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EFFICACY AND SAFETY OF SELADELPAR AS MONOTHERAPY IN PATIENTS WITH PRIMARY BILIARY CHOLANGITIS AND INTOLERANCE TO URSODEOXYCHOLIC ACID
No full textSeladelpar is a first-in-class delpar (selective PPAR-delta agonist) indicated in the UK for the treatment of primary biliary cholangitis (PBC) including pruritus in combination with ursodeoxycholic acid (UDCA) in adults with an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. In two Phase 3, placebo-controlled studies (ENHANCE [NCT03602560], RESPONSE [NCT04620733]), seladelpar led to a significantly higher rate of composite biochemical response (CBR; alkaline phosphatase [ALP] \u3c1.67 × the upper limit of normal [ULN], \u3e15% decrease in ALP, and total bilirubin [TB] 1.67 × ULN, and TB \u3c2 × ULN were randomized in 2 trials: ENHANCE (1:1:1 to daily placebo, seladelpar 5 mg, or seladelpar 10 mg for 52 weeks; study terminated early with endpoints amended to month 3) and RESPONSE (2:1 to daily seladelpar 10 mg or placebo for 52 weeks). Patients intolerant to UDCA were eligible if their last dose was \u3e3 months before study entry. This post hoc analysis presents pooled efficacy (CBR, ALP normalization, and other liver biochemistries) and safety data for seladelpar 10 mg monotherapy vs placebo from ENHANCE and RESPONSE through month 3. In total, 369 patients were randomized to seladelpar 10 mg or placebo across both studies, 16 of whom received seladelpar monotherapy and 6 received placebo without UDCA. Mean baseline ALP was similar between monotherapy patients receiving seladelpar vs placebo (380 U L vs 397 U L). At month 3, 8 13 patients (62%) receiving seladelpar monotherapy demonstrated a CBR vs 1 6 patients (17%) receiving placebo, and 3 13 patients (23%) on seladelpar achieved normalized ALP vs 0 6 patients on placebo. Mean percent change from baseline in ALP at month 3 was \u3e46% with seladelpar vs \u3e2% with placebo. At month 3, 9 16 patients (56%) on seladelpar monotherapy experienced an adverse event (AE) vs 5 6 patients (83%) on placebo. No serious AEs and no discontinuations due to AEs occurred through month 3 with seladelpar monotherapy. Efficacy and safety results for seladelpar monotherapy were similar to results previously observed for seladelpar combined with UDCA. Seladelpar 10 mg monotherapy led to notable CBR rates and ALP reductions. Seladelpar monotherapy was well tolerated and had a similar safety profile compared with placebo
Childhood adversity is associated with longitudinal white matter changes after adulthood trauma
No full textBACKGROUND: Childhood adversity is associated with susceptibility to posttraumatic stress disorder (PTSD) in adulthood. PTSD and childhood adversity are linked to white matter microstructure, yet the role of white matter as a potential neural mechanism connecting childhood adversity to PTSD remains unclear. The present study investigated the potential moderating role of previous childhood adversity on longitudinal changes in white matter microstructure and posttraumatic stress symptoms following a recent traumatic event in adulthood.
METHODS: As part of the AURORA Study, 114 recent trauma survivors completed diffusion weighted imaging at 2-weeks and 6-months after exposure. Participants reported on prior childhood adversity and PTSD symptoms at 2-weeks, 6-months, and 12-months post-trauma. We performed both region-of-interest (ROI) using fractional anisotropy (FA) and whole-brain correlational tractography using quantitative anisotropy (QA) analyses to index associations between white matter microstructure changes and prior adversity.
RESULTS: ROI-based analyses did not identify significant associations between childhood adversity and changes in FA. Whole-brain correlational tractography revealed that greater childhood adversity moderated the QA changes within threat and visual processing tracts including the cingulum bundle and inferior fronto-occipital fasciculus (IFOF). QA changes within cingulum bundle and IFOF were associated with changes in PTSD symptoms between 2-weeks and 6-months.
CONCLUSIONS: Our findings suggest temporal variability in threat and visual white matter tracts may be a potential neural pathway through which childhood adversity confers risk to PTSD symptoms after adulthood trauma. Future studies should take the temporal properties of white matter into consideration to better understand the neurobiology of childhood adversity and PTSD
Association Between Acute Plasma Glial Fibrillary Acidic Protein Levels and White Matter Integrity in Recent Trauma Survivors
No full textTraumatic brain injuries (TBIs) account for over 2.5 million emergency department (ED) visits each year in the United States. The bulk of TBI research in acute care settings has focused exclusively on individuals who receive computed tomography (CT) scanning. Recently, more sensitive TBI assessment tools have been identified, including blood biomarkers such as glial fibrillary acidic protein (GFAP) and magnetic resonance imaging (MRI) of white matter microstructural integrity. These methods can evaluate for evidence of TBI in CT-negative patients. However, limited prior work has investigated the relationship between blood GFAP levels and white matter microstructural integrity. The present study examined the association between acute (≤72 h) GFAP levels and white matter microstructural integrity at 2 weeks post-trauma among ED patients (n = 328) recruited after a qualifying traumatic experience. We hypothesized that acute GFAP concentrations would be associated with disrupted microstructural integrity, quantified with Tract-Based Spatial Statistics-derived diffusion tensor imaging (DTI) metrics (reduced fractional anisotropy and increased axial diffusivity [AD], radial diffusivity, and mean diffusivity), in tracts previously shown to be vulnerable to TBI. Our secondary hypothesis was that there would be a stronger association between GFAP levels and white matter integrity among female relative to male trauma survivors, in line with previous literature suggesting that females\u27 axons are less resilient to stretch injury. To test the primary hypothesis, we fit four sets of linear regression models to assess the association between natural log-transformed acute GFAP concentration and DTI metrics for 15 white matter regions of interest (ROIs). The false discovery rate (FDR) was controlled at 0.05 for each set of models. Models were adjusted for age, sex, neuroimaging site, and a composite lifetime traumatic stress variable. To test the secondary hypotheses, we fit identical sets of linear regression models, with an additional interaction term between sex and ln(GFAP). We followed up all significant results surviving FDR correction with correlational tractography to examine the location and direction of tracts associated with the DTI metric passing through those ROIs. We observed significant and positive associations between acute GFAP and AD in the parahippocampal cingulum (B = 1.416 × 10(-5), standard error [SE] = 4.806 × 10(-6), p = 0.003, FDR-corrected p = 0.026), and the sagittal stratum (B = 1.012 × 10(-5), SE = 3.438 × 10(-6), p = 0.003, FDR-corrected p = 0.026), including fibers of the inferior longitudinal fasciculus and the inferior fronto-occipital fasciculus. Furthermore, the association between GFAP and AD of the parahippocampal cingulum was stronger in female trauma survivors compared with male trauma survivors (B = 2.898 × 10(-5), SE = 9.352 × 10(-6), p = 0.002, FDR-corrected p = 0.032). Our results suggest that among ED patients with low rates of intracranial injuries observed on CT and MRI scans, acute peripheral levels of GFAP may be able to predict later disruption in structural connectivity
Isolated Facial Vein Thrombophlebitis Caused by Fusobacterium nucleatum: A Lemierre-Variant Case
No full textBackground: Lemierre\u27s syndrome is an uncommon yet potentially fatal infection, classically secondary to bacterial pharyngeal infections. It is typically characterized by bacteremia, most frequently due to Fusobacterium necrophorum and internal jugular vein thrombophlebitis. If untreated, septic embolization may result, potentially damaging the lungs, liver, brain, or other organs. This report describes a variant of Lemierre\u27s syndrome in a young woman with streptococcal pharyngitis, who developed Fusobacterium nucleatum bacteremia and isolated facial vein thrombophlebitis, highlighting the importance of early diagnosis and treatment.
Case Presentation: A 33-year-old woman with no significant past medical history presented with sore throat, chills, and right-sided facial and neck pain. Initially diagnosed with streptococcal pharyngitis at an urgent care clinic, she presented to the emergency department soon afterwards due to the development of severe rigors and fever. Blood cultures revealed growth of Fusobacterium nucleatum, raising suspicion for Lemierre\u27s syndrome in the setting of worsening facial and neck pain despite negative initial imaging of the soft tissue of the neck. A subsequent CT venogram confirmed isolated thrombosis of the right facial vein. The patient was treated and discharged in stable condition on a 4 week course of metronidazole and 2 weeks of ceftriaxone.
Conclusion: This case emphasizes the importance of maintaining suspicion for Lemierre\u27s syndrome in patients with bacterial pharyngitis, especially when atypical symptoms such as facial pain occur. Although the internal jugular vein is most commonly affected, facial vein thrombosis may also occur. Early antibiotic treatment is critical for preventing severe complications including septic shock and embolization
Assessing the risk factors of permanent pacemaker implantation following mitral valve surgery: A systematic review and meta-analysis
No full textBACKGROUND: Mitral valve surgery is a widely performed intervention for the treatment of various mitral valve pathologies. Postoperative conduction disturbances may necessitate permanent pacemaker (PPM) implantation. This study aims to identify and quantify patient-related, cardiovascular, procedural risk factors, and risk score-based predictors of PPM implantation following mitral valve surgery.
METHODS: The conduct of this systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. A systematic literature search was performed across PubMed, Cochrane Library, Google Scholar, and Embase, including studies published from inception until September 2024. Statistical analyses were conducted using RevMan 5.4 software.
RESULTS: The meta-analysis included 8 studies totaling 39,634 patients (PPM: 3417; no PPM: 36,217) and revealed multiple significant predictors of postoperative PPM implantation. Among demographics, advanced age (mean difference [MD] 3.54; P \u3c .00001) and female sex (odds ratio [OR] 1.19; P \u3c .00001) were found as independent risk factors. Comorbidities included hypertension (OR 1.71, P \u3c .00001), diabetes (OR 1.96, P \u3c .00001), renal disease (OR 1.96, P \u3c .00001), preexisting atrial fibrillation (OR 1.82, P \u3c .00001), prior stroke (OR 1.57, P \u3c .00001), chronic lung disease (OR 1.38, P \u3c .00001), peripheral vascular disease (OR 2.03, P = .01), and smoking history (OR 1.19, P \u3c .0001). Cardiovascular predictors comprised mitral stenosis (OR 1.77, P \u3c .00001), prior cardiac surgery (OR 1.48, P = .0002), New York Heart Association class III/IV (OR 1.38, P = .005), and New York Heart Association class I (OR 0.64, P = .03). Procedural factors showed longer cardiopulmonary bypass time (MD 9.89, P \u3c .00001) and aortic cross-clamp duration (MD 11.96, P \u3c .00001) increasing risk, along with concomitant atrial fibrillation ablation (OR 1.34, P = .002). Increased society of thoracic surgeons\u27 mortality risk (MD 1.14%, P = .04) and EuroScore (MD 2.16, P = .0005), both effectively predicted PPM need.
CONCLUSION: This meta-analysis represents the first comprehensive evaluation of risk factors associated with PPM implantation in patients undergoing mitral valve surgery. Several significant risk factors have been identified, warranting further research to validate and expand upon these findings
Reduced Versus Full-Dose Direct Oral Anticoagulants for Venous Thromboembolism in Cancer Patients: A Systematic Review and Meta-Analysis
No full textBACKGROUND: Venous thromboembolism (VTE) is a serious complication in cancer patients, with malignancy increasing the risk significantly. Direct oral anticoagulants (DOACs) have emerged as a convenient alternative to traditional therapies, though optimal dosing remains uncertain.
METHODS: We performed a systematic review and meta-analysis on three studies. A comprehensive literature search was performed on PubMed, Embase, the Cochrane Library, and ScienceDirect till April 2025. Analysis was carried out on RevMan 5.4. The risk of bias was assessed via RoB 2.0.
RESULTS: A total of three studies with 2416 participants were identified, including 1495 patients in the reduced-dose group and 1232 patients in the full-dose group. No significant difference was observed in recurrent VTE (OR 0.70, 95% CI 0.45-1.09, p = 0.11) or recurrent symptomatic VTE (OR 0.96, 95% CI 0.50-1.84, p = 0.91). However, reduced-dose DOACs were associated with a significantly lower incidence of incidental VTE (OR 0.31, 95% CI 0.14-0.69, p = 0.004). The reduced-dose group also had a lower incidence of CRNMB plus major bleeding (OR 0.69, 95% CI 0.55-0.88, p = 0.002).
CONCLUSIONS: In terms of venous thromboembolism, bleeding events, and all-cause mortality, reduced-dose DOACs demonstrated a safety profile that was either superior or comparable to that of full-dose DOACs.
TRIAL REGISTRATION: The authors have confirmed clinical trial registration is not needed for this submission
Cardiovascular Benefits of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Type 2 Diabetes Mellitus With Atherosclerotic Cardiovascular Disease: A Systematic Review of Randomized Controlled Trials
No full textThis systematic review evaluates the cardiovascular effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in adults with type 2 diabetes mellitus (T2DM) and established atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure (HF). A comprehensive literature search across four major databases identified eight eligible studies, including randomized controlled trials and prespecified or pooled post-hoc analyses. The findings demonstrate consistent cardiovascular benefits of GLP-1 RAs, particularly semaglutide and exenatide, with notable reductions in major adverse cardiovascular events, cardiovascular mortality, and HF-related outcomes. Mechanistically, these benefits may be attributed to anti-inflammatory effects, improved endothelial function, and metabolic improvements such as weight loss and blood pressure reduction. Despite some heterogeneity across subgroups and study designs, the overall evidence supports the integration of GLP-1 RAs into cardiovascular risk management for patients with T2DM
A novel HPβCD-Cu(DDC)(2) delivery system in patient derived orthotopic xenograft targeting MGMT-mediated temozolomide resistance in glioblastoma
No full textThe uniform lethality of glioblastoma (GBM) with a survival of less than 2 years despite best available therapy is attributed to treatment resistance due to DNA repair mechanisms that drive disease relapse and tumor heterogeneity. One prognostic factor identified as a reliable biomarker for GBM sensitivity to temozolomide (TMZ) and radiotherapy (RT) is the overexpression of O(6)-methylguanine-methyl-transferase (MGMT) enzyme. Patients with active MGMT were found to receive little benefit from TMZ and RT. They represent a group of great unmet need with no treatment options that significantly improve survival. Recently, several preclinical and clinical studies suggest that the alcohol aversion drug, disulfiram (DSF), inhibited MGMT and improved the efficacy of TMZ in GBM when combined with copper (Cu). However, phase II trial showed that there was no significant survival benefit from oral Cu/DSF. Nevertheless, the major limitation of oral Cu/DSF has been delivery of fragile DSF to the in vivo system. To address this limitation, we developed a novel delivery system using 2-hydroxypropyl beta cyclodextrin (HPβCD) encapsulating the Cu complex of DSF\u27s active metabolite, diethyldithiocarbamic acid (DDC). It was determined that HPβCD stabilized Cu(DDC)(2). In vitro cell culture study revealed that HPβCD-Cu(DDC)(2) inhibited MGMT through the ubiquitin-proteasome pathway. Inhibition of MGMT activity in cell cultures vastly increased the alkylation-induced DNA double-strand breaks, cytotoxicity, and the levels of apoptotic markers like histone family member X (γ-H2AX), JNK-P and cleavage of Poly [ADP-ribose] polymerase 1 (PARP-1). Preliminary intravenous delivery of HPβCD-Cu(DDC)(2) in combination with TMZ in an MGMT-positive patient derived orthotopic xenograft (PDOX) model demonstrated tumor size regression. HPβCD-Cu(DDC)(2) targets MGMT-145-cysteine and its unique cytotoxic mechanism circumvents MGMT-mediated TMZ resistance. This novel delivery system shows promise for overcoming MGMT-mediated resistance in GBM, offering a potential new therapeutic strategy
Young age, female sex, smoking, and worse area deprivation index associated with prolonged postoperative opioid use after rotator cuff repair
No full textBACKGROUND: Oral opioid analgesia is commonly used for postoperative pain control in arthroscopic rotator cuff repair (RCR). Concerns about opioid side effects and potential abuse persist. This study aimed to identify risk factors for prolonged opioid use (POU) after RCR and assess its impact on patient-reported outcomes.
METHODS: A retrospective chart review included patients over 18 years old who underwent primary arthroscopic RCR and had at least one preoperative and postoperative patient-reported outcomes measurement information system (PROMIS) score. POU was defined as at least one opioid prescription refill more than 30 days postoperatively. Demographic characteristics, clinical outcomes, and PROMIS scores up to one year postoperatively were collected.
RESULTS: A total of 318 patients were included, and 38 had POU. Logistic regression identified opioid refill within 30 days after surgery, younger age, female sex, smoking, higher area deprivation index, and higher preoperative PROMIS depression score was associated with POU. Patients with POU had higher reoperation rates (15.8% vs. 5.4%; P = 0.015) and worse PROMIS pain interference and PROMIS upper extremity scores postoperatively.
CONCLUSION: Risk factors for POU after arthroscopic RCR include younger age, female sex, smoking, depression, higher area deprivation, and early opioid refill. POU correlated with higher reoperation rates and poorer postoperative outcomes
Management of pott\u27s puffy tumor: a Delphi-method international clinical consensus statement
No full textPURPOSE: Pott\u27s puffy tumor (PPT) is a rare and complex condition that requires a comprehensive diagnostic approach and multi-faceted treatment strategy. It is associated with a significant risk of intracranial complications. The purpose of this clinical consensus statement (CCS) is to systematically assess diagnostic and therapeutic approaches of patients with PPT, using the best available evidence and expertise of the panel. The results and recommendations are intended to support clinicians in making informed decisions when managing patients with PPT and to standardize diagnostic, antibiotic, and surgical management across institutions. This consensus also aimed to provide a basis for a subsequent international prospective registry to inform data-driven care.
METHODS: A literature review was performed via PubMed, and an international panel of 23 experts judged 33 statements in two rounds using a modified Delphi method survey to establish expert recommendations on the diagnostic considerations, medical and surgical management, and postoperative considerations. Strong consensus was defined by a mean score of ≥ 8.00 with no outliers, and consensus by a mean score of ≥ 7.00 with no more than 1 outlier.
RESULTS: A strong consensus was reached on important aspects of the diagnosis and treatment of patients with PPT. Most pivotal are the importance of urgent imaging, imaging of the brain with a preference of MRI, the importance of broad spectrum intravenous antibiotic treatment, and the goal of surgery - resolution of the periosteal abscess and clearance of the frontal sinus drainage pathway - which can be established in various ways and is case and surgeon dependent.
CONCLUSION: In patients with PPT, a high index of suspicion of intracranial complications is important to prevent any delay in treatment initiation. The recommendations formulated in this international consensus statement aim to improve the diagnosis and care for patients with PPT and to address gaps and uncertainties in current guidelines. Items that did not reach consensus may serve as areas for further research