets, and values/sources of meaning were most commonly integrated into TF-EBPs. External supports and complementary coping skills (e.g., yoga, walking) were infrequently integrated. Differences were observed between veteran and clinician perspectives: (a) some veterans identified relationships as supportive that clinicians believed worsened TF-EBP engagement and posttraumatic stress disorder recovery, and (b) clinicians noted many internal assets that veterans did not see in themselves. Veterans bring many strengths to posttraumatic stress disorder therapy, yet these are often underused. There is a need to develop resources and adjunctive interventions for integrating strengths into TF-EBP delivery and to implement family involvement in care. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

This study aims to evaluate the efficacy and safety of adjunctive Belimumab therapy compared to standard therapy alone in patients with lupus nephritis (LN) within a real-world clinical setting. This single-center, retrospective observational study included patients with LN from January 2020 to December 2023. A total of 64 patients received belimumab as an adjunct to standard therapy. Patients were stratified into induction and maintenance treatment groups by renal remission status at belimumab initiation. A matched control group (n = 64) with comparable baseline characteristics was established. Clinical efficacy and safety were assessed by disease activity, glucocorticoid tapering, renal and extra-renal relapse rates, and treatment-emergent adverse events. During the induction phase in patients with LN, belimumab did not significantly enhance remission rates within the first six months. However, during maintenance therapy, belimumab effectively reduced disease activity, facilitated glucocorticoid tapering, and significantly decreased renal relapse rates. Furthermore, belimumab increased the cumulative rate of complete renal remission, improved lupus low disease activity state achievement, and slowed the decline in estimated glomerular filtration rate, with a more pronounced benefit observed in adolescents. The overall incidence of adverse events was comparable between the belimumab and control groups, whereas treatment-related comorbidities were reduced in the belimumab group. Belimumab demonstrates a favorable safety profile and contributes to the long-term management of LN, particularly in adolescents. These findings support its potential role as an effective adjunctive therapy for LN. Key Points • Belimumab significantly reduces renal relapse, facilitates glucocorticoid tapering, and helps preserve long-term renal function in lupus nephritis maintenance therapy. • Adolescent patients with lupus nephritis represent a key subgroup that derives pronounced therapeutic advantages from adjunctive belimumab treatment. • Belimumab is associated with fewer treatment-related comorbidities compared to standard therapy alone, supporting its safety in real-world use.

Background/Objectives: Pyoderma gangrenosum (PG) is a rapidly progressive, ulcerating condition that can cause large, painful lesions when uncontrolled. There is currently no standard of care treatment for severe PG ulcers refractory to systemic treatment. The present study aims to characterize the outcomes of placental allografts in treating severe PG lesions. Methods: A single institution retrospective chart review was conducted at the University of South Florida affiliated sites examining PG patients that received placental allograft treatment. Results: The review returned five patients with clinically diagnosed or biopsy-proven PG treated with placental allograft. In all five patients, application of placental allograft resulted in varying degrees of short-term (<1 month) improvement. Near-complete resolution was observed in one patient. Out of the 20 total allografts placed between the 5 patients, only one had an adverse event of infection within one week of placement. Grafts were otherwise very well tolerated by all patients. Conclusions: Placental allografts show promising adjunctive therapeutic potential for severe PG lesions with preliminary findings showing good viability and safety profiles. Future prospective controlled studies should be performed to further examine the viability of this adjunctive treatment in this disease.

Adverse Events and Intraocular Pressure-Lowering Effect of Topical 0.5% Apraclonidine in Childhood Glaucoma: A Retrospective Single-Center Study.

The role of 5-HT3 receptors in schizophrenia and associated depressive and addictive comorbidities.

Debilitating Symptom Complexes Attributed to Ticks (DSCATT) is a new term for an unexplained Australian syndrome-people who suffer from a chronic, multifaceted and debilitating illness, characteristically attributed to tick bites, but in a country without endemic Lyme disease. Despite the profound morbidity of DSCATT, no single causative agent has been identified and there are no recognised treatments for the illness at present. An increasing body of evidence shows psychological therapies such as Acceptance and Commitment Therapy (ACT) can be effective in reducing symptom-related disability and improving quality of life for other unexplained syndromes. Here we present a study protocol to assess the feasibility of an ACT-informed intervention for patients suffering from DSCATT, to be used adjunctively to their pre-existing healthcare. The study aims to assess the acceptability, practicality and demand for the treatment. Additionally, we will examine the effects of therapy on participants' health and well-being, its safety, potential mediators of response to therapy and its preliminary cost-effectiveness. We will assess the feasibility of a 32-week, randomised, waitlist-controlled, parallel convergent mixed-methods pilot trial for DSCATT. Participants will be randomised in a 1:1 ratio to receive either 16 sessions of ACT-informed therapy adjunctive to their pre-existing healthcare, delivered one-to-one with a trial therapist within a 20-week period or be assigned to the waitlist control group where they will continue their treatments as usual. We will collect quantitative and qualitative data to address study aims, with retention rate being the primary feasibility outcome. The study has ethical approval from Austin Health Human Research Ethics Committee (HREC). The outcomes will be published in peer-reviewed journals. Data from participants who have given extended consent will be available for other HREC-approved studies. ACTRN12623000372684, prospectively registered 13 April 2023, URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=385579&isReview=true; the last participant is expected to complete in November 2026.

Seltorexant, a selective orexin-2 receptor (OX2R) antagonist, has demonstrated antidepressant effects in major depressive disorder (MDD), particularly among patients with higher baseline insomnia symptoms. To investigate flexibly dosed seltorexant vs flexibly dosed quetiapine extended release (quetiapine-XR) as adjunctive treatment to a selective serotonin (SSRI) or serotonin-norepinephrine (SNRI) reuptake inhibitor. Outpatient. Randomized, active-controlled, multicenter, exploratory phase 2 study with screening (≤4weeks), double-blind treatment (24weeks), and post-treatment follow-up (2weeks) phases. Patients with MDD and inadequate response to 1-3 SSRIs/SNRIs, including an ongoing SSRI/SNRI, in the current depressive episode. Flexibly dosed seltorexant (20 or 40mg) or quetiapine-XR (150 or 300mg, with 2-day initial dosing of 50mg) once daily as adjunctive therapy to an SSRI/SNRI. Randomization (1:1) was stratified by baseline Insomnia Severity Index total score (≥15 vs <15). Safety, tolerability, and preliminary efficacy were evaluated. Primary efficacy endpoint was time to all-cause study drug discontinuation. Secondary efficacy endpoints included change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Subgroup analyses included MADRS change by mode dose (MD; most frequent daily dose received by a patient during the study). Safety and tolerability also were assessed. Time to all-cause discontinuation (estimated 25th percentile [80% CI]: seltorexant, 62 [38, 83] days vs quetiapine-XR, 42 [35, 61] days; hazard ratio [80% CI]: 0.83 [0.6, 1.2]) and all-cause discontinuation (seltorexant, 41.2% vs quetiapine-XR, 47.1%; 2-sided p=.5355) did not differ significantly between treatment groups. For the seltorexant 20-mg MD group, MADRS total scores consistently improved over time and reductions were numerically greater at Weeks 18 and 24 versus the seltorexant 40-mg MD and the combined quetiapine-XR groups, and patients with higher baseline insomnia symptoms had greater improvement in MADRS total score, consistent with prior studies showing efficacy at 20 but not 40mg (Savitz, et al. 2019; Mesens, et al. 2025). Treatment-emergent adverse event rates were 65.4% for seltorexant and 80.8% for quetiapine-XR. Results support the favorable tolerability and preliminary efficacy of seltorexant 20mg daily as adjunctive treatment in patients with MDD, especially those with insomnia symptoms, and suggest potential approaches to differentiate seltorexant from quetiapine-XR in future adequately powered studies. Trial registration. Clinicaltrials.gov identifier: NCT03321526.

Role of labor induction requiring cervical preparation for full-term, low-risk pregnant patients is under active investigation. The objective of this study was to describe nationwide temporal trends, characteristics, and outcomes associated with labor induction requiring cervical preparation at full-term gestation for low-risk pregnant patients in the United States. This cross-sectional study queried the Agency for Healthcare Research and Quality mechanism's Healthcare Cost and Utilization Project National Inpatient Sample. Study population included 5,003,348 hospital deliveries at 39-406/7weeks' gestation for singleton, cephalic low-risk pregnancy from 2018 to 2022, excluding historically known presumed pre-labor pregnancy risk factors. Exposure was labor induction status, defined as the performance of cervical preparation (ripening or mechanical dilation), with or without adjunctive intervention (artificial rupture of membranes or oxytocin administration). Main outcome measures were set as cesarean delivery as the primary outcome; induction failure, chorioamnionitis, umbilical cord prolapse, in-labor uterine rupture, postpartum hemorrhage, severe maternal morbidity and mortality as the secondary outcomes, assessed with multivariable generalized linear model. A total of 618,785 (12.4%) deliveries had labor induction requiring cervical preparation. The rate increased from 8.8 to 14.4% between QT1/2018-QT2/2020 (P-trend < .001), at which the rate started gradually decreasing when the COVID-19 pandemic occurred (14.4% at QT2/2020 to 13.4% at QT4/2022, P-trend = .04). The majority of cervical preparation was ripening alone (69.9%), followed by mechanical dilation alone (20.7%) and both ripening and mechanical dilation (9.4%). During the 5-year study period, cervical preparation with mechanical dilation alone (14.4% to 26.9%) and both ripening and mechanical dilation (4.6% to 11.4%) increased (both, P-trend < .001); adjunctive use of both oxytocin and artificial rupture of membranes (18.7% to 27.0%) and oxytocin alone (15.0% to 18.8%) increased while artificial rupture of membranes alone decreased (29.5% to 23.0%) (all, P-trend < .001). When compared to 4,384,563 deliveries without labor induction cervical preparation, induction was associated with cesarean delivery (17.1% vs 9.2%, adjusted-incidence rate ratio [aIR] 1.75, 95% confidence interval [CI] 1.74-1.76), chorioamnionitis (3.2% vs 1.9%, aIR 1.67, 95%CI 1.64-1.69), umbilical cord prolapse (0.2% vs 0.1%, aIR 1.67, 95%CI 1.58-1.77), in-labor uterine rupture (21.8 vs 7.8 per 100,000, aIR 2.66, 95%CI 2.17-3.25), postpartum hemorrhage (5.7% vs 3.9%, aIR 1.42, 95%CI 1.40-1.44), severe maternal morbidity (0.4% vs 0.2%, aIR 1.61, 95%CI 1.54-1.68), and maternal mortality (4.8 vs 0.7 per 100,000, aIR 7.34, 95%CI 4.37-12.33). In conclusion, this nationwide cross-sectional assessment suggests the increasing trend of full-term labor induction for study-defined low-risk pregnancy may have stopped during the COVID-19 pandemic in the United States. The observed association with cesarean delivery and adverse outcomes related to labor induction requiring cervical preparation warrant further investigation.