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PubMed2026

Apoptosis protein markers in comorbid type 2 diabetes mellitus and depression; relationships with cognitive performance, incident dementia, and white matter hyperintensities.

Type 2 diabetes mellitus (T2DM) and major depressive disorder (MDD) are reciprocal risk factors, and both elevate dementia risk. Dysregulation of programmed cell death is implicated in T2DM, MDD, and neurodegeneration, but proteomic markers of apoptosis have yet to be studied as dementia predictors in people with T2DM and/or MDD. This study examines apoptosis markers in comorbid T2DM and MDD, and their associations with cognitive, dementia, and neuroimaging outcomes. The retrospective sample (n = 15,765) consisted of UK Biobank participants (MDD only n = 1230; T2DM only n = 3644; comorbid T2DM + MDD n = 721). Individuals with T2DM + MDD comorbidity had poorer cognitive performance, and a higher 15-year dementia incidence (HR = 4.44, 95% CI = [3.23,6.11]). Among 60 apoptosis-related proteins identified by Kyoto Encyclopedia of Genes and Genomes pathway enrichment, 41 were significantly up-regulated in comorbid T2DM + MDD relative to controls, and 4 were higher in the comorbid group than both T2DM alone and MDD alone. Tumor necrosis factor ligand superfamily member 10 (TNFSF10), growth arrest and DNA damage-inducible protein GADD45 beta, tumor necrosis factor ligand superfamily member 6, and RAC-gamma serine/threonine-protein kinase were associated with dementia risk. Nine proteins (e.g. apoptosis-inducing factor 1, mitochondrial, caspase-2, mitogen-activated protein kinase kinase kinase 5, TNFSF10), were associated with white matter hyperintensity volumes in comorbid T2DM + MDD after FDR correction, but none were associated with cognitive performance, atrophy, or white matter microstructural changes. These findings identify peripheral apoptosis markers that were further elevated in comorbid T2DM + MDD compared to either alone, pointing to an important pathophysiological element underlying adverse outcomes in the context of mood and metabolic comorbidity.

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PubMed2026

PHACE syndrome: a systematic literature review and illustrative case report of a patient with severe cerebrovascular and neurodevelopmental sequelae.

BACKGROUND: PHACE syndrome is a rare neurocutaneous disorder defined by the association of large segmental infantile hemangiomas of the head and neck with malformations of the posterior fossa, cerebral and cervical arteries, heart, eyes, and ventral midline structures. Although facial hemangiomas are often the presenting feature, the cerebrovascular, neurodevelopmental, and airway manifestations are responsible for the greatest long-term morbidity. METHODS: A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Web of Science, EMBASE, and PsycINFO. After removal of duplicates and screening of 308 records, five studies meeting the inclusion criteria were retained for qualitative synthesis. We additionally present the case of a now 12-year-old girl with PHACE syndrome characterized by a left V1-distribution facial hemangioma, ocular abnormalities, multiple cerebrovascular venous and arterial malformations, neonatal intraventricular hemorrhage with hydrocephalus, and a subsequently diagnosed dural arteriovenous fistula requiring repeated embolization. RESULTS: The five included studies collectively describe epidemiology and early supportive care needs, long-term health outcomes and quality of life into adulthood, airway hemangioma prevalence and management, and the clinical spectrum of infantile hemangiomas with minimal or arrested growth (IH-MAG) as a cutaneous marker of PHACE syndrome. Across studies, cerebrovascular arteriopathy (72-91%) and facial hemangioma residua (> 90%) were the most consistent findings, while progressive arteriopathy, headaches, learning differences, and airway involvement emerged as the principal sources of long-term morbidity. The reported case illustrates an unusually severe cerebrovascular phenotype, including neonatal hemorrhagic hydrocephalus, dural venous sinus thrombosis, and a late dural arteriovenous fistula, culminating in ataxic cerebral palsy and mild intellectual disability. CONCLUSIONS: PHACE syndrome requires a multidisciplinary, lifelong follow-up strategy. The presented case underscores that cerebrovascular complications may evolve over years to decades after the initial diagnosis, reinforcing the need for long-term neuroradiological surveillance even after apparent clinical stability.

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PubMed2026

Breastfeeding Outcomes After Radiofrequency Ablation and Surgical Excision of Fibroadenomas Compared to Natural History: A Retrospective Cohort Study.

BACKGROUND: Fibroadenomas, common benign breast tumors in women of reproductive age, are increasingly managed with minimally invasive radiofrequency ablation (RFA) or surgical excision. However, their impact on breastfeeding outcomes remains underexplored. We aimed to assess breastfeeding ability and breast tissue changes in women treated with RFA or surgery compared to those with untreated fibroadenomas. METHODS: In this retrospective cohort study, we evaluated 153 women with biopsy-confirmed fibroadenomas across five groups: RFA with prior breastfeeding (RFA-PreBF; n = 26), RFA with posttreatment breastfeeding (RFA-PostBF; n = 22), surgical excision with prior breastfeeding (Surgical-PreBF; n = 30), surgical excision with posttreatment breastfeeding (Surgical-PostBF; n = 20), and noninterventional with breastfeeding (Observation-BF; n = 55). Breastfeeding ability was assessed using a 5-point scale, and breast tissue changes were evaluated via ultrasound at 18 months, and all breastfeeding attempts occurred at a minimum of 12 months postprocedure. Fisher's exact test compared complete lactation failure rates, and a power analysis validated the study design (Fig. 1). FINDINGS: The combined RFA group (n = 48) had a higher complete lactation failure rate (14.6%) than the Observation-BF group (3.6%; Fisher's exact test, p = 0.045). Similarly, the combined surgical group (n = 50) had a higher complete lactation failure rate (16.0%) than the Observation-BF group (p = 0.034). When pooled, the combined intervention group (n = 98) showed a complete lactation failure rate of 15.3% versus 3.6% in the Observation-BF group. Residual tissue correlated with lactation impairment in the RFA group (Spearman's ρ, p < 0.05). Ultrasound showed no tumor recurrence, with cystic changes in some cases not linked to breastfeeding impairment. Power analysis confirmed 80% power to detect a medium effect size (f = 0.25, Fig. 1), supporting the study's robustness.7 RFA-PreBF (n = 26), RFA-PostBF (n = 22), Surgical-PreBF (n = 30), Surgical-PostBF (n = 20), and Observation-BF (n = 55). Breastfeeding ability was assessed using a 5-point scale, and breast tissue changes were evaluated via ultrasound at 18 months. Fisher's exact test compared complete lactation failure rates, and a power analysis validated the study design (Fig. 1).[Figure: see text]Interpretation:RFA and surgical excision are effective for fibroadenoma management but increase the risk of complete lactation failure compared to untreated fibroadenomas. Careful patient selection, precise procedural techniques, and vigilant posttreatment monitoring are essential to optimize breastfeeding outcomes, particularly for women planning future pregnancies.

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PubMed2026

PGR expression as a pharmacogenomic companion biomarker to GENE70-derived genomic risk in ER-positive/HER2-negative breast cancer.

BACKGROUND: The biology of the estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancers is heterogeneous even when they are categorized by their risk via genomics. Transcriptomic PGR expression reflects endocrine pathway activity and may provide complementary biological information within established GENE70-derived genomic-risk categories. Whether this molecular marker improves the biological interpretation of genomic-risk stratification beyond conventional clinicopathological assessment remains uncertain. OBJECTIVES: The aim of this study was to determine whether transcriptomic PGR expression provides complementary biological and prognostic information within reconstructed GENE70-derived genomic-risk categories and refines the characterization of endocrine-related tumour biology in ER-positive/HER2-negative breast cancer. METHODS: This study analysed publicly available transcriptomic and clinical data from three cohorts: METABRIC (discovery cohort), GSE96058/SCAN-B cohort (validation cohort) and TCGA-BRCA cohort (molecular validation cohort). The GENE70-derived genomic-risk score was reconstructed for each cohort using matched genes. Cox regression, Kaplan-Meier analysis and subgroup comparisons were used to assess relationships between PGR expression, clinicopathologic variables, molecular features and survival outcomes. RESULTS: Across the three independent cohorts, low transcriptomic PGR expression was consistently associated with higher GENE70-derived genomic risk, increased MKI67 expression, reduced ESR1 expression and enrichment of the Luminal B subtype. Survival findings differed between cohorts. In the discovery METABRIC cohort, transcriptomic PGR expression showed heterogeneous associations with survival, particularly within GENE70-derived high-risk subgroups, whereas the external GSE96058/SCAN-B validation cohort demonstrated consistent associations between low PGR expression and poorer overall survival in both the overall ER-positive/HER2-negative population and GENE70-derived high-risk subgroups. CONCLUSION: These findings suggest that transcriptomic PGR provides complementary biological and prognostic information within GENE70-derived genomic-risk categories. However, because treatment response was not evaluated in the present study, the findings should not be interpreted as evidence of predictive or pharmacogenomic utility and prospective studies incorporating treatment-response analyses are required before such applications can be established.

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PubMed2026

[Comparative analysis of comprehensive treatment outcomes in patients with chronic bacterial prostatitis with the addition of the multicomponent complex AndrOPREN].

INTRODUCTION: Type II chronic bacterial prostatitis is characterized by persistent infection, insufficient efficacy of standard therapy, and a high recurrence rate, which necessitates the search for additional treatment options. AIM: To evaluate the efficacy and safety of adding the multicomponent complex AndrOPREN to comprehensive therapy for type II chronic bacterial prostatitis. MATERIALS AND METHODS: This prospective, comparative, randomized study included 233 patients allocated to the main group (n=126) and the control group (n=107). In both groups, patients received standard therapy; men in the main group additionally received the multi-ingredient complex AndrOPREN at a dose of two capsules of No. 1 and two capsules of No. 2 daily for 1-2 months. The follow-up period was 60 days. Changes in symptoms according to the IPSS and QoL scores, urinalysis parameters, microscopy findings of expressed prostatic secretions, pathogen eradication, and biochemical safety parameters were assessed. RESULTS: Improvement was observed in both groups and was more pronounced in the main group. By day 14, the median IPSS score was 14.0 [12.0; 16.0] vs. 18.0 [15.0; 20.0] in the control group (p<0.001); by day 60, the corresponding values were 7.0 [5.0; 9.0] and 11.0 [9.0; 13.0] (p<0.001). At the end of follow-up, the QoL score was 2.0 [1.0; 2.0] and 3.0 [2.0; 3.0], respectively. No microbial growth was detected in 91.2% and 80.4% of patients, respectively (p=0.026); Escherichia coli eradication was achieved in 91.7% and 76.9%, respectively. No biochemical changes indicative of nephrotoxicity or hepatotoxicity were detected. DISCUSSION: The addition of the multicomponent complex AndrOPREN was associated with more rapid symptom resolution, a reduction in inflammatory changes, restoration of the secretory function of the prostate, and greater microbiological efficacy. CONCLUSION: The addition of the multicomponent complex AndrOPREN to comprehensive therapy for type II chronic bacterial prostatitis improves treatment efficacy while maintaining a favorable safety profile.

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PubMed2026

Comparative Evaluation of Virtual Reality versus Standard Nursing Care in Managing Pain and Fear during Lumbar Puncture Procedures: A Randomised Controlled Trial.

BACKGROUND: Meningitis is a serious infectious disease that can cause significant morbidity and long-term neurological problems. Although a lumbar puncture is a necessary diagnostic procedure, it is often accompanied by discomfort, anxiety, and fear, which can severely impact the patient's experience. Although there is few data on its application prior to lumbar puncture in adult patients with meningitis, immersive virtual reality (VR) has become a promising non-pharmacological technique for lowering procedural distress. Thus, among individuals undergoing lumbar punctures, this randomized controlled research assessed how well pre-procedural VR reduced pain, anxiety, and fear while enhancing patient satisfaction. OBJECTIVE: This study aims to evaluate the effectiveness of virtual reality (VR) in reducing pain and fear among adults undergoing lumbar puncture (LP) compared with standard care protocol. METHODS: A randomised clinical trial was conducted from May to October 2025, using a single-blind, true experimental design. A total of 85 patients were randomly assigned to either the VR intervention group ( n = 41) or the control group receiving standard care ( n = 44). Pain levels were assessed using a visual analogue scale. Fear was assessed using the Multidimensional Fear-of-Injection Scale. Data were analysed using SPSS version 26. RESULTS: According to the study, the findings revealed a significant reduction in pain levels among the study group following the VR intervention, with mean pain scores dropping from 7.54 ± 1.925 to 2.49 ± 0.675. In contrast, the control group showed increased pain intensity, with mean scores rising from 6.84 ± 1.842 to 8.36 ± 1.348. The VR group showed a significant reduction in fear scores across all domains, whereas no significant changes were observed in the control group. Direct fear decreased from 20.12 ± 1.71 to 9.44 ± 2.00, indirect fear from 17.24 ± 1.46 to 8.66 ± 2.24, physiological response improved from 0.34 ± 0.66 to 3.00 ± 1.00 and avoidance behaviour decreased from 16.71 ± 1.49 to 7.80 ± 1.85. CONCLUSIONS: The research shows that the use of VR prior to LP significantly reduces level of pain and fear compared to standard care. These results support VR as a non-pharmacological intervention for fear and pain to improve patient experience during invasive procedures. In contrast, the control group experienced no improvement.Trial Registration: The IRCT code for the trial was IRCT ID 20250803066743N1.

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PubMed2026

International study of coronary microvascular angina (iCorMicA): A registry-based diagnostic study and nested randomized trial.

BACKGROUND: Angina is a debilitating condition caused by coronary artery disease and microvascular dysfunction. Following coronary angiography angina and no obstructive coronary arteries is a common outcome, and women are disproportionately affected. The objectives are first, to assess causes of angina in patients undergoing invasive management; and second, to assess effects of coronary function test-guided management on clinical outcomes. METHODS: This is an international, multicenter, prospective, registry-based study and nested, randomized, controlled, triple-blind, and endpoint trial. Participants, community care providers, and outcomes assessors are masked. Consented participants enter the registry. Participants without obstructive coronary artery disease (luminal stenosis <50%, or fractional flow reserve >0.80) are eligible for randomization. Index of microcirculatory resistance (IMR; abnormal ≥25) and coronary flow reserve (CFR; abnormal <2.0; gray zone 2.0-2.5) are measured by bolus thermodilution, and results are disclosed (intervention) or not (control group) to the attending cardiologist. RESULTS: The primary outcome of the registry is the Seattle Angina Questionnaire summary score at baseline described by coronary artery disease status. Secondary outcomes include the prevalence of obstructive coronary artery disease, patient reported outcome measures and clinical outcomes. The primary outcome of the randomized trial is the within-individual change in Seattle Angina Questionnaire summary score at 12-months from baseline. Secondary outcomes include safety, diagnostic accuracy, patient reported outcome measures for quality of life, physical and psychological function, cardiovascular risk, clinical outcomes, health economics and mechanistic biomarkers. The first patient was screened on December 18, 2020 and the last patient was enrolled on June 30, 2026. Forty sites were included in the United Kingdom (n = 35), Republic of Ireland (n = 2), Holland (n = 2), and Poland (n = 1). In total, 1,483 participants were enrolled into the registry of whom 1,047 were randomized and 386 were not randomized (registry-only). CONCLUSION: This international, registry-based clinical trial will provide novel evidence on the natural history of angina and stratified therapy for angina with no obstructive coronary arteries. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04674449. UNIQUE IDENTIFIER: NCT04674449.

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PubMed2026

CanDo (Canadian Donor Milk) randomised controlled trial: pasteurised human donor milk supplementation in the well-baby unit - protocol.

INTRODUCTION: Mother's milk is the gold standard for feeding newborns. Despite lactation support while in hospital, supplementation rates remain high in Canadian well-baby units at 35-50%. When supplementation is needed, the choice between formula milk and pasteurised human donor milk (donor milk) remains uncertain with a lack of clinical trials to inform this practice. This study aims to compare the effect of supplementing mother's milk with donor milk versus formula in infants at higher risk for supplementation (infants of diabetic mothers, infants born small for gestational age or with a birth weight less than 2.5 kg and late preterm infants born between 350/7 and 366/7 weeks gestation). METHODS AND ANALYSIS: This is an ongoing, open-label, single-centre, randomised controlled trial conducted at Mount Sinai Hospital, Toronto, Canada. A total of 112 infants (56 per group) will be randomised to receive donor milk or infant formula as a supplement to mother's milk during their initial hospital stay, when supplementation is deemed necessary by the family and/or healthcare team. The primary outcome is exclusive human milk feeding at 4 months of age. Secondary outcomes include any or exclusive human milk feeding at 1, 2 and 3 months; infant growth and health indicators and breastfeeding self-efficacy. Exploratory outcomes encompass infant temperament; parental mental health (assessed using the State-Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale); milk cortisol concentrations; and informal milk sharing comparing donor milk and formula supplementation. Follow-up includes monthly telephone assessments and a virtual or in-person visit at 4 months post partum. Data will be analysed using intention-to-treat principles. ETHICS AND DISSEMINATION: The CanDo trial has received ethics approval from the Mount Sinai Hospital Research Ethics Board and the University of Toronto. Results will be disseminated through peer-reviewed journals, conference presentations and stakeholder engagement with hospital and public health decision-makers. Findings will address a critical evidence gap regarding the use of donor milk supplementation in well-baby units and may inform future clinical practice and policy in newborn feeding. TRIAL REGISTRATION NUMBER: NCT06315127.

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PubMed2026

CT-Derived pelvic morphometry for preoperative risk assessment of recurrent unilateral inguinal hernia.

BACKGROUND: Recurrent inguinal hernia remains a significant challenge in abdominal wall surgery despite advances in mesh-based repair techniques and minimally invasive approaches. Although pelvic skeletal morphology has been implicated in inguinal hernia development, its association with recurrent disease remains incompletely understood. This study aimed to evaluate computed tomography (CT)-derived pelvic morphometric parameters and investigate their potential value in preoperative recurrence risk assessment. METHODS: This retrospective study included 251 male patients with preoperative abdominal CT examinations and complete clinical records who underwent elective inguinal hernia repair at a tertiary referral center. After applying the predefined eligibility criteria, 188 patients with unilateral inguinal hernias constituted the primary study cohort, including 162 primary and 26 recurrent unilateral hernias. The Radoievitch angle and Ami's line were measured independently by two blinded radiology residents using a standardized CT-based pelvic morphometric measurement protocol, and the mean values were used for analysis. Multivariable logistic regression and receiver operating characteristic (ROC) curve analyses were performed to evaluate the association between pelvic morphometric parameters and recurrent inguinal hernia. RESULTS: Patients with recurrent unilateral inguinal hernias demonstrated significantly greater affected-side Ami's line measurements (8.27 ± 0.63 vs. 7.90 ± 0.71 cm, p = 0.014) and larger Radoievitch angles (40.68 ± 4.02° vs. 38.80 ± 3.68°, p = 0.018) than patients with primary unilateral hernias. Both the Radoievitch angle (OR 1.14, 95% CI 1.01-1.28, p = 0.033) and Ami's line (OR 2.26, 95% CI 1.14-4.49, p = 0.020) remained independently associated with recurrent inguinal hernia after adjustment for age and body mass index. ROC analysis demonstrated modest discriminatory performance (AUC 0.634 for the Radoievitch angle and 0.633 for Ami's line), while the multivariable model incorporating age, body mass index, and Ami's line showed slightly improved discrimination (AUC 0.655). CONCLUSION: CT-derived pelvic morphometric parameters were independently associated with recurrent unilateral inguinal hernia. Although their individual discriminatory performance was modest, standardized CT-based pelvimetry may serve as an objective adjunctive tool for individualized preoperative recurrence risk assessment in patients who already undergo CT imaging for unrelated clinical indications. Prospective multicenter studies are warranted to validate these findings and determine their clinical applicability.

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PubMed2026

Addressing lignin composition and content via Arabidopsis arogenate dehydratase knockout and over-expression genotypes.

Following the down-selection of 14 Arabidopsis thaliana arogenate dehydratase (ADT) knockout and over-expression (OE) genotypes, the most highly contrasting quadruple knockout adt3/4/5/6 and ADT OE genotypes were subjected to proteomics, metabolomics, and scanning electron microscopy (SEM) analyses as needed, with results compared to Columbia wild-type (WT). The basal adt3/4/5/6 stem cross-sections, ∼70% lignin content reduced, exhibited buckled vessel cell walls and partially detached xylary fibers, in contrast to WT and ADT4m/5 m OE genotypes that did not. Anatomical defects primarily resulted from guaiacyl lignin level reductions in vessels with concomitant increased stem syringyl:guaiacyl (S/G) ratios. Phenylpropanoid and various upstream shikimate-chorismate pathway enzyme abundances, as well as specific monolignol oxidases (laccases/peroxidases), generally increased in adt3/4/5/6 at different stem and rosette leaf growth/development stages, relative to WT. Opposite effects were largely observed with the ADT5m OE genotype. By contrast, flavonoid and glucosinolate pathway enzyme amounts varied. Such enzyme abundance increases were overall unproductive as adt3/4/5/6 was unable to restore WT, ADT4 OE, ADT5 OE, ADT5m OE, and ADT4m/5 m OE secondary metabolite (lignin, phenylpropanoid, lignan, flavonoid, phenolic acid, and glucosinolate) levels. Conversely, ADT OE genotypes did not significantly increase programmed lignin levels or alter S/G compositions. In sum, proteomics analyses of adt3/4/5/6 and adt5 'perceived' that lignin and low molecular weight secondary metabolite amounts were not at 'programmed' levels as for WT and ADT OE genotypes but observed increases in relevant pathway protein abundances were futile. Notably though, proteomics analyses did not lead to predicting that lignin and associated biochemical pathways would have reduced metabolite levels, relative to WT and ADT OE genotypes. Genotype adt3/4/5/6, possibly the highest lignin level reduced genotype reported, did not utilize other phenolics to compensate. By contrast, the differential temporal and spatial deposition of cell wall oxidases again indicate the exquisite control over lignin deposition, and our lack of knowledge of precise lignin structure and assembly in subcellular regions of the lignified cell walls.

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PubMed2026

Aquablation/AquaBeam Waterjet Therapy for Benign Prostatic Hyperplasia: Three-Year Functional and Ejaculatory Outcomes in a Multicenter Real-World Italian Cohort.

OBJECTIVE: To evaluate the 3-year functional outcomes of Aquablation/AquaBeam waterjet therapy for bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH), with particular attention to urinary symptoms, quality of life, continence, ejaculatory function, and complications. METHODS: We performed a retrospective analysis of a prospectively maintained multicenter database including 218 consecutive men who underwent Aquablation/AquaBeam for symptomatic BPH between January 2019 and January 2022 at three referral centers. Functional outcomes assessed preoperatively and during follow-up included International Prostate Symptom Score (IPSS), IPSS quality-of-life item (IPSS-QoL), maximum urinary flow rate (Qmax), post-void residual urine (PVR), continence, and ejaculatory function. Median follow-up was 36 months. Ejaculatory preservation was evaluated only in patients with preserved antegrade ejaculation at baseline. RESULTS: Median age was 61 years (IQR 57-66), median prostate-specific antigen (PSA) was 2.52 ng/mL (IQR 0.40-21.60), and median prostate volume was 55 mL (IQR 40-73). Median operative time was 56 min, while median catheterization time and length of hospital stay were both 48 h. Functional improvements were evident from the 3-month follow-up and remained stable through 36 months. At 36 months, median IPSS improved to 5 and median Qmax to 18 mL/s. Median PSA changed modestly from 2.52 ng/mL at baseline to 2.75 ng/mL at 36 months. No cases of de novo urinary incontinence were observed throughout follow-up. Among patients with preserved antegrade ejaculation at baseline, 87% maintained antegrade ejaculation at 36 months. Most postoperative complications were minor (Clavien-Dindo grade I-II, 20.2%). One grade III rectal injury occurred (0.5%). Median hemoglobin decreased from 15.2 g/dL preoperatively to 14.0 g/dL before hospital discharge, and two patients required blood transfusion. During the 36-month follow-up, no surgical retreatment was required, whereas 11 patients (5.0%) received temporary medical retreatment. CONCLUSION: In this multicenter real-world cohort, Aquablation/AquaBeam was safe and effective over 3 years, providing durable improvement in lower urinary tract symptoms and quality of life while preserving continence and antegrade ejaculation in most patients. These findings support Aquablation/AquaBeam as a valuable minimally invasive surgical option for selected men with BPH, particularly those who prioritize preservation of ejaculatory function. Longer-term and comparative studies are warranted. TRIAL REGISTRATION: 48281.

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PubMed2026

Transpulmonary proteomic gradient analysis in women with pulmonary arterial hypertension associated with systemic sclerosis.

This study investigated proteomic alterations in the pulmonary circulation of patients with pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) by analyzing the transpulmonary protein gradient and comparing the proteomic profiles with systemic sclerosis (SSc) without PAH. Twenty women were included (10 PAH-SSc, 64.6 ± 10.8 years; 10 SSc, 62.8 ± 11.5 years). The transpulmonary gradient was defined as the difference in biomarker concentrations between wedge-position and pulmonary artery blood samples. Peptides were analysed using liquid chromatography-mass spectrometry, and differentially abundant proteins were identified with Proteome Discoverer. Protein-protein interaction networks were generated with STRING and visualized in Cytoscape. A total of 270 proteins were detected, with no significant transpulmonary gradient alterations. However, patients with PAH-SSc showed distinct proteomic profiles compared to SSc. Multivariate analysis identified 48 differentially abundant proteins in pulmonary artery plasma, with 15 overrepresented and 33 downregulated in PAH-SSc. Among these, the downregulation of transforming growth factor-beta-induced protein ig-h3 (TGFβI/ig-h3) points to a potential involvement of the TGF-β-related extracellular matrix remodelling pathway in PAH-SSc. However, further validation in larger and independent cohorts is required before its relevance as a biomarker or therapeutic target can be established. In conclusion, while no transpulmonary proteomic gradient was observed, the proteomic profiles of PAH-SSc and SSc were different. The profile in PAH-SSc was characterized by differences in immune response, lipid metabolism, and hemostatic proteins. SIGNIFICANCE: This study offers the first proteomic characterization of the transpulmonary gradient in PAH-SSc and SSc. Although no differences in the gradient were found, the pulmonary artery plasma proteome of PAH-SSc patients showed a distinct pattern compared to SSc. Several proteins associated with immune function, haemostasis, and cellular processes were altered, which may indicate specific pathophysiological features of PAH-SSc or suggest how lung dysfunction develops in SSc. Targeting dysregulated proteins like TGFβI/ig-h3 or addressing immune-coagulation imbalances may support future research studies. Overall, these findings refine the molecular profile of PAH-SSc and provide a basis for future large-scale studies aimed at clarifying disease mechanisms and identifying clinically relevant molecular signatures.

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PubMed2026

Assessing time to symptomatic progression, a patient-relevant efficacy endpoint, in the MARIPOSA study in non-small cell lung cancer.

INTRODUCTION: In the phase 3 randomized MARIPOSA study, amivantamab and lazertinib combination therapy demonstrated improved progression-free survival (PFS) and overall survival (OS) versus osimertinib in participants with previously untreated, epidermal growth factor receptor-mutated advanced non-small cell lung cancer. Time to symptomatic progression (TTSP) was introduced to assess clinical worsening and complement endpoints that investigate radiographic disease progression and patient-reported outcomes. TTSP provides an easily interpretable measure of disease-specific symptom worsening to further support patient experience. METHODS: In MARIPOSA, TTSP was quantitatively assessed as a secondary efficacy endpoint and defined as the time from randomization until participants experience disease-specific symptom worsening requiring a clinical intervention or treatment change, or death. To evaluate the impact of amivantamab and lazertinib on TTSP considering its established OS benefit against osimertinib, an exploratory analysis censoring death events was performed. RESULTS: At the final protocol-specified OS analysis (median follow up: 37.8 months), median TTSP was 43.6 months with amivantamab and lazertinib versus 29.3 months with osimertinib (hazard ratio [HR]: 0.69; 95% confidence interval [CI]: 0.57-0.83; p < 0.0001). Amivantamab and lazertinib reduced deaths following a TTSP event compared to osimertinib. A strong correlation between TTSP and PFS or OS was observed. CONCLUSIONS: Amivantamab and lazertinib significantly delayed TTSP versus osimertinib. TTSP offers a clinician-validated measurement of disease-specific symptom worsening, capturing symptoms perceived by patients that prompt clinical action. TTSP is highly correlated with PFS and OS, providing complementary insights alongside traditional endpoints. TTSP enhances understanding of treatment benefit and supports informed clinical decision-making by integrating patient experience.

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PubMed2026

Effects of Photobiomodulation Therapy in Lateral Luxation of Anterior Permanent Teeth: A Randomized, Double-Blind Clinical Trial.

BACKGROUND: Among the traumatic dental injuries (TDIs), lateral luxation may present poor prognosis due to frequent root resorption and consequent tooth loss. Photobiomodulation therapy (PBMT) modulates cellular activities (proliferation, differentiation, growth factor secretion) and may improve outcomes. OBJECTIVE: This randomized, double-blind, placebo-controlled trial evaluated PBMT (660 vs. 808 nm) for post-operative pain and pulp sensitivity recovery in lateral luxation of permanent anterior teeth. METHODS: Initially, 41 patients were included, with a total of 63 teeth traumatized by lateral luxation and were allocated to G1 (n = 21): Splinting + sham PBM (placebo), G2 (n = 21): Splinting + 808 nm infrared PBM and G3 (n = 21): Splinting + 660 nm red PBM. Four weekly sessions (3 J/point, 3 points) were administered. Pain (by numeric rating scale) and pulp sensitivity (by cold test) were assessed weekly. Pain was analyzed using the Kruskal-Wallis test, followed by multiple comparisons using Dunn's method with Bonferroni correction, and pulp sensitivity by a logistic regression model (p < 0.05). RESULTS: Three participants (total of 5 teeth) were excluded due to loss to follow-up. Fifty-eight teeth were analyzed (G1 = 21, G2 = 17, G3 = 20). Pain: All groups showed a significant reduction in pain over time (p < 0.001). Both G2 and G3 demonstrated a significantly greater reduction in pain compared to G1 (p < 0.001 and p = 0.026, respectively). No significant difference in pain reduction was observed between G2 and G3. Pulp sensitivity: G2 showed a significant improvement over time (p < 0.001), despite starting from a more unfavorable baseline. In contrast, no significant change in pulp sensitivity was observed for G1 or G3 between the initial and final assessments. CONCLUSION: Within the limitations of this clinical study, all intervention groups were effective in reducing pain in lateral luxation of permanent anterior teeth, with superior results for laser groups compared to the placebo. However, only the 808 nm laser irradiation protocol demonstrated a significant improvement in pulp sensitivity, suggesting it may offer a more complete therapeutic response.

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PubMed2026

Paramedian supracerebellar transtentorial approach for Yaşargil T2 tentorial incisura meningiomas.

OBJECTIVE: Tentorial incisura meningiomas, particularly those arising from the middle incisural region (Yaşargil T2), are surgically challenging because of their deep location and compression of critical neurovascular structures. These lesions typically have supratentorial or infratentorial extension but can also extend across both compartments. Although approach selection is often guided by the dominant compartment of tumor extension, for lesions with supratentorial-dominant extension, the optimal approach remains controversial, and a standardized strategy has not been established. Authors of this study evaluated the feasibility and outcomes of the paramedian supracerebellar transtentorial (PST) approach for Yaşargil T2 tentorial incisura meningiomas with a supratentorial-dominant or combined extension. METHODS: The authors retrospectively reviewed data from consecutive patients with radiographic and intraoperative findings consistent with a Yaşargil T2 tentorial incisura lesion treated via the PST approach from September 2005 through December 2025. Patients were placed in a semisitting position whenever feasible and in a semilateral position when semisitting was contraindicated. Collected data included demographics, tumor extension patterns, extent of resection on postoperative MRI, neurological outcomes, histopathology, rate of recurrence, and follow-up. RESULTS: Six patients, 1 male and 5 female, with an overall mean age of 43 years, underwent resection via the PST approach. Four lesions had predominantly supratentorial extension, and 2 had combined supra- and infratentorial growth, with no cases of isolated infratentorial extension. Five patients had been placed in the semisitting position and 1 in a semilateral position because of a cardiac contraindication to the semisitting position. No new permanent neurological deficits were observed. Postoperative MRI showed Simpson grade I resection in all 6 patients. The mean follow-up was 8.6 years. Histopathological analysis revealed 3 WHO grade 1 meningiomas, 1 WHO grade 2 meningioma (clear cell), and 2 solitary fibrous tumors (meningioma mimics). These diagnoses were evaluated according to the 2021 WHO classification. CONCLUSIONS: In this consecutive series, the PST approach was a viable single-corridor strategy for Yaşargil T2 tentorial incisura lesions, including supratentorial-dominant tumors, achieving Simpson grade I resection with no permanent neurological deficits. By providing early devascularization at the tentorial attachment and a gravity-assisted, retractorless working corridor with favorable deep venous visualization, the PST approach challenges compartment dominance as the primary determinant of approach selection.

Humans↗

PubMed2026

Combined Effects of Nicorandil and Enhanced External Counterpulsation on Coronary Microcirculation and Exercise Capacity in Patients With Coronary Slow Flow Phenomenon: A Randomized, Controlled, 3-Arm Trial.

PURPOSE: To evaluate the combined efficacy and safety of combined nicorandil and enhanced external counterpulsation (EECP) therapy compared with respective monotherapies in patients with coronary slow flow phenomenon (CSFP). METHODS: In this prospective, randomized, 3-arm clinical trial, 309 patients with angiographically defined CSFP based on corrected TIMI frame count were assigned (1:1:1) to the Nicorandil group (N group, n = 103), the EECP group (E group, n = 103), or the Combined therapy group (N+E group, n = 103). The trial was prospectively registered at ClinicalTrials.gov (NCT07534410). IMR and CFR were measured to characterize coronary microvascular physiological status and treatment response. The primary endpoint was corrected TFC at 6 months. Key secondary endpoints included invasive physiological indices (IMR and CFR), Seattle Angina Questionnaire scores, 6-minute walk test (6MWT) distance, peak oxygen uptake via cardiopulmonary exercise testing, and the 12-month rate of re-hospitalization due to recurrent angina. FINDINGS: At 6 months, the N+E group demonstrated superior improvement in coronary hemodynamics compared to the N and E monotherapy groups, with significantly lower TFC (30.4 ± 3.5 vs 38.2 ± 3.8 and 37.5 ± 4.0, respectively; P < 0.001) and IMR (21.2 ± 2.8 vs 28.4 ± 3.2 and 27.6 ± 3.5, respectively; P < 0.001). Clinical symptoms and functional capacity showed the most substantial gains in the N+E group, with significantly higher Seattle Angina Questionnaire angina frequency scores (87.5 ± 8.8) and 6MWT distances (506.8 ± 41.8 m) compared to monotherapy groups (all P < 0.001). Furthermore, peak oxygen uptake in the N+E group increased to 23.5 ± 2.6 mL/kg/min, significantly outperforming the N and E groups (P < 0.001). During the 12-month follow-up, the observed rate of re-hospitalization due to recurrent angina was lower in the N+E group (5.8%) than in the N group (17.5%, P = 0.017), although this clinical outcome should be interpreted cautiously because the trial was powered primarily for physiological endpoints. No significant differences were observed in the incidence of adverse reactions among the 3 groups (P = 0.954). IMPLICATIONS: For patients with CSFP, the combination of Nicorandil and EECP improved coronary microvascular function, anginal symptoms, and objective exercise tolerance more effectively than either active monotherapy. The lower observed rate of angina-related re-hospitalization suggests a potential clinical benefit, but this finding should be considered exploratory and requires confirmation in trials adequately powered for clinical outcomes.

Humans↗

PubMed2026

The impact of body mass index classification on operative characteristics and perioperative outcomes in lumbar microdiscectomy.

INTRODUCTION: Body mass index (BMI) stratification helps classify obesity severity. In patients undergoing microdiscectomy for symptomatic lumbar disc herniation, the effect of obesity on perioperative risk remains incompletely understood. This retrospective single-institution study evaluated whether BMI class influences perioperative risk in a large surgical cohort. METHODS: Adults older than 18 years who underwent primary, elective single-level lumbar microdiscectomy between June 2018 and March 2025 with at least 3 months of follow-up were included. Patients were grouped by BMI: without obesity (WO, BMI < 30), class I (CI, 30-34.9), class II (CII, 35-39.9), and class III (CIII, ≥40). Outcomes were analyzed separately for open microdiscectomy (OM), tubular microdiscectomy (TM), and endoscopic discectomy (ED). Continuous variables were compared using Kruskal-Wallis testing with Dunn post hoc analysis; categorical variables were compared with chi-square tests. Significance was set at p < 0.05. RESULTS: A total of 757 patients were included (OM 422, TM 190, ED 145). Higher obesity classes underwent ED more frequently (p = 0.038). In the OM cohort (WO 258, CI 97, CII 50, CIII 17), CI had a higher proportion of males and CII a lower proportion (p = 0.007). Operative time, length of stay, and estimated blood loss were greatest in CII and CIII patients (all p < 0.001). CII patients also had more emergency department visits within 1 year than other classes (p = 0.026). No differences were found in age, smoking status, disc herniation type, dural tears, intraoperative or postoperative complications, or revision presence/time. In the TM cohort (WO 117, CI 47, CII 21, CIII 5), WO patients were oldest and CIII youngest (p < 0.001), with no other significant differences. In the ED cohort (WO 79, CI 31, CII 20, CIII 15), WO patients were oldest and CIII youngest (p = 0.004). CIII patients had higher estimated blood loss (p = 0.028) and shorter time to revision (p < 0.001), while other variables were similar. CONCLUSIONS: ED was used more often in higher obesity classes. In OM, CII and CIII obesity were associated with longer operative time, longer hospital stay, and greater blood loss, likely due to increased exposure requirements. TM and ED showed few obesity-related differences in complications, suggesting minimally invasive approaches may mitigate obesity-related perioperative risk. However, the retrospective design and small number of CIII patients warrant further study.

Humans↗

PubMed2026

Soft Tissue Volume Augmentation at Single Implant Sites Applying Collagen Matrices or Connective Tissue Grafts: 10-Year Follow-Up of a Randomized Controlled Trial.

AIM: To compare up to 10 years clinical, profilometric and patient-reported outcomes of implant sites previously augmented using a volume-stable collagen matrix (VCMX) or connective tissue graft (SCTG) in the aesthetic zone. METHODS: The original non-inferiority randomized controlled trial (RCT) enrolled 20 patients who received soft tissue volume augmentation with VCMX or SCTG at single implant sites. Clinical assessments and standardized measurements were performed at baseline after crown insertion and at 6 months, 1, 3, 5, 7.5, and 10 years. The primary outcome was mucosal thickness. Secondary outcomes included marginal bone levels (MBL), probing depth (PD), bleeding on probing (BOP), plaque control record, Pink Aesthetic Score (PES), OHIP-14 and buccal profilometric changes. Group comparisons were performed using mixed-effects and generalized estimating equation (GEE) models, which account for within-patient correlations due to repeated measurements and allow inclusion of all available data without requiring imputation for missing observations. RESULTS: Of the 20 originally enrolled patients, 10 (5 in the SCTG group and 5 in the VCMX group) were available for re-examination at 10 years. The adjusted between-group difference in mucosal thickness was -0.02 mm (95% CI -0.99 to 0.96). As the lower bound of the confidence interval remained above the prespecified non-inferiority margin of -1 mm, non-inferiority of VCMX was shown. Buccal contour changes were comparable during the early follow-up, while a trend toward a greater long-term contour decrease was observed in group VCMX (-0.31 mm [95% CI, -0.65 to 0.03]; p = 0.07). Mean PES values were 10.6 in the SCTG group and 9.6 in the VCMX group, with no significant between-group differences (p = 0.45). Both groups revealed high levels of oral health-related quality of life, with low median OHIP-14 scores (SCTG, 0.0; VCMX, 1.0; p = 0.26). CONCLUSION: These preliminary long-term findings showed no clinically relevant differences between SCTG and VCMX in terms of clinical, profilometric and patient-reported outcomes. While SCTG remains the reference standard, VCMX represents a less invasive alternative but with a slight tendency toward greater long-term contour reduction. CLINICAL SIGNIFICANCE: Volume-stable collagen matrices serve as a viable alternative to autogenous connective tissue grafts for peri-implant soft tissue volume augmentation, particularly in patients seeking a reduced morbidity, without compromising long-term clinical or aesthetic outcomes. TRIAL REGISTRATION: German Clinical Trials Register: DRKS00017484.

Humans↗