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PubMed2026

Coordinated use of three homocysteine methyltransferases supports l-methionine biosynthesis and environmental adaptation among plant-associated bacteria.

Plant pathogens colonize multiple plant-associated habitats throughout their life cycle, encountering distinct nutrient conditions and microbial communities. l-methionine is required for bacterial growth and environmental adaptation. However, how plant pathogens coordinate l-methionine biosynthetic pathways to adapt to different plant-associated environments remains poorly understood. Here, using the plant pathogen Xanthomonas campestris pv. campestris strain XC1 as a model, we show that three homocysteine methyltransferase pathways allow XC1 to catalyze the final step of l-methionine biosynthesis using different methyl donors and cofactors under different environmental conditions. Bioinformatic and transcriptional analyses identified three homocysteine methyltransferase-associated operons in XC1, mesMXD, mmuPM, and metHRHaHb, corresponding to the MesD-, MmuM-, and MetHaHb-dependent pathways, respectively. MesD uses an endogenously synthesized methyl donor and functions as the dominant homocysteine methyltransferase under l-methionine-limiting conditions, supporting bacterial growth, intracellular l-methionine accumulation, and full virulence. Furthermore, MmuM enables XC1 to use plant-derived S-methylmethionine for l-methionine biosynthesis, whereas MetHaHb enables XC1 to use vitamin B12 supplied by a neighboring bacterium for l-methionine biosynthesis in co-culture. Expression analyses showed that mesMXD was the only homocysteine methyltransferase-associated operon that responded to l-methionine availability, and its expression also decreased when S-methylmethionine- or vitamin B12-dependent pathways supported l-methionine biosynthesis. Comparative genomic analysis further showed that the three-homocysteine methyltransferase configuration is conserved in Xanthomonas and is also present in other plant-associated bacteria. Together, these findings show that a plant pathogen can coordinate endogenous, plant-derived, and microbially supported homocysteine methyltransferase pathways to maintain l-methionine biosynthesis, providing a metabolic strategy for adaptation to plant-associated environments.

Methionine↗

PubMed2026

Prognostic Value of Frailty in Aortic Surgery: A Systematic Review and Meta-Analysis Comparing Frailty Assessment Tools.

BACKGROUND: Frailty is increasingly recognized as an important determinant of outcomes after aortic vascular surgery, but assessment methods vary substantially and the optimal tool for risk stratification remains uncertain. This systematic review and meta-analysis evaluated the prognostic value of preoperative frailty and compared the predictive performance of different frailty instruments in aortic surgery. METHODS: PubMed, Embase, and Cochrane Library were searched from inception to April 27, 2026. Eligible studies included patients undergoing open, endovascular, or hybrid aortic procedures involving abdominal, thoracic, thoracoabdominal, arch, and proximal aortic diseases, including aneurysms and dissections, assessed frailty preoperatively, and reported postoperative outcomes. RESULTS: Thirty studies comprising 419,459 patients were included. Frailty was associated with higher early mortality (odds ratio [OR] 2.20; 95% confidence interval [CI] 1.54-3.14) and late mortality (hazard ratio 2.18; 95% CI 1.64-2.90). Frail patients also had increased risks of major complications (OR 2.52; 95% CI 1.22-5.19), acute kidney injury (OR 1.64; 95% CI 1.34-2.02), and nonhome discharge (OR 5.50; 95% CI 3.05-9.92). Associations were consistent across surgical approaches and aortic segments. Judgment-based or phenotype-like tools yielded higher effect estimates than deficit-accumulation indices, although differences were not statistically significant; among index-based tools, Modified Frailty Index (mFI)-11 outperformed mFI-5. CONCLUSION: Preoperative frailty strongly predicts mortality, morbidity, and loss of functional independence after open, endovascular, and hybrid aortic surgery across different aortic segments and pathologies, including aneurysmal and dissecting aortic disease. Routine frailty assessment may improve risk stratification and perioperative decision-making.

Humans↗

PubMed2026

Long-term hormone therapy for perimenopausal and postmenopausal women.

BACKGROUND: Hormone therapy is widely provided to control menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005. OBJECTIVES: To assess the long-term effects of prolonged use (at least one year) of hormone therapy on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures and cognition in perimenopausal and postmenopausal women. SEARCH METHODS: We used the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, three other databases and two trial registers, together with reference checking, citation searching and contact with study authors to identify the studies included in the review. The latest search date was 26 September 2024. SELECTION CRITERIA: We included randomised, double-blind trials in which peri- or postmenopausal women took hormone therapy or placebo for at least one year. We included various oestrogen formulations, with or without progestogens. We focused on studies assessing hormone therapy's effects on long-term clinical outcomes, including death, coronary events and cancer. Hormone therapy's efficacy in managing menopausal symptoms was beyond the scope of this review, and is assessed in other Cochrane reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 24 studies - with two newly added in this update - involving 45,660 participants. We derived nearly 70% of the data from two well-conducted studies: the Heart and Estrogen/progestin Replacement Study (HERS 1998) and the large, multi-component Women's Health Initiative research programme, which included two hormone therapy arms (WHI 1998). Across all the studies, most participants were postmenopausal American women with one or more comorbidities. The mean participant age in most studies was over 60 years. Only one included study focused on perimenopausal women. We present full results for all included studies with available data in the main review. The results presented below are drawn from WHI 1998, in which the combined hormone therapy arm and the oestrogen-only arm were run concurrently, with women assigned to the appropriate trial based on their uterus status. One study with 16,608 postmenopausal women with an intact uterus compared combined continuous hormone therapy (conjugated equine oestrogen and medroxyprogesterone acetate) to placebo, and measured outcomes at an average of 5.6 years of follow-up. Based on this study, combined continuous hormone therapy probably makes little to no difference to the risk of a coronary event (RR 1.17, 95% CI 0.95 to 1.44; moderate-certainty evidence). It may increase the risk of stroke (RR 1.39, 95% CI 1.09 to 2.09; low-certainty evidence) and venous thromboembolism (RR 2.03, 95% CI 1.55 to 6.64; low-certainty evidence). Compared to placebo, combined continuous hormone therapy probably increases the risk of breast cancer (RR 1.27, 95% CI 1.03 to 1.56; moderate-certainty evidence) and probably makes little to no difference to the risk of lung cancer (RR 1.06, 95% CI 0.77 to 1.46; moderate-certainty evidence). It may increase gallbladder disease requiring surgery (RR 1.64, 95% CI 1.30 to 2.06; 14,203 participants; low-certainty evidence), and probably reduces the risk of all clinical fractures (RR 0.78, 95% CI 0.71 to 0.86; moderate-certainty evidence). One study including 10,739 postmenopausal women who had undergone a hysterectomy compared oestrogen-only (conjugated equine oestrogen) hormone therapy to placebo, and measured outcomes at an average of seven years' follow-up. Based on this study, oestrogen-only hormone therapy probably makes little to no difference to the risk of coronary events (RR 0.94, 95% CI 0.78 to 1.13), venous thromboembolism (RR 1.32, 95% CI 1.00 to 1.74) and breast cancer (RR 0.79, 95% CI 0.61 to 1.01), all with moderate-certainty evidence. It may make little to no difference to the risk of lung cancer (RR 1.04, 95% CI 0.73 to 1.48; low-certainty evidence). Oestrogen-only hormone therapy probably increases the risk of stroke (RR 1.33, 95% CI 1.06 to 1.67) and gallbladder disease requiring surgery (RR 1.78, 95% CI 1.42 to 2.24), and probably reduces the risk of all clinical fractures (RR 0.73, 95% CI 0.65 to 0.80), all with moderate-certainty evidence. We judged most included studies to have a low risk of bias for most domains. The overall certainty of evidence for the main comparisons was moderate. The main limitation was that only about 30% of women were 50 to 59 years old at baseline, the age group most likely to consider hormone therapy for vasomotor symptoms. AUTHORS' CONCLUSIONS: Long-term follow-up of women using hormone therapy suggests that the risk profiles vary between combined hormone therapy and oestrogen-only therapy. Oestrogen-only hormone therapy probably makes little to no difference to coronary events, and probably increases the risk of stroke and gallbladder disease. It probably makes little to no difference in the risk of breast cancer, and probably reduces the risk of all fractures. Combined hormone therapy may increase the risk of thromboembolism and probably increases the risk of breast cancer. These results should be interpreted with caution as they are based on one study using oral hormone therapy, which may not represent the risks of the hormone therapy currently used in clinical practice.

Humans↗

PubMed2026

Recurrence of peripartum cardiomyopathy in subsequent pregnancy stratified by left ventricular function: a systematic review and meta-analysis.

AIMS: Subsequent pregnancy in women with prior peripartum cardiomyopathy (PPCM) carries a risk of relapse and adverse maternal outcomes. This meta-analysis aimed to determine the recurrence of PPCM relapse and associated maternal and foetal outcomes during subsequent pregnancy, stratified by baseline (pre-subsequent pregnancy) left ventricular ejection fraction (LVEF). METHODS: A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. Nine databases were searched through June 2025 for cohort studies reporting subsequent pregnancy outcomes in women with prior PPCM, stratified as recovered (LVEF ≥50%) or non-recovered (LVEF <50%) groups. Outcomes included PPCM relapse, maternal mortality, LVEF during and after pregnancy, LV recovery, symptom worsening, and obstetric/neonatal events. Risk of bias was assessed with ROBINS-E, and random-effects models were used. RESULTS: Six cohort studies comprising 266 women were included (174 in recovered group and 92 in non-recovered group). Relapse occurred in both groups with no significant difference [rate ratio (RR) 0.77, 95% CI 0.50-1.19; I2 = 3%]. Maternal mortality was significantly lower in the recovered group (1.7% vs 10.9%; RR 0.27, 95% CI 0.09-0.87; I2 = 0%). Recovered group had higher mean LVEF during subsequent pregnancy (mean difference [MD] 17.0; P < .001), higher postpartum LVEF (MD 11.69; P = .005; I2 = 84%), and greater likelihood of LV recovery (RR 2.07; P = .005; I2 = 0%). No significant differences were observed in symptom worsening or obstetric/neonatal outcomes. CONCLUSION: Recovered LVEF prior to subsequent pregnancy is associated with improved maternal outcomes, yet relapse remains common. Left ventricular ejection fraction alone is insufficient for risk stratification, and individualized multidisciplinary care is essential for all women with prior PPCM.

Female↗

PubMed2026

Surgical management and outcomes of total colonic aganglionosis in children: A systematic review and meta-analysis.

AIM: Total colonic aganglionosis (TCA) is a rare form of Hirschsprung disease, and there is no consensus regarding its optimal surgical management. This systematic review and meta-analysis aimed to evaluate different surgical approaches and outcomes in children with TCA. METHODS: A systematic search of PubMed/MEDLINE and Embase was performed for studies published between January 2000 and December 2025. The review followed PRISMA guidelines and was prospectively registered in PROSPERO (CRD420251078401). Eligible studies included patients aged ≤18 years with TCA who underwent conventional pull-through procedures (CPT; Duhamel, Soave, Swenson, Rehbein, and Ikeda-Soper) or non-conventional techniques (NCPT; STATE procedure, J-pouch, right- or left-sided colonic patch pull-through, and ileocecal patch). A subgroup analysis comparing Duhamel and ileoanal pull-through procedures (IAPT) was also performed. Outcomes included fecal incontinence, Hirschsprung-associated enterocolitis (HAEC), requirement for additional interventions, postoperative intestinal obstruction, and mortality. Meta-analysis was performed using jamovi software, version 2.3.28, with p < 0.05 considered statistically significant. RESULTS: Seven studies including 134 patients compared CPT (n = 85) with NCPT (n = 49), and ten studies including 274 patients compared Duhamel (n = 143) with IAPT (n = 131). Across both comparisons, pooled odds ratios (ORs) showed no statistically significant differences in fecal incontinence, HAEC, requirement for additional interventions, postoperative intestinal obstruction (Duhamel vs IAPT only), or mortality. For CPT versus NCPT, the pooled ORs were 1.1 for fecal incontinence (95% CI, 0.44-2.73; p = 0.837), 1.1 for HAEC (95% CI, 0.49-2.71; p = 0.743), 4.3 for requirement for additional interventions (95% CI, 0.86-22.1; p = 0.074), and 3.4 for mortality (95% CI, 0.52-21.5; p = 0.198). For Duhamel versus IAPT, the pooled ORs were 1.4 for fecal incontinence (95% CI, 0.60-3.36; p = 0.423), 0.6 for HAEC (95% CI, 0.22-2.06; p = 0.503), 1.8 for requirement for additional interventions (95% CI, 0.62-5.50; p = 0.262), 1.1 for postoperative intestinal obstruction (95% CI, 0.21-6.01; p = 0.875), and 1.03 for mortality (95% CI, 0.25-4.20; p = 0.965). CONCLUSION: No statistically significant differences were identified between CPT and NCPT or between Duhamel and IAPT for the evaluated outcomes in children with TCA. However, the absence of statistically significant differences should not be interpreted as evidence of equivalence, particularly given the small sample sizes, wide confidence intervals, and clinical and methodological heterogeneity of the studies included. The choice of surgical approach should be individualized according to disease extent, patient-specific factors, institutional experience, and surgical expertise. TYPE OF STUDY: Meta-analysis. LEVEL OF EVIDENCE: III.

Humans↗

PubMed2026

Effects of erector spinae plane block on postoperative pain in patients undergoing implant-based breast reconstruction for breast cancer: a randomized controlled trial.

BACKGROUND: Implant-based breast reconstruction after mastectomy causes acute pain. OBJECTIVE: To determine whether a single-shot T5 erector spinae plane block (ESPB) reduces postoperative pain. DESIGN: Single-center, RCT with allocation concealment; blinded assessors and statisticians. SETTING: Tertiary cancer center in China. PATIENTS: 100 adults scheduled for radical mastectomy with implant reconstruction were randomized (1:1); follow-up complete. INTERVENTION: Before induction, ESPB was given under ultrasound guidance at T5 with 30 mL of 0.375% ropivacaine plus dexmedetomidine 1 μg/kg; controls received no block. Standardized general anesthesia and postoperative PCA for both groups. MAIN OUTCOME MEASURES: Resting NRS at 6 h (MCID=1). Secondary outcomes were opioid consumption, quality of recovery, and PONV. RESULTS: ESPB did not significantly reduce resting pain at 6 h at the median (τ =0.50; adjusted difference -0.9; p = 0.08). At the upper tail, pain intensity was lower (τ = 0.75; -1.8; p <0.01). Repeated measures provided additional time-point information, improving estimation precision and test sensitivity. ESPB get lower pain scores at 6, 12, and 24 hours (all p <0.01). But, the 95% CI includes the MCID, the clinical benefit remains uncertain. Opioid use decreased at 24 h (-13.5 mg; p <0.01) and 48 h (-6.6 mg; p <0.01). Quality of recovery improved at 24 h (difference 5 points; p <0.01), but not later. No differences were observed in intraoperative hemodynamics or PONV. CONCLUSIONS: Single-shot T5 ESPB with perineural dexmedetomidine may reduce postoperative pain and opioid requirements and improve early recovery. Further large trials are warranted. Clinical relevance remains to be confirmed. TRIAL REGISTRATION: ClinicalTrials.gov NCT06143020.

Humans↗

PubMed2026

Sutureless versus renorrhaphy in robot-assisted off-clamp partial nephrectomy: a systematic review and meta-analysis.

BACKGROUND: The necessity of routine parenchymal renorrhaphy during off-clamp robot-assisted partial nephrectomy (RAPN) remains uncertain. This study aimed to compare perioperative, functional, safety, and oncological outcomes between sutureless and conventional renorrhaphy. METHODS: We conducted a systematic review and meta-analysis following PRISMA 2020 guidelines. Comparative studies evaluating sutureless versus conventional renorrhaphy during purely off-clamp RAPN were included. Trifecta achievement was the primary outcome. Random-effects models were used for pooled analyses, with subgroup analysis according to study design. RESULTS: Four studies involving 787 patients, including one randomized controlled trial (RCT) and three propensity score-matched (PSM) studies, were included. The overall pooled estimate showed no statistically significant difference in Trifecta achievement (RR 1.17, 95% CI 0.97-1.41), with substantial heterogeneity (I² = 86.5%). The PSM studies favored the sutureless approach (RR 1.26, 95% CI 1.05-1.52), whereas the RCT yielded an RR of 0.97 (95% CI 0.92-1.04) and met the prespecified noninferiority criterion without demonstrating superiority. The sutureless approach was associated with a smaller perioperative eGFR decline (MD - 3.89, 95% CI - 6.16 to - 1.62), while no significant difference was observed in eGFR at 3 months. No statistically significant differences were identified in major complications, blood transfusion, or positive surgical margins; urinary and vascular complications were sparsely reported. CONCLUSIONS: In selected patients undergoing purely off-clamp RAPN, randomized evidence supports the noninferiority of a strategy that omits routine parenchymal renorrhaphy while permitting clinically necessary selective repair, but does not demonstrate superiority. Favorable estimates from PSM studies remain vulnerable to intraoperative treatment-selection bias. Current evidence is insufficient to determine whether omission of renorrhaphy affects urinary complications, long-term renal function, or oncological outcomes. REGISTRATION: This systematic review was registered prospectively in PROSPERO (CRD420261435995).

Humans↗

PubMed2026

Holmium laser enucleation of the prostate for the treatment of lower urinary tract symptoms in men with benign prostatic hyperplasia.

RATIONALE: A range of surgical options is available for the treatment of benign prostatic hyperplasia (BPH), including holmium laser enucleation of the prostate (HoLEP). The evidence is unclear regarding differences in functional, perioperative, and morbidity outcomes between these modalities. OBJECTIVES: To assess the effects of holmium laser enucleation of the prostate compared with other surgical treatments for lower urinary tract symptoms in men with benign prostatic hyperplasia. SEARCH METHODS: We searched multiple databases (including MEDLINE, Embase, CENTRAL, Web of Science, LILACS, and the International HTA database), trial registries, and conference abstracts through April 08, 2026. ELIGIBILITY CRITERIA: We only included randomized trials of men over 40 years of age with a prostate volume of at least 20 mL (assessed by digital rectal examination, ultrasound, or conventional imaging) who exhibited lower urinary tract symptoms (LUTS) defined by an International Prostate Symptom Score (IPSS) of eight or greater undergoing surgical interventions for BPH. OUTCOMES: The critical outcomes measured were the urologic symptoms score, the quality-of-life score, and major adverse events. The important outcomes measured were: re-treatment, erectile function, ejaculatory function, transfusions, acute urinary retention, indwelling urinary catheter duration, and hospital stay duration. RISK OF BIAS: We used the Cochrane risk of bias tool (RoB 1) to assess for potential sources of bias on a study and outcome level basis. SYNTHESIS METHODS: We pooled outcome data using the random-effects model and performed meta-analyses using the Mantel-Haenszel method. We assessed statistical heterogeneity in the pooled data by visually inspecting forest plots and using the I2 statistic to quantify it. We used the GRADE framework to assess the certainty of evidence. INCLUDED STUDIES: We included 52 trials that included 6242 participants that compared HoLEP to other surgical interventions for benign prostatic hyperplasia. The median age of participants across the studies ranged from 65 to 74 years. The baseline prostate volume ranged from 30 cc to 142 cc. Baseline IPSS scores ranged from 19.6 to 28.6 (range 0-35). SYNTHESIS OF RESULTS: We prioritized comparing HoLEP with transurethral resection of the prostate (TURP) at short-term follow-up (up to 12 months), because TURP is the long-standing reference standard and the predominant comparator in randomized surgical trials. Findings for the four remaining comparisons (laser ablation, alternative energy source enucleation, other minimally invasive therapies, and simple prostatectomy), for long-term follow-up, and for all remaining outcomes are reported in full in the review. Compared to TURP, at short-term follow-up: Critical outcomes - HoLEP may result in little to no difference in short-term urologic symptom scores measured using the IPSS (range 0 to 35; lower values reflect fewer symptoms) (MD -0.67, 95% CI -1.20 to -0.14; I² = 93%; 14 studies, 1666 participants, low-certainty evidence). - HoLEP may result in little to no difference in short-term quality of life (range 0 to 6; lower values reflect better quality of life) (MD -0.04, 95% CI -0.23 to 0.15; I² = 73%; 6 studies, 876 participants, low-certainty evidence). - HoLEP may result in little to no difference in short-term major adverse events (RR 0.75, 95% CI 0.35 to 1.58; I² = 0%; 10 studies, 1147 participants, low-certainty evidence). Important outcomes - HoLEP likely results in little to no difference in re-treatment (RR 0.45, 95% CI 0.14 to 1.50; I² = 0%; 8 studies, 813 participants, moderate-certainty evidence). - HoLEP likely results in little to no difference in erectile function (MD -0.03, 95% CI -0.47 to 0.42; I² = 0%; 3 studies, 518 participants, moderate-certainty evidence). - Ejaculatory function: we did not find any data for this outcome. - HoLEP likely reduces the need for blood transfusion (RR 0.19, 95% CI 0.09 to 0.42; I² = 0%; 15 studies, 1755 participants, moderate-certainty evidence). AUTHORS' CONCLUSIONS: Compared with TURP, HoLEP may achieve similar relief of urologic symptoms, similar quality of life, and similar rates of major adverse events in the first 12 months after surgery, and probably similar re-treatment rates and erectile function. HoLEP likely reduces the need for blood transfusion; this is the only advantage of HoLEP that the randomized evidence, as summarized here, supports as clinically important. There was insufficient evidence to assess outcomes in the subset of individuals with larger prostates or on anticoagulation. Future research should prioritize long-term trials reporting sexual function and urinary incontinence outcomes, recruit men with very large prostates (≥ 150 cc) or on anticoagulation therapy, and evaluate cost-effectiveness and training requirements. FUNDING: No external funding was received for this review. REGISTRATION: The protocol for this review was published in the Cochrane Database 2019 (https://doi.org/10.1002/14651858.CD013291).

Humans↗

PubMed2026

Repeated low-level red-light therapy for improving asthenopic symptoms and accommodation in presbyopia.

BACKGROUND: To assess the short-term effectiveness of repeated low-level red light (RLRL) therapy in relieving asthenopia and enhancing accommodation in presbyopia. METHODS: This randomized, parallel-group, double-masked clinical trial enrolled adults with presbyopia and self-reported asthenopia. Participants were allocated using computer-generated randomization and randomly assigned at a 1:1 ratio to RLRL or sham groups. Blinding included participants, examiners, assessors, and statisticians. The primary outcome was the change from baseline in the Computer Vision Syndrome Questionnaire (CVS-Q) score at day 31. Secondary outcomes were the change in accommodative amplitude (AA), Near Activity Visual Questionnaire (NAVQ) score, habitual near visual acuity, near-addition power, accommodative facility, positive and negative relative accommodation, binocular cross-cylinder response, and accommodative convergence-to-accommodation ratio. Continuous outcomes were analyzed using linear mixed-effects models. RESULTS: Sixty-four of 66 randomized participants (aged 41-62 years) completed the 1-month trial. At day 31, RLRL showed greater improvement than sham in CVS-Q score (adjusted mean difference, -1.75 points; 95% CI, -3.10 to -0.39), binocular AA (1.09 D; 95% CI, 0.37 to 1.82), and NAVQ score (-8.07 points; 95% CI, -14.17 to -1.97). The effect on AA was most pronounced in a subgroup of eyes with baseline amplitude >2.0 D (adjusted mean difference 1.33 D; 95% CI 0.32-2.34). Other measures did not differ between groups at each visit. No treatment-related adverse events were reported. Adherence was similar between groups (mean compliance: 98.2% vs 97.5%). CONCLUSIONS: Short-term treatment with RLRL significantly reduced asthenopic symptoms and improved accommodative amplitude in individuals with presbyopia.Trial registration: NCT06745661 (registered December 8, 2024).

Humans↗

PubMed2026

Clinical performance of two lithium disilicate CAD/CAM materials in posterior Class II inlay restorations: A 48-month randomised split-mouth clinical trial.

OBJECTIVES: To compare the clinical performance of Amber Mill (AM) and IPS e.max CAD (EM) lithium disilicate computer-aided design/computer-aided manufacturing (CAD/CAM) materials in posterior Class II inlay restorations and characterise their baseline properties. METHODS: Thirty-four adults received paired AM and EM posterior Class II inlays (68 restorations) in a triple-blind randomised split-mouth trial followed for 48 months. Restorations were evaluated at baseline and annually using revised World Dental Federation (FDI) criteria, with fracture and retention as the primary endpoint. Baseline characterisation included flexural strength, shear bond strength, translucency parameter, and scanning electron microscopy. McNemar, Wilcoxon signed-rank, Friedman, one-way analysis of variance, Tukey post hoc, and inter-rater agreement analyses were used. RESULTS: At 48 months, 18 paired participants were available for primary analysis. Failures occurred in 2 of 18 AM restorations and in 3 of 18 EM restorations, corresponding to success rates of 88.9% and 83.3%, respectively, with no significant between-material difference (McNemar p = 1.000). No catastrophic bulk ceramic fracture was observed. Secondary FDI scores remained mostly within the clinically acceptable range; marginal staining deteriorated over time in both groups (p < .001) without significant between-material differences. Baseline material testing showed significant material- and translucency-dependent differences in flexural strength, shear bond strength, and translucency. CONCLUSIONS: Within the limitations of the 48-month follow-up and the tested Class II inlay indication, AM showed clinical performance comparable to EM. Observed clinical complications were related to retention or marginal/interface behaviour. CLINICAL SIGNIFICANCE: For posterior Class II lithium disilicate CAD/CAM inlays, medium-term complications were mainly retention/interface-related, suggesting adhesive-interface durability may be as important as baseline ceramic strength.

Humans↗

PubMed2026

Proteome-level evidence that tebuconazole, both alone and in interaction with thiacloprid, affects epigenetic events in bumblebee heads.

Tebuconazole, a widely used ergosterol biosynthesis-inhibiting fungicide, can affect nontargets, especially when combined with insecticides. We employed label-free quantitative proteomics to investigate the effects of long-term exposure to sublethal concentrations (100 μg/L) of tebuconazole, either by itself or alongside the neonicotinoid thiacloprid (100 μg/L), on the heads of Bombus terrestris workers. A Bayesian factor power analysis revealed that the experiment produced conclusive proteomic results. Tebuconazole treatment revealed eleven differentially abundant proteins, which increased elevenfold with thiacloprid. The proteins that changed in the same direction in both treatments suggest the occurrence of epigenetic events because they are involved in histone trimethylation (H3K4me3), pre-mRNA processing, and folate (vitamin B9) metabolism. Following co-exposure, the abundance of histone H2A.V and its associated proteins was affected. Two important detoxification-related proteins, CYP6BE1 and CYP6AQ1 (honey bee homologs), were identified, as well as proteins that suggest hormonal and neurotoxic effects. Overall, this study suggests that tebuconazole affects key epigenetic processes in bumblebee heads at the proteome level, though this was not confirmed at the biological level or through orthogonal methods. The tested chemicals were previously found to affect trimethylations, but not H3K4me3. We suggest analyzing the different trimethylations, their interplay, and associated hallmarks, such as folate levels. SIGNIFICANCE: The effects of pesticides and their combinations on organisms can be unexpected until they are examined using modern, complex methods. High-throughput proteomics can provide data on important biochemical processes affected by pesticides, offering a different perspective to that at the expression level. Despite their low acute toxicity, a group of fungicides that inhibit (ergo)sterol biosynthesis (EBI or SBI) are considered dangerous to pollinators, including bumblebees. This is due to the increasing toxicity of insecticides through the inhibition of cytochrome P450 detoxification enzymes. We found that tebuconazole had a similar effect on epigenetic events when used alone or in combination with the insecticide thiacloprid. Key proteins suggest that H3K4 histone trimethylation (H3K4me3) was impacted. To our knowledge, this expands the existing evidence suggesting that tebuconazole/triazole fungicides affect histone trimethylation H3K27me3. Since literature shows that thiacloprid affects H3K9me3, it is possible that thiacloprid and tebuconazole interact in these epigenetic events that affect each other. Overall, our results suggest that tebuconazole affects proteins involved in histone trimethylation, pre-mRNA processing, and folate metabolism. These are all hallmarks of epigenetic processes and were further extended by the co-exposure of tebuconazole and thiacloprid to more differently abundant proteins. Additionally, the results provide data on cytochrome P450s of the CYP6 family, which act as detoxifying proteins, as well as proteins that indicate hormonal and neurotoxic effects in bumblebee heads. Finally, the results of the Bayesian power analysis confirmed the meaningfulness of the proteomic data analyzed in this study. If the new findings obtained at the proteome level are verified by different methods, the full extent of the side effects of tebuconazole can be revealed.

Animals↗

PubMed2026

Association between SGLT2 inhibitors and reporting of phimosis/paraphimosis: a comparative pharmacovigilance analysis of the WHO database.

PURPOSE: Recent data have discussed occurrence of phimosis with Sodium-glucose co-transporter-2 (SGLT2) inhibitors. However, the potential risk among the different SGLT2 inhibitors is unknown. METHODS: Using Individual Case Safety Reports (ICSRs) registered in the WHO pharmacovigilance database (01/01/2000-30/06/2025), comparisons between the different SGLT2 inhibitors and versus other drugs used in diabetes (DUD) were performed. Results are shown as Reporting Odds Ratios (ROR). RESULTS: Among 11 342 810 ICSRs, 227 were phimosis/paraphimosis with SGLT2 inhibitors, mainly between 45 and 64 years. The higher ROR value was found with empagliflozin followed by dapagliflozin and canagliflozin. ROR for SGLT2 inhibitors was higher that of all other DUD [34.72 (25.86-46.62)]. The reporting risk of phimosis/paraphimosis with SGLT2 inhibitors was also higher than that of each pharmacological class of DUD. CONCLUSION: The results suggest an association between SGLT2 inhibitors use and phimosis ICSRs. Empagliflozin had the higher reporting risk.

Humans↗

PubMed2026

Empagliflozin and functional aerobic capacity in individuals with increased risk of heart failure: The Empire Prevent Cardiac trial.

BACKGROUND: Higher maximal oxygen consumption (VO₂ max) is associated with lower risk of developing heart failure (HF). Empagliflozin improves VO2 max in HF with reduced ejection fraction, but the effect on VO2 max in individuals at risk of HF remain unknown. OBJECTIVE: This study aimed to evaluate the effect of 180 days treatment with empagliflozin compared to placebo on VO2 max, daily physical activity level, and quality of life (QoL) in individuals with overweight or obesity and risk of HF. METHOD: This investigator-initiated, double-blinded, randomized, placebo-controlled, multicenter trial included elderly individuals with body mass index >28 kg/m2 and at least one additional risk factor for HF, including hypertension, ischemic heart disease, stroke, or chronic kidney disease. Individuals with HF or type 2 diabetes mellitus were excluded. The primary endpoint was the mean difference in change of VO2 max. The secondary outcome was objectively measured physical activity level. QoL was an explorative outcome. RESULTS: Among 191 randomized individuals (94 empagliflozin, 97 placebo), 89% had hypertension and 66% ischemic heart disease. At baseline, 69% were male, median age was 68 years, median body mass index 31.9 kg/m², mean left ventricular ejection fraction 65 ± 9%, and mean VO₂ max 18.1 ± 4.3 mL/min/kg. Empagliflozin did not change VO2 max with an estimated treatment difference of -0.2 mL/min/kg (97.5% confidence interval -1.2 to 0.8), adjusted P = 1.00. No significant treatment differences were observed for neither daily physical activity nor QoL. CONCLUSIONS: Empagliflozin did not affect VO2 max, physical activity level, or QoL in elderly individuals with overweight or obesity and risk of HF.

Humans↗

PubMed2026

Novelty seeking and rapid symptom improvement across active and sham accelerated iTBS conditions: A pooled individual-patient data analysis.

INTRODUCTION: Major depressive disorder (MDD) is highly prevalent and often treatment-resistant. Accelerated intermittent theta burst stimulation (aiTBS) is a promising intervention for treatment-resistant depression (TRD), though outcomes vary. Personality traits have been examined in relation to rTMS outcomes, yet their role in aiTBS remains underexplored. This pooled individual-patient-data analysis of two randomized, sham-controlled trials examined associations between baseline Temperament and Character Inventory (TCI) traits and one-week symptom change, and whether they differed by condition. METHODS: The left dorsolateral prefrontal cortex was targeted for 20 sessions over 4 days. Personality was assessed with the TCI, depression severity with the 17-item Hamilton Depression Rating Scale (HDRS-17). TCI-symptom-change associations were examined with a robust linear mixed-effects model, adjusting for age, gender, repeated measurements, and study membership. RESULTS: 104 participants were included (M/F 45/59; mean age 40.9 ± 12.7; active/sham 50/54). The model yielded a Time × Novelty Seeking interaction (β = -1.70, p = 0.021): higher baseline Novelty Seeking was associated with faster symptom reduction, without a between-arm difference. However, the interaction did not survive Holm correction across 14 trait-interaction tests (adjusted p = 0.294) and is therefore exploratory. No other interaction reached the uncorrected threshold. CONCLUSIONS: Higher baseline Novelty Seeking showed a nominal association with faster symptom reduction, without a difference between active and sham conditions. Because it did not survive multiplicity correction and was not reproduced in within-arm analyses, it is preliminary and may reflect contextual or nonspecific processes. Independent replication is required before temperament assessment can be clinically informative.

Humans↗

PubMed2026

Physicochemical effects of bicarbonate-buffered solution versus compound sodium lactate during major abdominal surgery: A randomized, open-label, non-inferiority trial.

INTRODUCTION: Bicarbonate-buffered crystalloids avoid exogenous lactate and have physicochemical properties distinct from compound sodium lactate (CSL), but direct comparative evidence during major abdominal surgery remains limited. METHODS: This single-center, open-label, randomized non-inferiority trial enrolled high-risk adults undergoing elective major abdominal surgery. Participants received bicarbonate-buffered solution or CSL as the allocated intraoperative crystalloid. The primary estimand was the arithmetic mean difference in standard base excess (SBE) at skin closure (bicarbonate-buffered solution minus CSL). The non-inferiority margin was -1.5 mEq/L. The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619001228178). RESULTS: Fifty participants were randomized (25 per group) and received their allocated intervention. End-of-surgery arterial blood gas data were missing for two CSL participants. In the intention-to-treat analysis using multiple imputation, the estimated mean difference in end-of-surgery SBE was -0.42 mEq/L (95% confidence interval [CI], -1.92 to 1.09 mEq/L). The complete-case per-protocol estimate was -0.48 mEq/L (95% CI, -2.02 to 1.06 mEq/L). In both analyses, the lower CI bound was below the prespecified non-inferiority margin; non-inferiority was not established. Secondary outcomes were exploratory; observed end-of-surgery lactate was lower with bicarbonate-buffered solution (median 0.9 vs 1.2 mmol/L; unadjusted P = 0.031), without a corresponding difference in SBE or pH. CONCLUSIONS: In this small trial of hemodynamically stable adults undergoing elective major abdominal surgery, the primary non-inferiority result was inconclusive. The data did not establish interchangeability, equivalence, superiority, or inferiority of the two fluids. As the trial was powered for a physiologic endpoint, no comparative inference can be made about organ dysfunction, postoperative complications, recovery, or mortality. Larger trials with standardized co-interventions and patient-important outcomes are required before routine substitution for CSL can be recommended.

Humans↗

PubMed2026

Exploring China's Clean Air Act and associated cardiovascular disease risk: a prospective, quasi-experimental, and causal inference modelling study.

BACKGROUND: Substantial improvements in air quality have been recorded following the implementation of China's Clean Air Act (CCAA) in 2013. However, the association between CCAA implementation and individual-level cardiovascular disease (CVD) risk remains unclear. We aimed to examine the long-term association between CCAA implementation and individual-level predicted CVD risk. METHODS: In this prospective, quasi-experimental study, we used data from the China Kadoorie Biobank, a prospective cohort study that recruited participants from five urban and five rural areas across China between 2004 and 2008, with three resurveys conducted after the baseline survey (in 2008, 2013-14, and 2020-21). We included 34 862 individuals (mean age 51·3 years) who participated in at least one resurvey and had no history of CVD at baseline. Participants were classified into intervention (n=25 497) and control (n=9365) groups based on the local government's targets for particulate matter reduction. We estimated the 10-year risk of incident CVD morbidity or mortality using a validated risk prediction model. We used a difference-in-difference model to assess the long-term association between CCAA implementation and predicted risk, with adjustments made for regional confounders and individual-level characteristics, including demographics, lifestyle factors, medical history, and indoor air pollution exposure. The relationship between changes in long-term exposure to PM2·5, PM10, and O3 and predicted risk after CCAA implementation was analysed using a linear model. The estimated risk differences associated with air pollutant changes were estimated based on the magnitude of changes and their corresponding effect sizes. FINDINGS: After the CCAA was implemented, PM2·5 and PM10 concentrations declined in both groups, but O3 concentrations increased. The intervention group showed a 3·95% (95% CI 3·18-4·72%) lower increase in predicted risk than the control group, with larger estimated differences under stricter enforcement. Between 2013 and 2021, each 10 μg/m3 change in PM2·5 concentration was positively associated with a 1·80 (1·34-2·27) percentage point change in predicted CVD risk, whereas each 10 μg/m3 change in PM10 concentration was associated with a 1·24 (0·84-1·63) percentage point change and each 10 μg/m3 change in O3 concentration with a 0·58 (0·33-0·83) percentage point change. Overall, the observed changes in air pollutants during the study period were associated with an average 6·6 percentage point reduction in predicted CVD risk. INTERPRETATION: The CCAA and improved air quality were associated with a slower increase in predicted CVD risk, supporting the necessity for stricter, multipollutant air quality policies to maximise public health benefits. FUNDING: National Natural Science Foundation of China, Kadoorie Charitable Foundation, Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Key R&D Program of China, Chinese Ministry of Science and Technology, and UK Wellcome Trust.

Journal Article↗

PubMed2026

Genomic diversity and thermal niches of Aspergillus molds disrupting rind formation of surface-ripened cheeses.

Filamentous fungi play important roles in the development of surface-ripened cheese microbial communities and contribute to the aesthetics and flavors of these products. Much is known about the diversity and ecology of desirable cheese fungi, but our understanding of the natural history of cheese spoilage molds is limited. The goal of this work was to characterize the genomic diversity of Aspergillus species contaminating artisan cheeses and to identify how the abiotic environment of cheese (the substrate itself and temperature) may constrain the growth of Aspergillus. Comparative genomics identified two main species of Aspergillus, A. westerdijkiae and A. ostianus, as the spoilage molds across three different facilities in the Northeastern United States that experienced contamination events. Multiple genomic types of A. westerdijkiae were found across the different cheese production facilities, indicating that these contamination events are not caused by a single clonal strain. All A. westerdijkiae isolates produced ochratoxin A, but concentrations varied greatly across strains. RNA-sequencing of A. westerdijkiae on nutrient-rich lab media (malt extract agar) versus cheese curd agar identified a suite of pathways enriched in expression on cheese, including degradation of amino and fatty acids. Experiments measuring growth over a range of temperatures identified that spoilage Aspergillus species have a higher optimal growth temperature compared to desirable fungal species in cheese rinds and are outcompeted by Penicillium species at temperatures lower than 15°C. Global fungal metabarcoding databases suggest that A. westerdijkiae is not normally found in natural habitats of the Northeastern United States, and it may be introduced to this region.IMPORTANCEOver the past decade, disruptive contamination events of Aspergillus spoilage molds have occurred at cheese production facilities in Massachusetts, Connecticut, and Vermont in the United States, causing aesthetic, flavor, and potential safety issues. Our work highlights independent introductions of different strains of A. westerdijkiae into multiple cheese facilities and suggests that temperature could be used to control the abundance of Aspergillus spoilage molds. Based on our analysis of the global distribution of A. westerdijkiae, it is not invading cheese facilities from local fungal populations and may be a contaminant in materials used for cheese production.

Aspergillus↗

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.

Humans↗