Cement leakage is a common and occasionally serious complication of percutaneous vertebroplasty (PVP). We compared cement leakage (primary outcome) and post-operative pain (VAS) and disability (ODI) (secondary outcomes) between trial-defined lower-volume and higher-volume cement injection in osteoporotic vertebral compression fractures. We searched PubMed, Embase, Scopus, the Cochrane Library, CNKI and Wanfang from January 2018 to 31 December 2025 (last search date), and included randomized controlled trials (RCTs). Risk of bias was assessed with RoB 2. "Lower-volume" denotes each trial's smaller-volume arm. Reported lower-volume arms ranged from 1.5 to 2.5 mL to < 6 mL, whereas higher-volume arms ranged from 2.6 to 3.5 mL to 7.0 mL or ≥ 6 mL, depending on the trial definition. Risk ratios (RR) for leakage and mean differences (MD) for VAS/ODI were pooled with random-effects models; an exploratory subgroup (lower-arm ≤ vs. > ~ 3.5 mL) was examined, and sensitivity analyses included leave-one-out analysis, exclusion of the single cervical trial, and exclusion of trials with ambiguous volume labels. Differences in VAS/ODI were interpreted against established minimal clinically important difference (MCID) thresholds. Sixteen RCTs were included. Lower-volume injection was associated with a markedly lower risk of cement leakage (RR 0.30, 95% CI 0.22-0.40; I² = 0%), consistent across subgroups (test for interaction P > 0.30) and stable in leave-one-out analysis (RR 0.27-0.31) and on exclusion of the single cervical trial. Post-operative VAS differed negligibly between arms (MD 0.01 points, 95% CI -0.11 to 0.12), as did ODI among the 12 trials that actually measured it (MD -0.04 points, 95% CI -0.52 to 0.44); both were well below accepted MCID thresholds. Four trials did not measure ODI and were excluded from the ODI analysis. Trial-defined lower-volume cement injection was associated with a substantially reduced risk of cement leakage, while differences in post-operative pain and disability were negligible and below accepted MCID thresholds. Because no non-inferiority margin was pre-specified, these findings should not be read as statistical non-inferiority. Given the wide variation in volume definitions and procedural detail across trials, the evidence supports an individualized lower-volume strategy rather than a single universally optimal volume.
Gene fusions were thought to be unique features of neoplasia. However, more and more studies have identified fusion RNAs in normal physiology. Through RNA sequencing of human normal tissues from GTEx project, many chimeric RNAs were found. By analyzing the fusion transcriptome, we observed a close cluster between samples of the same or similar tissues, supporting the feasibility of using fusion RNA profiling to reveal connections between biological samples. To put the concept into use, we selected alveolar rhabdomyosarcoma (ARMS), a myogenic pediatric cancer whose exact cell of origin is not clear. PAX3-FOXO1 fusion RNA, which is considered a hallmark of ARMS, was found during normal muscle cell differentiation. We analyzed RNA sequencing from various time points during myogenesis and uncovered many chimeric fusion RNAs.
Exposure to particulate matter air pollution ≤2.5 µm (PM2.5) is associated with cardiovascular (CV) and kidney morbidity and mortality. This post hoc analysis of FIDELITY, a prespecified pooled analysis of phase 3 randomized clinical trials (FIDELIO-DKD [NCT02540993], FIGARO-DKD [NCT02545049]), determined the impact of PM2.5 exposure on CV and kidney events and the effects of finerenone on these outcomes across PM2.5 exposures in patients with CKD and T2D. Patients with CKD and T2D on optimized renin-angiotensin system blockade were randomized 1:1 to finerenone or placebo. Key outcomes included composite CV outcomes (CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure); composite kidney outcomes (kidney failure, sustained ≥57 % decrease in eGFR, kidney-related death); combined composite CV and kidney outcomes; and safety. Outcomes were stratified by PM2.5 exposure and patients grouped into quartiles of median PM2.5 exposure with interquartile range as cutoffs. Median PM2.5 exposure was 15.5 µg/m3 (N = 12 990). Increased PM2.5 exposure was associated with higher occurrence of CV and kidney events. Finerenone reduced composite CV (hazard ratio [HR], 0.86; 95 % CI, 0.78-0.95), kidney (HR, 0.76; 95 % CI, 0.66-0.88) and combined CV and kidney (HR, 0.83; 95 % CI, 0.76-0.90) outcomes versus placebo across PM2.5 exposures (P interaction=0.37, 0.14, and 0.74, respectively). Proportions of adverse events (AEs) and serious AEs were generally balanced between treatment arms. Across PM2.5 quartiles, hyperkalemia was more frequent with finerenone, but few led to hospitalization. Increased PM2.5 exposure is associated with higher occurrence of CV and kidney events. Finerenone lowered the risk of CV and kidney events regardless of PM2.5 exposure levels in patients with CKD and T2D.
This study evaluated mucosal remodeling across different corticosteroid regimens and identified barriers to treatment adherence in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). We enrolled 56 consecutive patients divided into two arms: Group 1 (n=22) underwent sinus surgery after topical, systemic, or combined corticosteroid therapy, with mucosal biopsies evaluated via a four-parameter histopathological (HP) score (infiltrate, eosinophils, edema, fibrosis). Group 2 (n=34; 15 excluded due to systemic steroid use) received exclusive medical treatment and was assessed for compliance using the Medication Adherence Questionnaire (MAQ) at baseline and three months. In Group 1, combined therapy (topical and systemic) demonstrated significantly lower HP scores compared with the topical-only group for inflammatory infiltrate (p=0.0280), tissue eosinophils (p=0.036), intramucosal edema (p=0.0400), and fibrosis (p=0.0393). In Group 2, a strong negative correlation was established between MAQ and Medication Adherence Report Scale-5 (MARS-5) (r=-0.9216, p<0.0001), confirming validity. Early treatment discontinuation and time constraints were the primary drivers of non-adherence. Combined topical and systemic corticosteroid therapy yields superior tissue remodeling outcomes by significantly reducing mucosal inflammation, eosinophilia, edema, and fibrosis compared to topical therapy alone. The MAQ is a valid clinical tool, highlighting early discontinuation and time constraints as key targets to optimize patient compliance and CRSwNP management.
Dysregulation of the phosphatidylinositol-3-kinase (PI3K) - AKT/mTOR signaling axis is a major molecular driver of tumor initiation, progression, and therapeutic resistance across diverse cancers, underscoring the need for improved targeted therapies amid a rising global and Indian cancer burden. This comprehensive review critically summarizes advances from 2021-2025 in the design of selective PI3K inhibitors based on the 1,3,5-triazine (s-triazine) scaffold, emphasizing how its symmetric 2/4/6 substitution vectors, electron-deficient hinge-binding profile, and modular cyanuric chloride - enabled SNAr synthesis accelerate structure - activity relationship (SAR) optimization. Medicinal chemistry and biological evidence across multiple triazine chemotypes (benzoyl-hydrazide, thiophene/thiophenyl-arylurea, aminopyrimidine, dimorpholinyl, benzimidazole, phenylamino, and pyrazolyl derivatives) reveal convergent design rules: heteroaryl/aminopyrimidine hinge binders, pocket-filling hydrophobic arms, and solvent-exposed polar groups (notably morpholine/dimorpholine or sulfonyl piperazine) collectively improve potency, isoform selectivity, and cellular efficacy. Mechanistically, representative compounds induce G0/G1 arrest and apoptosis with suppression of p-PI3K/p-AKT and downstream markers, supported by docking/MD interactions frequently involving Val851 (hinge), Asp810, Lys802, and Gln859. Despite substantial progress, pharmacokinetic liabilities, resistance pathways, and isoform-associated adverse effects remain key barriers to translation. Future development should prioritize rational isoform targeting, hybrid/multitarget designs, systematic ADME refinement, and AI-driven SAR modeling to advance s-triazine PI3K inhibitors toward clinically feasible cancer therapeutics.
Engineering artificial systems by twisting van der Waals materials provides an excellent platform for exploring emergent quantum phenomena. Recent advances in fabrication enable studies of interfacial superconductivity in twisted cuprates. In our work, we fabricate superconducting quantum interference devices (SQUID) that utilize the twisted interface of Bi2Sr2CaCu2O8+δ, a high-Tc cuprate superconductor. By measuring the magnetic field modulation of differential resistance, we find a π phase difference between the two Josephson junction arms of the SQUID reflecting chiral time-reversal symmetry-broken superconducting order - a crucial aspect inaccessible to single Josephson junction. Our observations also indicate co-tunneling of the Cooper pairs. Additionally, these SQUIDs are well-suited for use as state-of-the-art flux sensors near 77 K. Stabilizing superconducting orders using twisted interfaces and probing them via quantum interference opens avenues for understanding unconventional superconductors. Our architecture can probe charge transport and superconducting order symmetry at interfaces in other systems, demonstrating broad applicability beyond cuprates.
The movement of transposable elements (TEs) in somatic cells generates genetic and phenotypic diversity across the soma of individual organisms. This process is especially important in plants that display a sessile lifestyle, can regenerate from somatic cells, and continuously establish their germline from somatic stem cells. Yet, the scale and integration biases by which TEs may shape the plant soma remain unknown. We adapt high-throughput TE sequencing and introduce a new computational pipeline, "deNOVOEnrich", to identify and analyse somatic transposition events in Arabidopsis thaliana. We detect ~ 200,000 new TE insertions across wild-type and epigenetic mutant backgrounds, revealing en masse active transposition in the plant soma. Similar to germline dynamics, somatic integration is non-random and TE-specific. Focusing on the ONSEN, EVADE and AtCOPIA21 families, we find they preferentially integrate into chromosomal arms and genic DNA, and are enriched over H2A.Z, H3K27me3 and H3K4me1 labelled chromatin. However, ONSEN dynamically targets active chromatin, while EVADE displays a depletion in these regions, consistent with niche targeting at the local epigenetic level and spatial distribution across the genome ecosystem. We further demonstrate that environmentally-responsive genes such as resistance (R) genes and biosynthetic gene clusters are preferred integration targets, suggesting an adaptive potential of somatic transposition. Our work demonstrates that transposon amplification is an explosive and structured event that may contribute to the generation of cellular mosaicism in the soma of A. thaliana. We speculate that this phenomenon is common across plants under permissive conditions, both in experimental and natural settings.
TOPAZ-1 (NCT03875235) demonstrated improved overall survival (OS) with durvalumab plus gemcitabine and cisplatin vs. placebo plus gemcitabine and cisplatin with manageable safety in advanced biliary tract cancer (aBTC). The phase IIIb TOURMALINE study (NCT05771480) is evaluating the safety and efficacy of first-line durvalumab plus seven gemcitabine-based chemotherapy regimens in a close-to-real-world aBTC population, including participants with poor prognosis. Participants received 1500 mg IV durvalumab (first infusion: 60 minutes; subsequent infusions: 30 minutes) plus investigator's choice of one of seven gemcitabine-based chemotherapy regimens. The primary endpoint was incidence of Grade 3/4 adverse events (AEs) possibly related to treatment (PRAEs) within 6 months of first durvalumab dose. Secondary endpoints included progression-free survival (PFS), OS, objective response rate (ORR), and safety. As of 17 September 2025, 142 participants (median age 68.0 years) had follow-up ≥6 months and received ≥1 treatment dose; most had metastatic disease (72.5%). Participants received a median of 9 cycles of durvalumab; median (IQR) follow-up was 11.63 (6.87-17.25) months. Overall, 50.7% (95% confidence interval [CI] 42.19-59.19) of participants experienced Grade 3/4 PRAEs within 6 months of durvalumab initiation, with no serious AEs of special interest with an outcome of death. Median PFS was 7.39 months (95% CI 6.74-9.07); median OS was 13.50 months (95% CI 11.24-20.53); ORR was 33.1% (95% CI 25.44-41.48). Safety profiles of durvalumab plus seven gemcitabine-based chemotherapy regimens were manageable, and shorter durvalumab infusion duration (30 minutes vs. 60 minutes) did not increase infusion-related reactions. Efficacy data are indicative of potential clinical activity across treatment arms. These findings demonstrate the feasibility of combining durvalumab with alternative gemcitabine-based regimens in a broad aBTC population. The choice of gemcitabine-based chemotherapy backbones for the treatment of advanced biliary tract cancer (aBTC) varies globally and their use in conjunction with immunotherapy has not been fully investigated. The TOURMALINE phase IIIb study demonstrated manageable safety and efficacy data showed potential clinical activity in a close-to-real-world population of participants with aBTC receiving durvalumab plus one of seven gemcitabine-based chemotherapy regimens. These findings point towards the feasibility of combining durvalumab with different gemcitabine-based chemotherapy regimens, even in participants with less favourable disease characteristics. NCT05771480 TRIAL REGISTRATION: ClinicalTrials.gov: NCT05771480; https://clinicaltrials.gov/study/NCT05771480.
Persistent colonic inflammation disrupts epithelial integrity, alters microbial metabolites, and impairs gut function. Graptophyllum pictum (daun wungu) contains bioactive compounds with anti-inflammatory and mucosal-protective potential, but its impact on functional recovery and short-chain fatty acids (SCFAs) in colitis remains unclear. Thirty Wistar rats were randomized into five groups (n = 6/group): healthy control (K0), DSS colitis control (K-), 5-aminosalicylic acid (5-ASA, 120 mg/kg/day; K+), G. pictum extract (100 mg/kg twice daily; P1), and combination therapy (P2). Colitis was induced with 2% DSS for 7 days; treatments were given orally for 10 days. Primary outcomes were body weight and stool form (Bristol Stool Scale). Secondary outcomes included serum inflammatory mediators (IL-6, TNF-α, CRP, PDGF, COX-2, VEGF), fecal SCFAs (acetate, propionate, butyrate by GC-MS), leukocyte count, colonic macroscopic score, and histologic/tissue repair markers (fibroblasts, collagen density, M2 macrophages, CD34). Appropriate parametric/non-parametric tests with post-hoc analyses were used (α = 0.05). Ethical approval was obtained from the Faculty of Medicine, Universitas Diponegoro/Dr. Kariadi Hospital. All intervention groups gained more weight than K- (p < 0.05), with the largest increase in P2 (Δ 16.67 ± 0.52 g). Stool consistency improved significantly in K+ and P2 (Δ -4.17 ± 0.75; post-treatment median Bristol 1-2; p < 0.001). Pro-inflammatory mediators differed across groups (all p < 0.001): compared with K-, P1/P2 markedly reduced IL-6, TNF-α, CRP, PDGF, COX-2, and VEGF. SCFAs were restored toward baseline in treated groups, with P2 showing the highest acetate/propionate/butyrate recovery vs. K- (all p ≤ 0.01). Macroscopic injury scores and leukocyte counts were significantly lower in K+, P1, and P2 vs. K- (p ≤ 0.003). Fibroblast count, collagen density, M2 macrophages, and CD34 trended upward in treatment arms but were not statistically different among groups (p ≥ 0.075). In DSS-induced colitis, G. pictum-especially combined with 5-ASA-improves clinical (weight, stool form) and biological outcomes by suppressing inflammatory pathways and restoring SCFA profiles, with concordant reductions in macroscopic damage and leukocytosis. These data support G. pictum as a promising adjunct to standard therapy for promoting gut homeostasis and functional recovery.
We aimed to investigate the efficacy of lumbar transforaminal epidural steroid injection therapy in patients with radicular low back pain that had not been alleviated by conservative management strategies. This study included 252 patients with radiculopathy due to lumbar disc herniation who failed conservative treatment. This is a retrospective cohort study. Participants (aged 18-90) underwent C-arm fluoroscopy-guided transforaminal epidural steroid injections (TFESI) using a subpedicular approach. Pain severity and functional status were evaluated at baseline, 2 weeks, and 3 months post-procedure using the Visual Analog Scale (VAS) and the Oswestry Disability Index (ODI). Statistical analysis focused on sociodemographic characteristics and longitudinal changes in VAS and ODI scores. Out of 252 patients, 221 completed the full 3-month follow-up (mean age 54.5 ± 14.1 years; 57.5% female). The median symptom duration was 5 months, and the most frequent injection levels were L4-5 (51.1%) and L5-S1 (48.4%). Significant improvements were observed in both pain (VAS) and functional status (ODI) at the 2-week and 3-month months (p < 0.001). At the 3-month follow-up, treatment success (defined as >50%improvement) was achieved in 64.3% of patients for pain at rest, 57.5% for pain during movement, and 74.2% for nocturnal pain. Additionally, 55.7% of patients demonstrated a significant reduction in disability according to ODI scores. TFESI is an effective non-operative treatment intervention that provides significant mid-term pain reduction and functional improvement in a substantial proportion of patients with lumbar radiculopathy. The low rate of surgical conversion suggests its value as a key alternative to surgery. NCT07538765.
Ketamine has emerged as a promising rapid-acting antidepressant for treatment-resistant depression (TRD), yet its mechanisms of action and reliable biomarkers of treatment response remain poorly understood. Recent evidence suggests that the aperiodic exponent (1/f slope) of electroencephalography (EEG) power spectra reflects cortical excitation-inhibition balance (EIB), offering a potential non-invasive marker of treatment outcomes. Our study investigated whether subanesthetic ketamine modulates the EEG aperiodic exponent in patients with major depressive disorder (MDD), most of whom met criteria for TRD. We also examined whether pretreatment aperiodic exponent predicts antidepressant response. A placebo-controlled, single-blind, one-arm, fixed-sequence design without randomization trial of intravenous ketamine infusion in patients with MDD. Twenty-four MDD patients underwent both placebo and ketamine (0.54 mg/kg over 30 min) infusions. Resting-state EEG was recorded pre-, start-, end-, and 24 h post-infusion. Aperiodic exponent (1-40 Hz) was extracted using spectral parameterization. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale, with responders defined as ⩾33% symptom reduction 24 h post-infusion. Meta-analysis revealed substantial heterogeneity in ketamine's effect on aperiodic exponents. In our cohort, ketamine significantly reduced the aperiodic exponent across the scalp. Notably, responders exhibited higher pretreatment occipital aperiodic exponents than non-responders. A steeper pretreatment 1/f slope in the occipital region predicted better treatment outcomes. Subanesthetic ketamine alters cortical aperiodic dynamics in MDD, potentially reflecting EIB modulation. The EEG aperiodic exponent, particularly in occipital regions, may serve as a useful biomarker for predicting antidepressant response to ketamine. However, our meta-analysis underscores the complexity and variability of the EEG aperiodic exponent. Future large-scale, multimodal studies are needed to validate and expand on these findings. EudraCT Number: 2013-000952-17 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000952-17/CZ). Using brain wave patterns to predict who benefits from ketamine treatment for depression Ketamine is a fast-acting treatment that can reduce symptoms of severe depression, especially in people who have not improved with standard antidepressants. However, not everyone benefits from ketamine, and doctors currently have no reliable way to predict who will respond. In this study, we explored whether a simple, non-invasive brain test called electroencephalography (EEG) could help identify people who are more likely to improve after ketamine treatment. EEG measures the brain’s natural electrical activity using small sensors placed on the scalp. We focused on a specific pattern in brain activity that reflects the balance between two important brain processes: activation and inhibition. This balance helps regulate healthy brain function and may be altered in depression. Twenty-three adults with major depressive disorder received both placebo and ketamine infusions in a controlled study. We measured their brain activity before, during, and after treatment. We found that ketamine temporarily shifted overall brain activity toward greater activation. Importantly, people who showed stronger inhibitory patterns in the back part of the brain before treatment were more likely to experience improvement in their depression symptoms 24 hours later. These findings suggest that a simple brain wave measure could help predict who is most likely to benefit from ketamine. While more research with larger groups is needed, this approach may eventually support more personalized and targeted treatment decisions for people with difficult-to-treat depression.
The Myval Transcatheter Heart Valve (THV) was designed to address limitations of earlier devices, such as paravalvular leak and sizing restrictions. The LANDMARK trial showed non-inferior short-term outcomes versus established valves in a randomized population of patients with severe aortic stenosis eligible for TAVR with the compared devices. However, confirmation of these findings in routine clinical practice remains important. This study evaluates the real-world safety, efficacy, and mid-term durability of Myval in severe aortic stenosis. This study evaluates the real-world safety, efficacy, and mid-term durability of the Myval THV in patients with severe symptomatic aortic stenosis undergoing TAVR in a consecutive single-center registry. We conducted a retrospective, single-center, single-arm study including 214 consecutive patients who underwent Myval THV implantation between December 2020 and February 2025, with at least 30-day follow-up. Clinical events were reported as incidence rates per 100 patient-years, and hemodynamic performance was assessed using mean profile charts with 95% confidence intervals. Among 214 patients (mean age 77 years; 41% female), procedural success was 97.7%. Aortic valve area increased from 0.68 cm2 at baseline to 1.79 cm2 at 30 days, with mean gradients falling from 55.6 mmHg to 10.2 mmHg and remaining stable at 3 years. At 1 year, all-cause mortality was 9.0%, stroke 2.7%, and new pacemaker implantation 11.8%, while structural valve deterioration was rare (3.4%). In this real-world cohort, TAVR with the Myval THV showed high procedural success, sustained mid-term hemodynamic improvement, and complication rates comparable to benchmark devices. These findings support its potential as a safe and effective option for severe aortic stenosis, although confirmation in larger, multicentre studies with extended follow-up is warranted.
Established data describing the optimal duration of dual antiplatelet therapy (DAPT) after endovascular therapy (EVT) for patients with peripheral artery disease (PAD) are limited. This study is a prospective, multi-center single-arm study evaluating 1-month DAPT on clinical outcomes following EVT using drug-coated balloon (DCB) for patients with symptomatic femoropopliteal artery (FPA) disease. A total of 151 patients with de novo FPA lesions which planned DCB therapy were enrolled from seven centers. DAPT (aspirin 100 mg/day and clopidogrel 75 mg/day) was started prior to EVT and continued 1-month after EVT, and subsequent aspirin monotherapy was continued during follow-up period. The primary endpoint was 1-year primary patency, as assessed by duplex ultrasound. Secondary endpoints included re-occlusion, target lesions revascularization (TLR), major amputation, acute limb ischemia (ALI), and bleeding events at one year. Mean age was 74.6 ± 8.8 and critical limb ischemia were observed in 48 patients (31.8%). Mean lesion length was 14.1 ± 9.7 cm and chronic occluded lesions were 23.8%. The primary patency rate was 74.3% at 1-year (the median period: 12.9 months). The rate of freedom from re-occlusion, TLR, and major amputation was 84.0, 86.1, and 88.2% respectively. There were no incidence of ALI and life-threatening bleedings. One-month DAPT and subsequent aspirin monotherapy following EVT with DCB for FPA lesions might be an option in terms of the bleeding risk. Further investigations with large number of subjects are required to reveal the optimal antiplatelet therapy for PAD patients.
Severe sickle cell disease (SCD) leads to recurrent vaso-occlusive events (VOEs), progressive organ damage, and premature death. Autologous gene therapy has emerged as a potential curative strategy, but trial efficacy must be interpreted together with mobilization, apheresis collection, manufacturing, conditioning, cost, fertility preservation, and long-term surveillance requirements. To evaluate the efficacy, safety, and treatment-delivery feasibility of autologous gene therapy for SCD across lentiviral, shmiR-BCL11A, CRISPR-Cas9, CRISPR-Cas12a, and base-editing platforms. We searched PubMed, Embase, Scopus, Cochrane CENTRAL, ClinicalTrials.gov, FDA, and EMA sources, and ASH/EHA/EBMT/ASPHO conference proceedings through June 23, 2026. Eligible studies were interventional trials or long-term follow-up studies of autologous gene therapy for SCD. Two reviewers independently screened records, extracted data, and assessed risk of bias. Because endpoint definitions were heterogeneous and fewer than three prospectively comparable cohorts were available for the main efficacy outcomes, formal pooling and forest plots were not performed; outcome proportions are presented descriptively. The updated synthesis included 25 reports describing nine interventional clinical programs and associated follow-up reports, with 148 infused patients across lentiviral, shmiR, CRISPR-Cas9, CRISPR-Cas12a, and base-editing platforms. Prospectively defined VF12 was 96.7% (29/30) in the exa-cel pivotal cohort, and severe VOE resolution was 100% (25/25) in the lovo-cel pivotal cohort; both products achieved transfusion independence in evaluable patients. Reni-cel and risto-cel added contemporary Cas12a and base-editing evidence, with early follow-up showing high HbF induction and few or no reported post-infusion VOEs, but follow-up was shorter, and endpoints were not pooled with pivotal VF12 cohorts. Treatment-delivery outcomes differed across programs, including 44/46 infused for exa-cel and 35/47 infused for lovo-cel. Autologous gene therapy for SCD produces substantial short- to medium-term reductions in severe VOEs and improves hemoglobin biology, but certainty remains limited by single-arm designs, small samples, evolving protocols, and incomplete long-term follow-up. Successful delivery depends on separable processes: transfusion preparation, mobilization, apheresis collection, ex vivo manufacturing/editing, product release, conditioning, and reinfusion. Long-term safety, fertility, organ outcomes, reimbursement, and global scalability remain unresolved implementation barriers.
Arginase 1 Deficiency (ARG1-D) is a rare metabolic disorder characterized by marked hyperargininaemia and progressive neurological impairment. Dietary protein restriction alone is often insufficient to normalize plasma arginine (pArg) or prevent disease progression. Pegzilarginase, a recombinant human ARG1 enzyme therapy, has demonstrated pArg normalization and improved clinical outcomes in patients ≥2 years. This study evaluated safety, pharmacokinetics (PK), and activity of pegzilarginase in patients <2 years. In this phase 3, open-label, single-arm study (NCT06582524, EU CT 2024-510797-25), conducted in United Kingdom, Austria and Portugal, patients received once-weekly subcutaneous pegzilarginase. As primary endpoint, change in pArg at 12 weeks was assessed. Secondary endpoints included safety, PK, plasma ornithine and Gross Motor Function Measure (GMFM-66). Descriptive analyses were performed on the Full Analysis Set. Three patients (mean age 20.3 months) were included between 30 August 2024 and 17 June 2025. After 12 weeks, mean (SD) pArg decreased by 221.5 (81.3) μmol/L, a 70.6% (4.3) reduction, reaching normal range by Visit 4 (114.1 [68.4] μmol/L). Plasma ornithine increased and plasma ammonia remained largely normal. GMFM-66 total scores improved by 21.0 (13.9) points (18.1% [5.8%]). Pegzilarginase exposure was consistent with previous studies; AUC and half-life were similar, whereas clearance and volume of distribution were lower, as expected in infants. No new safety findings were observed. In patients with ARG1-D <2 years of age, pegzilarginase demonstrated pharmacokinetic and pharmacodynamic responses comparable to older children and a favourable safety profile. Immedica Pharma AB.
Intercostobrachial nerve (ICBN) syndrome is a common peripheral sensory nerve injury following axillary surgery for breast cancer. It is characterized by persistent numbness and burning pain extending from the affected axilla to the medial aspect of the upper arm, as well as restricted shoulder joint mobility, which severely impacts postoperative recovery and quality of life. Current interventions primarily focus on symptomatic analgesia and functional exercises, lacking standardized external treatment protocols to promote nerve repair. Transcutaneous electrical acupoint stimulation (TEAS) combines the advantages of acupuncture and transcutaneous electrical stimulation. It is non-invasive and has high patient acceptance. Preliminary studies suggest it can promote axonal regeneration and myelin formation, yet scientific evidence-based evidence for ICBN syndrome is lacking. This study aims to systematically evaluate the therapeutic effects and safety of TEAS on ICBN syndrome through a prospective, randomized, sham-controlled trial, providing evidence-based medical evidence for clinical practice. This prospective, randomized, sham-controlled clinical trial will be conducted at the Yunnan Provincial Hospital of Traditional Chinese Medicine. We plan to recruit 200 patients with ICBN syndrome after breast cancer surgery. Participants will be randomly assigned in a 1:1 ratio to either the TEAS group or the Sham TEAS group, with 100 cases in each group. Both groups will start receiving treatment on the first postoperative day, administered once every other day. Ten sessions will constitute one course, for a total of three courses. The primary outcome measure is CMS. Secondary outcome measures include MMT, EMG, VAS, SWMT, FACT-B, SF-36, and TCM-SD. Adverse events will be recorded throughout the study. https://itmctr.ccebtcm.org.cn/mgt/project/view/2041939715654978881, identifier, ITMCTR2024000864.
Mild cognitive impairment (MCI) is an intermediate clinical state between normal cognitive aging and dementia. MCI can impair complex daily activities and social functioning. Ayurveda recognizes age-related changes (Jarā) as a natural phenomenon; however, pathological cognitive decline is considered when influenced by doṣa-vaiṣamya. Descriptions of Buddhi-bhraṁśa and Smṛti-bhraṁśa can be correlated with cognitive decline. Current pharmacological and non-pharmacological approaches show variable outcomes, highlighting the need for supportive and integrative strategies. The single-arm, open-label clinical study evaluated 24 participants diagnosed with mild neurocognitive disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The patients were administered Trikatu Cūrṇa 3 g twice daily, after food, for 7 days, followed by Brahmi Ghṛta 5 mL twice daily with milk as Anupāna, after food, for 90 days. Out of the 27 enrolled participants, 24 completed the study and 3 dropped out. Cognitive assessment was carried out using the Montreal Cognitive Assessment (MoCA) Scale. This study is registered in the Clinical Trial Registry of India under CTRI/2024/07/070223 before enrolment of the first participant. Post-intervention assessment demonstrated a statistically significant improvement in overall cognitive scores compared to baseline (p < 0.001), with a large effect size and no adverse events. However, these findings are strictly limited by the open-label, single-arm design, lack of lifestyle standardization, and unrecorded concomitant medications. Trikatu Cūrṇa, through its Dīpana-Pācana action, may support Agni and help in Āma reduction, thereby improving metabolic efficiency and drug absorption. Brahmi (Bacopa monnieri) formulation, Brahmi Ghṛta, is traditionally described as a Medhya Rasāyana, and based on experimental and pharmacological evidence, it may support cognitive function through mechanisms such as modulation of cholinergic pathways, enhancement of synaptic plasticity, and neuroprotective effects in hippocampal circuits relevant to MCI. https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=MTEwODI2&Enc=&userName=.
Tactical athletes face disproportionately high rates of musculoskeletal injury, with associated mental health consequences including fear-avoidance behavior and functional decline. While holistic programs integrating physical training and psychological support have shown promise for whole-person recovery, evidence for the durability of such benefits beyond the immediate post-intervention period in tactical populations remains limited. To quantify the physiological, psychological, and quality-of-life effects of the Game Plan program at baseline, immediately post-program, and at 90 days and 6 months follow-up. Twenty adult participants engaged in a four-week Game Plan program. Assessments included Body Composition Analysis, Mental Health Evaluation, Quality of Life Survey (QOLS), Tampa Scale of Kinesiophobia (TSK), EXOS Pillar Pre-Requisite Assessment, and a daily sleep log. Data was collected at baseline, post-program, and during remote follow-ups at 90 days and 6 months. This single-arm, observational pilot study was not designed to establish causation. Longitudinal changes were evaluated using linear mixed-effects models. Twenty tactical athlete participants were enrolled in the study. All were white males with an average age of 41.4 (SD = 7.13) years old. A significant improvement in overall functioning was observed at 4 weeks compared with baseline (mean difference, 9.05; 95% CI: 2.20 to 15.90; p = 0.032; Cohen's d = 0.84). Kinesiophobia demonstrated a significant reduction at 90 days compared with baseline (mean difference, -4.40; 95% CI: -6.62 to -2.17; p < 0.001; Cohen's d = -1.37). Sleep duration showed a small but non-significant trend toward improvement at Week 4 compared with Week 1 (mean difference, 0.23; 95% CI: -0.03 to 0.49; Cohen's d = 0.22; p = 0.237. Larger studies are needed to confirm this observation. The Quality-of-Life domains, including Physical, Psychological, Social Health, and Environmental, showed no significant difference from baseline to 6 months. The four-week holistic training program with tactical athletes was associated with improvement in kinesiophobia, and overall functioning, with kinesiophobia gains persisting at six-month follow-up. A trend toward improved sleep duration was observed but did not reach statistical significance. The quality-of-life domains did not reach statistical significance. These pilot findings support further investigation through controlled trials to establish causal relationships.
Sustained prevention of type 2 diabetes (T2D) remains a major public health challenge, as benefits from traditional lifestyle and earlier pharmacologic interventions have often been difficult to maintain. Prediabetes is associated with increased cardiometabolic disease risk and mortality even without progression to diabetes. Interventions that achieve long-term metabolic health improvements are needed. This study reports five-year outcomes of a continuous remote care intervention (CCI) delivering individualized carbohydrate-reduced nutrition therapy in adults with prediabetes. A three-year prospective, single-arm longitudinal study extended a previously reported two-year trial (ClinicalTrials.gov NCT02519309). Adults 21-65 years with prediabetes were enrolled (n = 96) in the original two-year trial; 58 participants consented to a three-year extension. Outcomes assessed over 5 years included glycemic status, weight, insulin resistance, lipids, inflammatory markers, and liver and kidney function. Longitudinal changes were analyzed using generalized estimating equations and linear mixed-effects models as part of an extension cohort analysis. At five years, 45 participants (47% of the original cohort) completed follow-up with 22% achieving normoglycemia (P < 0.001), and 13% progressing to T2D (P < 0.01). The cumulative incidence (i.e., achievement at any time point) of regression to normoglycemia was 55.6%, and progression to T2D was 12.2% over five years. Fasting insulin, HOMA-IR, triglycerides, HDL-C, LDL-C, non-HDL-C, and hsCRP were maintained at or below baseline levels at five years; however, these differences were not statistically significant after adjustment, despite unadjusted P-values ≤ 0.05. Mean body weight was reduced by 5.8 kg (5.3%; P < 0.001), with 47%, 29%, and 13% achieving ≥5%, ≥10%, and ≥15% weight loss, respectively. Liver and kidney function was stable. Participation in a continuous remote care model delivering individualized carbohydrate-reduced nutrition therapy was associated with significant weight reduction and maintenance of glycemic status, insulin resistance, and cardiometabolic risk markers over five years among adults with prediabetes. Although mean glycemic markers were comparable to baseline at five years, a substantial proportion of participants achieved normoglycemia and relatively few progressed to T2D, suggesting potential for long-term diabetes prevention with a digitally supported, nutrition-focused intervention.
Tobacco use prevention among university students requires evidence on which educational program features students prefer. This study used a discrete choice experiment (DCE) embedded in a randomized controlled trial (RCT) to quantify Chinese never-tobacco-using university students' preferences for attributes of a tobacco control health education program. A DCE with six two-level attributes (organizer, content format, organization mode, frequency, educational content, delivery location) was administered to 260 never-tobacco-using university students enrolled in a Protection Motivation Theory (PMT)-based RCT. Seven choice sets, each containing two unlabeled alternatives, were presented via an online survey platform. Conditional logit models with cluster-robust standard errors estimated attribute preferences; Wald interaction tests assessed preference heterogeneity by trial arm, sex, parental smoking, and peer smoking. Of the 260 respondents, 192 (73.8%) were female, and 243 (93.5%) were undergraduates. Students significantly preferred video-based content (β= -0.1899; 95% CI: -0.2723 - -0.1074), online delivery (β= -0.1698; 95% CI: -0.2525 - -0.0872), and comprehensive cigarette-plus-e-cigarette content (β= -0.1320, 95% CI: -0.2147 - -0.0493). Content format (32.0%), delivery location (28.6%), and educational content (22.2%) together accounted for 82.8% of relative attribute importance. DCE preferences did not differ between trial arms (all Wald interaction p>0.33). A significant sex × delivery location interaction was observed (p=0.019). Chinese never-tobacco-using university students prefer video-based, online, comprehensive tobacco and e-cigarette education. These demand-side preferences may inform the design of future campus-based prevention programs. The absence of trial arm differences supports the validity of the embedded DCE-RCT design. The study is registered on the official website of Chinese Clinical Trial Registry. ChiCTR2300068240.