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PubMed2026

MicroRNAs in Oral Bio-Fluids as Predictive Biomarkers of Orthodontic Tooth Movement: A Systematic Review.

This systematic review was designed to assess scientific evidence of the association of microRNA expression during orthodontic tooth movement through various time points. A systematic review was performed in accordance with the PRISMA checklist. A search strategy was developed in electronic databases including Med Line, Scopus, EBSCO Host and ProQuest Dissertations & Theses Global until June 2025. Eligibility criteria included studies that investigated microRNA expression in saliva/GCF during orthodontic treatment. The risk of bias of the included studies was analysed using the QUADAS-2 and RoB-2 tools. The search retrieved 2800 records, of which nine studies were selected. Minor variations in GCF collection were noted, while stimulated saliva was collected in one study. RT-PCR and the Fluro meter accounted for the majority of miRNA estimation. Thirteen miRNAs were identified as target biomarkers for OTM regulation. Despite the high risk of bias, the evidence from the current systematic review indicates that microRNAs can be considered as potential biomarkers of orthodontic tooth movement in oral biofluids. Trial Registration: Prospero ID-CRD420251153064.

Humans↗
PubMed2026

Effectiveness of Platelet Rich Plasma in Reducing Oronasal Fistula and Scar Width in Primary Cleft Lip and Palate Repair-A Systematic Review and Meta-Analysis.

This review aimed to investigate platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) efficiency in reducing oronasal fistula during primary cleft lip and palate repair. An extensive search of PubMed, Google Scholar, Global Index Medics (WHO), PubMed Scopus, Cochrane Central, Proquest was performed up to march 2025. Eligible studies included prospective RCTs and non-randomized controlled trials in human subjects. Patients aged 6-24 months undergoing primary cleft lip and palate repair were involved. Interventions involved intraoperative use of PRP/PRF compared with controls without PRP/PRF. The primary outcome was occurrence of oronasal fistula; secondary outcomes were scar width, wound infection and postoperative bleeding with wound dehiscence. Study selection followed PRISMA guidelines, and the risk of bias was determined with the ROB-2 and ROBINS-I method of assessment. Seven studies met the required criterion and were qualitatively synthesized. Evidence suggested that PRP/PRF application was associated with a lower incidence of oronasal fistula and reduced scar width compared with controls. Additional benefits included accelerated wound healing and faster recovery. The use of autologous PRP was also reported to decrease the need for further surgical interventions. However, the certainty of evidence was limited due to small sample sizes and methodological heterogeneity. PRP and PRF show promising benefits in cleft lip and palate repair, particularly decreased fistula formation and reduced scar width. Nevertheless, current evidence is of low to very low certainty. Larger, well-designed randomized trials are required to validate the results obtained. Trial Registration: PROSPERO registration no. CRD420251032421.

Humans↗
PubMed2026

Cardiometabolic Multimorbidity Increases the Risk of Hip Fracture: A Longitudinal Cohort Study Based on CHARLS.

BACKGROUND: Cardiometabolic Multimorbidity (CMM) is defined as the co-occurrence of two or more conditions among heart disease, diabetes mellitus, stroke, and hypertension. Previous studies have shown associations between cardiometabolic diseases and fragility fractures; however, the relationship between CMM and hip fractures remains unclear in the Chinese population. This study therefore aims to investigate this association in a Chinese cohort to inform fracture prevention strategies. METHODS: This prospective cohort study used data from the China Health and Retirement Longitudinal Study (CHARLS) collected from 2011 to 2020. Participants from the 2011 baseline survey cohort were initially included. Subsequently, individuals were sequentially excluded if they were under 45 years of age, had incomplete baseline CMM information, had a history of hip fracture, lost to follow-up, or had missing data on confounders. Kaplan-Meier survival analysis, Cox proportional hazards regression, subgroup analyses, and sensitivity analyses were performed to evaluate the association between CMM and the risk of hip fracture. RESULTS: A total of 6314 participants aged 45 years and older were included, of whom 544 had CMM. Over a 9-year follow-up period, 287 incident hip fractures (4.55%) were identified. Among these, 36 participants had been diagnosed with CMM at baseline, whereas 251 had not. The incidence of hip fracture was significantly higher in participants with CMM than in those without CMM (13% vs. 8%, p = 0.015). After full adjustment for confounders, multivariable Cox regression showed that CMM was associated with a 70% increased risk of hip fracture (HR = 1.70, 95% CI: 1.318-2.47; p = 0.005). Subgroup analyses indicated that age and history of falls were significant effect modifiers. The association between CMM and hip fracture was more pronounced in participants under 60 years old (P for interaction = 0.048) and those with a history of falls (P for interaction = 0.014). CONCLUSION: These findings suggest that CMM increases the risk of hip fracture, particularly among relatively younger individuals and those with a history of falls.

Humans↗
PubMed2026

Hip Arthroscopy During Female Menstruation: A Retrospective Analysis of Safety and Clinical Outcomes With 24-Month Follow-Up.

OBJECTIVES: To investigate the safety and clinical outcomes of hip arthroscopy performed during menstruation in reproductive-age female patients, and to determine whether surgery during menstruation increases intraoperative risks or adversely affects postoperative recovery. Currently, clear clinical guidelines regarding the timing of elective orthopedic surgeries relative to the menstrual cycle are lacking, often leading to unnecessary surgical rescheduling. Therefore, this study aimed to provide evidence-based guidance for perioperative management and optimal surgical scheduling, thereby addressing a critical clinical need. METHODS: This retrospective cohort study included reproductive-age female patients who underwent hip arthroscopy at the First Medical Center of Chinese PLA General Hospital, the Fourth Medical Center of Chinese PLA General Hospital, and the Department of Sports Medicine at the Second Hospital of Shandong University from December 2018 to September 2023. Patients were categorized into the menstruation group (MP) and the non-menstruation group (NMP) based on whether they were menstruating on the day of surgery. The NMP group consisted of equally sized ovulatory (OP) and luteal (LP) phases. Perioperative outcomes included: intraoperative blood loss, anesthetic dosage, operative time, hemoglobin (Hb) change (within 24&#x2009;h postoperatively), prothrombin time (PT), and activated partial thromboplastin time (APTT). Postoperative outcomes included analgesic consumption, duration of analgesic use, time to first unassisted weight-bearing ambulation, complications, and urinary tract infections. Functional outcomes were assessed at 24-month follow-up using the Visual Analog Scale (VAS), Modified Harris Hip Score (mHHS), International Hip Outcome Tool-12 (iHOT-12), Hip Outcome Score-Activities of Daily Living (HOS-ADL), and Hip Outcome Score-Sports Specific Subscale (HOS-SSS). RESULTS: Of 884 eligible patients, 28 were included in the MP group and 56 matched patients in the NMP group. Operative time, anesthetic use, Hb change, PT, and APTT were comparable between the two groups (all p&#x2009;>&#x2009;0.05). No serious complications or urinary tract infections occurred in either group. At the 24-month follow-up, both groups demonstrated significant improvements in VAS, mHHS, iHOT-12, HOS-ADL, and HOS-SSS (all p&#x2009;<&#x2009;0.001), with no statistically significant differences observed between the groups. CONCLUSIONS: Hip arthroscopy during menstruation does not increase intraoperative bleeding, impair coagulation, or delay functional recovery for female patients. Menstruation should not be considered a contraindication when appropriate perioperative management is applied.

Humans↗
PubMed2026

Factors Associated With Accelerated Fracture Healing in Patients With Traumatic Brain Injury and Extremity Comminuted Fractures: A Retrospective Case-Control Study.

OBJECTIVE: Although traumatic brain injury (TBI) has been clinically associated with accelerated bone healing, the factors that determine which patients experience this phenomenon remain poorly defined, and previous findings are conflicting. This study aimed to investigate the clinical factors associated with accelerated fracture healing in patients with TBI combined with comminuted fractures of the limbs, so as to provide an evidence-based foundation for elucidating the clinical phenomenon of TBI-promoted fracture healing. METHODS: A retrospective case-control study design was employed. Patients between January 2020 and April 2024 with concurrent diagnoses of TBI and comminuted fractures were included. Based on radiographic findings and RUST/mRUST scores, patients were divided into an accelerated healing group (AHG) and a normal/delayed healing group (NDHG). Clinical data including demographics (age, sex, BMI), TBI characteristics (injury site, GCS score), admission laboratory indices (blood count, coagulation function, inflammatory markers), and fracture site/local soft tissue conditions, as well as functional outcomes assessed by the Short Musculoskeletal Function Assessment (SMFA) questionnaire at final follow-up were collected. Univariate analysis and multivariate logistic regression analysis were used to identify independent factors influencing accelerated fracture healing. Receiver operating characteristic (ROC) curves were plotted to evaluate their predictive value. RESULTS: A total of 119 patients were included, with 69 in the AHG and 50 in the NDHG. Significant differences were observed between the two groups in terms of age, BMI, GCS score, and platelet count (p&#x2009;<&#x2009;0.05). Univariate analysis showed that age, BMI, GCS score, red blood cell count, and platelet count were associated with accelerated fracture healing (p&#x2009;<&#x2009;0.20). Multivariate logistic regression analysis indicated that younger age (OR&#x2009;=&#x2009;0.875, 95% CI: 0.821-0.934) and lower GCS score (indicating more severe TBI; OR&#x2009;=&#x2009;0.490, 95% CI: 0.339-0.707) were independent predictors of accelerated fracture healing. ROC curve analysis showed that the area under the curve (AUC) for age and GCS score in predicting accelerated healing were 0.893 and 0.851, respectively. CONCLUSIONS: In patients with TBI combined with comminuted fractures, younger age and greater TBI severity (lower GCS score) are independent predictors of accelerated fracture healing. These findings assist clinicians in the early identification of patients with high healing potential to optimize treatment strategies, facilitate the early identification of high-risk patients, and provide clinical clues for further exploration of the molecular mechanisms underlying neurohumoral regulation of bone regeneration.

Humans↗
PubMed2026

Physical Appearance Anxiety and Eating Disorders Symptomatology: A Systematic Review and Meta-Analysis.

The present study aimed to assess the link between physical appearance anxiety (PAA) and eating disorder (ED) symptomatology by a meta-analysis of existing literature. Eligible studies were searched across six electronic databases up until November 20, 2025. Pooled effect sizes (r) were calculated using random-effects models. Potential variables that influence effect heterogeneity were analyzed by univariable and multivariable meta-regressions. Influence analyses and a three-parameter selection model (3PSM) were used to assess robustness of the results and publication bias. Twenty-seven effect sizes from 21 studies (N&#x2009;=&#x2009;5261) were obtained. The results indicated a strong association (i.e., r&#x2009;=&#x2009;0.559) between the two variables under consideration, which was notably stronger (i) among females compared to males; and (ii) for overall eating disorder symptoms rather than bulimic symptoms. The results of this study advocate for further investigation into the effectiveness of addressing anxiety responses related to personal body traits, particularly among females, within the context of preventing and treating eating disorders.

Humans↗
PubMed2026

Integration of Clinical Case Scenarios With Anatomical Dissection Teaching-Is Recall Improved Among Medical Students?

BACKGROUND: There is ongoing debate about how best to deliver anatomy teaching in a modern medical curriculum. Some studies suggest that the separation of basic sciences and clinical teaching can impact students' confidence in anatomy, which has potential long-term implications on their medical career. This suggests new pedagogic approaches to improve anatomy teaching may be beneficial. This study aimed to establish if integrating a clinical case into anatomy practical classes would improve students' anatomy recall compared to anatomy teaching alone. APPROACH: A ten minute clinical scenario was developed, which focused on the typical history, examination, investigations and management of a hip fracture patient. Medical students (n&#x2009;=&#x2009;220) currently studying lower limb anatomy were randomised by pre-assigned anatomy groups to become intervention or control. In the intervention group, students received the clinical case teaching, followed by their anatomy session. In the control group, students attended the anatomy session. Students in both groups were then assessed on hip anatomy. The intervention group also gave their perception of the clinical case. EVALUATION: This study showed that participants who received integrated teaching performed significantly better in the anatomy recall test (3.64 SD &#xb1; 0.574) than whose who had anatomy teaching only (1.95 SD &#xb1; 0.994) (chi2&#x2009;=&#x2009;185.51, p&#x2009;<&#x2009;0.00001). Most participants (93.5%; 101/108) strongly agreed/agreed that integrating clinical cases into anatomy teaching benefited their learning. IMPLICATIONS: These results suggest that students' anatomy recall may be improved by integrating clinical cases and anatomy teaching. It also suggests that students found this approach beneficial for their learning.

Humans↗
PubMed2026

Pharmacokinetics and safety of TBAJ-587, a novel antimycobacterial diarylquinoline, in healthy participants.

TBAJ-587 is a second-generation diarylquinoline with greater antimycobacterial activity and a potentially better safety profile than the first-generation bedaquiline. It is currently under development for the treatment of drug-susceptible and drug-resistant tuberculosis. A first-in-human trial of TBAJ-587, including single and multiple ascending oral doses and a dedicated food-effect cohort, was conducted in 92 healthy adults. Plasma exposures of TBAJ-587 were generally linear for AUCtau and slightly subproportional for Cmax, with the major circulating active metabolite, M3, remaining low relative to the parent. A high-fat meal increased the mean Cmax and AUClast 3.46- and 2.26-fold, respectively. TBAJ-587 accumulated with multiple dosing over the 28-day period, with mean accumulation ratios across the three tested doses ranging from 1.69 to 2.32 for Cmax and from 2.74 to 3.73 for AUCtau. However, steady-state conditions were not yet reached on day 28. Mean terminal half-lives after 28-day dosing of TBAJ-587 ranged from approximately 80 to 111 days. There were no deaths or serious adverse events, and TBAJ-587 was generally safe and well tolerated at single doses of 25-800 mg under fasting conditions and multiple doses of 50-200 mg once daily for 28 days after a standard breakfast. In addition, no dose- or time-dependent effects were noted for any of the other safety and tolerability parameters, including no clinically significant effects on the QTc interval. These results support further investigation of TBAJ-587 for the treatment of tuberculosis.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04890535.

Humans↗
PubMed2026

Dynamics and virulence of Enterobacteriaceae reservoirs harboring blaCTX-M group 1 in community wastewater.

UNLABELLED: Extended-spectrum beta-lactamase (ESBL)-producing bacteria are ubiquitous and can cause serious infections. Here, we examined untreated community wastewater influent as a reservoir for blaCTX-M group 1 organisms and their virulence potential. Raw influent samples (n = 268) were collected from four wastewater treatment plants (WWTPs) representing dense urban populations. We observed that blaCTX-M group 1 levels were high at all WWTPs and only ~1-2 log10 lower and not correlated to common human-specific microbiome fecal markers, Lachno3 and HF183, indicating a lack of connection to human fecal inputs. Concentrations of blaCTX-M group 1 genes and markers for presumptive host organisms Escherichia coli and Klebsiella pneumoniae were influenced by travel time and season. Amplicon sequencing revealed high diversity of blaCTX-M group 1-9 genes, with 63% belonging to group 1. Selective culture and 16S rRNA gene sequencing showed blaCTX-M group 1 isolates were 26% E. coli, 26% K. pneumoniae, 40% other Enterobacteriaceae, and 8% Aeromonas. Overall, E. coli averaged 3.6E7 cells/L, with 3% of all E. coli found to contain blaCTX-M group 1. Whole-genome sequencing of blaCTX-M group 1 E. coli from wastewater revealed resistance and virulence gene profiles similar to clinical isolates and distinct from other wastewater ESBL-resistant and non-resistant E. coli. Interpretation of wastewater data needs to consider both the existence of environmental reservoirs that contain potentially pathogenic organisms and the strong influence the dynamics of the conveyance system can have on final concentrations measured at the WWTP. IMPORTANCE: The CTX-M enzyme family is highly abundant in nosocomial, community, and environmental settings and is leading to treatment of infections with carbapenem antibiotics, a last-line therapeutic option. The progressive increase of the clinically relevant blaCTX-M group 1 resistance genes in the human population warrants investigation, particularly to understand the establishment and dynamics of environmental reservoirs. This study utilized molecular and culture methods to gain insight into the possible origin, abundance, and dynamics of blaCTX-M group 1 genes in untreated wastewater influent samples. We found extremely high levels of these genes, with Escherichia coli as a major host organism that closely resembled clinical strains, suggesting they are seeded and propagate in sewer pipe systems. The significance of our research is in developing approaches to monitor antimicrobial resistance reservoirs in community wastewater, which could shed light on global burdens and potential transmission cycles and indicate increasing inputs of clinically relevant strains originating from human populations.

E. coli↗
PubMed2026

The cellular protein TIAR mediates rapid initiation of West Nile virus genome RNA synthesis.

During the intracellular replication cycle of West Nile virus (WNV), genome RNA synthesis is initially inefficient but increases exponentially as viral replication complexes are sequestered in invaginations in the endoplasmic reticulum. In this study, we investigated the functional role of the cellular protein TIAR (T-cell intracellular antigen-related protein) in the transcription of WNV genome RNA. Close colocalization of cytoplasmic TIAR with viral double-stranded RNA was detected by a proximity ligation assay in WNV-infected cells. TIAR binds specifically to the WNV 3'(-) SL but not to the complementary WNV 5'(+) SL in in vitro RNA binding assays. Only the 3' end of the WNV minus-strand RNA was enriched by immunoprecipitation of infected cell lysates with anti-TIAR antibody. Stable overexpression of TIAR in clonal A549 cells increased the ratio of intracellular viral plus-strand to minus-strand RNA in a dose-dependent manner. TIAR contains three RNA recognition motifs (RRMs). Biophysical data indicated that only RRM2 directly contacts RNA and that up to three TIAR molecules can bind cooperatively to the WNV 3'(-) SL RNA. These data provide additional evidence that TIAR functions as a proviral host factor facilitating exponential amplification of WNV genome production in infected cells.IMPORTANCEWest Nile virus (WNV) is a mosquito-borne orthoflavivirus associated with increasing global human disease incidence. The molecular mechanisms underlying viral replication are not fully understood. In early stages of infection, viral genome transcription is inefficient; however, in late stages, viral genome transcription increases exponentially. T-cell intracellular antigen-related (TIAR) protein is a cellular protein that has been shown to interact with the 3' end of the WNV negative-sense antigenomic RNA. We obtained data showing colocalization of cellular TIAR with viral replication complexes in infected cells and an increased ratio of intracellular genomic to antigenomic viral RNA in TIAR-overexpressing cells, and confirmed preferential binding of TIAR to the 3' end of the WNV antigenome both in vitro and in infected cell extracts. We also demonstrated that multiple TIAR proteins can bind cooperatively to the WNV 3'(-) stem-loop RNA. These data provide supporting evidence for a model of TIAR-mediated rapid initiation of nascent genome RNA synthesis in infected cells.

TIAR↗
PubMed2026

Identification of a novel plant polerovirus in the whitefly Aleuroclava gordoniae.

We report the genome sequence of Aleuroclava gordoniae-associated polerovirus (AgAP), identified from the whitefly Aleuroclava gordoniae. The 5,650-nt AgAP genome contains 6 open reading frames. Phylogenetic analysis places AgAP within the genus Polerovirus, which comprises plant-infecting viruses. This study provides a genomic resource for further investigation of virus-insect associations.

plant virus↗
PubMed2026

Neonatal outcomes following antenatal corticosteroid administration before planned caesarean birth at late preterm or early term (36-38 weeks' gestation): a retrospective cohort study.

OBJECTIVE: To investigate the benefits and harms associated with antenatal corticosteroids (ACS) prior to planned caesarean birth at late preterm or early term. DESIGN: Retrospective cohort study. SETTING: South Australia, Australia, 2005-2018. PATIENTS: Women with singleton pregnancies undergoing planned caesarean birth between 36+0 and 38+6 weeks' gestation. METHODS: We used routinely collected electronic maternity and neonatal data. Adjusted risk differences (aRD) with 95% CIs were calculated for neonatal and maternal outcomes. OUTCOME MEASURES: Neonatal outcomes included respiratory distress requiring oxygen, hypoglycaemia requiring glucose, neonatal unit (NNU) admission and prolonged NNU admission (&#x2265;48&#x2009;hours). RESULTS: Among the cohort of 4049 women, the proportion receiving ACS was 54.8%, 48.4% and 5.6% at 36, 37 and 38 completed weeks' gestation, respectively. ACS administration was associated with a significant reduction in respiratory distress across all gestations, with the greatest reduction seen at 36 weeks' gestation (aRD -12.5%; 95% CI -21.4% to -3.6%). At 38 weeks' gestation, ACS administration was associated with an increased risk of neonatal hypoglycaemia (aRD 5.7%; 95% CI 1.1% to 10.2%), NNU admission (aRD 5.4%; 95% CI 0.1% to 10.7%) and prolonged NNU admission (aRD 4.6%; 95% CI 0.2% to 8.9%). CONCLUSIONS: ACS administration prior to late preterm and early term planned caesarean birth was associated with reduced risk of respiratory distress. The net benefit of ACS administration before planned caesarean birth remains unclear; however, there was evidence of potential neonatal harm when birth occurred after 37 weeks' gestation.

Epidemiology↗
PubMed2026

Patient expectations assessed before randomisation and after the first treatment session, and their associations with pain outcome at 3 months in patients with tennis elbow: a secondary analysis of a randomised controlled feasibility trial in Norwegian secondary care.

OBJECTIVE: To evaluate patients' expectations of pain improvement before randomisation (T1) and after the first treatment (T2), and to examine how expectations at these two time points were associated with pain outcome measured at 3&#x2009;months (T3). DESIGN: Exploratory secondary analyses of a three-arm, randomised controlled feasibility trial in patients with tennis elbow comparing heavy slow resistance training, shock wave therapy and advice (1:1:1). SETTING: Outpatient clinic at Oslo University Hospital. PARTICIPANTS: Adults with lateral epicondylalgia, commonly known as tennis elbow. MAIN OUTCOME MEASURES: Expected pain was rated on a Numeric Rating Scale (NRS, 0-10) at T1 and T2. Present pain (NRS, 0-10) was reported at 3&#x2009;months (T3). Changes in expectations from T1 to T2 were summarised descriptively. Univariable linear regressions assessed associations between T3 pain and expectations at T1 and T2, treatment group and baseline factors. Explained variance was quantified by R2. Multivariable models including demographics and baseline pain were evaluated via adjusted R2. RESULTS: Fifty-four participants were included. In the shock wave group, nine (47%) came to expect greater improvement from T1 to T2; by contrast, in the advice group, seven (41%) expected less improvement. Expectations at T1 were not associated with T3 pain, whereas expectations at T2 were positively associated with T3 pain (b=0.61, 95%&#x2009;CI 0.33 to 0.89, p<0.01, R2=0.27), suggesting that higher expected pain at T2 was associated with higher reported pain at T3. Adding education and baseline pain increased explained variance modestly (R2 from 0.27 to 0.32). CONCLUSION: In this study, expectations measured after randomisation and one treatment session were associated with pain at 3&#x2009;months for patients with tennis elbow. Larger, prospectively designed studies should investigate how postrandomisation expectations relate to clinical outcomes in non-blinded musculoskeletal trials. TRIAL REGISTRATION NUMBER: NCT04803825.

Humans↗
PubMed2026

Evaluating the need for late angiography for complete obliteration of AVMs after endovascular treatment: collaborative AVM center experience and a systematic review.

Brain arteriovenous malformations (bAVMs) can be treated curatively by endovascular embolization. However, limited data exist on late recanalization rates. We investigated the rate of late bAVM recanalization following complete endovascular obliteration, confirmed by primary control angiography.We performed a single-center retrospective cohort study on late recurrences in adult patients with bAVMs after complete endovascular obliteration at a Radboud - Isala - MUMC+ (RIM) collaborative AVM center in the Netherlands between 2014 and 2022.Additionally, we conducted a systematic review to evaluate the rate of late recanalization following complete endovascular obliteration, confirmed on primary control angiography, in adults with bAVMs. The protocol for this review was registered in PROSPERO (CRD42024546875).Our retrospective study revealed 42 adult patients treated by endovascular means only; 90.5% (38 patients with mean age of 48.1 years) had confirmed complete obliteration. Both primary (6 months post-treatment) and secondary (more than 1 year post-treatment) angiographic control confirmed complete obliteration in 21 of 23 patients with complete follow-up. Mean follow-up was 47.8 months. Two late recurrences (9.5%) were detected at 5- and 6-years' follow-up imaging.Our systematic review included two studies encompassing a total of 19 patients with mean angiographical follow-up of 20.8 months. There were no late recurrences.Late bAVM recurrence after endovascular treatment with proven complete obliteration may be underestimated owing to limited long-term follow-up. Our findings suggest that after a 6-month angiographic confirmed obliteration, a 5-year angiographic imaging control is justified.

Humans↗
PubMed2026

Pathogenic properties of myasthenia gravis AChR autoantibodies associate with clinical response to efgartigimod.

BACKGROUND: Efgartigimod, a neonatal Fc receptor (FcRn) blocker, effectively reduces total IgG, including pathogenic acetylcholine receptor (AChR) autoantibodies in myasthenia gravis (MG); however, clinical responses vary. To investigate this variability, we studied how efgartigimod impacts AChR-specific autoantibody profiles and associated pathogenic mechanisms, including complement activation, AChR internalisation and ACh-binding site blockade. METHODS: Serum samples (N=150) were sourced from 50 AChR autoantibody-positive generalised MG patients participating in the phase 3 ADAPT study, randomised to receive efgartigimod (N=40) or placebo (N=10) in cycles of 4-weekly infusions. Samples were collected at baseline, day 29 and day 57 during the first cycle. Live cell-based assays quantified AChR-specific IgG subclasses and isotypes and assessed their capacity to mediate pathomechanisms. RESULTS: Efgartigimod decreased all detectable AChR-specific IgG subclasses. At baseline, AChR autoantibody-mediated C3b deposition, AChR internalisation and ACh-binding site blockade were detected in 42 (84%), 41 (82%) and 10 (20%) patients, respectively. After 4-weekly infusions of efgartigimod, the magnitude of all three pathomechanisms was significantly decreased. However, the extent of this reduction varied across individuals. Double responders on both MG-activities of daily living and quantitative MG scores demonstrated a greater reduction in complement activity and AChR internalisation compared with patients who responded on only one score or were double non-responders. In addition, efgartigimod reduced IgG-dependent IgM binding to AChR. CONCLUSIONS: These findings suggest that clinical efficacy may be more closely associated with functional modulation of the AChR-specific autoantibodies than with their absolute quantity alone. These results support the evaluation of mechanistic pathway monitoring as a potential strategy to predict or guide efgartigimod treatment response.

Humans↗
PubMed2026

A Phase II Feasibility Study Combining Pembrolizumab and Metformin in Patients with Metastatic Head and Neck Cancer.

PURPOSE: Survival for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) remains low with <20% immunotherapy response. Metformin increases tumor-infiltrating CD8+ T and natural killer (NK) cells, which harbor PD-1. In this phase II clinical trial (NCT04414540), we combined metformin and pembrolizumab to evaluate the overall response rate (ORR) in R/M HNSCC and assess NK-cell activity. PATIENTS AND METHODS: Eligible patients were randomized 1:1 into two arms: (i) metformin extended-release (ER) dose escalation to 2,000 mg over 14 days followed by combination with pembrolizumab 200 mg every 3 weeks or (ii) pembrolizumab 200 mg every 3 weeks followed by combination with metformin ER 2,000 mg daily. The primary endpoint was ORR per RECIST 1.1. Nineteen evaluable patients were planned to estimate the proportion of approximately 32% ORR. Safety was evaluated according to Common Terminology Criteria for Adverse Events v5.0. The distribution, activation, and cytotoxic function of NK cells were analyzed via flow cytometry. RESULTS: Twenty-one patients were enrolled; 76% were male, 52% were smokers, and the median age was 64 years. Ten patients had oropharyngeal tumors, of which nine were p16+. Eighteen patients were evaluable for response, including four complete and five partial responses for an ORR of 50% [95% confidence interval (29-71)]. Combination therapy was well tolerated with no unexpected adverse events (AE). Five grade 3 AEs occurred: nausea, diarrhea, fatigue, and weight loss. Metformin led to increased peripheral NK-cell maturation and cytotoxic ability. CONCLUSIONS: The combination of metformin and pembrolizumab was well tolerated with mild gastrointestinal AEs and promising activity, warranting further investigation in a randomized trial.

Humans↗
PubMed2026

Trio-based whole-exome sequencing identifies convergent epithelial junction-related pathways in syndromic hidradenitis suppurativa.

INTRODUCTION: Hidradenitis suppurativa (HS)-related autoinflammatory syndromes, simply termed as syndromic HS (sHS), represent a group of rare immune-mediated inflammatory disorders in which HS coexists with systemic or cutaneous autoinflammatory features like PASH (pyoderma gangrenosum-PG-, acne and HS), PAPASH (PASH, pyogenic arthritis), PASS (PG, acne, HS, and ankylosing spondylitis), and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis). In recent years, genetic studies identified several novel pathogenic variants underlying sHS; however, most investigations rely exclusively on affected individuals sequencing and the absence of parental genomic information limits the possibility to determine inheritance patterns. METHODS: To address these gaps, we performed trio-based whole-exome sequencing (WES) on five individuals diagnosed with sHS and their unaffected parents. RESULTS: The pathway related to epidermal adhesion and desmosome organization was the most represented across our cohort, encompassing seven genes: DSC3, DSG1, FAT1, LAMA3, MICALL2, PLEC and TJP2. Integrin-extracellular matrix (ECM) adhesion signaling pathway, represented by ten genes (CSPG4, FERMT3, ITGA3, LAMA3, LAMA5, LIMS2, LTBP3, PLEC, TGM2, TNC) was also retrieved. Also, variants affecting innate immune pathways, including cytokine signalling and antigen presentation, have been observed. CONCLUSION: Our exploratory findings suggest that genetically heterogeneous variants in syndromic HS converge on biological processes involving epithelial junction organisation, extracellular matrix interactions and innate immune regulation. Although not establishing a unique pathogenic mechanism, these observations identify epithelial barrier biology as a candidate pathway warranting validation in larger cohorts and functional studies.

Journal Article↗
PubMed2026

Bempedoic Acid and First and Recurrent Limb Outcomes in Statin-Intolerant Patients With Peripheral Artery Disease: Insights From the CLEAR Outcomes Trial.

BACKGROUND: Patients with peripheral artery disease (PAD) are at high risk of major adverse limb events (MALE) and major adverse cardiovascular events (MACE). Recently, bempedoic acid was shown to reduce MACE in primary and secondary prevention patients. Whether bempedoic acid reduces the risk of MALE in patients with PAD is unknown. METHODS: CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid [ETC1002], an ACL-Inhibiting Regimen) randomized 13&#x2009;970 patients to bempedoic acid 180 mg or placebo from December 22, 2016, to August 14, 2019. The trial primary end point was MACE-4, defined as death resulting from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. A clinical history of PAD was reported by investigators at baseline. Two blinded vascular medicine specialists independently adjudicated MALE, including adverse events indicating worsening PAD symptoms leading to revascularization, chronic limb-threatening ischemia, and acute limb ischemia. Outcomes were assessed as time to first event and total (including recurrent) events with a negative binomial approach. RESULTS: A total of 1624 of the enrolled patients (mean&#xb1;SD age, 63.9&#xb1;9.9 years; 915 [56.3%] female) had PAD at baseline. In patients with PAD in the placebo group, 69 (8.3%) had MALE over a median of 40.6 months, with rate of recurrent events of 4.0%/y. Bempedoic acid reduced the risk of MALE by 36% (hazard ratio, 0.64 [95% CI, 0.44-0.93]; P=0.018). Bempedoic acid reduced total MALE by 45% (relative risk, 0.55 [95% CI, 0.35-0.85]; P=0.007). First MACE-4 or MALE was reduced overall by 13% (hazard ratio, 0.87 [95% CI, 0.80-0.95]) with consistent effects with PAD (hazard ratio, 0.82 [95% CI, 0.64-1.04]) and without PAD (hazard ratio, 0.87 [95% CI, 0.79-0.86]; Pinteraction=NS) but not statistically significant within the PAD subgroup alone. Total MACE-4 or MALE was reduced (relative risk, 0.81 [95% CI, 0.73-0.90]) overall with consistent effects in PAD (relative risk, 0.71 [95% CI, 0.54-0.95]) and without PAD (relative risk, 0.82 [95% CI, 0.73-0.92]; Pinteraction=NS). CONCLUSIONS: Patients with PAD are at high risk of MALE and MACE. Bempedoic acid reduces both MACE and MALE in patients with atherosclerotic vascular disease, with notable absolute benefits in patients with PAD. These findings support (1) the importance of lowering low-density lipoprotein cholesterol in patients with PAD to reduce overall vascular risk and (2) the benefits of bempedoic acid in this population.

Humans↗