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PubMed2026

Perioperative analgesic efficacy of ultrasound-guided erector spinae plane block and posterior transversus abdominis plane block in paediatric patients undergoing open pyeloplasty: A prospective randomised trial.

PURPOSE: Open pyeloplasty in the paediatric population involves extensive tissue dissection and manipulation, resulting in significant postoperative pain. Ultrasound-guided fascial plane blocks have emerged as an important component of multimodal analgesia in abdominal surgeries. This study compared the analgesic efficacy of ultrasound-guided Erector spinae plane block (ESP) and posterior transversus abdominis plane (pTAP) block in children undergoing open pyeloplasty. METHODS: It is a prospective, randomised, double-blind study conducted at a single paediatric centre in a tertiary care hospital in Asia from January 2022 to June 2023. 40 ASA I-II children were randomised to receive either the ESP block (Group E) or the pTAP block (Group T). Both groups received 0.4 ml/kg, 0.2% ropivacaine with 1 mcg/kg dexmedetomidine. Children with an allergy to local anaesthetics, cardiac, renal or hepatic dysfunction and local site infection were excluded. The primary outcome was cumulative 24 h postoperative acetaminophen consumption. Secondary outcomes included the effects on intraoperative hemodynamics, perioperative opioid consumption, FLACC and Watcha scores, time to first rescue analgesia, and any block-related complications. RESULTS: Weight-normalised 24 h postoperative acetaminophen consumption was significantly lower in the ESP group (13.5 ± 4.7 mg/kg) compared to the pTAP group (25.4 ± 8.3 mg/kg), with a mean difference of -12 mg/kg (p < 0.001, 95%CI -16 to -7.6). The median time to first rescue analgesia was significantly longer in the ESP group (18 h [95% CI, 18-24]) than in the TAP group (9 h [95% CI, 6-12]), p < 0.001. Although FLACC scores were significantly lower in the ESP group at 30 min and 12 h postoperatively, the overall longitudinal analysis using a linear mixed-effects model showed no significant difference in the trend of FLACC scores over time between the two groups. There were no block-related complications. CONCLUSION: Ultrasound-guided ESPB provides better, longer-lasting analgesia than posterior TAP block in children undergoing open pyeloplasty. Hence, it may serve as an effective component of multimodal pain management in paediatric open pyeloplasty. CTRI REGISTRATION (CTRI/2022/04/041876) DATED 13/04/2022): https://ctri.nic.in/Clinicaltrials/rmaindet.php?trialid=67747&EncHid=42257.14515&modid=1&compid=19.

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PubMed2026

Effect of Local Anesthetic Solution at Different Temperatures for Epidural Labor Analgesia on Intrapartum Fever: A Randomized Clinical Trial.

BACKGROUND: Whether heating local anesthetic solutions to core body temperature (37°C) for epidural labor analgesia reduces intrapartum fever incidence remains undefined in the current literature. METHODS: This double-blind randomized controlled trial (RCT) enrolled 220 nulliparous parturients (18-35 years, American Society of Anesthesiologists [ASA] physical status II, term singleton pregnancy). Participants were randomized to receive epidural labor analgesia with 0.075% ropivacaine + 0.5 µg/mL sufentanil at 37°C (warmed group) or 22°C (room-temperature group). Epidurals were placed at L3-L4 with a test dose of 3 mL of 1.5% lidocaine at room temperature, followed by programmed bolus epidural analgesia (initial 10 mL, 10 mL/h) and patient-controlled epidural analgesia (PCEA) 5 mL (30-minute lockout). Tympanic temperature was measured every 30 minutes from epidural initiation to delivery, defining intrapartum fever as ≥38°C. The primary outcome was fever incidence, on which the power analysis was based, and also maximum temperature and shivering. Secondary outcomes comprised analgesia onset, block level, labor durations, neonatal Apgar scores, umbilical cord blood pH and BE, and maternal adverse events. RESULTS: A total of 220 parturients were included (warmed group, n = 110; room-temperature group, n = 110). The warmed group had a lower intrapartum fever incidence (15.5% [17/110] vs 30.9% [34/110], relative risk [RR] 0.5 [95% confidence interval {CI}, 0.298-0.840]; P = .007); however, the reduction of 49.8% did not reach the preset clinically meaningful difference of 60% reduction proposed in the power analysis. The maximum body temperature was also lower in the warmed group: median (interquartile range [IQR]) 37.4 (IQR, 37.2-37.7) °C vs 37.6 (IQR, 37.3-38.0) °C, median difference -0.2 (95% CI, -0.3 to -0.1) °C ( P = .006). Shivering incidence was not different between groups (10.9% [12/110] vs 14.5% [16/110]; P = .418). No statistically significant differences were observed between groups in any of the secondary outcomes assessed, including block characteristics, local anesthetic consumption, labor duration, neonatal outcomes, and maternal adverse events. CONCLUSION: Although we found a 50% reduction in the incidence of temperature rise using warmed (37°C) local anesthetics for epidural labor analgesia, this did not reach our preset threshold of 60% reduction.

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PubMed2026

HSK21542 for Postoperative Analgesia in Gynecological Surgery: A Pooled Post-Hoc Analysis of Two Phase III Randomized Controlled Trials.

BACKGROUND: Effective postoperative pain management in gynecological surgery is challenging because of complex visceral-somatic pain interactions and the adverse effects of conventional analgesics. HSK21542, a novel peripherally restricted kappa-opioid receptor (KOR) agonist that selectively targets visceral pain pathways enriched with KORs, may provide adequate analgesia without systemic adverse events. METHODS: We conducted a pooled post-hoc analysis of data from two phase III, multicenter, triple-blinded, randomized controlled trials (Study 301, HSK21542 vs placebo; Study 303, HSK21542 vs tramadol vs placebo). Eligible patients undergoing elective gynecological surgery were included. The primary outcome was the summed pain-intensity difference over 12 and 24 hours (SPID 12h and SPID 24h ). Secondary outcomes were pain-relief quality (proportion of patients relieved from severe pain with a pain numerical rating score ≤ 3 between 0 and 24 hours) and rescue-analgesic requirements (number of doses and time to first rescue analgesic). Adverse events were also assessed. RESULTS: A total of 370 patients were analyzed: 150 received HSK21542, 139 received a placebo, and 81 received tramadol. After inverse probability of treatment weighting (IPTW) adjustment, baseline characteristics were well-balanced across treatment groups (all standardized mean differences [SMD] <0.1; see Table 1 for 95% CIs). HSK21542 produced greater reductions in pain intensity over 12 and 24 hours than placebo (least-squares mean differences -8.1 and -16.3 for SPID 12h and SPID 24h , respectively. Both P < .001) and no statistically significant difference was observed between HSK21542 and tramadol ( P > .05). Significantly more patients in the HSK21542 group were relieved from severe pain at 0 to 12 hours (92.7% vs 82.7%, P < .001) and required fewer rescue doses at 0 to 12 hours (0.00 [IQR 0.00-1.00] vs 1.00 [IQR 0.00-2.00], P < .001) and 0 to 24 hours (0.00 [IQR 0.00-1.00] vs 1.00 [IQR 0.00-2.00], P < .001) than those in the placebo group, whereas no significant differences with tramadol both in 0 to 12 and 0 to 24 hours. HSK21542 was also associated with significantly lower incidences of nausea (24.7% vs 66.7%) and vomiting (21.3% vs 60.5%) than tramadol. Only one case of dizziness occurred in the tramadol group. CONCLUSIONS: HSK21542 could provide adequate postoperative analgesia with few adverse events in patients undergoing gynecological surgery.

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PubMed2026

Specialized pro-resolving mediator (SPM)-enriched supplementation modulates inflammatory biomarkers in patients with symptomatic knee osteoarthritis: Blood plasma analysis from the GAUDI study.

BACKGROUND: Osteoarthritis (OA) is a leading cause of chronic pain and functional impairment, associated with persistent inflammation, potentially due to impaired resolution. Specialized pro-resolving lipid mediators (SPMs) regulate inflammation resolution and restore homeostasis. The GAUDI study previously demonstrated that SPM supplementation reduces pain and improves quality of life (QoL) in patients with knee OA. This analysis assesses the impact of SPM supplementation on inflammatory biomarkers (IB) and SPM levels and their relationship with clinical outcomes. METHODS: This is a secondary analysis of the GAUDI trial, a randomized, multicenter, double-blind, placebo-controlled study conducted in Spain in adults with symptomatic knee OA who received daily supplementation with SPMs or placebo for 12 weeks. Endpoints included changes in plasma IB and SPM levels and their correlation with clinical outcomes. RESULTS: Changes in IL-1 (15.9 vs. -1.1 pg/ml, p-value: 0.051) and IL-18 (10.3 vs. -1.4 pg/ml, p-value: 0.29) showed a tendency toward reduction in the SPM group compared to the placebo group. Changes in IL-1 and IL-8 positively correlated (r = 0.707, p-value: 0.005 and r = 0.551, p-value: 0.04; respectively) with changes in WOMAC score and negatively correlated (r = -0.797, p-value <0.001 and r = -0.804, p-value <0.001; respectively) with changes in EuroQoL-5 VAS score. Changes in IL-1 (r = 0.554, p-value: 0.048) and IL-6 (r = 0.631, p-value: 0.014 and r = 0.572, p-value: 0.031) correlated with changes in OMERACT-OARSI pain score. No significant differences in IB levels were observed between groups during the intervention. Minor changes in SPM levels point to metabolic pathways at work with SPM supplementation. In patients with a BMI ≥25 kg/m², most IB tended to decrease following SPM consumption. CONCLUSIONS: This analysis suggests a potential association between SPM supplementation, decreased inflammation, and improved pain and QoL in patients with knee OA. Subtle changes in blood plasma SPM levels were detected that indicate, through bioinformatics analysis, a pathway-specific metabolome activation induced by SPM supplementation. TRIAL REGISTRATION: NCT05633849. Registered December 1st, 2022. Retrospectively registered, https://clinicaltrials.gov/ct2/show/study/NCT05633849.

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PubMed2026

Descemet Stripping Only in Fuchs Endothelial Corneal Dystrophy: Results of a Randomized Clinical Trial of Topical Ripasudil and Directions for Future Innovation.

PURPOSE: To review history of Descemet stripping only (DSO) in Fuchs endothelial corneal dystrophy, describe the results of a clinical trial of topical ripasudil after DSO (K-321-201 study), and discuss future directions. METHODS: A 1-year, phase 2, randomized, placebo-controlled multicenter clinical trial of two doses of K-321 (ripasudil) administered for 12 weeks after DSO surgery in Fuchs endothelial corneal dystrophy was performed. The primary endpoint, central corneal endothelial cell density (ECD) at 12 weeks after surgery, was determined by an independent reading center that was masked to study group assignment. Duration of corneal edema, need for medical or surgical rescue therapy, corneal thickness, and central ECD throughout the entire study period were also examined. Adverse events and exploratory endpoints were collected. RESULTS: Sixty-five subjects were enrolled (21 in the QID group, 22 in the BID, and in the placebo group). Over 95% of subjects completed the trial. The QID group had a higher central ECD 12 weeks after DSO than the placebo group (531 ± 312 cells/mm2 vs 228 ± 298 cells/mm2, P = .0065). Corneal edema cleared in 17/21 (81.0%) of the QID group at 12 weeks, compared with 2/22 (9.1%) of the placebo group (P < .0001). Rescue was required in 2/21 (9.5%) subjects in the QID group and 6/22 (27.3%) subjects in the placebo group (P = .0092). Adverse events were mild and did not lead to discontinuation of treatment. CONCLUSIONS: Topical K-321 given QID improves DSO outcomes, as demonstrated by a higher ECD, more rapid resolution of corneal edema, and reduced failure rate. The medication was well-tolerated.

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PubMed2026

Targeted Nrf2 activation improves vascular endothelial function with aging and prevents vascular dysfunction following disuse in younger and older adults.

Aging and physical inactivity/disuse contribute to cardiovascular disease, which is attributable, in part, to vascular endothelial dysfunction associated with impaired nuclear-factor erythroid 2-related factor 2 (Nrf2) signaling. However, the ability to augment Nrf2 activation and its effects on age- and disuse-related vascular dysfunction in humans remains limited. In a double-blind, randomized, placebo-controlled study design 20 younger adults (8M/12F, age 27 ± 7 y) and 24 older adults (12M/12F, age 67 ± 8 y) were randomized to receive either placebo or PB125 (200 mg/day, Nrf2 activator) across three visits: baseline, 2 weeks of supplementation, and following either 5 days of bed rest (old) or 2 weeks of limb immobilization (young). Brachial and popliteal artery flow-mediated dilation (FMD), passive leg movement-induced (PLM) leg blood flow (LBF) and vascular conductance (LVC) and serum antioxidant status (superoxide dismutase, SOD) were assessed at each timepoint. Compared to placebo, 2 weeks of PB125 increased brachial (PB125: 2.8 ± 1.5 to 3.8 ± 1.3%, p < 0.0001) and popliteal FMD (PB125: 1.5 ± 1.5 to 2.3 ± 1.4%, p = 0.033) in older, but not younger adults (both, p > 0.27). During bed rest, PB125 preserved brachial (3.8 ± 1.3 to 3.6 ± 1.4%, p = 0.543) and popliteal FMD (2.3 ± 1.4 to 2.7 ± 1.4%, p = 0.269), LVC (1.1 ± 0.8 to 1.1 ± 1.5 AUC, p = 0.530) and circulating SOD concentrations (28.3 ± 7.2 to 28.6 ± 8.6 U/mL, p = 0.888) in older adults compared to placebo (all, p < 0.05). Following limb immobilization, PB125 preserved popliteal FMD (4.4 ± 2.8 to 3.4 ± 1.8%, p = 0.302) in younger adults compared to placebo (p < 0.05). These findings demonstrate targeted Nrf2 activation with PB125 improves age-related vascular endothelial dysfunction while preserving vascular function and antioxidant capacity following periods of disuse.

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PubMed2026

Comparison of summative assessments between simulated electronic health records versus traditional paper-based patient cases: A non-inferiority randomized controlled trial.

INTRODUCTION: Electronic health records are fundamental to contemporary pharmacy practice, yet evidence supporting their use in pharmacy education is lacking. This single-center, non-inferiority randomized controlled trial with blinded outcome assessment evaluated whether delivering patient cases via a simulated academic EHR (aEHR) was non-inferior to a traditional paper-based format in student exam performance. METHODS: 53 third-year PharmD students at the University of British Columbia were randomized 1:1 to complete a mock summative examination using either the aEHR or paper-based case delivery, stratified by self-reported EHR comfort level. The primary outcome was mean written exam score (%). Non-inferiority was pre-specified at a margin of 14%. Adjusted linear regression was used for the primary analysis, with a multiple imputation sensitivity analysis. Student perceptions were explored through post-exam focus groups analyzed using inductive thematic analysis. RESULTS: 42 students (21 per group) completed the exam and were included in the primary analysis. Mean scores were 66% (SD 11) in the aEHR group and 68% (SD 10) in the paper group. The adjusted mean difference (paper minus aEHR) was -2.2% (95% CI -9.2% to +4.8%), satisfying non-inferiority but not superiority. Sensitivity analysis (n = 53) yielded consistent results (-2.3%; 95% CI -7.1% to +4.1%). Focus groups revealed initial student anxiety with the aEHR but recognized its alignment with clinical practice. DISCUSSION: These findings support the feasibility of integrating simulated EHRs into summative pharmacy assessments without compromising performance. CONCLUSION: Simulated EHRs are a non-inferior assessment medium compared with paper-based formats and represent a viable step toward technology-driven pharmacy practice environments.

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PubMed2026

Clinical Trial: Phase 3 Trial of Resmetirom Versus Placebo in Metabolic Dysfunction-Associated Steatohepatitis-Reanalysis of Fibrosis Stage 2-3 Subset.

BACKGROUND: Resmetirom is an oral thyroid hormone receptor beta agonist clinically used to treat metabolic dysfunction-associated steatohepatitis (MASH) among adults with stage F2 or F3 fibrosis. AIMS: Because the pivotal, 52-week, randomized, controlled, phase 3 MAESTRO-NASH trial (once-daily oral resmetirom 80 or 100 mg or placebo) included patients with F1, F2, or F3 fibrosis, we conducted a post hoc analysis aimed at assessing treatment response in the subset of patients with stages F2 and F3 fibrosis, consistent with the approved label population. METHODS: Co-primary end points were MASH resolution (hepatocellular ballooning score 0, lobular inflammation score ≤ 1, and ≥ 2-point nonalcoholic fatty liver disease activity score [NAS] reduction from baseline) with no fibrosis worsening, and ≥ 1-stage fibrosis improvement with no NAS worsening at Week 52. RESULTS: Among 917 patients with F2 or F3 fibrosis, metabolic risk factor prevalence was high (hypertension, 78.0%; dyslipidemia, 71.1%; type 2 diabetes, 67.0%). MASH resolution was achieved by 25.7% in the 80-mg group, 29.9% in the 100-mg group, and 9.5% in the placebo group (p < 0.0001 for both comparisons with placebo). Respective percentages with fibrosis improvement were 26.5%, 28.9%, and 17.3% (p < 0.01 for both comparisons). From baseline to Week 24, low-density lipoprotein cholesterol decreased by 11.7% and 13.7% in the 80- and 100-mg resmetirom groups, respectively, and increased by 2.3% with placebo (p < 0.0001 for both comparisons). No new safety signals emerged. CONCLUSION: Results among patients with F2 and F3 fibrosis were consistent with the primary MAESTRO-NASH analysis population, demonstrating efficacy and safety of resmetirom after 52 weeks.

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PubMed2026

A Phase I Study Assessing the Safety, Tolerability, and Pharmacokinetics of Yinfenidone: A Novel, Potent Drug for Idiopathic Pulmonary Fibrosis Treatment in Healthy Chinese Subjects.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with a median survival of only 2-3 years after diagnosis. Yinfenidone (HEC585) possesses the potential to inhibit the proliferation of pulmonary fibroblasts, making it a promising candidate for the treatment of IPF. This study assessed the safety, tolerability, pharmacokinetics, and metabolic profile of Yinfenidone hydrochloride capsule in healthy Chinese subjects. METHODS: This single-center, randomized, double-blind, placebo-controlled, single ascending-dose trial included seven dose groups(20, 50, 100, 200, 400, 600, and 800 mg). Each group enrolled8 healthy subjects: 6 received Yinfenidone hydrochloride capsules and 2 received matching placebo under fasting conditions. Serial pharmacokinetic (PK) blood samples were collected pre-dose and post-dose, liquid chromatography-tandem mass spectrometry was used to analyze the plasma concentrations of Yinfenidone. Additionally, metabolic biotransformation of Yinfenidone in plasma were conducted in the 100 mg dose group. Safety and tolerability endpoints were monitored via physical examinations, vital signs measurements, clinical laboratory tests, 12-lead electrocardiography (ECG), and adverse events (AEs) documentation throughout the trial. FINDINGS: Yinfenidone was rapidly absorbed, with a median maximum plasma concentration (Tmax) of 1.8-3.0 hours, and had a mean half-life (t1/2) ranging from 31.9 to 62.0 hours. Within the 20-100 mg dose range, systemic drug exposure generally increased with ascending dose, above 100 mg, exposure increased less than proportionally to dose. Metabolite profiling in the 100 mg group revealed that the parentcompound predominated in plasma, with metabolic pathways including mono-oxygenation and N-dealkylation. All reported AEswere mild, classified as Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade 1. No serious AEs observed; no subject discontinued the trial due to AEs. Single oral doses of 20-800 mg Yinfenidone hydrochloride capsules administered under fasting conditions demonstrated favorable safety and tolerability profiles in healthy Chinese subjects. IMPLICATIONS: Yinfenidone exhibited rapid absorption (median Tmax, 1.8-3.0 hours) and a long terminal t1/2 ranging from 31.9 to 62.0 hours in this single ascending-dose study, indicating that Yinfenidone can be taken once a day in subsequent clinical studies. Yinfenidone mainly exists in human plasma as the original drug and is metabolized through a variety of metabolic pathways. The AEs observed with Yinfenidone in this study, such as diarrhea, nausea, and dizziness, were similar to those reported with pirfenidone. Overall, Yinfenidone demonstrated a favorable safety and tolerability profile in this cohort of healthy subjects.

Adult↗

PubMed2026

Pain outcomes of pediatric circumcision patients following administration of pre-operative ketorolac: A randomized clinical trial.

INTRODUCTION: Circumcision is a common surgical intervention, and pain is the most common complaint. Poorly managed pain can increase morbidity and reduce patient and parent satisfaction. Ketorolac, a non-steroidal anti-inflammatory drug (NSAID), provides analgesia and may be effective in reducing pain after circumcision in pediatric patients. STUDY OBJECTIVES: The primary objective was to determine the effect of pre-operative intravenous ketorolac versus normal saline placebo on parental perception of postoperative pain at 24 h. We also explored the effect of ketorolac on postoperative pain scores, incidence of bleeding, incidence of vomiting, and analgesic use. MATERIALS AND METHODS: A prospective, randomized, single-blinded trial was conducted at a single tertiary children's hospital. Patients aged 1-17 presenting for circumcision were included and randomized to either normal saline injectate or ketorolac (0.5 mg/kg, maximum 30 mg). Postoperative delirium and pain scores were recorded in the post-anesthetic care unit. Parents completed the parents' postoperative pain measure (PPPM) at 24 h. The CONSORT criteria and checklist were used to guide reporting of this randomized controlled trial. RESULTS: A total of 100 participants were included. 50 participants were in each group. Mean (SD) PPPM score 24 h after normal saline and ketorolac was 6.1 (3.4) and 5.5 (3.3), respectively for a mean difference of -0.55 points [95% CI: -1.9 to 0.83; p = 0.427]. The mean (95% CI) fixed effect size of ketorolac on post anesthetic care unit reported Face, Leg, Activity, Cry, Consolability score was -0.17 (-0.77 to 0.43, p = 0.585) points, while the mean (95% CI) effect size of ketorolac on numerical rating scale was -1.2 (-2.2 to -0.18, p = 0.026) points. DISCUSSION: Pre-operative intravenous ketorolac, compared to normal saline placebo, did not result in a difference in parental perception of postoperative pain at 24 h after circumcision surgery. As part of exploratory analyses, those receiving ketorolac had modestly lower mean immediate postoperative pain scores, likely not of clinical importance. Ketorolac has often been avoided due to concerns of increased bleeding risk, however it is important to consider that there is no substantial evidence to support this. This is the first study to our knowledge evaluating the effect of ketorolac in pediatric circumcision patients. While the PPPM score is a family centered outcome, it is an indirect measurement of pediatric pain. CONCLUSIONS: Pre-operative intravenous ketorolac was not associated with lower parental reported pain scores at 24 h compared to normal saline placebo after pediatric circumcision surgery. CLINICAL TRIAL REGISTRATION: NCT02973958.

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PubMed2026

Relationships between cannabis and cocaine use in a randomized trial of combined buprenorphine and naltrexone for DSM-IV cocaine dependence.

BACKGROUND: Cannabis is the most commonly used drug in the United States, and among people who use cannabis, polysubstance use is common and understudied. We aimed to examine the association of tetrahydrocannabinol (THC) positive urine drug screen (+UDS) with the odds of submitting a cocaine + UDS during cocaine use disorder treatment. METHODS: We conducted a secondary data analysis of a previously reported double-blind, placebo-controlled clinical trial, CTN0048. Participants meeting criteria for opioid abuse/dependence were assigned to receive extended-release naltrexone and one of three conditions of buprenorphine (placebo, 4 mg/day, 16 mg/day) for 8 weeks. Generalized estimating equations (GEE) were used to analyze urine samples (Liu et al., 2018) collected over time, examining the association between THC + UDS and cocaine + UDS during treatment. RESULTS: Participants (n = 301) averaged 46 (SD = 8.64) years of age, were majority male (78.41 %), non-Hispanic (89.70 %), and African American (66.45 %). GEE results indicated that patients who submitted THC + UDS had significantly higher odds of submitting cocaine + UDS compared to participants who submitted THC-negative UDS across the 25 time points examined (OR = 1.47, 95 % CI = 1.21-1.79, p = 0.00). Time (OR = 0.9998, 95 % CI: 0.9997, 0.9999, p = 0.018) and the covariate of sex assigned at birth (OR = 1.77, 95 % CI = 1.13-2.77, p = 0.013) were also significant in the model, indicating very small decreases in the odds of submitting a cocaine + UDS over time for all patients and 77 % higher odds of submitting cocaine + UDS for females. CONCLUSION: THC + UDS was associated with increased odds of submitting a cocaine + UDS during treatment. Further investigation is needed to discern whether decreasing THC use will result in reduced cocaine use; however, these results suggest that it may be beneficial to counsel patients on cannabis use cessation both before and during treatment for cocaine use, as it is related to cocaine use treatment outcomes. TRIAL REGISTRATION: Secondary data analysis of ClinicalTrials.gov, TRN: NCT01402492 ("A randomized study to test the safety and effectiveness of buprenorphine in the presence of naltrexone for the treatment of cocaine dependence"; National Drug Abuse Treatment Clinical Trials Network (CTN) clinical trial: CTN0048), Registration date: 27 July 2011.

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PubMed2026

Bempedoic Acid and First and Recurrent Limb Outcomes in Statin-Intolerant Patients With Peripheral Artery Disease: Insights From the CLEAR Outcomes Trial.

BACKGROUND: Patients with peripheral artery disease (PAD) are at high risk of major adverse limb events (MALE) and major adverse cardiovascular events (MACE). Recently, bempedoic acid was shown to reduce MACE in primary and secondary prevention patients. Whether bempedoic acid reduces the risk of MALE in patients with PAD is unknown. METHODS: CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid [ETC1002], an ACL-Inhibiting Regimen) randomized 13 970 patients to bempedoic acid 180 mg or placebo from December 22, 2016, to August 14, 2019. The trial primary end point was MACE-4, defined as death resulting from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. A clinical history of PAD was reported by investigators at baseline. Two blinded vascular medicine specialists independently adjudicated MALE, including adverse events indicating worsening PAD symptoms leading to revascularization, chronic limb-threatening ischemia, and acute limb ischemia. Outcomes were assessed as time to first event and total (including recurrent) events with a negative binomial approach. RESULTS: A total of 1624 of the enrolled patients (mean±SD age, 63.9±9.9 years; 915 [56.3%] female) had PAD at baseline. In patients with PAD in the placebo group, 69 (8.3%) had MALE over a median of 40.6 months, with rate of recurrent events of 4.0%/y. Bempedoic acid reduced the risk of MALE by 36% (hazard ratio, 0.64 [95% CI, 0.44-0.93]; P=0.018). Bempedoic acid reduced total MALE by 45% (relative risk, 0.55 [95% CI, 0.35-0.85]; P=0.007). First MACE-4 or MALE was reduced overall by 13% (hazard ratio, 0.87 [95% CI, 0.80-0.95]) with consistent effects with PAD (hazard ratio, 0.82 [95% CI, 0.64-1.04]) and without PAD (hazard ratio, 0.87 [95% CI, 0.79-0.86]; Pinteraction=NS) but not statistically significant within the PAD subgroup alone. Total MACE-4 or MALE was reduced (relative risk, 0.81 [95% CI, 0.73-0.90]) overall with consistent effects in PAD (relative risk, 0.71 [95% CI, 0.54-0.95]) and without PAD (relative risk, 0.82 [95% CI, 0.73-0.92]; Pinteraction=NS). CONCLUSIONS: Patients with PAD are at high risk of MALE and MACE. Bempedoic acid reduces both MACE and MALE in patients with atherosclerotic vascular disease, with notable absolute benefits in patients with PAD. These findings support (1) the importance of lowering low-density lipoprotein cholesterol in patients with PAD to reduce overall vascular risk and (2) the benefits of bempedoic acid in this population.

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PubMed2026

Efficacy of a high-frequency repetitive transcranial magnetic stimulation for craving reduction in adolescents with gaming disorder: a 4-week randomized control trial with 24-week follow-up.

BACKGROUND: With the widespread popularity of online gaming, gaming addiction has come under scrutiny. While there is ongoing research on the diagnosis and treatment of gaming disorder among adolescents, the clinical robustness and reliability of intervention strategies remain uncertain. METHODS: A 4-week, double-blind, randomized, sham-controlled clinical trial was conducted to evaluate the efficacy of noninvasive, high-frequency repetitive transcranial magnetic stimulation (rTMS) in alleviating psychological craving in adolescents diagnosed with gaming disorder. Sham rTMS was administered to the control group using the tilted-coil method. Both groups of participants were treated with SSRI medications. A total of 80 adolescents with gaming disorder participated in this study, and 73 ultimately completed the 24-week follow-up. The primary outcome was the change in craving levels before and after the rTMS intervention, as assessed by the Visual Analogue Scale (VAS). Secondary outcomes included changes in anxiety and depression levels before and after the intervention, as assessed by the HAMA and HAMD. RESULTS: We assessed levels of psychological craving, anxiety, and depression among adolescents with gaming disorder at baseline, after completing a 4-week intervention, and at a 24-week follow-up post-intervention. Our repeated-measures MANOVA results, adjusted for course variables, revealed a significant main effect of rTMS intervention on psychological craving levels in adolescents addicted to online games (F(11, 781) = 11.238, P < 0.001, partial η² = 0.142), as well as significant main effects on time (F(11, 781) = 6.809; P < 0.001, partial η² = 0.091) and group effects (F(1, 71) = 26.707, P < 0.001, partial η² = 0.282). In addition, repeated-measures ANOVA results showed significant time effects for anxiety (F(2, 142) = 20.747, P < 0.001, partial η² = 0.234) and depression levels (F(2, 142) = 22.277, P < 0.001, partial η² = 0.285) among adolescents with gaming disorder, with nonsignificant between-group effects and no intergroup interaction. In the active stimulation group, changes in psychological craving levels after 4 weeks of treatment were significantly and positively correlated with changes in anxiety levels after 4 weeks of treatment in adolescents addicted to online games (r = 0.335, P < 0.05). CONCLUSION: Our findings indicate that high-frequency rTMS targeting the left dorsolateral prefrontal cortex may be a promising approach for reducing psychological craving in adolescents with gaming disorder. TRIAL REGISTRATION: ChiCTR2500102979 in chictr.org.cn, registered on May 22, 2025.

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PubMed2026

Efficacy of CagriSema for Reaching Anthropometric Treatment Targets and Cardiometabolic Outcomes: A Secondary, Post hoc Analysis of REDEFINE 1.

AIMS: To assess the added value of absolute anthropometric targets alongside percentage weight loss in the clinical management of obesity. MATERIALS AND METHODS: The phase 3a, 68-week REDEFINE 1 trial randomised adults without diabetes with BMI ≥ 30 kg/m2, or ≥ 27 kg/m2 with ≥ 1 obesity-related complication, to once-weekly CagriSema 2.4 mg/2.4 mg, semaglutide 2.4 mg, cagrilintide 2.4 mg, or placebo, plus lifestyle intervention. This secondary, post hoc analysis assessed the proportions of participants achieving BMI < 27 kg/m2 and/or WHtR < 0.53 targets, and percentage weight loss by anthropometric target. The association between the proportion of participants maintaining or achieving normalisation of four cardiometabolic outcomes: normoglycemia (glycated haemoglobin < 5.7% and fasting plasma glucose < 5.6 mmol/L); blood pressure (< 130/80 mmHg); triglycerides (< 1.7 mmol/L); lipids (high-density lipoprotein cholesterol ≥ 1.3 mmol/L [female] or ≥ 1.0 mmol/L [male]) and reaching anthropometric targets or change in body weight (%) was also assessed. RESULTS: The proportion of participants achieving both BMI < 27 kg/m2 and WHtR < 0.53 targets at week 68 was 30.3%, 19.1%, 9.0%, and 3.3% in participants who received CagriSema, semaglutide, cagrilintide, or placebo respectively. Both BMI and WHtR performed similarly as indicators for all four cardiometabolic outcomes. At more stringent cut-off values, anthropometric targets were better measures than percentage weight loss. CONCLUSIONS: The proportion of participants achieving anthropometric targets was greater with CagriSema Versus other treatments. These findings support further validation of BMI and WHtR anthropometric treatment targets and indicate a potential for indicating amelioration of clinical outcomes in obesity and a greater emphasis on target-based treatment strategies.

Humans↗

PubMed2026

Effects of essential amino acid supplementation on musculotendinous recovery following eccentric plantar flexor exercise: a randomized controlled trial.

BACKGROUND: Exercise-induced muscle damage (EIMD) resulting from eccentric contractions leads to transient impairments in muscle function. Essential amino acids (EAAs) stimulate muscle protein synthesis and may support recovery following damaging exercise. However, limited research has examined the effects of EAAs on muscle function following eccentric plantar flexor exercise. The purpose of this study was to examine the effects of EAA supplementation on indirect markers of muscle and musculotendinous recovery following EIMD. METHODS: Thirty-six recreationally active males (age: 21.2 ± 2.7 years) were randomly assigned to an EAA group (10 g of EAAs), placebo (10 g of maltodextrin), or control (no supplementation). Supplements were consumed 30 minutes before and immediately after an eccentric plantar flexor protocol (4 × 50 repetitions followed by one set to failure) and during the 72 hours recovery period. Indirect markers of muscle damage were assessed pre-exercise, immediately post-exercise, and 24, 48, and 72 hours post-exercise, consisting of perceived soreness (NPRS), pain pressure threshold (PPT), calf muscle thickness and Achilles tendon thickness (ultrasound), and calf circumference. RESULTS: The eccentric protocol elicited responses consistent with EIMD, including increased soreness (p < 0.001), increased calf muscle thickness and circumference (p < 0.001), and reduced PPT (p = 0.018). EAA supplementation attenuated soreness at 24 hours compared with placebo. Calf muscle thickness increased following exercise in both groups; however, swelling returned to baseline by 72 hours in the EAA group but remained elevated in placebo (Condition × Time, p < 0.001). Achilles tendon thickness decreased immediately post-exercise (p = 0.005) but was not influenced by supplementation. CONCLUSIONS: EAA supplementation modestly reduced soreness and was associated with faster recovery of muscle swelling but did not influence tendon morphology within 72 hours.

Humans↗

PubMed2026

Long-term safety and efficacy of ponesimod, an oral S1P1 receptor modulator, in relapsing-remitting multiple sclerosis (RRMS): Results from randomized phase 2b core and extension studies spanning up to 13 years.

BACKGROUND: Ponesimod demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in 24-week phase-2 core study, further confirmed by an interim combined analysis of the core and open-label long-term extension (LTE) studies (NCT01093326; up to 8 years). Current study evaluated safety and efficacy of ponesimod using combined core and LTE studies data for up to 13 years. METHODS: Of 393 participants completing the core study, 353 (90%) entered LTE, having 3 treatment periods (TP). In TP1 (∼1.85 years), participants continued core treatment (ponesimod: 10, 20, or 40 mg QD) whereas placebo-treated participants were re-randomized (1:1:1) to respective ponesimod doses. In TP2 (TP2 and TP3 combined duration: ∼10.4 years), participants on 40 mg were re-randomized (1:1) to 10/20 mg, while others continued same dose; in TP3 all participants received 20 mg. Study outcomes included safety and efficacy (ARR, time-to 24-week confirmed-disability-accumulation [24-week CDA], total T1-weighted Gadolinium-enhanced (T1 Gd+) lesions, new/enlarging T2 lesions and Combined Unique Active Lesions [CUALs]). RESULTS: For 20 mg dose, total 92.4% participants experienced ≥1 TEAEs (73.1% mild/moderate severity) and 19 (13%) participants discontinued study. Mean (95% CI) ARR=0.14 (0.10-0.20); Kaplan-Meier estimate (95% CI) of confirmed relapse and 24-week CDA=52.5% (42.3-63.5) and 31.3% (22.6-42.3). Mean [SD] T1 Gd+ lesions decreased from ponesimod baseline (2.62 [7.06]) to 12.4 years (0.26 [1.48]), mean (95% CI) CUALs per participant/year=3.97 (2.75-5.73). CONCLUSION: Ponesimod treatment for up to 13 years was not associated with new safety concerns. Participants continued to experience low levels of disease activity consistently across clinical and MRI outcomes.

Humans↗

PubMed2026

Colchicine to prevent cardiovascular events in thoracic surgery patients with or without coronary artery disease: a secondary analysis.

OBJECTIVES: This exploratory post hoc secondary analysis of the Colchicine for the Prevention of Perioperative Atrial Fibrillation (COP-AF) randomised controlled trial evaluated the association between coronary artery disease (CAD) and postoperative ischaemic outcomes after non-cardiac thoracic surgery and assessed whether colchicine had differential effects by CAD status. METHODS: Patients were randomised to colchicine 0.5 mg or placebo two times per day for 10 days. Follow-up was 14 days. The primary outcome was myocardial injury after non-cardiac surgery (MINS). A key secondary outcome was the composite of death, MINS and stroke. Cox proportional hazards models assessed the association between CAD and outcomes, with interaction terms to explore whether colchicine had differential effects by CAD status. RESULTS: Of 3209 patients enrolled, 331 (10.3%) had CAD. MINS occurred in 29.3% (n=97) and 18.2% (n=523) of patients with and without CAD, adjusted HR (aHR) 1.53 (95% CI 1.22 to 1.92; p<0.001). For colchicine versus placebo, the HR for MINS was 0.82 (95% CI 0.55 to 1.22) in CAD versus 0.91 (95% CI 0.77 to 1.08) in non-CAD patients (p for interaction=0.61). Death, stroke or MINS occurred in 30.2% (n=100) vs 18.6% (n=535), respectively (aHR 1.53, 95% CI 1.22 to 1.91; p<0.001). Colchicine HRs were 0.77 (95% CI 0.52 to 1.14) vs 0.91 (95% CI 0.76 to 1.07; p for interaction=0.45). CONCLUSIONS: Patients with CAD undergoing thoracic surgery had a higher risk of MINS and other ischaemic outcomes than non-CAD patients. There was no evidence that the effect of colchicine differed between patients with and without CAD; however, these analyses were limited by sample size and do not exclude modest differences between subgroups.

Humans↗

PubMed2026

Effects of semaglutide and empagliflozin on markers of endothelial function in persons with type 2 diabetes: A post hoc analysis of a randomized clinical trial.

AIMS: The endothelium maintains vascular health by regulating blood flow and protecting against inflammatory damage. In type 2 diabetes (T2DM), however, hyperglycemia, hypertension, and hyperlipidemia place a significant burden on the endothelium, potentially leading to atherosclerosis and cardiovascular disease (CVD). While semaglutide and empagliflozin have been shown to reduce CVD risk in T2DM, it remains unclear whether these benefits are mediated by improved endothelial function. This post-hoc analysis explores the effects of these agents on markers of endothelial function, i.e. the reactive hyperaemic index (RHI) and the endothelial-derived cell adhesion molecules (CAMs) E-Selectin, ICAM-1, P-Selectin, and VCAM-1. METHODS: This was a post-hoc analysis of a 32-week randomized trial evaluating the separate and combined effects of semaglutide and empagliflozin on cardio-renal organ damage. One hundred and twenty participants with type 2 diabetes, age ≥ 50 were randomized to four groups (semaglutide, empagliflozin, the combination or placebo). An increase in RHI and/or a decrease in CAMs were considered beneficial. RESULTS: RHI increased compared to baseline (0.11, 95%CI [0.008;0.21], p = 0.03) but not compared to placebo in the semaglutide group (0.11, 95%CI [-0.04;0.24], p = 0.16). There was no effect on RHI in the empagliflozin group. Compared to placebo, E-Selectin decreased significantly in the semaglutide and combination groups (-9, 95%CI [-14.1;-5.1] p < 0.01 and - 9, 95%CI [-14.3; -5.2] p < 0.01, respectively). VCAM-1 increased in the same groups, compared to placebo (12.3, 95%CI[2.8;20.8] p = 0.01 and 16.2, 95%CI [7.2;24.3], p < 0.01, respectively).P-Selectin and ICAM-1 was not significantly affected in any of the groups, compared to placebo (p ≥ 0.11 and p ≥ 0.09, respectively). CONCLUSION: Semaglutide improved endothelial function compared to baseline, but not significantly versus placebo, which likely is due to limited power. CAM responses were heterogeneous, suggesting distinct roles in endothelial dysfunction and atherosclerosis. ClinicalTrialsRegister.eu: EudraCT 2019-000781-38.

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