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PubMed2026

Multiplexed CRISPR/Cas9 mediated knockdown of BCH gene in potato enhances beta-carotene to combat vitamin A deficiency.

The inadequate amounts of provitamin A carotenoids in crops contribute to the widespread vitamin A deficiency, leading to malnutrition and blindness in humans. Suppression of the β-carotene hydroxylase (BCH) increases β-carotene levels. In the current study, we utilized the multiplexed CRISPR/Cas9 approach by designing three targets against the BCH gene in a local potato cultivar. Transformation efficiency was recorded as 15%, the successful integration of the CRISPR/Cas9-BCH multiplex construct in potatoes was confirmed through PCR. When analysed using TIDE software, Sanger sequencing revealed the highest indel efficacy of 92.1% in plant 7 and 26.6% in plant 1. qRT-PCR (quantitative real-time PCR) analysis indicated a significant 89-fold reduction in BCH transcript levels in genome-edited potato lines compared to control plants. Spectrophotometry demonstrated a notable increase in beta-carotene levels in genome-edited potato plants, ranging from 0.831 µg/mL FW to 4.236 µg/mL FW, compared to the control plant with the lowest beta-carotene concentration (0.344 µg/mL FW). HPLC analysis further confirmed increased beta-carotene levels in genome-edited potato plants, ranging from 0.11 mg/mL FW to 0.36 mg/mL FW, compared to the unmodified control plant with a minimum beta-carotene value of 0.09 mg/mL. Our results revealed that the multiplexed CRISPR-Cas9 approach targeting the BCH gene results in enhanced beta-carotene contents in potato tubers.

Solanum tuberosum↗

PubMed2026

Short-term psychodynamic psychotherapy for functional neurological disorder: A pilot randomized controlled trial.

BACKGROUND: Evidence-based psychotherapeutic treatments for Functional Neurological Disorder (FND) remain limited. This pilot trial evaluated the preliminary efficacy of Short-term Psychodynamic Psychotherapy (STPP) plus Standard Medical Care (SMC) compared with SMC alone in reducing FND symptom frequency. METHODS: Adults with FND were randomized (1:1) to receive either SMC alone or 12 weekly sessions of STPP plus SMC. The primary outcome was symptom frequency (days with symptoms in the last 4 weeks) assessed at the end of treatment (3 months) and at 6-month follow-up. Secondary outcomes included treatment response (≥50% reduction in symptom frequency) and scores on the Hamilton Depression Rating Scale (HAM-D), Hamilton Anxiety Rating Scale (HAM-A), and World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). RESULTS: Of 91 randomized patients (mean age 38.2 years, 75.8% female), 81.3% completed follow-up. Intention-to-treat analysis using Linear Mixed Models showed that STPP plus SMC significantly reduced symptom frequency compared with SMC alone (estimated mean difference -5.72 [95% CI -8.68 to -2.77]; Cohen's d = 0.77; p < 0.001).Treatment response was achieved by 65.8% in the intervention group versus 16.7% in controls (OR 8.21 [95% CI 2.79-24.19]; p < 0.001; NNT 2.0).Significant improvements were also observed for depression (HAM-D: estimated mean difference -10.80; d = 1.45), anxiety (HAM-A: -7.94; d = 1.06), and disability (WHODAS 2.0: -5.77; d = 0.74), all p < 0.001. CONCLUSIONS: STPP was associated with clinically meaningful improvements in FND symptom frequency and all secondary outcomes, with large effect sizes and high treatment response rates. These findings support the preliminary efficacy of STPP for FND and justify larger, multicenter confirmatory trials.

Humans↗

PubMed2026

Oliceridine used for patient-controlled analgesia on postoperative quality of recovery in patients undergoing laparoscopic gynecological tumour resection: a randomized clinical trial.

BACKGROUND: Oliceridine, a novel biased μ-opioid receptor agonist, is widely used perioperatively, yet limited data exists regarding its impact on postoperative quality of recovery. This study investigated the effect of oliceridine-based patient-controlled intravenous analgesia (PCIA) on postoperative quality of recovery among patients undergoing laparoscopic gynecological tumour resection. METHODS: Ninety‑four female patients scheduled for elective laparoscopic gynecological tumour resection were included. Patients were randomized to two groups: oliceridine group (loading dose 1.5 mg, PCIA 0.55 mg/kg) or sufentanil group (loading dose 10 μg, PCIA 3 μg/kg). The primary outcome was the Quality of Recovery-40 (QoR-40) score on postoperative day 1. The secondary outcomes included the QoR-40 score, the numeric rating scale (NRS) pain score, the Hospital Anxiety and Depression Scale-Anxiety (HADS-A) score, the Fatigue, Resistance, Ambulation, Illness and Loss of weight (FRAIL) index and adverse events within 3 postoperative days. RESULTS: Higher QoR-40 scores were found in the oliceridine group on postoperative day 1 (182.9 ± 3.1 versus 177.5 ± 3.9, p < 0.001). Compared with the sufentanil group, the oliceridine group showed better QoR-40 scores within 3 days after operation. No significant differences were observed in NRS pain scores or HADS-A scores between the two groups (all p > 0.05). However, the median FRAIL score in the oliceridine group was lower on postoperative day 2 (p = 0.018). CONCLUSION: Oliceridine used in PCIA improves early postoperative recovery quality of patients undergoing laparoscopic gynecological tumour resection. It provides analgesic effect comparable to sufentanil and lowers incidences of postoperative frailty, nausea and vomiting. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR.org.cn, identifier: ChiCTR2400094271.

Humans↗

PubMed2026

The clinical value of adding immune checkpoint inhibitors to radiotherapy for cancer: a systematic review and meta-analysis.

BACKGROUND: While several randomized clinical trials (RCTs) have explored the addition of immune checkpoint inhibitor (ICI) treatment for patients undergoing radiotherapy, studies systematically assessing the clinical value of such interventions are lacking. METHODS: PubMed, Embase, and Cochrane Library databases were searched for relevant RCTs of cancers that received ICIs plus radiotherapy or radiotherapy. Eligible studies were those published in English as of 14 April 2024. Two independent reviewers screened the included studies and extracted relevant data, then selected the random or fixed-effects model based on the I2 statistic. The main outcomes were hazard ratios (HRs) with 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS); Odds ratios (ORs) with 95% CIs for objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Stratified analysis was performed based on cancer type, ICI type, and the timing of ICI addition. The study was registered on PROSPERO (CRD42024551008). RESULTS: 15 RCTs with 7947 patients were included. Pooled HRs were 0.865 (95% CI, 0.730-1.000; I2 = 72.1%) for OS and 0.799 (0.677-0.922; I2 = 82.0%) for PFS in cancer patients. In cancer types, adding immunotherapy to radiotherapy significantly improved patients with non-small-cell lung cancer (OS: 0.544 [0.371-0.717]; PFS: 0.527 [0.438-0.617]) and cervical cancer (OS: 0.722 [0.578-0.867] and PFS: 0.754 [95%CI, 0.621-0.887]). Regarding the ICIs schedule, adjuvant ICI therapy with pooled HRs was 0.742 (0.649-0.834) for OS and 0.638 (0.579-0.697) for PFS. In addition, the pooled ORs for the incidence of grade 3 or higher treatment-related and immune-related adverse events were 1.227 (1.059-1.421; I2 = 71.9%) and 2.217 (1.743-2.821; I2 = 74.0%), respectively. CONCLUSION: Adding immunotherapy to radiotherapy can provide significant clinical benefits for patients with NSCLC and cervical cancer, and the addition of these ICIs in the adjuvant stage is supported.

Humans↗

PubMed2026

Dynamic lysine acetylation and succinylation of platelet proteins regulates platelet storage lesion: mechanistic insights from multi-omics.

OBJECTIVES: Platelet storage lesion (PSL) severely impairs platelet function during storage, presenting a major hurdle in transfusion medicine; however, the dynamic interplay between global proteomic changes and post-translational modifications (PTMs) underlying these functional deteriorations remains insufficiently characterized. Here, we report the first comprehensive multi-omics analysis integrating global proteomics, acetylomics, and succinylomics to dissect the molecular dynamics during platelet storage. METHODS: We performed quantification of global proteomics, acetylome and succinylome based on TMT-labeled LC-MS/MS analysis, combined with antibody-affinity enrichment and purification. Dynamic molecular changes and functional transformation of platelet were also characterized under proper conditions stored for 1, 3, 5, 7 days, respectively. RESULTS: We systematically characterized 3,609 proteins, 1,308 acetylation sites, and 1,947 succinylation sites across multiple storage time points (D1, D3, D5, D7). We distinct temporal patterns of post-translational modifications, with succinylation showing more extensive coverage than acetylation in platelets. Pathway enrichment analysis revealed extensive metabolic reprogramming involving complement activation, energy metabolism, and cellular detoxification processes. The identification of specific motif patterns provided mechanistic insights into the functional specificity of these modifications. Random forest machine learning identified 20 core regulatory proteins representing critical nodes in PSL development. Furthermore, we employed real - time quantitative polymerase chain reaction (RT - QPCR) to measure the expression levels of key genes related to platelet function and PTM - associated pathways. CONCLUSION: By mapping the interplay between proteomic abundance shifts and PTM dynamics, this study provides a multidimensional understanding of PSL, establishing a foundational framework for optimizing storage protocols and enhancing transfusion safety.

Blood Platelets↗

PubMed2026

Engineering copper ferrite (CuFe2O4) nanocomposites for enhanced eco-friendly photocatalysis: a systematic critical review on mechanisms, performance, and environmental applications.

Water pollution caused by organic and inorganic contaminants, particularly dyes and pharmaceuticals, represents a major environmental challenge. Advanced oxidation processes based on photocatalysts have emerged as efficient and sustainable approaches for water and wastewater treatment. Copper ferrite (CuFe2O4) is considered a promising photocatalyst owing to its narrow bandgap, visible-light activity, chemical stability, and magnetic properties. Despite extensive experimental investigations, a comprehensive systematic comparison of CuFe2O4-based photocatalysts under diverse operational conditions has remained limited. In this study, a systematic review following PRISMA guidelines was conducted using studies published between January 2014 and November 2025 indexed in Scopus, PubMed, Web of Science, and ScienceDirect. From an initial pool of 397 studies, 98 articles met the inclusion criteria. Key parameters - including pollutant type, pH, catalyst dosage, initial pollutant concentration, irradiation time, light source, and degradation efficiency - were quantitatively compared to identify performance trends and operational optima. The results demonstrate that CuFe2O4-based nanocomposites, particularly heterojunction, Z-scheme, and S-scheme architectures combined with TiO2, g-C3N4, graphene, and metal oxides, achieve high degradation efficiencies (often >90 %) for a wide range of organic pollutants and selected inorganic contaminants (e.g., Cr(VI)). Enhanced charge separation and suppressed electron-hole recombination were identified as the primary factors contributing to improved photocatalytic activity. In addition, the intrinsic magnetic properties of these nanocomposites enable facile catalyst recovery and reuse. In conclusion, CuFe2O4-based nanocomposites, especially those incorporating advanced heterojunction architectures, emerge as highly efficient and magnetically recoverable photocatalytic platforms for sustainable water and wastewater treatment, with strong potential for scalable implementation and real-wastewater applications.

Catalysis↗

PubMed2026

A horizontally acquired gene mediates insect cocoon pigmentation in the eri silkmoth, Samia ricini.

Holometabolous insects make cocoons during larval-pupal metamorphosis to protect the pupal phase. The materials used for cocoon construction vary widely. Lepidopteran insects typically secrete silk to form cocoons, which display diverse colors. The eri silkworm, Samia cynthia ricini, is an economically important domesticated species that mostly produces white cocoons, with some varieties producing red cocoons. The enzyme kynureninase (KYNU), acquired from bacteria by horizontal gene transfer, has previously been implicated in insect coloration, while the tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) has been identified as a red pigment. However, exactly how KYNU is involved in cocoon pigmentation remains unclear. Here, we report that a horizontally transferred bacterial gene encoding KYNU regulates red cocoon formation. Metabolomic analysis revealed a high accumulation of 3-HAA in red cocoons, confirming its role as the primary pigment and associating the coloration with tryptophan metabolism. Quantitative real-time polymerase chain reaction (qPCR) analysis indicated that SrKYNU is highly expressed in the silk glands and significantly downregulated in the red cocoon strain compared to the white cocoon strain. Genomic sequencing identified a 141 bp deletion in the upstream regulatory region of KYNU in the red cocoon strain compared to the white cocoon strain. Dual-luciferase assays confirmed that this deletion significantly reduced promoter activity. CRISPR/Cas9 knockout of SrKYNU in the white-cocoon strain resulted in mutants producing red cocoons with elevated 3-HAA content. These findings reveal that the horizontally transferred gene SrKYNU exhibits tissue-specific expression and regulates cocoon coloration in S. ricini, illustrating that horizontal gene transfer can play an important role in regulating an insect physiological process.

Animals↗

PubMed2026

Cardiorespiratory training for people with stroke.

RATIONALE: Low levels of cardiorespiratory fitness are common after stroke and are associated with post-stroke disability and increased risk of secondary stroke. Cardiorespiratory training interventions aim to increase cardiorespiratory fitness, improve physical function, reduce disability, and help prevent future strokes. Clinical guidelines recommend exercise as part of lifestyle modification for secondary prevention, and strongly recommend exercise for rehabilitation. This review is one of three reviews that were originally a single review on physical fitness training for stroke. OBJECTIVES: The primary objective of this review was to determine whether cardiorespiratory training after stroke has an effect on death, disability, adverse events, risk factors, fitness, walking, and indices of physical function when compared to a non-exercise control. SEARCH METHODS: In April 2025, we searched nine bibliographic databases and two trials registers to identify studies for inclusion in the review. We checked reference lists, tracked citations, and contacted experts. ELIGIBILITY CRITERIA: We included randomised controlled trials comparing cardiorespiratory training interventions with usual care, no intervention, or a non-exercise intervention in people with stroke. OUTCOMES: Our critical outcomes were death, disability, adverse events, risk factors, fitness, walking, and indices of physical function, assessed at the end of the intervention and the end of the longest follow-up. RISK OF BIAS: We used the Cochrane RoB 1 tool to assess the risk of bias in the included studies. SYNTHESIS METHODS: The studies evaluated different comparisons (e.g. cardiorespiratory training versus no intervention/waiting list control or versus attention control or versus usual care), which we synthesised into a single comparison: cardiorespiratory training versus control. We used random-effects meta-analysis on arm-level data (risk difference (RD) for dichotomous data, and mean difference (MD) or standardised mean difference (SMD) for continuous data, with 95% confidence intervals (CIs)). For outcome data that we did not meta-analyse, we followed Synthesis Without Meta-analysis (SWiM) guidance. We used GRADE to assess the certainty of the evidence for critical outcomes. INCLUDED STUDIES: We included 53 studies (2672 participants, with an average age of 61.9 years). Most studies recruited ambulatory participants in the early subacute (7 days to 3 months) or chronic (> 6 months) phases of recovery. Exercise duration recommendations were met in 49 studies, and frequency recommendations in 48. Twenty-eight studies lacked balanced exposure between groups. Programme duration was 12 weeks or more in 16 studies (maximum: 24 weeks). Sixteen studies had a post-intervention follow-up period (12 weeks to 12 months from baseline). One study planned a six-month follow-up but did not report it. SYNTHESIS OF RESULTS: Cardiorespiratory training does not increase or decrease deaths at the end of intervention (RD 0.00, 95% CI -0.01 to 0.01; 36 studies, 1563 participants; high-certainty evidence) or the end of follow-up (RD -0.00, 95% CI -0.02 to 0.02; 10 studies, 713 participants; high-certainty evidence). Cardiorespiratory training may improve indices of disability slightly at the end of intervention (SMD 0.35, 95% CI 0.12 to 0.57; 17 studies, 1073 participants; very low-certainty evidence), but the evidence is very uncertain. Re-expressed using the Barthel Index (0 to 20), the equivalent effect is MD 1.68, 95% CI 0.59 to 2.74. It is unclear if the effect is clinically meaningful (the minimal clinically important difference (MCID) is +1.85). The effect is unclear at the end of follow-up (SMD -0.14, 95% CI -0.36 to 0.08; 5 studies, 347 participants; low-certainty evidence). Cardiorespiratory training does not increase or decrease the incidence of secondary cardiovascular or cerebrovascular events at the end of intervention (RD -0.00, 95% CI -0.03 to 0.02; 8 studies, 544 participants; high-certainty evidence) and probably does not affect them at the end of follow-up (RD -0.02, 95% CI -0.08 to 0.04; 4 studies, 412 participants; moderate-certainty evidence). It is very uncertain whether cardiorespiratory training affects systolic blood pressure (mmHg) at the end of intervention (MD -2.12, 95% CI -5.81 to 1.57; 9 studies, 535 participants; very low-certainty evidence) (MCID -2 mmHg) or follow-up (MD 0.93, 95% CI -4.30 to 6.16; 3 studies, 155 participants; very low-certainty evidence); the 95% CIs include the MCID. Cardiorespiratory training probably results in a slight improvement in cardiorespiratory fitness (VO2 ml/kg/min) at the end of intervention (MD 2.37, 95% CI 1.39 to 3.36; 13 studies, 608 participants; moderate-certainty evidence); it is unclear if the effect is clinically meaningful (MCID +3.5 ml/kg/min). The effect may be similar at the end of follow-up (MD 2.76, 95% CI 1.36 to 4.16; 5 studies, 237 participants; low-certainty evidence). Subgroup analysis favoured longer interventions. Cardiorespiratory training probably results in a slight increase in comfortable walking speed (metres per second) at the end of intervention (MD 0.08, 95% CI 0.04 to 0.12; 16 studies, 647 participants; moderate-certainty evidence), but the effect is not clinically meaningful (MCID +0.13). The effect is unclear at the end of follow-up (MD 0.02, 95% CI -0.05 to 0.10; 3 studies, 182 participants; low-certainty evidence). Cardiorespiratory training may improve indices of balance at the end of intervention (SMD 0.31, 95% CI 0.15 to 0.47; 18 studies, 772 participants; very low-certainty evidence), but the evidence is very uncertain. Re-expressing using the Berg Balance Scale, the equivalent effect is MD 2.09, 95% CI 1.10 to 3.07; and it is unclear if it is clinically meaningful (MCID of +2). The effect is unclear at the end of follow-up (MD 0.90, 95% CI -1.32 to 3.12; 6 studies, 253 participants; low-certainty evidence). Overall, our certainty about the evidence is limited for most outcomes by imprecision (small number of studies and participants) or risks of bias (e.g. imbalanced exposure doses) or both. AUTHORS' CONCLUSIONS: Cardiorespiratory training after stroke does not affect mortality or the incidence of secondary events at the end of the aerobic exercise training programme or end of follow-up. It may increase fitness, reduce disability, increase walking speed, and improve balance at the end of intervention, but it is unclear if these improvements are clinically meaningful. Further well-designed randomised trials are needed to fully understand the potential benefits and long-term effects of cardiorespiratory training and the optimal exercise prescription. FUNDING: No dedicated funding REGISTRATION: Protocol (and previous versions) available via DOI 10.1002/14651858.CD003316.

Humans↗

PubMed2026

Contact tracing for hepatitis C: perspectives of people with experience of substance use and hepatitis C on intervention acceptability.

INTRODUCTION: Chronic hepatitis C (HCV) is a major cause of cirrhosis and hepatocellular carcinoma. In the UK, the principal risk factor for HCV is injecting drug use. The introduction of direct acting anti-virals (DAA's) have transformed HCV care, with cure rates of over 95%. However, HCV is often asymptomatic, and reinfection is a concern. Modelling and real-life studies demonstrate the potential effectiveness of a contact tracing approach for finding people who have acquired HCV through injecting drug use. However, it is not used routinely in the UK. This qualitative study was undertaken to assess the acceptability of a contact tracing approach to identify people who have injected drugs with an index patient recently diagnosed with HCV. METHODS: Twelve people with lived or living experience of injecting drug use and an HCV diagnosis were interviewed using semi-structured interview topic guides. Participants were purposefully selected according to the inclusion criteria and to ensure there was an even spread of male and female participants. Sekhon's Theoretical Framework of Acceptability, incorporating seven components (affective attitude, burden, ethicality, intervention coherence, opportunity cost, perceived effectiveness, and self-efficacy) was used to analyse data from interview transcripts. RESULTS: A sample of 12 people who inject drugs in the UK indicated that a contact tracing approach was acceptable across two components of Sekhon's acceptability framework: affective attitude and ethicality. Participants broadly found the idea of tracing people who may be at risk of contracting HCV acceptable, and the approach aligned with their value systems. A contact tracing approach would help alleviate concerns about putting other people's lives at risk through HCV transmission and was seen as a 'sensible' way of finding people at risk. However, there were caveats to this acceptability. Contact tracing approaches delivered by mainstream health, or governmental organisations increased burden, opportunity costs and perceived effectiveness of a contact tracing approach for HCV, particularly within contexts of exclusion and criminalisation of people who inject drugs. Burden and opportunity costs were also affected by individual experiences and risks of violence, sexual violence and abuse. There was a lack of knowledge of contact tracing approaches amongst respondents, leading to a lack of intervention coherence and misunderstandings of what contact tracing was and how it would work. Trusted relationships with NGOs and HCV specialist nurses reduced burden and increased confidence and ability (self-efficacy) to engage with a contact tracing approach. CONCLUSION: People who inject drugs broadly perceive contact tracing as an acceptable method of finding people who are at risk of HCV. However, this acceptability is based on specific modes of delivery through trusted organisations. Findings further highlight the importance of naming and describing contact tracing approaches appropriately, as well as assessing and mitigating against potential risk to index patients, to increase self-efficacy and capacity to engage. Considering these findings, the potential for expanding existing contact tracing approaches should be explored to ensure the UK reaches and maintains its elimination targets.

Humans↗

PubMed2026

Pharmacological therapies for the prevention of fractures in men.

RATIONALE: Pharmacological therapies for fracture prevention usually target osteoporosis, a skeletal disorder characterised by compromised bone mass or quality (or both). As most participants in osteoporosis trials are women, a review of pharmacological therapies for fracture prevention in men was warranted. OBJECTIVES: To determine the benefits and harms of bisphosphonates, parathyroid (PTH) or parathyroid-related protein (PTHrP) analogues, denosumab, and romosozumab therapy for the prevention of fractures in men. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registries (ClinicalTrials.gov and WHO ICTRP) until 14 October 2025, with no restrictions on date or language of publication. ELIGIBILITY CRITERIA: We included randomised controlled trials that compared bisphosphonates, PTH or PTHrP analogues, denosumab, or romosozumab (alone or with calcium or vitamin D, or both) with placebo, other drugs, or non-pharmacological therapies in men aged 50 years or older. Our primary comparison was bisphosphonates versus placebo. OUTCOMES: Critical outcomes were incidence of hip fractures, symptomatic vertebral fractures, other (not hip or vertebral) fractures, disability, participants with adverse events, study withdrawals due to adverse events, and participants with serious adverse events. Our primary time point was the final time point reported in the trials. RISK OF BIAS: We used Cochrane's RoB 2 tool to assess risk of bias. SYNTHESIS METHODS: We used a random-effects model for meta-analysis employing the Mantel-Haenszel approach, and the DerSimonian and Laird method to estimate between-trial variance. We assessed the certainty of evidence using GRADE. INCLUDED STUDIES: Seventeen trials (4132 participants) met our inclusion criteria. The average age of participants ranged from 52 to 73 years. Twelve trials used a placebo comparator versus bisphosphonate (7 trials, 2548 participants), PTH or PTHrP analogues (4 trials, 569 participants), denosumab (1 trial, 240 participants), and romosozumab (1 trial, 244 participants). For the other planned comparisons, a bisphosphonate was compared to vitamin D/vitamin D analogues (2 trials, 434 participants), to calcitonin (1 trial, 32 participants), to PTH or PTHrP analogues (1 trial, 19 participants), or to another bisphosphonate (1 trial, 301 participants), and one trial compared a bisphosphonate plus calcium to calcium tablets alone (46 participants). SYNTHESIS OF RESULTS: Placebo-controlled trials were largely susceptible to bias in selection of the reported result (83%), while most trials without a placebo control were also susceptible to bias arising from the randomisation process (100%) and in measurement of the outcome (80%). We are very uncertain about the effect of bisphosphonates on the incidence of hip fractures, symptomatic vertebral fractures, or other (non-hip non-vertebral) fractures compared to placebo at the final follow-up (up to two years). We downgraded the certainty of evidence once for risk of bias, twice for imprecision (very low event rates), and once for suspected publication bias. The certainty of evidence for incidence of other fractures was further downgraded for indirectness, as it was unclear if hip fractures were also included in the outcome. At up to two years, 2/875 participants (2 per 1000) in the bisphosphonate group reported hip fractures compared with 2/760 (3 per 1000) in the placebo group (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.06 to 8.51; I² = 36%; 4 trials, 1635 participants); 5/1021 (4/1000) participants in the bisphosphonate group had a symptomatic vertebral fracture compared to 7/855 (8/1000) participants in the placebo group (RR 0.49, 95% CI 0.14 to 1.74; I² = 0%; 5 trials, 1876 participants); 25/1130 participants (16/1000) in the bisphosphonate group reported other (non-hip non-vertebral) fractures compared to 19/913 participants (21/1000) in the placebo group (RR 0.78, 95% CI 0.42 to 1.45; I² = 0%; 6 trials, 2043 participants). Bisphosphonates probably do not increase the risk of adverse events: 1024/1374 participants (746/1000) receiving bisphosphonates reported adverse events compared to 826/1174 participants (704/1000) receiving placebo (RR 1.06, 95% CI 0.93 to 1.19; I² = 75%; 7 trials, 2548 participants; moderate-certainty evidence) or serious adverse events: 329/1329 participants (272/1000) receiving bisphosphonate reported serious adverse events compared to 323/1128 participants (286/1000) receiving placebo (RR 0.95, 95% CI 0.84 to 1.08; I² = 0%; 6 trials, 2457 participants; moderate-certainty evidence). We downgraded the certainty of evidence once due to potential bias for adverse events and serious adverse events. We are very uncertain if bisphosphonates result in more withdrawals due to adverse events: 41/1374 participants (25/1000) in the bisphosphonate group withdrew due to adverse events compared with 43/1174 participants (37/1000) in the placebo group (RR 0.68, 95% CI 0.39 to 1.18; I² = 37%; 7 trials, 2548 participants; very low-certainty evidence). We downgraded the certainty of evidence once for risk of bias, once for indirectness, and once for imprecision. No trial reported disability. We are very uncertain about the effects of PTH or PTHrP analogues, denosumab, or romosozumab compared to placebo on fracture outcomes. We are very uncertain about the effects of PTH/PTHrP analogues on total adverse events, withdrawals due to adverse events, and serious adverse events. Denosumab may not increase the risk of adverse events or serious adverse events compared to placebo, while the evidence for withdrawals due to adverse events is very uncertain. Romosozumab probably does not increase the risk of adverse events and may not increase the risk of serious adverse events or result in more withdrawals due to adverse events. AUTHORS' CONCLUSIONS: We are very uncertain about the effects of bisphosphonates compared to placebo on the incidence of hip fractures, symptomatic vertebral fractures, or other (non-hip non-vertebral) fractures in men at up to two years of use. Bisphosphonates probably do not increase the risk of adverse events or serious adverse events, and we are very uncertain if they result in more withdrawals due to adverse events. We downgraded the certainty of evidence for indirectness, imprecision (low event rate), and serious risk of bias in selection of the reported result, as it was unclear if all studies fully reported every fracture. We found similar results for PTH or PTHrP analogues, denosumab, or romosozumab versus placebo. Larger, longer placebo-controlled studies are needed to determine whether pharmacological therapies are beneficial for reducing fractures in men. FUNDING: This Cochrane review had no dedicated funding. REGISTRATION: Protocol (2021): https://doi.org/10.1002/14651858.CD014707.

Humans↗

PubMed2026

Comparing the efficacy and safety of unilateral versus bilateral spinal anesthesia: a meta-analysis and systematic review.

BACKGROUND: Unilateral spinal anesthesia has gained increasing attention in recent years. Emerging evidence suggests that it provides comparable analgesia to conventional bilateral spinal anesthesia while reducing adverse effects, and its efficacy and safety compared to bilateral spinal anesthesia remains controversial. OBJECTIVE: This systematic review and meta-analysis aims to evaluate and compare the efficacy and safety of unilateral versus bilateral spinal anesthesia. DESIGN: Systematic reviews and meta-analysis of randomized controlled trials (RCTs). DATA SOURCES: A systematic search was conducted across PubMed, EMBASE, and Cochrane Library from inception to December 10, 2024. ELIGIBILITY CRITERIA: Included studies were randomized controlled trials involving adult patients (≥18 years) undergoing surgery under spinal anesthesia, comparing unilateral versus bilateral spinal anesthesia for efficacy and adverse effects. Studies that focused exclusively on either unilateral or bilateral spinal anesthesia were excluded. The comparator group used the same local anesthetic as the experimental group, with no restrictions on adjuncts (e.g. fentanyl, morphine). RESULTS: Nineteen randomized controlled trials including 1191 patients met the inclusion criteria. Compared with bilateral spinal anesthesia, unilateral spinal anesthesia has a longer onset of sensory blockade (MD = 2.58, 95% CI: 0.93 to 4.22, p = 0.002), a shorter duration of sensory blockade (MD = -27.83, 95% CI: -39.25 to -16.42, p < 0.00001). In addition, unilateral spinal anesthesia significantly reduced the incidence of hypotension (RR = 0.40, 95% CI: 0.31 to 0.52, p < 0.0001), nausea and vomiting (RR = 0.20, 95% CI: 0.07 to 0.56, p = 0.002), and post-dural puncture headache (RR = 0.44, 95% CI: 0.23 to 0.81, p = 0.009). No statistically significant differences were observed in bradycardia and urinary retention. Collectively, these findings support unilateral spinal anesthesia as a strategy that may enhance perioperative safety while maintaining adequate anesthetic efficacy in appropriately selected patients. CONCLUSIONS: Unilateral spinal anesthesia may offer a favorable balance between anesthetic efficacy and safety compared with bilateral spinal anesthesia, although its clinical utility may depend on surgical duration and patient characteristics.

Humans↗

PubMed2026

Whole genome sequencing of unusual Hepatitis C virus subtypes and drug resistance analysis during direct-acting antiviral therapy in India.

INTRODUCTION AND OBJECTIVES: Pangenotypic direct-acting antivirals (DAA) are effective against highly prevalent Hepatitis C virus (HCV) subtypes, but have been clinically validated almost exclusively in high-income countries. Unusual HCV subtypes may carry natural polymorphisms, potentially impacting DAA susceptibility. We conducted full-genome characterization and resistance analysis of unusual HCV subtypes in patients receiving DAA treatment. PATIENTS AND METHODS: In this prospective hospital-based study, eligible patients were screened for anti-HCV antibodies and active infection was confirmed by diagnostic 5'NCR-based HCV RNA detection. Genotyping was performed by core region sequencing, and viral load quantified by real-time PCR. For whole genome sequencing, multiplex primers were designed using alignments of global reference sequences. Sequencing was carried out using the Oxford Nanopore Technology platform. Phylogenetic analysis used multiple sequence alignment and the HCV-GLUE resource for resistance-associated substitution (RAS) analysis. RESULTS: Predominant genotype was genotype 3 in 64.3% (n = 45); genotype 6 in 21.4% (n = 15); and genotype 1 in 14.2% (n = 10). Unusual HCV subtype 6xa was detected in two patients and showed no NS5A resistance mutations. One genotype 3b patient relapsed at 24 weeks post-DAA treatment completion and carried NS5A resistance-associated substitutions 30 K and 31 M both at baseline and at relapse, conferring high-level resistance to NS5A inhibitors. CONCLUSION: This is the first report from India of whole genome sequencing of HCV subtype 6xa. The identification of NS5A resistance mutations in the 3b relapse case underscores challenges for global HCV elimination strategies.

Humans↗

PubMed2026

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

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

Humans↗

PubMed2026

Acupuncture improves depressive symptoms and prefrontal cortical function in mild to moderate depressive disorder: A randomized sham-controlled trial and fNIRS study.

BACKGROUND: Depressive disorder is a common mental illness associated with substantial functional impairment. Although pharmacotherapy is widely used, its effectiveness is often limited by adverse effects and poor adherence. Acupuncture has been increasingly applied as a complementary treatment for depression, and its neurobiological characteristics remain unclear. OBJECTIVE: This randomized, sham-controlled trial aimed to evaluate the clinical efficacy of acupuncture for mild to moderate depressive disorder and to investigate its effects on prefrontal cortical function using functional near-infrared spectroscopy (fNIRS). METHODS: Patients with mild to moderate depressive disorder were randomly assigned to a real acupuncture (RA) group or a sham acupuncture (SA) group and received standardized treatment for 8 weeks. Clinical outcomes were assessed using the Self-Rating Depression Scale (SDS), Self-Rating Anxiety Scale (SAS), Short Form-36 Health Survey (SF-36), and a traditional Chinese medicine syndrome score. A subset of participants underwent fNIRS assessment during resting-state and task-based conditions to evaluate prefrontal cortical activation and functional connectivity. RESULTS: Compared with baseline, the RA group showed significant reductions in SDS and SAS scores and significant improvements in SF-36 emotional domains, with effects emerging at Week 4 and persisting up to 12 weeks after treatment. Improvements were greater and more stable in the RA group than in the SA group. fNIRS analyses revealed enhanced activation in dorsolateral and medial prefrontal regions and strengthened prefrontal functional connectivity following acupuncture, whereas neural changes in the SA group were limited. CONCLUSION: Acupuncture is effective for improving depressive and anxiety symptoms and quality of life in patients with mild to moderate depressive disorder. Modulation of prefrontal cortical activation and connectivity may underlie its antidepressant effects.

Humans↗

PubMed2026

Osimertinib With or Without Chemotherapy in Advanced Non-Small Cell Lung Cancer With EGFR and Concurrent TP53 Mutations: A Randomized Clinical Trial.

IMPORTANCE: Combination therapy has emerged as a promising therapeutic approach for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, its clinical benefit-risk profile remains a focus of ongoing debate. Identifying patients most likely to derive benefit from such regimens remains an unmet clinical need. OBJECTIVE: To prospectively compare the efficacy and safety of first-line osimertinib plus chemotherapy with osimertinib monotherapy for patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized, open-label, phase 3 study conducted at 17 sites in China. Between March 25, 2021, and July 11, 2024, a total of 294 eligible patients with treatment-naive, stage IV or recurrent nonsquamous NSCLC harboring concurrent TP53 and EGFR-sensitizing mutations were enrolled. INTERVENTIONS: Patients were randomized (1:1) to receive osimertinib plus chemotherapy (pemetrexed and carboplatin every 3 weeks for 4 cycles, followed by maintenance therapy of osimertinib plus pemetrexed; n = 146) or osimertinib monotherapy (n = 148). MAIN OUTCOMES AND MEASURES: The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival, response, safety, and quality of life. RESULTS: Among 294 enrolled patients, the median age was 57 years (range, 26-79 years), and 159 (54.1%) were female. The data cutoff date was November 11, 2025. At a median follow-up of 25.1 months for the osimertinib-chemotherapy group and 26.1 months for the osimertinib monotherapy group, median progression-free survival was significantly longer with osimertinib plus chemotherapy than with osimertinib monotherapy (34.0 vs 15.6 months; difference, 18.4 months [95% CI, 9.9-22.3]; hazard ratio, 0.44 [95% CI, 0.32-0.60]; P < .001). This benefit was consistent across prespecified subgroups, including those with brain metastases and L858R mutations. The overall survival data remained immature (30.6% maturity); however, a trend toward overall survival benefit with combination therapy was observed. The incidence of grade 3 or higher treatment-related adverse events was higher in the combination group, with no new safety signal identified. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, osimertinib plus chemotherapy significantly increased progression-free survival among patients with EGFR-mutated advanced NSCLC harboring concurrent TP53 mutations. These findings provided a clinical rationale for individualized combination strategies in the management of patients with EGFR-mutated NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04695925.

Adult↗

PubMed2026

Chronic postsurgical pain: risk assessment and mitigation.

PURPOSE OF THE REVIEW: Chronic postsurgical pain (CPSP) and persistent postoperative opioid use (PPOU) are two of the most common complications of a number of surgical interventions, which can cause significant personal and economic negative consequences. This review outlines known and potential risk factors for CPSP and PPOU and approaches to reduce these risk factors. RECENT FINDINGS: Modifiable risk factors for developing CPSP include psychological distress, preoperative pain intensity, and perioperative opioid exposure. Although less studied, psychological comorbidities are also risk factors for PPOU. Evidence-based mitigation strategies include psychological interventions and perioperative opioid sparing. SUMMARY: A number of perioperative risk factors for developing CPSP and PPOU have been identified, and anesthesiologists should be cognizant of these risk factors and potential risk mitigation strategies. Additional prospective studies are needed to further develop easily adoptable, evidence-based interventions to reduce the incidence of CPSP and PPOU.

Humans↗

PubMed2026

Comprehensive analysis of mRNA-microRNA-lncRNA expression profiles in post-traumatic elbow heterotopic ossification using RNA sequencing and experimental validation.

BACKGROUND: This study aimed to profile the molecular signatures of post-traumatic elbow heterotopic ossification (HO) to identify key regulators and potential therapeutic targets. METHODS: Total RNA from post-traumatic elbow HO tissues (n=4) and normal bone tissues (n=6) was subjected to high-throughput sequencing to identify differentially expressed mRNAs (DEGs), microRNAs (DEMs), and lncRNAs (DELs). Bioinformatics analyses included Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, protein-protein interaction network construction, and transcription factor (TF)-microRNA-mRNA network analysis. The expression trends of four most upregulated and four most downregulated DEGs were validated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: We identified 2,138 DEGs, 40 DEMs, and 905 DELs. DEGs were significantly enriched in biological process "bone mineralization," cellular component "plasma membrane," molecular function "integrin binding," and pathways including PI3K-Akt, NF-κB, JAK-STAT, and TNF signaling pathways. Hub genes with high connectivity included MMP9, IL6, MMP3, CTSK, and BGLAP. Integrated network analysis highlighted the transcription factor JUN and key microRNAs (hsa-miR-124-3p, hsa-miR-548c-3p, and hsa-miR-135b). The qRT-PCR results confirmed the expression trends of selected DEGs. CONCLUSIONS: This study, for the first time, profiled the differentially expressed mRNAs, microRNAs, and lncRNAs in post-traumatic elbow HO using high-throughput RNA sequencing. These findings provide valuable insights into the molecular mechanisms of HO following elbow trauma. The identified hub genes (MMP9, IL6, MMP3, CTSK, and BGLAP), key TF (JUN), and key microRNAs (hsa-miR-124-3p, hsa-miR-548c-3p, and hsa-miR-135b) may serve as potential therapeutic targets for preventing and treating post-traumatic elbow HO.

Humans↗

PubMed2026

Estrone disrupts early reproductive development in juvenile male Siniperca chuatsi and is associated with brain and gonadal responses.

Whether estrone (E1)-associated disruption of early reproductive development in fish is accompanied by brain responses in addition to direct gonadal effects remains unclear. Here, juvenile Siniperca chuatsi, a non-model but economically important freshwater species, were exposed for 60 d to 0, 0.01, 0.1, and 1.0 μg/L E1, spanning environmentally reported and elevated concentrations. By integrating waterborne concentration monitoring, histopathology, transcriptomics, and quantitative real-time PCR (qPCR) validation, we evaluated E1-associated changes in brain and gonadal tissues during early reproductive development. Waterborne E1 concentrations remained generally stable throughout the exposure period. At the highest tested concentration (1.0 μg/L), E1 caused neuronal vacuolation and pyknosis in the hypothalamic region and induced distinct ovarian-like structures in the gonads of genetic males. In the brain, cyp19a1, crhr1, and adcy2a were significantly upregulated, whereas egr1 was significantly downregulated, indicating transcriptional changes in genes associated with local estrogen conversion, stress-response/cAMP signaling, and neuronal activity-related regulation within a broader injury/stress-response background. In the gonad, RNA-seq analysis showed significant downregulation of star2, hsd3b1, cyp17a1, and cyp11b and significant upregulation of hsd17b1, suggesting alterations in steroidogenesis-related gene expression at the transcriptomic level. qPCR analysis of selected gonadal candidate genes showed expression directions generally consistent with the RNA-seq results, and these molecular patterns were consistent with the feminized histological phenotype. Together, these results indicate that E1 can disrupt early reproductive development in juvenile S. chuatsi and support a cautious working model in which E1 exposure is accompanied by concurrent brain and gonadal responses. This study provides new evidence for understanding the toxic effects and ecological risk implications of natural estrogen E1 during early fish development.

Animals↗