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Spermidine and melatonin ameliorate heat stress-induced decline in sheep semen quality.

Heat stress impairs reproductive performance in sheep through endocrine disruption and oxidative stress. This study evaluated the protective effects of spermidine (SPD) and melatonin (MT) supplementation on semen quality in Dorper rams during summer. Twenty-four rams were randomly assigned to a control group, an SPD group (5&#x202f;mg/kg, dietary supplementation), or an MT group (60&#x202f;mg, subcutaneous implantation) and treated for 60 days. The temperature-humidity index (THI) was monitored throughout the experimental period. Compared with the control group, MT significantly reduced serum cortisol concentration on day 30 (P&#x202f;<&#x202f;0.05), whereas no significant differences were observed at the other sampling time points. Serum testosterone, spermidine, and melatonin concentrations remained unchanged throughout the study (P&#x202f;>&#x202f;0.05). SPD supplementation significantly increased ejaculate volume on day 35 and sperm motility on day 42 (P&#x202f;<&#x202f;0.05), whereas MT did not significantly affect these parameters. Neither treatment reduced the overall sperm abnormality rate. However, both SPD and MT significantly decreased the proportion of acephalic and decaudated sperm on day 56 (P&#x202f;<&#x202f;0.05). Neither treatment significantly affected pregnancy rate, delivery rate, or the expression of PMFBP1 and SUN5 proteins in semen (P&#x202f;>&#x202f;0.05). Regarding oxidative stress, MT significantly downregulated CAT protein expression (P&#x202f;<&#x202f;0.05), whereas SPD significantly reduced MDA content and SOD1 protein expression (P&#x202f;<&#x202f;0.05); MT showed similar but non-significant trends for these two markers (P&#x202f;>&#x202f;0.05). Collectively, these findings demonstrate that SPD and MT exert distinct protective effects against heat stress, with SPD improving selected semen quality traits and both treatments reducing sperm head-tail separation, although these benefits did not translate into improved reproductive performance.

Animals

First evaluation of a novel recombinant eCG molecule in ewes reveals a discrepancy between ovulatory response and pregnancy outcome.

This study evaluated the reproductive performance and clinical safety of a novel recombinant eCG (r-eCG) in ewes. Two weeks prior to study onset (Day 0: intravaginal progesterone device insertion), 45 ewes were randomly assigned to negative control (NC; no eCG; n&#x202f;=&#x202f;10), positive control (PC; 400IU commercial non-recombinant eCG; n&#x202f;=&#x202f;20), or treatment group (T; 400IU r-eCG; n&#x202f;=&#x202f;15). Ewes were inseminated with fresh-diluted semen (200&#x202f;&#xd7;&#x202f;106 sperm). Ultrasonography assessed follicle count/diameter (days 11, 13), ovulation (day 13), corpus luteum (CL) number/characteristics (day 20), and pregnancy (day 44). Serum progesterone was measured on day 20; Group T underwent clinical/hematological evaluations (days 0, 20, and 44). Estrus signs were more frequent (P&#x202f;<&#x202f;0.01) in T (100%) than NC (50%), while PC (85%) did not differ. Ovulation rates were similar between T (93%) and PC (95%), but higher than NC (50%; P&#x202f;<&#x202f;0.05). On day 13, largest follicle diameter did not differ (P&#x202f;>&#x202f;0.05) among groups; however, fewer follicles > 2&#x202f;mm occurred in PC than NC and T (P&#x202f;<&#x202f;0.05). CL number was higher in T than PC (2.0&#x202f;&#xb1;&#x202f;0.3 vs. 1.0&#x202f;&#xb1;&#x202f;0.0, P&#x202f;<&#x202f;0.01), while NC did not differ (1.0&#x202f;&#xb1;&#x202f;0.25). Conversely, pregnancy rate was higher (P&#x202f;<&#x202f;0.05) in PC (70%) than T (28.6%) and NC (20%). Among ovulated ewes, progesterone concentration and progesterone/CL ratio did not differ among groups (P&#x202f;=&#x202f;0.92 and P&#x202f;=&#x202f;0.08, respectively). No relevant r-eCG-related clinical or hematological alterations occurred. In conclusion, 400IU r-eCG effectively induces estrus and ovulation without adverse effects; however, the discrepancy between ovulatory response and pregnancy rate underscores the need for further study refinement to improve fertility.

Animals

Safety and efficacy of recombinant botulinum toxin type A (Eveotox&#xae;) in patients with post-stroke upper limb spasticity: Results from a Phase Ib/II clinical trial.

Upper limb spasticity is a common and disabling complication of stroke. Botulinum toxin type A (BoNT-A) is widely used for focal spasticity treatment, but naturally derived products may present limitations related to immunogenicity and manufacturing variability. Recombinant botulinum toxin type A, produced by genetic engineering without complexing proteins, may provide improved product consistency. This Ib/II study evaluated the safety, tolerability, and preliminary efficacy of recombinant botulinum toxin type A in adults with post-stroke upper limb spasticity. This multicenter, seamless Ib/II clinical study included an open-label dose-escalation Ib phase and a randomized, double-blind, placebo-controlled II phase. Adult patients with post-stroke upper limb spasticity received a single intramuscular injection of recombinant botulinum toxin type A or placebo. The primary endpoint in Phase II was the change from baseline in the Modified Ashworth Scale (MAS) score of the primary target muscle group at Week 4. Secondary endpoints included MAS and Tardieu scale changes in individual muscle groups, Disability Assessment Scale (DAS), Physician's Global Assessment (PGA), and immunogenicity. The Ib phase showed improvements in MAS, DAS, and PGA, indicating an early efficacy signal. In Phase II, recombinant botulinum toxin type A produced a significant reduction in MAS score of the primary target muscle group at Week 4 compared with placebo, with effects sustained through Week 12. At Week 4, the PGA score in the Eveotox&#xae; group showed a statistically significant improvement compared with the placebo group. While MAS and PGA scores showed significant improvement, DAS functional scores did not differ statistically from the placebo group at week 4. The treatment was generally well tolerated, and low incidence of antibodies were observed. Recombinant botulinum toxin type A was safe and effective in reducing post-stroke upper limb spasticity after a single administration. These results support further Phase III clinical evaluation.

Humans

Efficacy of afoxolaner (NexGard&#xae;) for the treatment of myiasis caused by the zoonotic tumbu fly, Cordylobia anthropophaga, in domestic dogs under field conditions.

Cordylobia anthropophaga is a major cause of furuncular myiasis in dogs and humans in sub-Saharan Africa, yet evidence for pharmacological control remains limited. Current management relies mainly on mechanical larval removal, and no controlled studies have assessed the efficacy of modern antiparasitic agents. This study evaluated the curative and preventive efficacy of a single dose of afoxolaner (NexGard&#xae;) in dogs with naturally acquired C. anthropophaga infestation under field conditions and explored a possible indirect protective effect in puppies after maternal treatment. A randomized, blinded, negative-controlled field study was conducted in Samburu County, Kenya, and included 104 naturally infested dogs allocated to a treated group (n&#x202f;=&#x202f;53) or an untreated control group (n&#x202f;=&#x202f;51). Clinical evaluations were performed on Days 0, 15 (&#xb1;2), 30 (&#xb1;2), and 45 (&#xb1;2). Efficacy was assessed based on the presence of active nodules and clinical scores. Additional observational data were collected from puppies born to or nursing from treated bitches. Compared to the control group, parasiticide efficacy was 94% on Day 15 and 100% on Day 30. The number of parasite-free dogs reached 86.3% on Day 15, 100% on Day 30, and 95.3% on Day 45. Treated dogs showed a significant clinical improvement from the first post-treatment assessment, whereas infestation persisted in controls (nodules: OR = 0.003, 95% CI 0.001-0.017; skin lesions: OR = 0.010, 95% CI 0.002-0.051; lymph node: OR = 0.013, 95% CI 0.002-0.074; body condition: OR = 0.073, 95% CI 0.027-0.195; all p&#x202f;<&#x202f;.001), with large effect sizes at the final visit for all outcomes (r&#x202f;=&#x202f;0.521-0.793). No C. anthropophaga infestations were detected in examined puppies from treated dams, including puppies exposed during pregnancy or lactation, up to 4 weeks after birth and up to 11 weeks of age, respectively. Afoxolaner appears effective to control canine cordylobiosis and may offer indirect protection to puppies, warranting further investigation.

Animals

Experimental validation of an AI-driven digital healthcare platform for oral health behavior and plaque assessment among vietnamese children.

BACKGROUND: Oral health among children in developing countries, including Vietnam, remains a significant public health concern. Innovative approaches leveraging artificial intelligence AI-based digital health platforms may offer effective strategies for managing dental plaque and promoting better oral hygiene behaviors among school-aged children. This study aimed to evaluate the effectiveness of an AI-driven oral healthcare platform (Denti-i Vietnam) in improving oral hygiene and behavioral outcomes among Vietnamese primary school students. METHODS: A total of 204 primary school students aged 8-10&#xa0;years in Hanoi, Vietnam, participated in this experimental study. Participants were randomly assigned to an intervention group (n&#xa0;=&#xa0;107), which used the AI-driven oral healthcare platform, and a comparison group (n&#xa0;=&#xa0;97), which received traditional oral health education via pamphlets. Oral health behaviors, dental plaque levels (Simplified Oral Hygiene Index; OHI-S), and caries indices (dft/DMFT) were assessed at baseline and after the intervention period. RESULTS: The intervention group demonstrated a significant reduction in the OHI-S score compared to baseline (2.49&#xa0;&#xb1;&#xa0;0.60 to 1.70&#xa0;&#xb1;&#xa0;0.76, p&#xa0;<&#xa0;0.001), particularly in the debris component, indicating enhanced plaque control. Notable improvements were also observed in oral hygiene behaviors, including increased frequency of toothbrushing before and after breakfast (p&#xa0;<&#xa0;0.01) and more frequent parental assistance during brushing (p&#xa0;=&#xa0;0.03). Furthermore, parental awareness of dental caries significantly increased in the intervention group (p&#xa0;=&#xa0;0.001). CONCLUSIONS: The AI-driven oral healthcare platform significantly improved both oral hygiene behaviors and plaque control among Vietnamese primary school children. These findings suggest that AI-driven digital health tools can serve as practical and scalable solutions for promoting oral health in developing countries.

Humans

High-dose radiotherapy in patients with high-risk prostate cancers treated with long-term androgen deprivation therapy (GETUG AFU 18): a randomised, phase 3 trial.

BACKGROUND: For patients with high-risk prostate cancer, the role of dose-escalated radiotherapy in combination with long-term androgen deprivation treatment (ADT) is controversial, without any demonstrated benefit on cancer-specific or overall survival. We aimed to evaluate the effect of a 10 Gy dose increase, from 70 Gy to 80 Gy, on progression-free survival in men with high-risk prostate cancer. METHODS: In this multicentre, open-label, randomised, phase 3 trial, we enrolled patients with high-risk prostate cancer, defined as prostate-specific antigen of 20 ng/mL or more, Gleason score of at least 8, or clinical stage T3-T4, from 25 centres in France. Participants were randomly assigned (1:1) by minimisation, stratified by centre and previous pelvic lymph node dissection, to receive prostate-targeted dose-escalated external beam radiotherapy (80 Gy; 2 Gy per fraction for 8 weeks) or standard-dose external beam radiotherapy (70 Gy; 2 Gy per fraction for 7 weeks), combined with long-term ADT. Neither the participants nor the investigators were masked to the allocated treatment. The primary endpoint was 5-year progression-free survival defined as the time from randomisation to first biochemical (defined as prostate-specific antigen >nadir plus 2 ng/mL) or clinical (ie, local, regional, or metastatic) disease progression, analysed in the intention-to-treat population, with 197 events required. 5-year progression-free survival was the prespecified endpoint, and 10-year progression-free survival was additionally reported (post hoc) in view of the low number of events at 5 years. The trial is registered at ClinicalTrials.gov, NCT00967863, and is complete. FINDINGS: Between April 6, 2009, and Jan 24, 2013, 505 patients with high-risk prostate cancer were enrolled; 250 were assigned to receive dose-escalated radiotherapy (80 Gy) and 255 to receive standard dose radiotherapy (70 Gy). All participants were male and ethnicity data were not collected. At a median follow-up of 9&#xb7;5 years (IQR 8&#xb7;5-10&#xb7;3), 5-year progression-free survival was 91&#xb7;4% (95% CI 87&#xb7;0-94&#xb7;4) in the dose-escalation group versus 88&#xb7;1% (83&#xb7;2-91&#xb7;6) in the control group, and 10-year progression-free survival was 83&#xb7;6% (77&#xb7;8-88&#xb7;0) versus 72&#xb7;2% (65&#xb7;3-78&#xb7;0; stratified HR 0&#xb7;56, 95% CI 0&#xb7;40-0&#xb7;78, p<0&#xb7;0001). Grade 3 or worse adverse events assessed at 6 months (acute toxicity) were observed in 60 (24%) of patients in the dose-escalation group and 62 (25%) in the control group. The most frequent grade 3 or worse adverse events were sexual disorders (28 [11%] in the dose-escalation group vs 20 [8%] in the control group) and bladder or urethra disorders (12 [5%] vs 19 [8%]). Adverse events assessed at 5 years (late toxicity) occurred in 118 (70%) of 168 in the dose-escalation group and 122 (73%) of 168 in the control group; grade 3 or worse late toxicities occurred in 19 (8%) participants in the dose-escalated radiotherapy group versus 17 (7%) participants in the control group. The most common late grade 3 adverse event was bladder or urethra disorders (seven [4%] vs three [2%], respectively). Serious adverse events occurred in nine (4%) patients in the dose escalation group and nine (4%) in the control group; none were considered to be treatment related. There were no treatment-related deaths. INTERPRETATION: For patients with high-risk prostate cancer, radiotherapy at a total dose of 80 Gy, in combination with long-term ADT, improved progression-free survival and could be a potential option in this situation. However, given the low number of events, further research is needed to consolidate and confirm the benefit in dose-escalation in prostate cancer-specific survival and overall survival. FUNDING: French National Cancer Institute and AstraZeneca.

Aged

Adjuvant alectinib versus chemotherapy in resected ALK-positive non-small-cell lung cancer (ALINA): health-related quality-of-life and safety outcomes from a randomised, open-label, phase 3 trial.

BACKGROUND: For patients with resected, ALK-positive non-small-cell lung cancer (NSCLC), adjuvant alectinib significantly improved disease-free survival versus platinum-based chemotherapy in the global, phase 3, open-label, randomised ALINA trial. We report safety and health-related quality-of-life (HRQoL) outcomes from the ALINA trial. METHODS: Eligible patients aged 18 years or older with resected, ALK-positive, stage IB (&#x2265;4 cm)-IIIA NSCLC (per the American Joint Committee on Cancer and the Union for International Cancer Control Cancer Staging Manual 7th edition) and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) via a block-stratified randomisation method to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy for four 3-week cycles. Randomisation was stratified according to disease stage and race. The primary endpoint, previously reported, was disease-free survival. Safety was a secondary endpoint and HRQoL was an exploratory endpoint. Safety was assessed by the investigator as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5&#xb7;0 until 28 days after the last alectinib dose or chemotherapy cycle. HRQoL was assessed via the Short-Form 36-item health survey version 2 (SF-36v2) questionnaire at baseline, every 3 weeks to week 12, then every 12 weeks until disease recurrence, consent withdrawal, death, or week 96. Norm-based scoring was applied; clinically meaningful changes were defined using the SF-36v2 manual. Safety was assessed in the safety-evaluable population and HRQoL in the intention-to-treat population. This study is registered with ClinicalTrials.gov (NCT03456076) and is ongoing. FINDINGS: Between Aug 16, 2018, and Dec 8, 2021, 257 patients were assigned to receive alectinib (n=130) or chemotherapy (n=127). 123 (48%) patients were male and 134 (52%) were female; 143 (56%) were Asian. The safety-evaluable population comprised 128 patients who received alectinib and 120 patients who received chemotherapy; median duration of safety follow-up was 24&#xb7;8 months (IQR 22&#xb7;0-24&#xb7;9) in the alectinib group and 3&#xb7;7 months (IQR 3&#xb7;7-3&#xb7;8) in the chemotherapy group. The safety of adjuvant alectinib was generally consistent with its known profile. The most common grade 3-4 adverse events were blood creatine phosphokinase increased (eight [6%] of 128), alanine aminotransferase increased (two [2%] of 128), and blood bilirubin increased (two [2%] of 128) in the alectinib group, and neutrophil count decreased (12 [10%] of 120), neutropenia (ten [8%] of 120), and nausea (five [4%] of 120) in the chemotherapy group. Serious treatment-related adverse events occurred in two (2%; one each with appendicitis and pneumonitis) of 128 patients in the alectinib group and eight (7%) of 120 patients in the chemotherapy group ( most common were gastrointestinal disorders in three [3%] patients). No deaths due to adverse events were reported in either group. There were fewer discontinuations due to adverse events with alectinib (seven [5%]) versus chemotherapy (15 [13%]). A clinically meaningful difference in improvement from baseline was seen at week 12 for bodily pain, role physical, mental health, social functioning, and vitality SF-36v2 domains with alectinib; improvements in physical and mental HRQoL were maintained over 2 years of active treatment (at week 96, mean Mental Component Summary score: 49&#xb7;9 [SD 10&#xb7;4]; mean Physical Component Summary score: 48&#xb7;8 [SD 7&#xb7;2]) and reached levels similar to the general population (population norm: 50). INTERPRETATION: For patients with resected ALK-positive NSCLC, adjuvant alectinib had a manageable safety profile; HRQoL improved and was maintained over 2 years of active treatment. Together with the disease-free survival benefit seen in ALINA, these data support adjuvant alectinib as an important new standard-of-care for patients with resected ALK-positive NSCLC. FUNDING: F&#x2008;Hoffmann-La Roche.

Adult

Effect of semaglutide on kidney outcomes in the SELECT, FLOW, and SOUL trials: a prespecified pooled analysis.

BACKGROUND: The GLP-1 receptor agonist semaglutide reduces clinically important kidney outcomes in people with type 2 diabetes and chronic kidney disease (CKD). We aimed to assess the pooled effects of semaglutide on kidney outcomes in prespecified analyses of participant-level data from the diverse populations of the SELECT, FLOW, and SOUL randomised placebo-controlled trials. METHODS: Participants with CKD (FLOW) or atherosclerotic cardiovascular disease (SELECT and SOUL) were randomly assigned semaglutide (once-weekly subcutaneous 1&#xb7;0 mg [FLOW], once-weekly subcutaneous 2&#xb7;4 mg [SELECT], or once-daily oral 14 mg [SOUL]) or matching placebo, added to standard of care. The primary outcome in this pooled analysis was time to first occurrence of a kidney composite, defined as onset of persistent 50% or greater reduction in estimated glomerular filtration rate (eGFR), kidney failure (persistent eGFR <15 mL/min per 1&#xb7;73 m2, or initiation of kidney replacement therapy), kidney-related death, or cardiovascular-related death. Safety was also assessed. FINDINGS: The pooled participants from the trials (N=30&#x2008;787) had a mean follow-up of 39&#xb7;5-47&#xb7;5 months. Among participants assigned to semaglutide, 973 first events of the primary kidney composite occurred compared with 1134 first events for placebo (hazard ratio [HR] 0&#xb7;84 [95% CI 0&#xb7;77-0&#xb7;91]). First events of a narrower secondary kidney composite (excluding cardiovascular-related death from the primary outcome) were also reduced with semaglutide versus placebo (347 and 416, respectively; 0&#xb7;80 [0&#xb7;69-0&#xb7;92]). Safety outcomes were overall similar between groups, and in line with other GLP-1 receptor agonist trials. Serious adverse events were numberically lower with semaglutide than with placebo. INTERPRETATION: Data pooled from three large phase 3 trials suggest that semaglutide reduces the risk of major kidney outcomes in a broad population with cardio-kidney-metabolic disease while having a favourable risk-benefit profile. In people with cardio-kidney-metabolic disease, with and without diabetes, semaglutide (oral or injected) prevents kidney-related and cardiovascular complications and induces adverse events in line with GLP-1 receptor agonist studies, regardless of baseline characteristics within the cardio-kidney-metabolic spectrum. This was a participant-level analysis conducted in a large database of three randomised controlled trials of similar design and examining the same treatment, but there were some differences in participants' baseline characteristics, and in the dose and route of administration of treatment. This pooled analysis adds evidence for the benefit of GLP-1 receptor agonists in general, and semaglutide in particular, in a broad population of people with cardio-kidney-metabolic disease, suggesting that the benefit of semaglutide might not be explained only by its glycaemic effects, weight-management effects, or both. FUNDING: Novo Nordisk.

Humans

Open Dialogue versus treatment as usual for adults presenting in crisis to mental health services in England (the ODDESSI Trial): a multisite cluster-randomised trial.

BACKGROUND: Open Dialogue is a person-centred, transdiagnostic model of mental health care that emphasises continuity, therapeutic relationships, and collaboration with the service user's social network. Open Dialogue is a service-wide approach to care involving network meetings with the service user, members of their social network, and usually two practitioners who support the network throughout the duration of care. In this cluster-randomised trial, we aimed to evaluate the clinical effectiveness of Open Dialogue versus treatment as usual for adults presenting in crisis to community mental health services in England. METHODS: This multicentre, parallel two-arm, cluster-randomised, controlled superiority trial was conducted in mental health services in five National Health Service trusts in London and the South of England. Clusters were defined at the level of primary care practices within service catchment areas. Participants were adults aged 18 years or older presenting in crisis to mental health services and registered with a practice within trial clusters. Randomisation was done at the cluster level (1:1), stratified by catchment area, and balanced on average general practice (GP) list size and Index of Multiple Deprivation (2015). The chief investigator, senior statistician, and assessors of the primary outcome were masked in the study. Participants either received Open Dialogue or treatment as usual, which refers to the functional team model currently implemented throughout English mental health services. The primary outcome was time (days) to first relapse following initial recovery from the index crisis censored at the end of the 2-year follow-up period. Participant-reported secondary outcomes were EuroQol Visual Analogue Scale, Social Provisions Scale, Lubben Social Network Scale, Questionnaire about the Process of Recovery, and the Client Satisfaction Questionnaire, measured at five timepoints over 2 years, and clinical measures were extracted from electronic health records. People with relevant lived experience were involved in the design and execution of the study. Fidelity to the model of care in Open Dialogue and treatment as usual, and adherence to the delivery of Open Dialogue, were measured prior to each site starting participant recruitment, then every 6 months thereafter until the final participant follow-up in that site. The trial was retrospectively registered (ISRCTN52653325) and is complete. FINDINGS: 185 general practices associated with six mental health Trusts across England were identified for screening. 105 practices were excluded, and 80 were included in cluster formation, forming 32 clusters that were randomly assigned (16 to treatment as usual and 16 to the Open Dialogue intervention). One mental health trust (two clusters) withdrew, resulting in five mental health trusts (30 clusters) participating in the trial. Between June 25, 2019, and Dec 9, 2021, 494 participants (266 [54%] female gender, 221 [45%] male gender, 341 [69%] White British) with a mean age of 38&#xb7;1 years (SD 13&#xb7;4) provided consent for study inclusion (223 in the treatment as usual group and 271 in the Open Dialogue group). Of these, 174 (78%) in the treatment as usual group and 225 (83%) in the Open Dialogue group recovered and had data enabling relapse determination; there was no significant difference between groups on the primary outcome of time to relapse following initial recovery (marginal hazard ratio 0&#xb7;95 [95% CI 0&#xb7;67-1&#xb7;32]). For secondary outcomes, Open Dialogue was associated with significantly lower probabilities of psychiatric inpatient admission and re-referral to crisis care or secondary mental health services, and with improvements in self-rated recovery, health-related quality of life, and satisfaction with services. There were no significant differences in social network quality or size. There were 386 serious adverse events (281 in the treatment as usual group and 105 in the Open Dialogue group); 376 (97%) were deemed to be unrelated to the intervention. INTERPRETATION: Open Dialogue did not reduce time to first relapse compared with treatment as usual, the primary outcome, but it reduced acute inpatient bed use, improved service user reported outcomes and experience, and there were no significant safety concerns. Further investigation is required to determine whether Open Dialogue can enhance the effectiveness and acceptability of crisis care and continuing care in community mental health services. FUNDING: National Institute for Health Research.

Humans

Cost-effectiveness analysis of a virtually administered pain coping skills training intervention in women with breast cancer in underserved areas.

OBJECTIVES: Women with cancer who live in medically underserved areas could benefit from behavioral pain interventions, but access is limited. A randomized trial reported that a 4-session virtual program incorporating pain coping skills training (mPCST) was effective in improving pain outcomes compared to an attention-control condition. We performed a cost-effectiveness analysis of mPCST vs. control. METHODS: Data on medical resource use, therapist time, and participants' attendance at intervention sessions and time associated with travel and using a mobile app were collected. The 5-level EuroQol 5-Dimension (EQ-5D-5L), a preference-weighted measure of health-related quality of life (HRQOL), was administered at baseline, after the intervention period, and 3 and 6 months later. Medicare payments were used to value medical resource use and therapist time to deliver mPCST. Patient time was valued using the average US wage. RESULTS: Medical resource utilization was similar for both groups, but hospitalizations trended higher in the mPCST group. EQ-5D-5L preference weights were higher by an average of 0.066 (p&#xa0;=&#xa0;0.04) with mPCST across the follow-up period, representing an incremental gain of 0.04 quality-adjusted life years (QALYs) (95% CI: 0.00-0.08). When including the base-case cost of mPCST of \$500 vs. \$0 for the control group, the incremental cost-effectiveness ratio (ICER) was \$12,725 per QALY (95% CI: 5,566-69,343). Including the value of patient time added \$303 to mPCST costs resulting in an ICER of \$20,438 per QALY (95% CI: 9,051-111,403). SIGNIFICANCE OF RESULTS: mPCST is a cost-effective&#xa0;program that improves HRQOL for women with cancer living in medically underserved areas.

Humans

Implementation outcomes of a dementia-focused intervention for family care partners and clinicians in home hospice care.

OBJECTIVES: End-of-life care for persons living with dementia in home hospice relies heavily on coordination between family care partners (FCPs) and clinicians (e.g., hospice social workers and nurses). FCPs and clinicians have reported support and knowledge gaps in end-of-life dementia care. Interventions are needed to improve FCPs' support and clinicians' educational gaps. METHODS: A pilot randomized controlled trial was designed to examine implementation outcomes for a dementia-focused end-of-life intervention for FCPs (n&#xa0;=&#xa0;37) and clinicians (n&#xa0;=&#xa0;15). Data on survey completion and acceptability were collected at baseline, during 4 follow-up visits, and at the conclusion of the study. RESULTS: Twenty-eight (75%) caregivers completed the post-study survey, and 10 (27%) reported using the structured worksheet. Thirteen (87%) clinicians completed the post-training survey, 8 (53%) completed the post-study survey, and 8 (100%) used the worksheet. Clinicians (n&#xa0;=&#xa0;8) were satisfied or highly satisfied with the instructional videos, and half (50%) used the information frequently with patients. Both groups reported the worksheet helpful, easy to use, and satisfactory, though clinicians rated helpfulness slightly higher (mean&#xa0;=&#xa0;3.88 vs. 3.70 for FCPs). Clinicians liked the worksheet's structured guidance and the enhanced collaboration. SIGNIFICANCE OF RESULTS: This study provides preliminary evidence for implementation outcomes of a dementia-focused end-of-life intervention in home hospice. Findings suggest the intervention can be implemented in a hospice setting, with moderate worksheet uptake and perceived value among FCPs and clinicians.

Humans

Effect of knee and hip joint positions on passive stiffness of the rectus femoris and vastus lateralis in healthy individuals.

Passive muscle stiffness is a key determinant of musculoskeletal function and is influenced by structural components such as titin, connective tissue, and fascia. However, the effects of joint position, muscle depth, and sex on quadriceps passive stiffness remain unclear. To investigate the passive stiffness of the rectus femoris (RF) and vastus lateralis (VL) under different joint configurations, muscle depths, and between sexes using shear wave elastography (SWE). Thirty-six healthy young adults (18 men and 18 women) participated in this randomized crossover study. Passive stiffness was assessed in four positions of knee flexion: supine with 60&#xb0; (SUP60), supine with 20&#xb0; (SUP20), sitting with 60&#xb0; (SIT60), and sitting with 20&#xb0; (SIT20). SWE measurements (m/s) were obtained from 30 regions of interest (ROIs) per muscle, categorized into superficial, intermediate, and deep levels. Data were analyzed using Generalized Estimating Equations (GEE). A significant effect of position was observed, with higher stiffness values in the SUP60 condition for both RF and VL (p&#x2009;<&#x2009;0.001). Superficial regions consistently exhibited greater stiffness compared to intermediate and deep regions across all positions (p&#x2009;<&#x2009;0.001). Additionally, men demonstrated significantly higher stiffness values than women (p&#x2009;<&#x2009;0.001). Significant interactions were found between position and muscle, as well as position and depth. Quadriceps passive stiffness is influenced by joint position, muscle depth, and sex. The SUP60 position elicits the highest stiffness, while superficial muscle regions are consistently stiffer. These findings highlight the non-uniform mechanical behavior of the quadriceps and may have implications for clinical assessment, rehabilitation, and exercise prescription. Clinical trial registration: This study was registered at Clinicaltrials.gov in June 06th, 2023. Register number NCT05905406. Link to access https//clinicaltrials.gov/study/NCT05905406.

Humans

Efficacy of prescription-eligible digital health applications for depression and generalized anxiety disorder in Germany: a systematic review and meta-analysis.

In Germany, prescription-eligible digital mental health applications (DiGA) were introduced in 2020 as promising interventions to address, among others, depression and anxiety disorders, two of the most prevalent mental health conditions worldwide. Despite growing interest in DiGAs, their overall efficacy remains uncertain. This study aimed to systematically evaluate and quantify the efficacy of prescription-eligible digital interventions for depression and generalized anxiety disorder by synthesizing evidence from randomized controlled trials (19 trials; total N&#x2009;=&#x2009;4,078; pooled mean age&#x2009;=&#x2009;38.7 years, SD&#x2009;=&#x2009;12.1). Here we show that prescription-eligible digital applications for depression and generalized anxiety disorder reduce symptom severity compared with control conditions. For depression, effects were observed both immediately after the intervention (number of apps&#x2009;=&#x2009;5; k&#x2009;=&#x2009;17; SMD = -&#x2009;0.49; 95% CI -&#x2009;0.65 to -&#x2009;0.32) and at follow-up (number of apps&#x2009;=&#x2009;1; k&#x2009;=&#x2009;4; SMD = -&#x2009;0.35; 95% CI -&#x2009;0.46 to -&#x2009;0.29), while evidence for generalized anxiety disorder was limited due to a small number of available studies (number of studies&#x2009;=&#x2009;2). These findings support the integration of evidence-based digital tools into mental health treatment strategies in Germany. However, the available evidence is currently dominated by a small number of applications, particularly Deprexis, and should therefore not be interpreted as equally representative of all DiGAs currently listed for depression in Germany. The findings also highlight methodological limitations of current research and underscore the need for real-world evaluations, which address not only efficacy but also the effectiveness, content, quality and implementation.

Generalized Anxiety Disorder

Characterizing Caregiver-Child Interactions Through a Transactional Lens: A Baseline Analysis of a Caregiver-Implemented Intervention.

PURPOSE: This study was motivated by the transactional model of development and examined the reciprocal influences that children and caregivers have on caregiver-child interactions (CCXs) prior to a caregiver-implemented intervention. We tested whether child communication characteristics were associated with caregiver strategy use and whether these strategies, in turn, influenced children's communication to understand how caregivers and children mutually shaped the language learning environment. METHOD: Caregiver-child dyads (N = 105) were participants in a randomized controlled trial. CCXs were collected when children were approximately 30 months of age, transcribed, and coded for four caregiver language facilitation strategies and child communication variables. RESULTS: Least Absolute Shrinkage and Selection Operator regression and postselection inference indicated that child communication characteristics in CCXs were associated with both the frequency and type of strategies caregivers used. Children's overall communication acts were significantly associated with caregiver use of vocabulary strategies, whereas children's vocabulary diversity was significantly associated with caregiver use of sentence strategies. Mixed-effects logistic regression demonstrated that all four caregiver strategies significantly increased the likelihood of spontaneous lexical overlap in subsequent child turns. CONCLUSIONS: Prior to the intervention, caregivers and children reciprocally shaped the language environment. This supports a transactional perspective and warrants further consideration of reciprocal influences when assessing the impact of caregiver-implemented interventions. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.32995796.

Humans

Characterizing Submental Neuromuscular Activity of Swallowing Rehabilitation: An Electromyographic Evaluation of Rehabilitative Maneuvers in Healthy Adults.

PURPOSE: The effortful swallow (ES), the Mendelsohn maneuver (MM), and isometric tongue presses (TPs) are widely used swallowing maneuvers/exercises to improve elements of swallowing, such as muscle strength and biomechanics. However, the underlying neuromuscular mechanisms of these exercises remain unclear, potentially limiting our ability to specify treatment targets and improve treatment efficacy. This study aimed to compare submental neuromuscular activation patterns during the ES, MM, TPs, and typical swallows in healthy young and older adults. METHOD: As part of a larger randomized crossover validation study, 60 healthy adults (30 young and 30 older) completed typical swallows and three maneuvers using a wearable submental surface electromyographic (sEMG) system (i-Phagia). Outcome variables included (a) normalized mean sEMG amplitude and (b) time to peak sEMG amplitude. Linear mixed models were used to examine effects of task, age, and sex on both outcomes. RESULTS: Normalized mean amplitude was significantly different across tasks. Post hoc pairwise comparisons confirmed that all three maneuvers produced higher normalized mean sEMG amplitude than typical swallows, with the ES eliciting the highest amplitude across age groups. Time to peak amplitude differed significantly across tasks, with typical swallows requiring the shortest time to reach peak amplitude, followed by the ES, MM, and TP. CONCLUSIONS: The ES required the highest neuromuscular effort with the shortest time to reach peak amplitude, suggesting its potential for targeting submental muscle power. Typical swallows required the least neuromuscular effort with the shortest time to reach peak amplitude, suggesting their potential for training submental muscle speed. The MM and TP may also improve submental muscle strength; however, given their temporal requirements (longer durations), they may be more beneficial for targeting coordination and endurance, though more research in this area is warranted. These findings underscore the importance of task-specific neuromuscular profiling to inform mechanism-based swallowing rehabilitation. SUPPLEMENTAL MATERIAL: https://doi.org/10.23641/asha.32948549.

Humans

Induction Paclitaxel-Cisplatin-Capecitabine for Nasopharyngeal Carcinoma.

BACKGROUND: We previously reported higher failure-free survival (FFS) with induction paclitaxel, cisplatin, and capecitabine (TPC) compared with cisplatin and fluorouracil (PF) in high-risk locoregionally advanced nasopharyngeal carcinoma (LA-NPC). We now report 5-year FFS, with prespecified secondary outcomes. METHODS: In this multicenter, randomized trial, patients with high-risk LA-NPC (T4N0-2M0 or TanyN3M0) received two 21-day cycles of induction chemotherapy with TPC or PF, followed by concurrent chemoradiotherapy. The primary endpoint was FFS; secondary endpoints included distant metastasis-free, locoregional relapse-free, and overall survival (OS), tumor response, and safety. RESULTS: Among 238 patients (TPC, n=118; PF, n=120), with median follow-up of 89.1 months, 5-year FFS was 77.6% in the TPC group and 62.9% in the PF group (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.34-0.82). At 5 years, distant metastasis-free survival was 87.8% in the TPC group and 78.8% in the PF group (HR, 0.51; 95% CI, 0.28-0.95); locoregional relapse-free survival was 92.0% and 82.1%, respectively (HR, 0.43; 95% CI, 0.21-0.88); and OS was 89.6% and 82.2%, respectively (HR, 0.51; 95% CI, 0.27-0.95). Among patients with pretreatment Epstein-Barr virus (EBV) DNA <3000 copies/ml, 5-year OS was 92.3% in the TPC group and 84.4% in the PF group. Among those with higher EBV DNA levels, rates were 84.2% in TPC group and 81.1% in PF group. Grade 3 or 4 adverse events occurred in 68 patients (57.6%) receiving TPC and 79 patients (65.8%) receiving PF. Treatment adherence was similar in the two groups. CONCLUSIONS: Among patients with high-risk LA-NPC, TPC induction chemotherapy was associated with higher 5-year FFS than PF. (Funded by National Natural Science Foundation of China and State Key Laboratory of Respiratory Disease; ClinicalTrials.gov number, NCT02940925.).

Humans

Balanced Fluid or 0.9% Saline in Children Treated for Septic Shock.

BACKGROUND: Whether treatment with balanced crystalloid fluid leads to better outcomes than 0.9% saline in children treated for septic shock is debated. METHODS: In this pragmatic clinical trial conducted at 47 emergency departments in five countries, patients (2 months to <18 years of age) with suspected septic shock and abnormal perfusion were randomly assigned to receive fluid resuscitation with either balanced fluid or 0.9% saline for up to 48 hours. The primary outcome was a major adverse kidney event (a composite of death, new renal-replacement therapy, or persistent kidney dysfunction) at 30 days after enrollment or hospital discharge, whichever occurred first. RESULTS: Of 9041 enrolled patients, 277 (6.1%) in the balanced-fluid group and 282 (6.2%) in the 0.9%-saline group withdrew from the trial, leaving 4235 and 4247 patients, respectively, for analysis. A primary-outcome event occurred in 137 patients (3.4%) in the balanced-fluid group and in 124 (3.0%) in the 0.9%-saline group (difference, 0.4 percentage points; 95% confidence interval [CI], -0.5 to 1.3; risk ratio, 1.10; 95% CI, 0.88 to 1.40; P&#x2009;=&#x2009;0.85). The median number of hospital-free days during 28 days after enrollment was 23 (interquartile range, 19 to 25) in both groups. Hyperchloremia occurred in 868 patients (31.4%) in the balanced-fluid group and in 1383 (49.0%) in the 0.9%-saline group; hypernatremia in 52 (1.8%) and 89 (3.1%), respectively; and hyperlactatemia in 260 (19.8%) and 228 (16.7%). No differences in other safety outcomes or adverse events were seen. CONCLUSIONS: Among children treated for septic shock, no significant difference was seen in the incidence of death, new renal-replacement therapy, or persistent kidney dysfunction when fluid resuscitation was administered with balanced fluid as compared with 0.9% saline. (Funded by Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; PRoMPT BOLUS ClinicalTrials.gov number, NCT04102371.).

Adolescent

Changes in sexual behavior among women in studies evaluating the dapivirine vaginal ring for HIV prevention.

BACKGROUND: Access to novel HIV prevention technologies often raise concerns of risk compensation. This analysis examined changes in the sexual behaviors of MTN 020/ASPIRE participants, a placebo controlled randomized control trial, who subsequently enrolled in MTN-025/HOPE, an open-label extension using the dapivirine vaginal ring. METHODS: Both studies enrolled healthy, sexually active, HIV-negative women from Malawi, South Africa, Uganda and Zimbabwe. Longitudinal data on participants' sexual behaviors, specifically sex with a nonprimary partner (past 3&#xa0;months), and use of male or female condoms at the last vaginal sex act were compared between ASPIRE and HOPE. Conditional and mixed ordinal logistic regression models evaluated associations between study and sexual behaviors at enrollment,&#xa0;and quarterly over the first 12&#xa0;months. RESULTS: Of the 2629 individuals enrolled in ASPIRE, 1456 (55%) participated in HOPE. At enrollment, the proportion of participants who reported sex with a nonprimary partner and condom use at last vaginal sex act did not differ by study. Across all quarterly follow-up visits, sex with a nonprimary partner was more common in HOPE (13.9-18.7%) than ASPIRE (10.7-12.6%); adjusted OR&#xa0;1.47, 95% CI 1.24-1.75, P&#xa0;<&#xa0;0.001. There was no difference in condom use at the last vaginal act across all quarterly follow-up visits between ASPIRE (36.5-42.7%) and HOPE (43.6-46.7%); adjusted OR&#xa0;1.05, 95% CI 0.94-1.18. CONCLUSION: More women reported sex with nonprimary partners in HOPE, with little change in condom use over time between the two studies. Understanding behavior changes during PrEP use allows for tailored, holistic reproductive health programming.

Humans