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PubMed2026

Orbital involvement in sickle cell disease: A systematic review.

Orbital involvement in sickle cell disease (SCD) is rare but potentially vision-threatening and is often misdiagnosed due to overlap with infectious orbital disease. We conducted a systematic review of case reports and series describing orbital complications in patients with confirmed SCD, following PRISMA and MOOSE guidelines. Across 53 studies, 76 cases were identified. Patients were predominantly male (77.6%), with an average age of 13.2 years. Orbital disease was the initial SCD manifestation in 6.6%. Presentations included periorbital edema in all, proptosis in 64.1%, restricted ocular motility in 56.5%, reduced visual acuity in 28.1%, and bilateral involvement in 38.2%. Laboratory findings commonly included leukocytosis (73%) and raised inflammatory markers (86.7%). Radiologically, orbital subperiosteal hematoma were observed in 70%, combined orbital bone infarction and hematoma in 38.2%, and orbital bone infarction alone in 19.7%. Magnetic resonance imaging is critical for accurate diagnosis. Intracranial hemorrhage was present in 9.2%. Less frequent manifestations included orbital apex syndrome, lacrimal gland disease, and nonspecific soft tissue swelling. Management was primarily conservative (82.9%), and surgery was reserved for vision-threatening or intracranial complications. Complete recovery was achieved in 93.1% of cases. While severe vision-threatening complications are uncommon, early recognition remains critical to optimising outcomes in sickle cell orbitopathy.

Humans↗

PubMed2026

Weight-bearing locomotion mitigates the progression of post-traumatic knee osteoarthritis in male rodents: A systematic review and meta-analysis.

OBJECTIVE: Although knee post-traumatic osteoarthritis (PTOA) has been associated with altered loading, how weight-bearing (WB) activities should be modulated post-injury to preserve knee health remains unknown. This systematic review and meta-analysis examined the effects of WB locomotion on knee PTOA in rodents to provide insight into potential clinical implications. DESIGN: Studies published in PubMed, Cochrane Library, Embase, and CINAHL through 02/2025 and meeting the following criteria were included: 1) rodents with knee PTOA, 2) compared locomotor exercises (treadmill/wheel) to no exercise, 3) outcome measures of PTOA (OARSI/Mankin OA scores, bone quality, osteophyte condition, cartilage quality/morphology). If significant heterogeneity across studies was observed, locomotion speed, time/number of intervention sessions, frequency and duration of intervention, exercise initiation, follow-up time, animal species, PTOA model were analyzed as potential moderator variables that may influence findings. RESULTS: Twenty-two studies met the criteria, resulting in a total of 156 effect sizes (ESs) for meta-analysis (all males). A positive ES denotes less PTOA. Based on the CAMARADES checklist, 5 studies were ranked low risk of bias and 14 studies were ranked moderate risk of bias. Locomotion significantly reduced PTOA severity evaluated using OARSI/Mankin scores (ES=0.927, 95% CI: [0.590, 1.264]) and improved bone quality (ES=0.379, 95% CI: [-0.023, 0.780]) with substantial heterogeneity across studies. Follow-up analyses indicated that greater ESs for reducing OA scores were associated with a shorter duration of each training session, more training sessions, longer intervention duration, and longer follow-up time (all P≤0.004). Greater ESs for improving bone quality were associated with a longer follow-up time and later exercise initiation post-injury (both P≤0.014). Locomotion resulted in small to moderate but non-significant positive effects for isolated measures assessing osteophyte condition (ES=0.379, 95% CI: [-0.023, 0.780]), cartilage quality (ES=0.430, 95% CI: [-0.034, 0.893]), and cartilage morphology (ES=0.464, 95% CI: [-0.006, 0.934]). CONCLUSION: WB locomotion reduced the overall degree of knee PTOA in male rodents. Composite knee OA scores may be more responsive to exercise interventions than isolated cartilage/osteophyte measures. The benefits of locomotion may be more prominent with a longer follow-up time or with exercise protocols consisting of shorter but more individual sessions and longer overall intervention durations.

Animals↗

PubMed2026

Seed-derived mucilage polysaccharides as biomaterials for in vivo tissue regeneration: A systematic review.

Chronic wounds, bone defects, and cartilage injuries represent persistent clinical challenges requiring biomaterial platforms that actively regulate inflammation, oxidative stress, angiogenesis, and extracellular matrix remodeling. Conventional synthetic dressings often provide limited biological activity in these contexts. Seed-derived mucilages - polysaccharide-rich hydrocolloids obtained from chia (Salvia hispanica), flaxseed (Linum usitatissimum), fenugreek (Trigonella foenum-graecum), psyllium (Plantago ovata), guar (Cyamopsis tetragonoloba), quince (Cydonia oblonga) etc. - have emerged as biocompatible, biodegradable, and chemically versatile platforms for tissue engineering. This systematic review, conducted according to PRISMA 2020 guidelines, synthesized in vivo evidence on seed-derived mucilage-based biomaterials across wound healing, bone repair, cartilage regeneration, and related applications. PubMed, Scopus, and Web of Science Core Collection were searched for original in vivo experimental studies published in English between 2020 and 2026. Eligible studies reported at least one measurable regenerative outcome. Data were extracted independently by two reviewers, and methodological quality was assessed using the SYRCLE Risk of Bias tool. Forty-three studies were included. Hydrogels were the dominant biomaterial format, followed by films, scaffolds, sponges, nanoparticle systems, and bilayer or Janus composites. Included systems generally improved wound closure, re-epithelialization, collagen deposition, angiogenesis, antioxidant defense, and inflammatory regulation. However, most studies used small animals with short follow-up periods, and many incorporated nanoparticles or bioactive agents, limiting attribution of efficacy to the mucilage matrix alone. Risk of bias was predominantly unclear due to insufficient reporting of randomization and blinding. Blank mucilage controls, standardized characterization, long-term biosafety data, and clinically relevant models are essential prerequisites for translational progress.

Humans↗

PubMed2026

Orthoplastic management of open calcaneal fractures: A systematic review of flap selection and complications.

BACKGROUND: Open calcaneal fractures are rare, high-energy injuries involving extensive soft-tissue loss and comminuted bone disruption. Successful management depends on coordinated orthoplastic reconstruction to achieve stable fixation and durable coverage. Multiple flap types have been described, yet comparative outcomes remain poorly defined. METHODS: A systematic review was performed in accordance with PRISMA guidelines (PROSPERO: CRD420251138394). MEDLINE, Embase, Cochrane CENTRAL, and Scopus were searched from January 2000 to July 2025. Studies reporting flap-based reconstruction for open calcaneal fractures in adults were included. Extracted data included flap type, fixation method, follow-up duration, and complications such as infection, necrosis, vascular crises, flap loss, and amputation. RESULTS: Thirteen studies comprising 88 major flap reconstructions were analysed. Overall flap survival was 97.7%, with two failures (both muscle/myocutaneous). Fasciocutaneous flaps showed the lowest complication rates (8.3%) with no reported cases of infection, while muscle/myocutaneous flaps demonstrated cases of infection (20%) and accounted for both flap failures and the only reported amputation. Chimeric flaps were increasingly used in recent series (n = 32), achieving reliable survival but higher vascular compromise (6.3%). Osteocutaneous flaps were rare (n = 4) and primarily used for defects with bone loss, showing infection in 50% of cases. Meta-analysis was not possible due to heterogeneity and small sample sizes. CONCLUSIONS: Fasciocutaneous flaps provide reliable, low-complication coverage for clean wounds, while muscle flaps remain valuable for contamination or complex cases with extensive tissue loss. Chimeric, and osteocutaneous flaps show promise, but larger, standardised studies are needed to clarify their roles in hindfoot reconstruction.

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

Efficacy and Safety of Elagolix Versus Dienogest for Treatment of Moderate-to-Severe Endometriosis Pain: A Phase III, Multicentric, Double-Blind, Active-Controlled, Non-Inferiority Study.

OBJECTIVE: To compare the efficacy, safety and tolerability of elagolix with dienogest in women with moderate-to-severe endometriosis-associated pain. DESIGN: A multicentre, double-blind, double-dummy, randomised, parallel-group, active-controlled, non-inferiority phase III study. SETTING: Nineteen clinical centres across India. STUDY POPULATION: Women (18-49 years) diagnosed with endometriosis and experiencing moderate-to-severe pain. METHODS: Participants were randomised (1:1) to receive oral elagolix (150 mg once daily) or dienogest (2 mg once daily) for 24 weeks. OUTCOME MEASURES: The primary outcome was change in endometriosis-related pain (Numeric Rating Scale [NRS]) from baseline to Day 85. Secondary outcomes included changes in NRS (Day 169), dysmenorrhoea, non-menstrual pelvic pain (NMPP) scores (Days 85 and 169), rescue medication use, patient global impression of change (PGIC), adverse events and bone mineral density. RESULTS: Of 340 patients screened, 230 were randomised (115 per group). At Day 85, both arms showed similar reductions in NRS pain scores with a treatment difference of 0.04 (95% CI: -0.3, 0.37) [p = 0.9747] demonstrating non-inferiority as upper 95% CI was below pre-specified margin of 1.5. At Day 169, both arms showed comparable improvements in overall pain, dysmenorrhoea and NMPP from baseline (p = 0.9372, p = 0.8884, and p = 0.9616, respectively). Rescue medication use and PGIC were comparable between treatment arms. Adverse event incidence was similar (elagolix: 14.8%; dienogest: 19.1%), with no serious TEAEs or discontinuations. No significant bone mineral density changes were observed. CONCLUSIONS: Elagolix demonstrated non-inferiority to dienogest with an acceptable safety and tolerability profile, supporting its use in managing endometriosis-associated pain. TRIAL REGISTRATION: ClinicalTrials.gov identifier: CTRI/2023/01/049292.

Humans↗

PubMed2026

Can ChatGPT Replace Human Clinical Coders? A Comparative Study in Otology Billing.

OBJECTIVE: Evaluate the utility of the large language model (LLM), ChatGPT, for the analysis of operative notes and the generation of Current Procedural Terminology (CPT) codes in comparison to human clinical coders. STUDY DESIGN: CPT billing codes assigned by ChatGPT were compared to existing billing data. Otology practice within a tertiary academic center. METHODS: About 191 operative notes from a single surgeon (9/2022-10/2023) were analyzed. ChatGPT-3.5 and 4 models were prompted for CPT codes based on operative notes. Assessment included determining exact and partial match rates, sensitivity and specificity for targeted procedures, and work Relative Value Units (wRVU) differences between ChatGPT-generated and human-assigned codes. RESULTS: ChatGPT-3.5 achieved exact matches in 22% of cases and partial matches in 32%, while ChatGPT-4 achieved 14% exact and 33% partial matches. When cochlear implantation (CI) was excluded, performance dropped significantly. For CI, ChatGPT-3.5 demonstrated a sensitivity of 94% and specificity of 90%, while ChatGPT-4 showed a sensitivity of 96% and specificity of 92%. In contrast, performance on cartilage grafting was poor, with sensitivities of 4.2% for ChatGPT-3.5 and 0% for ChatGPT-4. ChatGPT-3.5 and 4 showed moderate CPT code matching accuracy among themselves, with slight agreement to human coders. Both models tended to underbill for wRVUs compared to human coders, with significant differences in the values generated. CONCLUSION: This study assessed ChatGPT's effectiveness in automating CPT code assignment for otologic surgeries. While the models achieved high sensitivity values for assigning codes related to cochlear implantation, both models struggled with complex cases, failed to apply modifiers, and often assigned fewer wRVUs. The findings highlight ChatGPT's potential in medical billing but indicate a need for further refinement.

Humans↗

PubMed2026

Transverse Tibial Transport for Limb Salvage in Ischemic Lower Extremity Disease: Technique, Mechanisms, and Clinical Outcomes-A Systematic Review.

Transverse tibial transport (TTT) is a surgical technique derived from Ilizarov's distraction osteogenesis principles that stimulates angiogenesis and microcirculatory regeneration in the ischemic lower limb without directly manipulating macrovascular anatomy. By creating a proximal tibial cortical bone window and distracting it transversely using an external fixator, TTT triggers converging cascades of growth factor release, endothelial progenitor cell mobilization, and immunomodulation that translate into improved distal limb perfusion and wound healing. Combined TTT plus endovascular therapy improves amputation-free survival versus endovascular therapy alone. Prospective randomized trials and standardized international protocols are needed to consolidate TTT's role in multidisciplinary limb salvage pathways.

Humans↗

PubMed2026

A phase I clinical study of the safety, tolerability, pharmacokinetics and pharmacodynamics of SHR-2106, an anti-CD40 antibody, following single intravenous or subcutaneous administration in healthy participants.

BACKGROUND: SHR-2106 is a humanized IgG1 monoclonal antibody that blocks CD40-CD40L interactions and has demonstrated immunosuppressive activity and graft-prolonging effects in preclinical studies. This first-in-human Phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of single intravenous or subcutaneous doses of SHR-2106 in healthy adults. METHODS: This randomized, double-blind, placebo-controlled Phase I study enrolled healthy participants. Fifty-one participants were enrolled in seven cohorts and received five intravenous doses (50-1200 mg) or two subcutaneous doses (300 and 600 mg). Safety, serum pharmacokinetics, CD40 occupancy on B cells, and anti-drug antibodies were assessed using standard clinical and bioanalytical methods. RESULTS: SHR-2106 demonstrated a favorable safety and tolerability profile, and most treatment-emergent adverse events were mild to moderate laboratory abnormalities with incidence rates comparable to placebo. SHR-2106 exhibited nonlinear pharmacokinetics consistent with target-mediated drug disposition, with a dose-dependent increase in geometric mean terminal half-life following intravenous administration (1.83-10.7 days). Absolute bioavailability after subcutaneous administration was approximately 60%. CD40 occupancy exceeded 80% within 24 h at all doses, with saturation duration increasing from 7 to 70 days across the intravenous dose range and remaining comparable between routes at matched doses. Anti-drug antibody incidence decreased with increasing intravenous dose and did not significantly affect pharmacokinetics or pharmacodynamics. CONCLUSION: SHR-2106 was well tolerated and achieved rapid and sustained CD40 engagement, supporting dose and route selection for Phase II studies.

Humans↗

PubMed2025

Impact of subthreshold troponin levels and temporal trends on short term adverse cardiovascular outcomes in patients discharged from the emergency department: a RACE-IT trial substudy.

BACKGROUND: High-sensitivity cardiac troponin I assays enable early exclusion of myocardial infarction in the emergency department. However, the clinical implications of detectable troponin values below the 99th percentile upper reference limit (4-18 ng/L) remain unclear. OBJECTIVE: To assess the association between subthreshold troponin levels and 30-day outcomes in patients from the RACE-IT trial, using exact troponin values when available. METHODS: This post-hoc analysis of the RACE-IT stepped-wedge randomized controlled trial included patients with troponin ≤ 18 ng/L across nine EDs. Patients were stratified by initial troponin, peak value, absolute change, and percent change. The primary outcome was a 30-day composite of all-cause death, acute MI, percutaneous coronary intervention, and coronary artery bypass grafting. Logistic regression analysis after adjusting for age, sex, race, and coronary artery disease was performed. RESULTS: Among 19,194 patients with troponin ≤ 18 ng/L, 117 (0.6%) experienced the composite outcome. Higher troponin levels were associated with increased event rates in unadjusted analyses. Adjusted analyses showed no independent associations overall, though patients whose highest troponin values fell within the ≥ 11- ≤ 18 ng/L range continued to demonstrate significantly worse outcomes than those with lower peak levels. Elevated troponin values correlated with older age, male sex, and greater comorbidity burden. CONCLUSION: In this post-hoc analysis of patients with troponin values below the 99th percentile URL, absolute levels and temporal changes were not independently associated with 30-day adverse outcomes. These findings support the use of subthreshold troponin values in rapid rule-out protocols, emphasizing the need to consider clinical context and comorbidities in risk assessment.

Humans↗

PubMed2026

Pulmonary artery catheters or central venous catheters for cardiac surgery: the PUMA Pilot randomised clinical trial.

INTRODUCTION: Pulmonary artery catheters are used widely in cardiac surgery despite observed associations with worse outcomes and guidelines that recommend against their routine use. No adequately powered randomised trials are available. METHODS: The PUMA Pilot was a multicentre, randomised, parallel assignment, open-label, pilot and feasibility trial conducted at three tertiary cardiac surgery centres. Eligible patients were adults undergoing coronary artery bypass grafting, aortic valve replacement or surgery on the aortic root or ascending aorta with or without aortic valve replacement, with a predicted surgical mortality of < 2%. Patients were allocated randomly to receive a pulmonary artery catheter or a central venous catheter inserted immediately before surgery. The primary feasibility outcome was protocol compliance, defined as receiving the assigned intervention without crossover. Secondary feasibility outcomes were eligibility rate; recruitment proportion and rate; data completeness; and rate of clinician refusal. RESULTS: We screened 480 patients and 206 (43%) were eligible; 150/203 (74%) approached provided informed consent. Three of 206 (1%) eligible patients were not included due to clinician refusal. Of 149 patients who were randomised, 76 were assigned to the pulmonary artery catheter group and 73 to the central venous catheter group. For the primary feasibility outcome, 147 patients (99%) received the allocated intervention. Data were complete for 144 (97%) patients. Median (IQR [range]) days alive and at home at 30 days was 23.7 (21.9-24.7 [7.0-26.0]) in the pulmonary artery catheter group and 22.9 (20.8-23.9 [8.6-25.8]) in the central venous catheter group. Acute kidney injury occurred in 26/76 (34%) patients in the pulmonary artery catheter group and 14/73 (19%) in the central venous catheter group. DISCUSSION: A randomised trial of pulmonary artery catheters compared with central venous catheters in low-risk cardiac surgery is feasible. Such a trial would address significant practice variability and inform international guidelines.

Humans↗

PubMed2026

Mitochondrial translocation of DNMT3L suppresses oxidative phosphorylation and restrains megakaryopoiesis.

DNMT3L, a catalytically inactive member of the DNA methyltransferase family, is identified here as a negative regulator of megakaryopoiesis. In K562 cells undergoing PMA-induced megakaryocytic differentiation, DNMT3L protein levels declined progressively, and shRNA-mediated depletion enhanced differentiation, whereas overexpression attenuated it. Consistent with these findings, Dnmt3l-knockout mice exhibited elevated peripheral blood platelet counts and expanded bone marrow megakaryocytes. Mechanistically, megakaryocytic differentiation triggered rapid mitochondrial translocation of DNMT3L within 6 h; mitochondrial DNMT3L suppressed oxidative phosphorylation (OXPHOS) capacity and ATP production and downregulated mitochondrial-encoded genes spanning Complex I, III, IV, and ATP synthase, without altering mitochondrial DNA copy number. This metabolic suppression was mediated through compartment-specific remodeling of DNMT3L-containing protein complexes: upon differentiation, DNMT3L selectively dissociated from DNMT1 and DNMT3B in mitochondria, relieving the repressive constraint on OXPHOS, whereas in the nucleus DNMT3L remained associated with DNMT3A, which concomitantly accumulated during differentiation. These findings reveal a previously unrecognized mechanism by which a catalytically inactive epigenetic co-regulator spatially redistributes to coordinate mitochondrial metabolic output with nuclear epigenetic control, thereby facilitating terminal megakaryocytic maturation.

Animals↗

PubMed2026

ER proteostasis failure in HYOU1 deficiency alters B cells, neutrophils, and interferon signalling.

Hypoxia upregulated 1 (HYOU1) is a stress-inducible ER chaperone. We investigated 2 unrelated patients carrying biallelic HYOU1 variants and presenting with primary immunodeficiency. Patient 1, homozygous for p.Pro444His, displayed failure to thrive, hypoglycemia, B cell lymphopenia, and neutropenia. Patient 2, compound heterozygous for p.Arg262Gln and p.Pro757_Glu758insAla, exhibited recurrent infections, enteropathy, and hypogammaglobulinemia. In Patient 1, while HYOU1 transcription was preserved, the protein was severely reduced. Tunicamycin treatment of dermal fibroblasts showed a blunted unfolded protein response and defective induction of ER stress-responsive genes. Immunophenotyping showed near-absence of circulating B cells, and single-cell RNA sequencing of bone marrow identified an arrest at the pro-B cell stage. Neutrophils displayed hypogranulation and dysregulated IFN- and apoptosis-associated transcriptional signatures, unresponsive to G-CSF. HYOU1 deficiency hence results in ER stress-induced proteostasis failure that simultaneously impairs adaptive immunity through B cell developmental arrest and innate immunity through neutrophil dysfunction and IFN pathway imbalance. This work expands the spectrum of HYOU1 deficiency and further identifies ER proteostasis as a central determinant of immune homeostasis.

Journal Article↗

PubMed2026

Imaging techniques for assessing the hand in systemic sclerosis: a systematic review.

BACKGROUND: Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease frequently associated with hand involvement, leading to significant functional impairment. Imaging techniques provide unique opportunities to visualize and quantify structural and functional abnormalities of the hand, supporting diagnosis, monitoring, and treatment evaluation. This systematic review summarizes the imaging techniques used in SSc. METHODS: A systematic search of PubMed and Embase was conducted. Eligible studies included original research articles in English that applied or evaluated imaging techniques of the hands in SSc, published after 2000. Ultrasound and nailfold capillaroscopy were excluded, given their established use. Screening was performed independently by two authors. Findings were synthesized by clinical manifestations, study quality was assessed using the QUADAS-2 tool. RESULTS: Sixty-one studies met the inclusion criteria. In total, 25 distinct imaging techniques were identified, enabling assessment of various hand structures, including vascular involvement, inflammation, fibrosis, calcifications, erosions, and bone marrow edema. Vascular imaging was most extensively studied, particularly in the context of Raynaud's phenomenon and digital ischemia, with multiple techniques demonstrating impaired perfusion and altered thermoregulatory responses. MRI consistently detected subclinical inflammatory and erosive changes of joints and soft tissues,. CT-based techniques provided detailed assessment of calcinosis cutis, while optical and photoacoustic methods showed promise for quantifying skin fibrosis. CONCLUSION: Imaging techniques provide valuable, complementary insights into hand involvement in SSc, often revealing subclinical disease. Despite promising results, limited standardization and longitudinal validation currently restrict clinical implementation. Future studies should focus on harmonizing protocols and validating against clinically meaningful outcomes.

Humans↗

PubMed2026

Measurable Residual Disease and the Unresolved Biology of Leukemic Stem Cells.

Measurable residual disease (MRD) testing has transformed the management of hematologic cancers by enabling detection of residual malignant cells after therapy. Current approaches rely on qPCR and next-generation sequencing to monitor leukemia-associated somatic mutations, while multiparameter flow cytometry identifies aberrant leukemic immunophenotypes. Although these methods provide valuable prognostic and therapeutic information, MRD negativity remains an imperfect surrogate for cure. Most MRD platforms evaluate CD45+, rapidly dividing leukemic populations and fail to detect quiescent cells that may survive cytotoxic therapies which efficiently target proliferating hematopoietic cells. Relapse frequently occurs despite deep molecular remission, suggesting persistence of rare leukemic stem cells (LSCs) that are intrinsically resistant to chemotherapy and targeted therapies. The paradox of relapse despite molecular remission could be explained by the presence of very small embryonic-like stem cells (VSELs) which are pluripotent, quiescent stem cells sitting at the top of cellular hierarchy in multiple adult tissues including bone marrow. A pluripotent VSEL divides through asymmetrical cell division to give rise to two cells of different sizes and fates, smaller cell is to self-renew while the bigger is lineage-restricted and tissue-committed progenitor which undergoes extensive epigenetic changes, divides rapidly and undergoes clonal expansion before further differentiation. Dysfunctions of VSELs initiate both solid and hematologic cancers. Based on this view, somatic mutations monitored during MRD assessment possibly represent downstream consequences of clonal expansion rather than the initiating drivers of disease persistence. Thus, exclusive monitoring of somatic mutations and CD45 + leukemic populations possibly overlook rare, small-sized, CD45- VSELs that contribute to therapeutic resistance and relapse.

Humans↗

PubMed2026

Metformin Adherence and Risk of Polyneuropathy in Type 2 Diabetes Mellitus: An International Matched Cohort Study with Independent Validation.

BACKGROUND: Metformin is a popular first-line glucose-lowering medication for type 2 diabetes mellitus (T2DM). Although metformin reduces the risks of various complications of diabetes, its potential to cause polyneuropathy by depleting vitamin B12 levels is concerning. This study investigated whether the adherence or discontinuation of metformin after adding-on a second-line antiglycemic agent increases the risk of polyneuropathy in patients with T2DM. METHODS: Data from TriNetX were obtained, and patients with T2DM who were receiving second-line antiglycemic agents were divided into metformin-adherent and metformin-nonadherent groups based on prescription claims data. Neuropathy incidence was evaluated using diagnostic claims and nerve conduction examinations. For independent confirmation and external validation of the primary findings, we used data from the National Health Insurance Research Database (NHIRD) of Taiwan. RESULTS: After matching, 58,027 patients were included in each group. Compared with metformin adherent patients, metformin nonadherent patients had a higher risk of polyneuropathy (adjusted hazard ratios [aHR] 1.26; 95% confidence interval [CI] 1.23-1.29; P < 0.001). Risks of diabetic foot ulcer, amputation, neuropathy-related medication use, and bone fracture were also higher among nonadherent patients. Sensitivity analyses confirmed the robustness of findings. In the validation NHIRD cohort (31,384 matched pairs), metformin nonadherence remained associated with increased polyneuropathy risk (aHR 1.25; 95% CI 1.10-1.42; P < 0.001). CONCLUSIONS: Metformin adherence in patients with T2DM who require second-line treatment may reduce the risk of polyneuropathy; vitamin B supplementation may enhance this benefit.

Humans↗

PubMed2026

High-Dose Intravenous Vitamin C and Mortality and Organ Dysfunction in Severe Burn Injury: The VICTORY Randomized Clinical Trial.

IMPORTANCE: Severe burn injury triggers systemic inflammation that can lead to multiple organ dysfunctions and death. High-dose intravenous vitamin C has been proposed to mitigate these effects, but strong evidence in patients with burn injury is lacking. OBJECTIVE: To evaluate the efficacy of high-dose intravenous vitamin C in patients with severe burn injury. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled phase 3 trial conducted across 24 burn centers in North, Central, and South America; Europe; and Asia. Adults (≥18 years) with deep second- and/or third-degree burns covering 20% or more of total body surface area and requiring skin grafting were enrolled between August 18, 2020, and September 12, 2025. Final follow-up was completed in March 2026. The trial was stopped early after the first prespecified interim analysis for futility/harm. INTERVENTIONS: Patients were randomly assigned (1:1) to receive intravenous vitamin C (50 mg/kg every 6 hours for 96 hours) or matched placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was a composite of 28-day mortality and persistent organ dysfunction (defined as dependence on mechanical ventilation, kidney replacement therapy, or vasopressor/inotrope support at day 28). The main secondary outcome was time to discharge alive from hospital within 90 days. RESULTS: Among 238 patients enrolled (mean age, 48.9 [SD, 19.1] years; 79% male; mean total body surface area, 37.0% [SD, 14.6%]), 120 were assigned to vitamin C and 118 to placebo. The primary composite outcome occurred in 49 patients (40.8%) in the vitamin C group and 35 patients (29.7%) in the placebo group (adjusted risk ratio [RR], 1.28 [95% CI, 0.99-1.65]; P = .06), crossing the prespecified futility/harm threshold and prompting early trial termination. Time to discharge alive from hospital within 90 days was not improved (adjusted subdistribution hazard ratio, 0.85 [95% CI, 0.62-1.16]; P = .31). Twenty-eight-day mortality was higher in the vitamin C group (15.0% vs 7.6%; adjusted RR, 1.96 [95% CI, 1.32-2.90]; P = .001), as was hospital mortality (23.3% vs 16.1%; adjusted RR, 1.44 [95% CI, 1.03-2.00]; P = .03). CONCLUSIONS AND RELEVANCE: Among patients with severe burn injury, high-dose intravenous vitamin C did not reduce 28-day mortality and persistent organ dysfunction and is possibly harmful. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04138394.

Humans↗

PubMed2026

Effects of umbilical cord mesenchymal stem cell-derived exosomes on periodontal ligament stem cells: An exploratory study.

OBJECTIVE: To investigate whether exosomes derived from human umbilical cord mesenchymal stem cells (UCMSCs) at two osteogenic induction stages (undifferentiated and late-stage) differentially affect periodontal ligament stem cells (PDLSCs), and to explore the potential molecular basis. DESIGN: UCMSCs and PDLSCs were isolated and cultured. Exosomes were harvested from undifferentiated UCMSCs (Exo-D0) and UCMSCs after 14 days of osteogenic induction (Exo-D14). PDLSCs were treated with both exosome types. Proliferation and migration were analyzed using EdU and scratch assays, the latter under serum-free conditions. Early osteogenic differentiation was assessed by alkaline phosphatase staining and quantitative reverse transcription PCR (qRT-PCR). Differentially expressed miRNAs were identified by high-throughput sequencing and further analyzed through Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. RESULTS: Both exosome types promoted PDLSC migration. Exo-D0 enhanced early osteogenic differentiation, whereas Exo-D14 enhanced proliferation but reduced early osteogenic marker expression. Sequencing identified 21 differentially expressed miRNAs (13 upregulated, 8 downregulated). Bioinformatic prediction suggested that the putative target genes were enriched in Ras signal transduction, regulation of kinase activity, and focal adhesion, and further predicted significant enrichment in the MAPK, Ras, and PI3K-Akt signaling pathways, which are central to cell proliferation and osteogenic differentiation. CONCLUSIONS: Exosomes from undifferentiated and osteogenically induced UCMSCs exerted distinct effects on PDLSCs, potentially associated with differentially packaged miRNAs. These findings offer a basis for hypotheses about exosome-mediated mechanisms and support matching exosome sources to the intended therapeutic outcome as potential cell-free strategies for periodontal tissue regeneration and alveolar bone repair.

Humans↗