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PubMed2026

Repetitive transcranial magnetic stimulation in substance use disorders is safe and tolerable: A Systematic review of 141 clinical trials including 4299 participants.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation intervention investigated as a treatment for substance use disorder (SUD) and its co-occurring disorders. As the number of rTMS SUD clinical trials increase, the safety and tolerability profile should be assessed. In this systematic review, we investigate adverse events (AEs) of rTMS in individuals with SUD and factors that may influence their occurrence. METHODS: We performed a systematic PubMed search to identify all controlled trials of rTMS in SUD published up to January 2025. Eligible studies were assessed, and safety information was extracted for analysis. RESULTS: A total of 141 clinical trials with 4299 participants were included in their active arms. rTMS trials recruited participants who were engaged in active substance use, were in the pre-treatment phase, in early recovery, or in sustained recovery. Twenty-two studies explicitly reported no AEs. Sixty-nine studies reported only mild AEs, while only six studies reported moderate AEs. Thirty-five studies did not report safety-outcomes/AEs. As expected, participants reported mild and temporary AEs such as headaches, pain or discomfort under the coil, or dizziness. Only nine studies reported serious AEs (7 studies in active TMS and 2 in sham TMS). Importantly, no seizures attributable to active rTMS were reported in these SUD samples. CONCLUSION: Overall, rTMS in SUD samples is safe and well-tolerated regardless of recovery stage and substance. Most reported side effects were mild, self-limiting, and tolerable. However, AE reporting was incomplete, as 35 of 141 trials reported no safety data, limiting conclusions to reported outcomes. This evidence supports the safety of rTMS as a potential stand-alone or adjunctive treatment for SUD.

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PubMed2026

Multimodal Therapy With Metformin, Inositol and Dietary Restriction Improves Insulin Resistance and Endocrine Outcomes in Women With Polyendocrine Metabolic Ovarian Syndrome: A Randomized Controlled Trial.

INTRODUCTION: Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is a common endocrine-metabolic disorder characterized by insulin resistance, hyperandrogenism and ovulatory dysfunction. Metformin, inositol supplementation and lifestyle modification are widely used treatments, but direct comparative evidence remains limited. Multimodal therapy combining metformin, inositol and dietary restriction produces greater metabolic and reproductive improvement than single-modality interventions. METHODS: We conducted a 12-week randomized controlled trial in 192 women aged 18-35 years diagnosed with PMOS according to Rotterdam criteria. Participants were allocated to metformin (1500-2000 mg/day), inositol (myo-inositol 2 g plus d-chiro-inositol 50 mg twice daily), calorie-restricted diet (1200-1500 kcal/day), or combination therapy. Primary outcomes included changes in body mass index (BMI) and insulin resistance assessed by HOMA-IR. Secondary outcomes included testosterone, LH/FSH ratio and menstrual regularity. Analysis was performed using analysis of covariance (ANCOVA), with post-intervention values as dependent variables and corresponding baseline values as covariates. Categorical outcomes were compared using the Chi-square test. RESULTS: All interventions improved metabolic and endocrine parameters. Combination therapy resulted in the greatest reduction in HOMA-IR (- 2.64, 95% CI - 2.82 to -2.46, p < 0.001) and BMI (- 2.8 kg/m2, 95% CI - 3.05 to -2.55, p < 0.001). Menstrual cyclicity improved across all groups, with the highest proportion of participants reporting cycle regularisation in the combination therapy group (85.4%), compared with dietary restriction (72.9%), inositol (64.6%), and metformin (39.6%) (p < 0.001). Given the short follow-up duration, these findings reflect early improvements rather than sustained normalisation. CONCLUSION: Multimodal therapy was associated with superior metabolic and reproductive outcomes compared with single-modality interventions in women with PMOS. CLINICAL TRIAL REGISTRATION: ClinicalTrials. gov (NCT07380841).

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PubMed2026

Clinical performance evaluation of single-shade versus multi-shade composite resins in non-carious cervical lesions: a 36-month randomized clinical trial.

BACKGROUND: Composite resins are widely used as the material of choice for definitive restorations due to their ability to integrate functional and aesthetic aspects in dental rehabilitation. Recently, one-shade composite resins have been introduced to simplify the clinical workflow. OBJECTIVES: This study aimed to compare the clinical performance of a "chameleon effect" composite resin with that of a multi-shade composite resin in non-carious cervical lesions after 36 months of follow-up. METHODS: This study was a randomized, controlled, double-blind clinical trial with an equivalence design using a split-mouth approach. The sample consisted of 60 patients presenting at least two non-carious cervical lesions, totaling 120 restorations. Restorations were performed using two materials from the same commercial brand: Vittra Unique (one-shade group) and Vittra APS (multi-shade group). The clinical performance of the restorations was longitudinally evaluated according to the FDI criteria. Survival analysis was performed using Kaplan-Meier curves and the log-rank test, while other clinical parameters were compared using the chi-square test (α = 0.05). RESULTS: At baseline, no statistically significant differences were observed between the groups regarding the evaluated biological, functional, and aesthetic parameters (p > 0.05). Both materials demonstrated clinically acceptable performance according to the FDI criteria, with no significant differences between them. CONCLUSIONS: After 36 months, no significant differences were observed between the one-shade and the multi-shade composite resins in the restoration of non-carious cervical lesions. CLINICAL SIGNIFICANCE: This 36-month randomized clinical trial demonstrates that single-shade composite resins achieve structural durability and aesthetic integration equivalent to traditional multi-shade layering when restoring non-carious cervical lesions. This evidence validates a simplified, single-shade restorative workflow, significantly reducing chairside time and operator-dependent variables without compromising the clinical longevity.

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PubMed2026

Predictors of Efficacy Maintenance After Vunakizumab Discontinuation in Patients With Moderate-to-Severe Plaque Psoriasis: A Post Hoc Analysis of a Randomized Controlled Trial.

BACKGROUND: Efficacy cannot be maintained in some psoriasis patients after biological discontinuation. This study aimed to explore predictors of efficacy maintenance after vunakizumab discontinuation in patients with moderate-to-severe plaque psoriasis. METHODS: This post hoc analysis used data from a phase III trial (NCT04839016); 291 patients with moderate-to-severe plaque psoriasis who achieved 100% improvement in Psoriasis Area and Severity Index (PASI) score at Week 52 were enrolled. Efficacy maintenance was defined as patients who maintained PASI 90 or PASI 100 after 20 weeks of vunakizumab discontinuation. RESULTS: There were 44.7% and 72.5% of patients with PASI 100 and PASI 90 maintenance, respectively. In the multivariate logistic regression model, body mass index (BMI) (odds ratio [OR] = 0.922, p = 0.024) and treatment interruption (OR = 0.550, p = 0.020) were independently associated with a lower possibility of PASI 100 maintenance; however, the association of family history of psoriasis and the first time of PASI 100 achievement with PASI 100 maintenance did not achieve statistical significance. Duration of psoriasis (OR = 0.972, p = 0.049) and treatment interruption (OR = 0.257, p < 0.001) were independently associated with a lower possibility of PASI 90 maintenance. Two nomograms for predicting PASI 90 and PASI 100 maintenance were constructed based on the multivariate models, which disclosed good calibration performance. CONCLUSIONS: PASI 90 and PASI 100 maintenance rates are 72.5% and 44.7% after 20 weeks of vunakizumab discontinuation in patients with moderate-to-severe plaque psoriasis. BMI, treatment interruption, and duration of psoriasis predict a lower possibility of efficacy maintenance after vunakizumab discontinuation.

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PubMed2026

Effect of intraoperative 40-hz gamma-frequency auditory stimulation on postoperative delirium in older adults undergoing major surgery: a randomized clinical trial protocol.

INTRODUCTION: Postoperative delirium (POD) is a common and clinically significant complication among older adults undergoing major surgery under general anesthesia. Gamma-frequency (40-Hz) auditory stimulation has demonstrated potential neuroprotective and cognition-enhancing effects, suggesting a plausible role in perioperative delirium prevention. However, direct clinical evidence supporting intraoperative 40-Hz auditory stimulation in reducing POD remains limited, warranting rigorous evaluation in a randomized trial. PATIENTS AND METHODS: This prospective, parallel-group, randomized controlled trial will enroll 550 older adults scheduled for major noncardiac, nonneurosurgical surgery under general anesthesia. Participants will be randomized in a 1:1 ratio to either the active stimulation group, receiving intraoperative 40-Hz gamma-frequency auditory stimulation delivered via headphones for 2 h following successful anesthesia induction, or the sham stimulation group, wearing headphones without active auditory output. The primary outcome is the incidence of POD on postoperative day 1 though 3, assessed using the Confusion Assessment Method (CAM) or the CAM for the ICU (CAM-ICU). Secondary outcomes include POD severity, sleep quality, pain scores, analgesic consumption, the incidence of postoperative nausea and vomiting (PONV), rescue antiemetic use, duration of post-anesthesia care unit (PACU) stay, length of hospital stay, quality of postoperative recovery, incidence of perioperative adverse events; postoperative morbidity, health-related quality of life, and all-cause 30-day mortality. DISCUSSION: This trial will determine whether intraoperative 40-Hz gamma-frequency auditory stimulation reduces the incidence of POD among older adults undergoing major surgery under general anesthesia. If efficacious, this noninvasive intervention could constitute a feasible perioperative strategy to mitigate delirium risk and enhance postoperative recovery. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2500115156).

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PubMed2026

Efficacy of smartphone- and bibliotherapy-delivered multicomponent lifestyle medicine interventions for probable depression: A three-arm randomized controlled trial.

BACKGROUND: This study examined the efficacy of smartphone- (AG) and bibliotherapy-delivered (BG) lifestyle medicine (LM) interventions compared with a waitlist control group (WLG) in reducing depressive symptoms. METHODS: A total of 122 adults with probable depression were randomized to AG (n = 41), BG (n = 40), or WLG (n = 41). AG and BG received the same core 8-week multicomponent LM intervention via a smartphone application or booklets, respectively. The core content included lifestyle psychoeducation, physical activity, diet and nutrition, stress and sleep management, goal-setting, and motivational techniques. Outcomes were assessed at baseline and immediate post-intervention (Week 9) in all groups, with 1-month (Week 13) and 3-month (Week 21) follow-ups conducted in the intervention groups only. RESULTS: At Week 9, AG (d = 0.89) and BG (d = 0.64) showed significantly greater reductions in depressive symptoms than WLG, with within-group improvements maintained at 1- and 3-month follow-ups (ps <.001, d = 0.77-0.96). Clinically significant improvement was achieved by 78% of AG and 55% of BG participants, both significantly higher than WLG (19.5%; ps <.001). Compared with WLG, both interventions yielded greater improvements in overall lifestyle and physical activity (d = 0.59-0.91) at Week 9. The AG showed additional benefits for perceived stress, health responsibility, nutrition, spiritual growth, and stress management (d = 0.58-0.73), whereas BG uniquely improved insomnia symptoms (d = 0.83). CONCLUSION: Smartphone- and bibliotherapy-delivered LM interventions are efficacious for managing probable depression. Further RCTs comparing them with established treatments are warranted.

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PubMed2026

Short-term safety of dual versus single antiplatelet therapy in flow diversion for distal intracranial aneurysms: results from the DART trial.

BACKGROUND AND PURPOSE: Flow diverters (FDs) have become one of the primary treatments for intracranial aneurysms (IAs). However, their use in distal IA has been associated with higher complication rates compared with other techniques. The development of coated FDs, in combination with novel antiplatelet regimens, offers promising strategies to improve the safety profile of FDs in this context. This trial aimed to compare mono antiplatelet therapy (MAPT) using prasugrel versus dual antiplatelet therapy (DAPT) with aspirin and prasugrel for the treatment of distal IA using the p48 MW HPC FD (WallabyPhenox). METHODS: This was a multicenter, prospective, parallel-group, single-blind, non-inferiority randomized trial. Between February 2021 and February 2025, 140 patients were enrolled. After excluding 11 patients, 129 were included in the final analysis. The primary endpoint was the absence of new neurological deficits, defined as no shift in the modified Rankin Scale (mRS) score. The secondary endpoint was the incidence of any stroke. RESULTS: At the 30-day follow-up, 66 patients (98.5%) in the MAPT group and 59 patients (95.2%) in the DAPT group showed no new neurological deficits. With a predefined non-inferiority margin of 5%, the difference of 3.35% confirmed the non-inferiority of MAPT compared with DAPT (p=0.002). The incidence of any stroke was 4/67 (5.9%) in the MAPT group and 6/62 (9.6%) in the DAPT group (p=0.431). CONCLUSION: Prasugrel monotherapy for the treatment of distal IAs using the p48 MW HPC was non-inferior to DAPT within the first 30 days following treatment. CLINICAL TRIAL REGISTRATION: https://ensaiosclinicos.gov.br/rg/RBR-3q9zb73. UTN code: U1111-1290-2489. Research Ethics Committee of the Hospital das Clínicas de Ribeirão Preto - Universidade de São Paulo. CAAE number: 29848720.0.1001.5440.

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PubMed2026

HPV Testing Versus Cytology for Cervical Cancer Screening Among Women 50 Years and Older: Evidence From the HPV FOCAL Randomized Controlled Trial.

Evidence on the comparative effectiveness of HPV testing versus cytology specifically in women aged ≥ 50 years who are approaching screening cessation remains limited. This analysis included 6471 women aged ≥ 50 at baseline screening in the HPV FOCAL randomized clinical trial. Women were randomly allocated to receive cytology (Control Group, n = 3248, 50.19%) or HPV testing (Intervention Group, n = 3223, 49.81%) at baseline, with co-testing at 48-month exit. We calculated incidence rates and risk ratios for CIN2+ detection over follow-up and compared missed lesions at exit by screening method. At the 48-month exit, CIN2+ detection was lower among HPV baseline-negative women than among those in the cytology group (1.61/1000 [95% CI, 0.52-3.76] vs. 3.15/1000 [95% CI, 1.51-5.78]; risk ratio, 0.51 [95% CI, 0.11-0.91]), reflecting higher baseline detection with HPV testing and fewer prevalent lesions at exit. Even with cytology re-screening at 2 years, 50% of CIN2+ cases were missed compared to 30% with HPV testing. After adjusting for age, education, smoking status, and lifetime sexual partners, the hazard ratio for CIN2+ comparing HPV to cytology was 0.44 (95% CI, 0.22-0.88). Among women aged ≥ 50 years, HPV primary screening was more effective than cytology at detecting CIN2+ lesions and was associated with a continued lower subsequent risk following a negative HPV test, supporting its use in cervical cancer screening programs in this age cohort.

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PubMed2026

Enhancing Self Care Among Oral Cancer Survivors Using a Digital Approach: The Empowered Survivor Trial.

BACKGROUND: Oral and oropharyngeal cancer survivors experience debilitating physical and psychosocial challenges. Little knowledge exists on the efficacy of interventions to enhance self-efficacy in managing these challenges, increase survivorship preparedness, and improve health-related quality of life (HRQoL). METHODS: Individuals (n = 643) diagnosed with oral or oropharyngeal cancer diagnosed within past 3 years were randomized to a digital intervention, Empowered Survivor (ES) or a Generic Online Intervention (GO). Primary (self-efficacy, preparedness, HRQoL) and secondary outcomes (self-care activities) were measured at Baseline, 2-months, and 6-months. RESULTS: Participants assigned to ES reported greater self-efficacy and increased self-care activities of oral self-exams, swallowing, and mobility exercises than those assigned to GO (self-efficacy: 2 months, p = 0.003, 6-months, p < 0.001; self-care activities). CONCLUSIONS: The ES enhanced self-efficacy and increased self-care activities. Further examinations of survivorship preparedness and HRQoL in oral and oropharyngeal cancer are warranted. TRIAL REGISTRATION: Registered on clinicaltrials. gov as NCT04713449.

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PubMed2026

Efficacy of Proton Pump Inhibitor Therapy for Nocturnal GERD Symptoms and Associated Sleep Disturbances: A Systematic Review of Randomized Controlled Trials.

GOALS: A systematic review was conducted to evaluate the efficacy and safety of proton pump inhibitor (PPI) therapy in relieving nocturnal reflux symptoms and sleep disturbances. BACKGROUND: Nocturnal gastroesophageal reflux disease (GERD) is commonly associated with sleep disturbances. The benefits of PPI therapy for GERD-related nocturnal reflux and sleep disturbance remain unclear. STUDY: We searched the MEDLINE, EMBASE, and Cochrane CENTRAL databases from inception to March 1, 2026, for randomized controlled trials (RCTs) in adults with GERD and sleep disturbances that compared any PPI to placebo or an alternative therapy. The primary outcome was the proportion of patients experiencing relief from nighttime heartburn. Secondary outcomes included relief from GERD-related sleep disturbances, changes in subjective sleep quality, work productivity, and treatment-emergent adverse events (TEAEs). RESULTS: Five RCTs involving 1495 patients met the inclusion criteria. Three placebo-controlled trials consistently showed that PPI therapy improved nighttime heartburn relief and GERD-related sleep disturbances compared with placebo. Subjective sleep quality and sleep-related daytime functioning also generally improved with PPI therapy. However, the findings were more heterogeneous across trials because of differences in study populations, comparators, and outcome measures. Across the placebo-controlled studies, TEAEs were generally similar between the PPI and placebo groups. CONCLUSIONS: PPI therapy was associated with improvement in nighttime heartburn and reflux-related sleep disturbances, especially in patients with reflux-driven nocturnal symptoms. The available evidence also suggests potential improvement in subjective sleep quality and sleep-related daytime functioning.

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PubMed2026

Randomized Trial of Intensive Nurse-Led Follow‑Up Versus Standard Care in Inflammatory Bowel Disease.

BACKGROUND:  Nurses play a key role in inflammatory bowel disease (IBD) management. This randomized controlled trial evaluated intensive nurse-led program in patients with IBD starting advanced therapy. METHODS:  Patients were randomized (1:1) to intensive nurse follow‑up (Arm A) or standard care (Arm B). Both arms received baseline nurse education; Arm A additionally had scheduled nurse calls and visits. Primary outcome was reduction in IBD‑Disk score in W12. Secondary outcomes were W52 reduction, robust response (> 20-point improvement), and IBD-Disk remission (score < 40). RESULTS: Overall, 98 patients were randomized (Arm A: n = 50; Arm B: n = 48) with similar baseline characteristics. Mean baseline IBD‑Disk scores were 49.2 ± 20.7 in Arm A and 42.0 ± 19.8 in Arm B (p = 0.07). At W12, both groups improved, with greater IBD-Disk reductions in Arm A (16.1 ± 22.9 vs. 10.1 ± 20.1, p = 0.09). At W52, improvement was greater in Arm A (18.4 ± 20.7 vs 9.4 ± 17.8; p = 0.08). More patients achieved robust response in Arm A (49% vs 21%, p = 0.013) at W12. By W52, IBD-Disk remission was achieved by 22/25 (88%) patients in Arm A vs 18/28 (64%) in Arm B (p = 0.045). CONCLUSIONS:  In this pilot randomized trial, intensive nurse-led follow-up did not significantly improve IBD-Disk at week 12, yet favorable trends of functional outcomes were observed. Intensive nurse‑led follow‑up program may improve quality of life in patients with IBD. These findings support the integration of specialist IBD nurses to improve patient‑centered outcomes.

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PubMed2026

Liposomal bupivacaine versus ropivacaine for surgical site infiltration in lumbar fusion: a prospective randomized controlled trial.

INTRODUCTION: Effective postoperative pain control after lumbar spine surgery remains challenging, and excessive opioid use is associated with adverse outcomes. Evidence comparing liposomal bupivacaine (LB) with conventional long-acting local anesthetics in spine surgery is limited. PATIENTS AND METHODS: In this single-center, prospective, randomized, patient- and outcome assessor-blinded trial, adult undergoing one- or two-level posterior lumbar decompression and fusion were assigned (1:1) to surgical site infiltration with either LB (266 mg) plus 25 mg plain bupivacaine (LB group) or ropivacaine (R group). The primary outcome was 72 h cumulative opioid consumption (morphine milligram equivalents, MME). Secondary outcomes included time-profile opioid consumption, pain scores, rescue analgesia, safety, and functional recovery. RESULTS: A total of 202 patients were included in the modified intention-to-treat analysis. Cumulative MME within 72 h was significantly lower in the LB group compared with the R group [43.0 (37.0, 58.0) mg vs. 58.0 (46.0, 73.0) mg], corresponding to a 22% relative reduction (GMR 0.78, 95% CI 0.71-0.85; p < 0.001). The reduction was most pronounced during 8-24 h and 24-48 h postoperatively. Overall pain scores at rest and with movement, as well as 72-h pain AUC, were lower in the LB group. No significant between-group differences were observed in rescue analgesia, adverse events and functional recovery. CONCLUSION: In patients undergoing one- or two-level posterior lumbar decompression and fusion, surgical site infiltration with an LB-based combined regimen, compared with ropivacaine monotherapy, reduced 72-h opioid consumption and cumulative postoperative pain burden without an observed increase in adverse events or impairment of early functional recovery.

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PubMed2026

Desmodium styracifolium Total Flavone Capsules for Urolithiasis: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: No oral medication is currently approved for the management of urolithiasis. Guang Jing Qian Cao (Desmodium styracifolium total flavone capsules; hereinafter, Guang Jing), a traditional Chinese herbal extract, has shown clinical benefits for urolithiasis, but randomized clinical trials are needed to assess its effectiveness. OBJECTIVE: To evaluate whether Guang Jing improves stone passage rates (SPRs) compared with placebo in adults with urolithiasis. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, placebo-controlled, phase 3 randomized clinical trial was conducted at 34 sites in China from December 2017 to April 2020. Participants included adults (aged 18-70 years) with diagnosed ureteral stones. Data analysis was conducted on November 4, 2020. INTERVENTION: Participants were randomized 3:1 to receive oral Guang Jing (0.6 g) or matching placebo 3 times daily for 28 days, in addition to investigator-prescribed background medication. MAIN OUTCOMES AND MEASURES: The primary outcome was SPR by day 28, confirmed by computed tomography. Secondary outcomes included SPR by day 14, stone migration rate, and stone migration distance. Between-group comparisons were performed using the Cochran-Mantel-Haenszel test for categorical outcomes and t tests for continuous outcomes. RESULTS: A total of 606 participants were randomly assigned to receive Guang Jing (n = 458) or placebo (n = 148). Their mean (SD) age was 43.0 (12.0) years, 474 (78.2%) were male, and the mean (SD) stone size was 0.6 (0.1) cm. The SPR by day 28 was significantly higher for the Guang Jing group compared with the placebo group (204 of 457 [44.6%] vs 50 of 148 [33.8%]; relative risk, 1.32 [95% CI, 1.03-1.69]; P = .03), with an absolute risk difference of 10.9 (95% CI, 2.0-19.7) percentage points. No significant between-group differences in SPR by day 14 (Guang Jing vs placebo: 133 [29.1%] vs 33 [22.3%]; P = .14) or stone migration distance (mean [SD], 29.5 [51.8] mm vs 29.7 [43.8] mm; P = .11) were observed. Adverse event rates were similar for the Guang Jing and placebo groups (88 [19.3%] vs 27 [18.2%]). CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, treatment with Guang Jing significantly increased the expulsion of 5- to 10-mm ureteral stones by day 28, with a favorable safety profile. These findings suggest that Guang Jing may be an additional medical expulsive therapy option for appropriately selected patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry Identifier: ChiCTR-IIR-17013275.

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PubMed2026

Safety of insulin eye drops in the treatment of open angle glaucoma: a randomized phase I clinical trial.

OBJECTIVE: The progression of glaucoma despite adequate intraocular pressure (IOP) control highlights the need for neuroprotective and neuroregenerative therapies. Preclinical studies suggest insulin promotes retinal ganglion cell survival and regeneration, but its safety in higher concentrations (100 and 500 units/mL), administered topically, has been poorly characterized in humans. We aim to assess the safety and tolerability of these two concentrations of insulin eye drops in patients with open-angle glaucoma (OAG). DESIGN: A phase I, randomized, double-blind, placebo-controlled, single-centre clinical trial. PARTICIPANTS: Patients with mild to moderate OAG were randomized 2:2:1 to receive once-daily topical insulin U-100, U-500, or placebo in 1 eye for 5 days, with follow-up visits at 1, 3, and 6 months. The primary safety outcomes include glycemia, serum potassium, ocular adverse events (AEs), and ocular tolerability scores. Secondary outcomes included IOP, best-corrected visual acuity (BCVA), retinal nerve fibre layer thickness, ganglion cell complex, visual field, and OCT angiography. RESULTS: Eighteen open-angle glaucoma patients were enrolled (mean age: 66.2 ± 10.1 years). No serious AEs related to insulin were observed. One asymptomatic, transient near-hypoglycemia event occurred in a fasting participant (3.9 mmol/L), with no recurrence after dietary adjustment. No significant changes were found in serum potassium, IOP, BCVA, visual fields, or OCT. Ocular symptoms in the insulin groups were limited to transient, mild burning sensation upon application. One participant experienced cystoid macular edema at 3 months, which was attributed to pre-existing ocular pathology. CONCLUSION: Topical insulin at 100 and 500 units/mL concentrations was well tolerated in patients for short-term use and did not result in significant systemic or ocular toxicity.

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PubMed2026

Risk-Benefit of Phase 2 Monotherapy Trials in Adult Solid Cancers: A Systematic Review and Meta-Analysis.

Phase 2 (and phase 1 dose expansion, which we label phase 2 for the purposes of this study) cancer trials are the first direct tests of a new drug's efficacy. Because efficacy evidence is lacking, the therapeutic status of drug administration during ethical review is uncertain. We compared the efficacy and safety of cancer monotherapies in phase 2 with phase 3, where clinical equipoise underwrites a therapeutic status for drug administration. In this systematic review and meta-analysis, we searched Clinicaltrials.gov for phase 2 and 3 investigational monotherapy drug trials in six solid malignancies, with primary completion dates 2015-2020, inclusive. Two independent reviewers completed data extraction. Effects were estimated using an inverse-variance weighted random-effects model meta-analysis of proportions using the R package meta. We analyzed 130 phase 2 and 52 phase 3 trial arms, enrolling 6665 and 18,694 patients. The pooled objective response rate was 7% (95% CI 5%-11%) in phase 2 versus 24% in phase 3 (95% CI 17%-31%; p < 0.0001). The median PFS and OS were shorter in phase 2 compared to phase 3 (3.23 vs. 5.43 months, p < 0.0001; 9.46 vs. 14.44 months, p = 0.0001). The pooled rate of drug-related grade 3-4 adverse events was 30% (95% CI 23%-37%) in phase 2 and 25% (95% CI 19%-32%) in phase 3. Monotherapies delivered in phase 2 cancer trials present diminished risk-benefit compared with phase 3 and align with historic estimates for phase 1. Though there may be exceptions, risks for drug administration in phase 2 should generally be justified by appeals to research rather than therapeutic value.

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PubMed2026

Acetate- Versus Lactate-Buffered Crystalloids for Prevention of Post-ERCP Pancreatitis in Patients Without Access to Rectal NSAIDs: A Multicentre Double-Blind Randomized Trial.

BACKGROUND: Aggressive peri-procedural intravenous fluid (IVF) therapy with lactated Ringer's solution (LR) reduces the risk of post-ERCP pancreatitis (PEP), but the standard 8-h protocol is impractical in outpatient settings and the optimal fluid type remains uncertain. We compared LR with an acetate-buffered balanced crystalloid (AC) using a symptom-guided 4-h aggressive IVF protocol. METHODS: This multicentre, double-blind, randomized superiority trial was conducted at three academic hospitals in Korea where rectal NSAIDs are unavailable. Adults with native papillae and moderate-to-high PEP risk were randomized to receive LR or AC. The IVF protocol comprised 10 mL/kg boluses before and after ERCP, followed by 3 mL/kg/h for 4 hours and extended to 8 hours if abdominal pain developed or worsened. The primary outcome was PEP incidence; secondary outcomes included early post-ERCP pain and adverse events. RESULTS: Of 813 patients (404 LR, 409 AC), PEP occurred in 12.4% of the LR group and 11.5% of the AC group (relative risk [RR] 0.93; 95% CI, 0.64-1.35; P = 0.70). Rates of mild (7.9% vs. 7.1%) and moderate (4.5% vs. 4.4%) PEP were similar, and no severe PEP or fluid overload occurred. Among the 68.3% of patients who remained asymptomatic at 4 hours and required only 4-h IVF, PEP occurred in 7.4%, with no cases of severe PEP. CONCLUSION: In this superiority trial, acetate-buffered crystalloid did not reduce PEP compared with lactated Ringer's solution, and no significant safety differences were observed between the two agents. Lactated Ringer's remains the recommended first-line crystalloid for aggressive hydration when rectal NSAIDs are unavailable. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05832047).

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PubMed2025

Treatment preference for once-weekly versus once-daily DPP-4 inhibitors in patients with type 2 diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND/OBJECTIVE: Although once-weekly and once-daily DPP-4 inhibitors have gained widespread market recognition, patient preference differences remain a key focus. This meta-analysis compares treatment preferences for once-weekly versus once-daily DPP-4 inhibitors in T2DM, offering evidence to guide clinical decisions and healthcare policies. METHODS: PubMed, OVID, EBSCO, Web of Science, CNKI, Wanfang, and clinical trial registries were searched up to June 30, 2025. After screening literature against predefined criteria, a systematic review was conducted to compare the effects of once-weekly and once-daily DPP-4 inhibitors on the treatment preferences of patients with T2DM. RESULTS: 8 RCTs with 1,575 participants were analyzed. No significant difference in medication adherence and DTSQ total score between the once-weekly and once-daily groups (p > 0.05). HbA1c percentage (MD = -0.21, 95% CI [-0.42, -0.01], p < 0.05) decreased significantly with once-weekly dosing, while GA and FPG showed no change (p > 0.05), this suggests greater improvement in HbA1c percentage levels following a switch to once-weekly DPP-4 inhibitors. Once-weekly DPP-4 inhibitors showed higher musculoskeletal/connective tissue disorder risk (RR = 2.63; 95% CI [1.18, 5.83]), but no significant differences in other adverse events (p > 0.05). No significant differences in treatment burden between both groups (p > 0.05). CONCLUSION: No statistically significant association between treatment preferences for once-weekly versus once-daily DPP-4 inhibitors among T2DM patients and medication adherence, treatment satisfaction, glycemic level changes, safety, or treatment burden for these two dosing regimens. Further research is needed to elucidate the influence of physician prescribing behavior on these preferences.

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PubMed2026

Clinical Performance of Bulk-Fill Versus Incremental Composite Placement Approaches in Vital Posterior Teeth: A 24 Months Randomized Controlled Trial.

BACKGROUND: Composite resin placement technique may influence marginal integrity, polymerization stress distribution, and long-term clinical performance of posterior restorations. This randomized controlled clinical trial evaluated the 24-month clinical performance of four different placement techniques in Class I posterior composite restorations. METHODS: Fifty patients aged 20-35 years presenting with four occlusal carious lesions each were enrolled, resulting in 200 restorations. Cavities (4-5 mm depth) were prepared according to caries extension. Restorations were randomly allocated into four equal groups (n = 50) according to placement technique: stamp technique, snowplow technique, modified incremental "pizza" technique, and bulk-fill technique. All materials were applied following manufacturers' instructions. Clinical evaluation was performed at baseline and after 6, 12, and 24 months using FDI criteria. Functional (fracture/retention, marginal adaptation), esthetic (marginal staining, anatomical form), and biological (postoperative sensitivity, secondary caries) properties were assessed by two calibrated evaluators. Statistical analysis was performed at a significance level of α = 0.05. RESULTS: Thirty-eight patients with a total of 152 restorations were evaluated at the end of the 24 months in line with FDI at the end of the study with 76% recall rates. No statistically significant differences were observed among groups regarding fracture/retention or secondary caries (p > 0.05). Marginal adaptation and marginal staining demonstrated minor deterioration over time across all groups, with statistically significant intergroup differences found (p < 0.05). Postoperative sensitivity was minimal and transient in all groups with no significant difference (p = 0.181). CONCLUSIONS: Within the limitations of this 24-month follow-up, the four placement techniques demonstrated comparable clinical performance in Class I posterior composite restorations. Selection of technique may therefore be guided by clinical preference and procedural efficiency rather than differences in short-term clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT07415317.

Humans↗