Tag: pubmed

JAMA Cardiol. 2025 Mar 12. doi: 10.1001/jamacardio.2025.0103. Online ahead of print.

ABSTRACT

IMPORTANCE: Excess body fat plays a pivotal role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). HU6 is a novel, controlled metabolic accelerator that enhances mitochondrial uncoupling resulting in increased metabolism and fat-specific weight loss.

OBJECTIVE: To assess efficacy and safety of HU6 in reducing body weight, improving peak volume of oxygen consumption (VO2) and body composition among patients with obesity-related HFpEF.

DESIGN, SETTING, AND PARTICIPANTS: The Exploratory Phase 2A, Double-Blind, Placebo-Controlled Dose Escalation Study of Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of HU6 for Subjects With Obese HFpEF (HuMAIN-HFpEF) trial was a multicenter, dose-escalation randomized clinical trial among patients with chronic stable HFpEF and obesity. Data were analyzed from July to October 2024.

INTERVENTION: HU6 treatment for 19 weeks, starting at 150 mg per day and potentially up titrated to 450 mg per day based on safety and tolerability vs placebo.

MAIN OUTCOMES AND MEASURES: The primary end point was change in body weight.

RESULTS: Of 66 participants randomized (mean [SD] age, 64.5 [12] years; 38 female [58%]; mean [SD] weight, 110.9 [22.4] kg), 56 completed the trial. HU6 (vs placebo) significantly decreased weight (between-group difference, -2.86 kg; 95% CI, -4.68 to -1.04 kg; P = .003), total fat mass (between-group difference, -2.96 kg; 95% CI, -4.50 to -1.42 kg; P < .001), and percentage visceral fat (between-group difference,-1.3%; 95% CI, -2.1 to -0.5%; P = .003), with no significant loss of muscle mass. There were no statistically significant changes in peak VO2, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire score, high-sensitivity C-reactive protein level, N-terminal pro-brain natriuretic peptide level, or diastolic function. Serious adverse events were noted in 5 participants (4 in the HU6 group; 1 in the placebo group), including 1 death, all judged unrelated to treatment.

CONCLUSIONS AND RELEVANCE: Among patients with obesity-related HFpEF, treatment with HU6 for 19 weeks led to modest but statistically significant weight loss without significant changes in peak VO2. Larger trials of longer duration are warranted to determine whether longer-term administration of HU6 can improve exercise function, quality of life, and cardiovascular outcomes in this increasingly common disorder.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05284617.

PMID:40072462 | DOI:10.1001/jamacardio.2025.0103

JAMA Psychiatry. 2025 Mar 12. doi: 10.1001/jamapsychiatry.2025.0085. Online ahead of print.

ABSTRACT

IMPORTANCE: Expectancy effects are significant confounding factors in psychiatric randomized clinical trials (RCTs), potentially affecting the interpretation of study results. This narrative review is the first, to our knowledge, to explore the relationship between expectancy effects, compromised blinding integrity, and the effects of active treatment/placebo in psychiatric RCTs. Additionally, we present statistical and experimental approaches that may help mitigate the confounding impact of expectancy effects. The review concludes with recommendations to enhance the reliability of RCTs in psychiatry.

OBSERVATIONS: The placebo response comprises both specific and nonspecific elements, with expectation being a key specific component. Evidence from experimental and clinical studies suggests that expectancy can influence treatment responses in RCTs. Blinding integrity may be compromised by perceived treatment efficacy and adverse effects, introducing bias into outcome assessments. Treatment expectations can lead to unblinding during RCTs, and meta-analytic data from studies in the fields of psychedelics and anxiety disorders indicate that this can influence effect sizes. Therefore, controlling for expectancy effects is essential when interpreting RCT results. Novel statistical methods, though still in need of further validation, offer strategies to address this issue. Another approach may involve experimental medicine models, which aim to develop objective improvement markers (readouts) less affected by expectancy effects.

CONCLUSIONS AND RELEVANCE: Expectancy effects represent a significant confound in psychiatric RCTs. We recommend collecting data on treatment expectations alongside monitoring blinding integrity to more accurately interpret study results. Additionally, developing objective readouts that are less confounded by expectancy effects offers another promising avenue for mitigating these confounding influences in psychiatric RCTs.

PMID:40072447 | DOI:10.1001/jamapsychiatry.2025.0085

JAMA Dermatol. 2025 Mar 12. doi: 10.1001/jamadermatol.2025.0113. Online ahead of print.

ABSTRACT

IMPORTANCE: There is a need to identify the best performing risk prediction model for sentinel lymph node biopsy (SLNB) positivity in melanoma.

OBJECTIVE: To comprehensively review the characteristics and discriminative performance of existing risk prediction models for SLNB positivity in melanoma.

DATA SOURCES: Embase and MEDLINE were searched from inception to May 1, 2024, for English language articles.

STUDY SELECTION: All studies that either developed or validated a risk prediction model (defined as any calculator that combined more than 1 variable to provide a patient estimate for probability of melanoma SLNB positivity) with a corresponding measure of model discrimination were considered for inclusion by 2 reviewers, with disagreements adjudicated by a third reviewer.

DATA EXTRACTION AND SYNTHESIS: Data were extracted in duplicate according to Data Extraction for Systematic Reviews of Prediction Modeling Studies, Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. Effects were pooled using random-effects meta-analysis.

MAIN OUTCOME AND MEASURES: The primary outcome was the mean pooled C statistic. Heterogeneity was assessed using the I2 statistic.

RESULTS: In total, 23 articles describing the development of 21 different risk prediction models for SLNB positivity, 20 external validations of 8 different risk prediction models, and 9 models that included sufficient information to obtain individualized patient risk estimates in routine preprocedural clinical practice were identified. Among all risk prediction models, the pooled weighted C statistic was 0.78 (95% CI, 0.74-0.81) with significant heterogeneity (I2 = 97.4%) that was not explained in meta-regression. The Memorial Sloan Kettering Cancer Center and Melanoma Institute of Australia models were most frequently externally validated with both having strong and comparable discriminative performance (pooled weighted C statistic, 0.73; 95% CI, 0.69-0.78 vs pooled weighted C statistic, 0.70; 95% CI, 0.66-0.74). Discrimination was not significantly different between models that included gene expression profiles (pooled C statistic, 0.83; 95% CI, 0.76-0.90) and those that only used clinicopathologic features (pooled C statistic, 0.77; 95% CI, 0.73-0.81) (P = .11).

CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found several risk prediction models that have been externally validated with strong discriminative performance. Further research is needed to evaluate the associations of their implementation with preprocedural care.

PMID:40072444 | DOI:10.1001/jamadermatol.2025.0113

Stat Med. 2025 Mar 15;44(6):e10345. doi: 10.1002/sim.10345.

ABSTRACT

Based on data from a randomized, controlled vaccine efficacy trial, this article develops statistical methods for assessing vaccine efficacy (VE) to prevent COVID-19 infections by a discrete set of genetic strains of SARS-CoV-2. Strain-specific VE adjusting for possibly time-varying covariates is estimated using augmented inverse probability weighting to address missing viral genotypes under a competing risks model that allows separate baseline hazards for different risk groups. Hypothesis tests are developed to assess whether the vaccine provides at least a specified level of VE against some viral genotypes and whether VE varies across genotypes. Asymptotic properties providing analytic inferences are derived and finite-sample properties of the estimators and hypothesis tests are studied through simulations. This research is motivated by the fact that previous analyses of COVID-19 vaccine efficacy did not account for missing genotypes, which can cause severe bias and efficiency loss. The theoretical properties and simulations demonstrate superior performance of the new methods. Application to the Moderna COVE trial identifies several SARS-CoV-2 genotype features with differential vaccine efficacy across genotypes, including lineage (Reference, Epsilon, Gamma, Zeta), indicators of residue match vs. mismatch to the vaccine-strain residue at Spike amino acid positions (identifying signatures of differential VE), and a weighted Hamming distance to the vaccine strain. The results show VE decreases against genotypes more distant from the vaccine strain, highlighting the need to update COVID-19 vaccine strains.

PMID:40072429 | DOI:10.1002/sim.10345

JAMA Psychiatry. 2025 Mar 12. doi: 10.1001/jamapsychiatry.2025.0033. Online ahead of print.

ABSTRACT

IMPORTANCE: Peripheral (blood-based) biomarkers for psychiatric illness could benefit diagnosis and treatment, but research to date has typically been low throughput, and traditional case-control studies are subject to potential confounds of treatment and other exposures. Large-scale 2-sample mendelian randomization (MR) can examine the potentially causal impact of circulating proteins on neuropsychiatric phenotypes without these confounds.

OBJECTIVE: To identify circulating proteins associated with risk for schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) as well as cognitive task performance (CTP).

DESIGN, SETTING, AND PARTICIPANTS: In a 2-sample MR design, significant proteomic quantitative trait loci were used as candidate instruments, obtained from 2 large-scale plasma proteomics datasets: the UK Biobank Pharma Proteomics Project (2923 proteins per 34 557 UK individuals) and deCODE Genetics (4719 proteins per 35 559 Icelandic individuals). Data analysis was performed from November 2023 to November 2024.

EXPOSURE: Genetic influence on circulating levels of proteins in plasma.

MAIN OUTCOMES AND MEASURES: Outcome measures were summary statistics drawn from recent large-scale genome-wide association studies for SCZ (67 323 cases and 93 456 controls), BD (40 463 cases and 313 436 controls), MDD (166 773 cases and 507 679 controls), and CTP (215 333 individuals). MR was carried out for each phenotype, and proteins that showed statistically significant (Bonferroni-corrected P < .05) associations from MR analysis were used for pathway, protein-protein interaction, drug target enrichment, and potential druggability analysis for each outcome phenotype separately.

RESULTS: MR analysis revealed 113 Bonferroni-corrected associations (46 novel) involving 91 proteins across the 4 outcome phenotypes. Immune-related proteins, such as interleukins and complement factors, showed pleiotropic effects across multiple outcome phenotypes. Drug target enrichment analysis provided support for repurposing of anti-inflammatory agents for SCZ, amantadine for BD, retinoic acid for MDD, and duloxetine for CTP.

CONCLUSIONS AND RELEVANCE: Identifying potentially causal effects of circulating proteins on neuropsychiatric phenotypes suggests potential biomarkers and offers insights for the development of innovative therapeutic strategies. The study also reveals pleiotropic effects of many proteins across different phenotypes, indicating shared etiology among serious psychiatric conditions and cognition.

PMID:40072421 | DOI:10.1001/jamapsychiatry.2025.0033

Dent Med Probl. 2025 Mar 12. doi: 10.17219/dmp/187834. Online ahead of print.

ABSTRACT

BACKGROUND: Chlorhexidine digluconate (CHG) is considered the most effective and safe antimicrobial agent in dentistry. Recently, it has often been produced in the form of preparations with additional substances that may modify its effect.

OBJECTIVES: The aim of the present study was to compare the efficacy of various simple and combined CHG rinses against selected bacterial and yeast strains.

MATERIAL AND METHODS: This research followed the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines, using the disk diffusion method. The study was carried out on the following reference strains: Staphylococcus aureus ATCC 43300; Streptococcus pyogenes ATCC 19615; Pseudomonas aeruginosa ATCC 27853; Enterococcus faecalis ATCC 29212; Candida albicans ATCC 10231; C. glabrata ATCC 15126; C. krusei ATCC 14243; and C. parapsilosis ATCC 22019. The disinfection efficacy of 9 commercial mouthwashes with CHG was assessed (4 simple preparations, with different concentrations (0.5%, 0.2%, 0.12%, and 0.05%), and 5 combined preparations (0.2% CHG with adjuvants)) by comparing the size of the growth inhibition zones (GIZs) of microorganisms after 24 h of incubation.

RESULTS: Growth inhibition zones were observed around all tested substances, for all assessed strains. In simple preparations, the greatest reduction in growth was observed for Gram-positive bacteria. Statistically significantly smaller GIZs were recorded for P. aeruginosa and all Candida strains. The size of GIZ also depended on the CHG concentration used. In combined preparations, the greatest reduction in growth was also observed for Gram-positive bacteria (especially large GIZs for S. aureus when using 0.2% CHG with colostrum). Statistically significantly smaller GIZs were observed for P. aeruginosa and all yeasts. None of the evaluated adjuvants impaired the disinfecting effect of CHG.

CONCLUSIONS: The evaluated combined preparations of CHG showed disinfecting efficacy against selected bacterial and fungal strains comparable to that of simple formulations. The combination of 0.2% CHG with colostrum showed the additive synergism of antimicrobial activity against the S. aureus ATCC 43300 strain.

PMID:40072412 | DOI:10.17219/dmp/187834

Int J Radiat Oncol Biol Phys. 2025 Mar 10:S0360-3016(25)00141-5. doi: 10.1016/j.ijrobp.2025.02.003. Online ahead of print.

ABSTRACT

PURPOSE: The FAST-Forward study paved the way for ultrahypofractionation (UHF) in breast cancer. We prospectively registered and analyzed our case series receiving UHF + simultaneous integrated boost (SIB) to further reduce the treatment to a total of 5 days. The study aimed to present the 6-month early side effects results of the first patients treated with this scheme in 16 radiation oncology centers in Spain.

METHODS AND MATERIALS: A total of 242 breast cancer patients received adjuvant radiation therapy between April and December 2020. The median age was 61 years (interquartile range, 53-70). All patients underwent breast-conserving surgery. Chemotherapy (QT) was administered to 27.7%, and endocrine therapy to 85.1%. A SIB of 29 Gy was applied to 60.7% of the patients, while 39.3% did not have a boost indication. Breast radiation therapy (RT) with SIB to the tumor bed and regional node irradiation was done in 5.4 % of patients.

RESULTS: Most patients were treated with Volumetric modulated arc therapy (66.1%) and intensity modulated RT (30.6%). One patient received treatment by 3-dimensional techniques (0.4%) and 7 patients (2.9%) a combined intensity modulated RT-3-dimensional technique. Deep inspiration breath-hold was used in 16.9% of cases. At the end of treatment, erythema grade (G) 0 was presented in 56.1%, G1 in 43.1%, and G2 in 0.8%. G1 edema was observed in 14.6% and less than 1% had G2. After 6 months, 97% had G0 erythema, 3% G1, and 0% G2, while G1 edema was observed in 11.4% and G2 in 2.5%. No statistically significant impact on side effects was found for planning target volume breast and planning target volume boost volumes.

CONCLUSIONS: UHF with SIB of 29 Gy to the tumor bed in patients with early-stage breast cancer is clinically feasible, safe, and free of an excess of early side effects. Further analysis of late toxicity is needed.

PMID:40072398 | DOI:10.1016/j.ijrobp.2025.02.003

Am J Orthod Dentofacial Orthop. 2025 Mar 11:S0889-5406(25)00061-7. doi: 10.1016/j.ajodo.2025.02.006. Online ahead of print.

ABSTRACT

INTRODUCTION: This longitudinal study assessed the intermaxillary and intraarch relationships from mixed to permanent dentitions during a 4-year follow-up.

METHODS: The sample comprised 352 children evaluated for crowding, midline maxillary diastema, anterior spacing, overjet, overbite, and sagittal and transverse relationships in mixed (T1) and permanent (T2) dentition. Data between different time points were compared using McNemar and Bowker symmetry tests, with a significance level of 5%.

RESULTS: Of the 352 children evaluated over a 4-year follow-up period, significant changes were observed in the intraarch and intermaxillary relationships from T1 to T2. The intraarch relationship showed significant decreases in crowding (61.3%), maxillary midline diastema (74.3%), and anterior spacing (82.2%) (P <0.0001). Regarding the intermaxillary relationship, statistically significant changes were observed in the overjet (P = 0.003), overbite (P = 0.004), and anteroposterior (P <0.0001) and transverse relationships (P <0.0001). In addition, 43.1% of children had increased overjet at T1 and normal overjet at T2, 29.3% of children with a Class II relationship at T1 and Class I relationship at T2, 70.5% of children with posterior crossbite and normal transverse relationship at T2, and 73.9% of children with anterior open bite and normal overbite at T1 and average overbite at T2.

CONCLUSIONS: Significant favorable changes in intraarch relationships were observed during the transition from mixed to permanent dentition. Children also show changes in intermaxillary relationships, with a potential improvement in occlusion of the permanent dentition.

PMID:40072391 | DOI:10.1016/j.ajodo.2025.02.006

Crit Rev Food Sci Nutr. 2025 Mar 12:1-10. doi: 10.1080/10408398.2025.2466758. Online ahead of print.

ABSTRACT

This study aims to review the evidence from Mendelian randomization (MR) studies on the causal role of vitamin D in type 2 diabetes (T2D). A systematic search (registered on PROSPERO (CRD42024551731)) was performed in PubMed, Embase and Web of Science for publications up to June 2024. MR studies including vitamin D as the exposure and T2D as the outcome were included. Among the 22 studies included, which were mainly in European populations, half used single nucleotide polymorphisms (SNPs) located on vitamin D synthesis and metabolism genes, while others selected SNPs based on statistical thresholds. Negative associations implying that vitamin D protects against T2D were reported in three one-sample and three two-sample MR studies. The remaining studies reported null associations between genetically predicted circulating 25-hydroxyvitamin D and risk of T2D regardless of MR design, study population, data source or SNP selection. Findings from MR studies on circulating 25-hydroxyvitamin D and risk of T2D do not consistently support the causal role of vitamin D in T2D in the general population. Future MR studies to examine the non-linear association of vitamin D with T2D or disease progression from prediabetes are warranted to clarify the use of vitamin D in the prevention of T2D.

PMID:40072362 | DOI:10.1080/10408398.2025.2466758

Int J Surg. 2025 Mar 12. doi: 10.1097/JS9.0000000000002331. Online ahead of print.

ABSTRACT

OBJECTIVE: Persistent postoperative sensory loss significantly limits breast reconstruction following mastectomy. In addition, the absence of sensation profoundly impacts patients’ physical well-being and overall quality of life. New surgical techniques involving nerve autograft intercostal nerve elongation have been introduced to neurotize reconstructed breasts. However, patient quality of life after neurotization has not been well evaluated. This study aimed to investigate improvements in patient quality of life in association with breast neurotization.

METHODS: A prospective cohort study of 132 patients treated at (blinded for review) between January 2018 and December 2022 was conducted. Two groups of patients who underwent nipple-sparing mastectomy (NSM) and breast reconstruction were compared: those with (n = 67) and without (n = 65) breast neurotization. Patient-reported outcomes were assessed via the BREAST-Q reconstruction module questionnaire and an additional questionnaire measuring sensation, nipple satisfaction, and breast symptoms. Objective measurements were conducted via the Semmes-Weinstein monofilaments test.

RESULTS: With respect to patient-reported outcomes, the innervated group had significantly higher scores for nipple sensation and on the BREAST-Q domains of psychosocial well-being (71.6 ± 18.1 vs. 62.8 ± 18.6, P = 0.006), sexual well-being (56.9 ± 22.1 vs. 47.3 ± 20.7, P = 0.015), satisfaction with the medical team, as well as less frequent post-operative breast symptoms. In the subgroup analysis, the innervated group demonstrated higher scores in both autologous flap and implant-based reconstruction. Linear regression revealed a statistically significant relationship between objectively measured monofilament value and subjectively examined patient-reported outcomes: nipple sensation, breast sensation, and BREAST-Q score for the psychosocial well-being domain (coefficient: – 4.922, P = 0.033).

CONCLUSION: Breast reconstruction with autologous nerve graft neurotization yields improved sensory outcomes and has a statistically significant positive impact on the quality of life of breast reconstruction patients.

PMID:40072353 | DOI:10.1097/JS9.0000000000002331