Impact of Aficamten on Disease and Symptom Burden in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

BACKGROUND: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined. OBJECTIVES: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten. METHODS: Patients who were symptomatic of oHCM were randomized to aficamten (n = 142) or placebo (n = 140) daily for 24 weeks. Outcomes assessed included the proportion of patients with complete hemodynamic response (rest and Valsalva gradient <30 mm Hg and <50 mm Hg, respectively), relief in limiting symptoms (≥1 improvement in NYHA functional class and/or ≥10-point change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score), enhanced exercise capacity (≥1.5 mL/kg/min change in peak oxygen uptake), and ≥50% reduction in N-terminal pro-B-type natriuretic peptide. Eligibility for septal reduction therapy was also evaluated. RESULTS: At 24 weeks, patients treated with aficamten vs placebo showed significant improvement in limiting symptoms (71% vs 42%), were more likely to have complete hemodynamic response (68% vs 7%), demonstrated enhanced exercise capacity (47% vs 24%), and showed a decrease ≥50% in N-terminal pro-B-type natriuretic peptide (84% vs 8%) (P ≤ 0.002 for all). An improvement in ≥1 of these outcome measures was achieved in 97% of patients treated with aficamten (vs 59% placebo), including 23% on aficamten who achieved all 4 outcomes compared with none in placebo. Among 32 patients receiving aficamten and 29 patients receiving placebo who were eligible for septal reduction therapy, 28 (88%) from the aficamten group were no longer eligible at 24 weeks compared with 15 (52%) from the placebo group (P = 0.002). CONCLUSIONS: Treatment with aficamten was associated with substantial improvements across a broad range of clinically relevant efficacy measures. These results underscore the wide-ranging potential of aficamten for treatment of patients with symptomatic oHCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults with oHCM [SEQUOIA-HCM]; NCT05186818).

Pembrolizumab-Induced Myasthenia Gravis With Myocarditis in the Setting of Metastatic Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) like pembrolizumab are increasingly used for treating renal cell carcinoma (RCC), offering benefits such as enhanced specificity and activation of immunological memory. However, ICIs can lead to immune-related adverse events (irAEs), including rare but serious neurologic consequences such as myasthenia gravis (MG). We present a case of pembrolizumab-induced MG with concurrent orbital myositis and myocarditis. A 69-year-old male with a history of pT3aN1 kidney cancer presented with abdominal pain, night sweats, and weight loss. Initial imaging revealed a retroperitoneal mass and a thyroid mass, and a biopsy confirmed papillary RCC. The patient began neoadjuvant therapy with pembrolizumab and axitinib. Three weeks post-initiation, he developed dysphagia, ptosis, and proptosis, which progressed with each pembrolizumab infusion. Hospitalization was required after the third cycle due to bilateral ptosis, heart block, and elevated troponins. Despite initial steroid treatment, symptoms persisted. Diagnoses of ICI-related MG (irMG) and myocarditis were established, and treatment included cessation of pembrolizumab, high-dose steroids, IVIGs, and a pacemaker for heart block. Post-discharge, the patient showed a slight improvement in ptosis but persistent dysphagia. MG induced by ICIs is a rare but severe complication with rapid onset and progression, often presenting with bulbar involvement and a significant risk of respiratory failure. The therapeutic regimen for our patient, including high-dose methylprednisolone and IVIG, aligns with current recommendations. This case underscores the importance of recognizing cardiac irAEs like myocarditis in patients on ICIs, as early intervention can significantly affect outcomes. Despite therapeutic interventions, complete resolution of irMG symptoms is rare, and persistent sequelae are common. This case highlights the critical need for vigilant monitoring and prompt management of neurologic and cardiac irAEs in patients undergoing ICI therapy. Clinicians should maintain a high index of suspicion for MG and myocarditis to improve diagnostic accuracy and patient outcomes.

Implementing the Infectious Diseases Society of America Antimicrobial Stewardship Core Curriculum: Survey Results and Real-World Strategies to Guide Fellowship Programs.

Background: The Infectious Diseases Society of America (IDSA) developed the Core Antimicrobial Stewardship (AS) Curriculum to meet the increasing demand for infectious diseases (ID) providers with AS expertise. Notable diversity in implementation approaches has been observed among ID fellowship programs using the curriculum. We sought to describe individual approaches and develop a curriculum implementation roadmap. Methods: We surveyed ID fellowship programs that had previously implemented the IDSA Core AS curriculum. The survey included questions regarding program characteristics, curriculum participants and presentation format, resources and barriers, and implementation strategies. Commonly reported program features were summarized in the context of the self-reported implementation strategies. Implementation guides were developed based on the most common characteristics observed. Results: Of 159 programs that had purchased the curriculum, 37 responded, and 34 (21%) were included in the analysis. The curriculum was primarily taught by AS physicians (85%) and AS pharmacists (47%). The most common conference structure was a longitudinal conference series (32%), and eLearning was the most common presentation format. Limited AS faculty time (76%) and limited first-year fellow availability (62%) were frequently reported as barriers, and dedicated AS curricular time was a resource available to most programs (67%); implementation guides were created for these 3 program features. Conclusions: Programs reported a variety of implementation barriers and resources, with several common themes emerging, allowing for the development of tailored curriculum planners for 3 commonly observed program characteristics. This work will equip fellowship programs with curriculum implementation strategies and guide future enhancements of the IDSA Core and Advanced AS curricula.

Development of a core descriptor set for parastomal hernia repair.

AIM: Parastomal hernia repair is a poorly evidenced area, with uncertainty around the optimum management. There is considerable heterogeneity within the patient cohort, and currently there is no standardization of patient descriptors in the reporting of parastomal hernia repair. The aim of this study was to develop a core descriptor set of key patient characteristics for patients undergoing surgical repair of a parastomal hernia for reporting in all parastomal hernia research. METHOD: A longlist of descriptors was generated from a review of the existing literature. The longlist was discussed with patients with lived experience of parastomal hernia repair. Colorectal, general and hernia surgeons took part in a three-round international modified Delphi process using a nine-point Likert scale to rank the importance of descriptors. Items meeting predetermined thresholds were included in the final set and discussed and ratified at the consensus meeting. RESULTS: Seventy seven respondents completed round one, with 23 (29.8%) completing round three. Eighty six descriptors were rated across the three rounds, with 52 descriptors shortlisted. The consensus meeting ratified a final core descriptor set with 19 descriptors across eight domains: anatomy, contamination, disease, previous treatment, risk factors, symptoms, pathway and other hernia. CONCLUSION: The core descriptor set reflects characteristics that are important to surgeons when reporting on parastomal hernia repair. The use of this agreed core descriptor set may aid the reporting of future studies.

Intrapatient Changes in CT-Based Body Composition After Initiation of Semaglutide (Glucagon-Like Peptide-1 Agonist) Therapy.

Background: The long-acting glucagon-like peptide-1 receptor agonist semaglutide is used to treat type 2 diabetes or obesity in adults. Clinical trials have observed associations of semaglutide with weight loss, improved diabetic control, and cardiovascular risk reduction. Objective: To evaluate intrapatient changes in body composition after initiation of semaglutide therapy by applying an automated suite of CT-based artificial intelligence (AI) body composition tools. Methods: This retrospective study included adult patients with semaglutide treatment who underwent abdominopelvic CT both within 5 years before and within 5 years after semaglutide initiation, between January 2016 and November 2023. An automated suite of previously validated CT-based AI body composition tools was applied to pre-semaglutide and post-semaglutide scans to quantify visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) area, skeletal muscle area and attenuation, intermuscular adipose tissue (IMAT) area, liver volume and attenuation, and trabecular bone mineral density (BMD). Patients with ≥5-kg weight loss and ≥5-kg weight gain between scans were compared. Results: The study included 241 patients (mean age, 60.4±12.4 years; 151 women, 90 men). In the weight-loss group (n=67), the post-semaglutide scan, versus pre-semaglutide scan, showed decrease in VAT area (341.1 vs 309.4 cm2, p<.001), SAT area (371.4 vs 410.7 cm2, p<.001), muscle area (179.2 vs 193.0, p<.001), and liver volume (2379.0 vs 2578 HU, p=.009), and increase in liver attenuation (74.5 vs 67.6 HU, p=.03). In the weight-gain group (n=48), the post-semaglutide scan, versus pre-semaglutide scan, showed increase in VAT area (334.0 vs 312.8, p=.002), SAT area (485.8 vs 488.8 cm2, p=.01), and IMAT area (48.4 vs 37.6, p=.009), and decrease in muscle attenuation (5.9 vs 13.1, p<.001). Other comparisons were not significant (p>.05). Conclusion: Patients using semaglutide who lost versus gained weight demonstrated distinct patterns of changes in CT-based body composition measures. Those with weight loss exhibited overall favorable shifts in measures related to cardiometabolic risk. Muscle attenuation decrease in those with weight gain is consistent with decreased muscle quality. Clinical Impact: Automated CT-based AI tools provide biomarkers of body composition changes in patients using semaglutide beyond that which is evident by standard clinical measures.

Delaying post-exercise carbohydrate intake impairs next-day exercise capacity but not muscle glycogen or molecular responses.

AIM: To investigate how delayed post-exercise carbohydrate intake affects muscle glycogen, metabolic- and mitochondrial-related molecular responses, and subsequent high-intensity interval exercise (HIIE) capacity. METHODS: In a double-blind cross-over design, nine recreationally active men performed HIIE (10 × 2-min cycling, ~94% W˙peak) in the fed state, on two occasions. During 0-3 h post-HIIE, participants drank either carbohydrates ("Immediate Carbohydrate" [IC], providing 2.4 g/kg) or water ("Delayed Carbohydrate" [DC]); total carbohydrate intake over 24 h post-HIIE was matched (~7 g/kg/d). Skeletal muscle (sampled pre-HIIE, post-HIIE, +3 h, +8 h, +24 h) was analyzed for whole-muscle glycogen and mRNA content, plus signaling proteins in cytoplasmic- and nuclear-enriched fractions. After 24 h, participants repeated the HIIE protocol until failure, to test subsequent HIIE capacity; blood lactate, heart rate, and ratings of perceived effort (RPE) were measured throughout. RESULTS: Muscle glycogen concentrations, and relative changes, were similar between conditions throughout (p > 0.05). Muscle glycogen was reduced from baseline (mean ± SD mmol/kg dm; IC: 409 ± 166; DC: 352 ± 76) at post-HIIE (IC: 253 ± 96; DC: 214 ± 82), +3 h (IC: 276 ± 62; DC: 269 ± 116) and + 8 h (IC: 321 ± 56; DC: 269 ± 116), returning to near-baseline by +24 h. Several genes (PGC-1ɑ, p53) and proteins (p-ACCSer79, p-P38 MAPKThr180/Tyr182) elicited typical exercise-induced changes irrespective of condition. Delaying carbohydrate intake reduced next-day HIIE capacity (5 ± 3 intervals) and increased RPE (~2 ratings), despite similar physiological responses between conditions. CONCLUSION: Molecular responses to HIIE (performed in the fed state) were not enhanced by delayed post-exercise carbohydrate intake. Our findings support immediate post-exercise refueling if the goal is to maximize next-day HIIE capacity and recovery time is ≤24 h.

Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial.

Importance: Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures. Objective: To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates. Design, Setting, and Participants: This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024. Interventions: Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed. Results: Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, -0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05). Conclusions and Relevance: This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten. Trial Registration: ClinicalTrials.gov Identifier: NCT05186818.

Surgical practices in emergency umbilical hernia repair and implications for trial design.

INTRODUCTION: There is variation in the investigation, management, and surgical technique of acutely symptomatic umbilical hernias and optimal strategies remain to be established. This survey aimed to identify key variables influencing decision-making and preferred surgical techniques in emergency umbilical hernia care to help inform trial design and understand potential challenges to trial delivery. METHODS: A survey was distributed to surgeons through social media, personal contacts, and ASGBI lists. It comprised five sections: (i) performer of repair, (ii) repair preferences, (iii) important outcomes, (iv) perioperative antibiotic use, and (v) potential future trial design. RESULTS: There were 105 respondents, of which 49 (46.6%) were consultants. The median largest defect surgeons would attempt to repair with sutures alone was 2 cm (IQR 2-4 cm). In the acute setting, the most common mesh preferences are preperitoneal plane placement (n = 61, 58.1%), with synthetic non-absorbable mesh (n = 72, 68.6%), in clean (n = 41, 39.0%) or clean-contaminated (n = 52, 49.5%) wounds. Respondents believed suture repair to be associated with better short-term outcomes, and mesh repair with better long-term outcomes. Pre-/intra-operative antibiotics were very frequently given (n = 48, 45.7%) whilst post-operative antibiotics were rarely (n = 41, 39%) or very rarely (n = 28, 26.7%) given. The trial design felt to most likely influence practice is comparing mesh and suture repair, and post-operative antibiotics versus no post-operative antibiotics. Respondents indicated that to change their practice, the median difference in surgical site infection rate and recurrence rate would both need to be 5%. CONCLUSION: This survey provides insight into surgical preferences in emergency umbilical hernia management, offering guidance for the design of future trials.

Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial.

BACKGROUND AND AIMS: The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy (oHCM) is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate effect of treatment with aficamten on biomarker concentrations. METHODS: Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and to evaluate whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. RESULTS: Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% CI 83%-76%, P < .001) and hs-cTnI by 41% (95% CI 49%-32%, P < .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. NT-proBNP reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints. CONCLUSIONS: NT-proBNP and hs-cTnI concentrations are associated with key variables in oHCM. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy.

Effect of Aficamten on Cardiac Structure and Function in Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM CMR Substudy.

BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and left atrial dilation, which can be associated with progressive heart failure, atrial fibrillation, and stroke. Aficamten is a next-in-class cardiac myosin inhibitor that reduces outflow tract obstruction by modulating cardiac contractility, with the potential to reverse pathological remodeling and, in turn, reduce cardiovascular events. OBJECTIVES: This study sought to investigate the effect of aficamten on cardiac remodeling compared with placebo using cardiovascular magnetic resonance (CMR) and its association with key clinical endpoints in the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) CMR substudy. METHODS: SEQUOIA-HCM was a phase 3 double-blind, placebo-controlled trial for adults with symptomatic oHCM who were randomized 1:1 to 24 weeks of aficamten (dose range: 5-20 mg) or placebo. Eligible participants were offered enrollment in the CMR substudy with studies performed at baseline and week 24. Image analysis was performed in a blinded fashion by a core laboratory. RESULTS: Of the 282 randomized patients, 57 (20%) participated in the substudy, and of those, 50 (88%) completed both baseline and week 24 CMR. Baseline characteristics of the CMR cohort were similar to the overall study population. Of these 50 patients, 21 received aficamten and 29 received placebo. Relative to placebo, patients receiving aficamten demonstrated significant reductions (Δ least-squares mean) in LV mass index (-15 g/m2; 95% CI: -25 to -6 g/m2; P = 0.001), maximal LV wall thickness (-2.1 mm; 95% CI: -3.1 to -1.1 mm; P < 0.001), left atrial volume index (-13 mL/m2; 95% CI: -19 to -7 mL/m2; P < 0.001), native T1 relaxation time (-37 ms; 95% CI: -69 to -5 ms; P = 0.026), indexed extracellular volume fraction (-3.9 g/m2; 95% CI: -7.0 to -0.9 g/m2; P = 0.014), and indexed myocyte mass (-14 g/m2; 95% CI: -23 to -4 g/m2; P = 0.004), while there were no significant changes in LV chamber volumes, LV replacement fibrosis (late gadolinium enhancement mass -0.7 g; 95% CI: -2.9 to 1.6 g; P = 0.54), or extracellular volume (0.7%; 95% CI: -2.2% to 3.6%; P = 0.61). CONCLUSIONS: The CMR substudy of SEQUOIA-HCM demonstrated that treatment with aficamten relative to placebo for 24 weeks resulted in favorable cardiac remodeling. These changes, particularly with regard to LV mass, wall thickness, and left atrial size, could potentially lead to reduced cardiovascular events including heart failure and atrial fibrillation with longer follow-up. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).

Predicting peritumoral glioblastoma infiltration and subsequent recurrence using deep-learning-based analysis of multi-parametric magnetic resonance imaging.

Purpose: Glioblastoma (GBM) is the most common and aggressive primary adult brain tumor. The standard treatment approach is surgical resection to target the enhancing tumor mass, followed by adjuvant chemoradiotherapy. However, malignant cells often extend beyond the enhancing tumor boundaries and infiltrate the peritumoral edema. Traditional supervised machine learning techniques hold potential in predicting tumor infiltration extent but are hindered by the extensive resources needed to generate expertly delineated regions of interest (ROIs) for training models on tissue most and least likely to be infiltrated. Approach: We developed a method combining expert knowledge and training-based data augmentation to automatically generate numerous training examples, enhancing the accuracy of our model for predicting tumor infiltration through predictive maps. Such maps can be used for targeted supra-total surgical resection and other therapies that might benefit from intensive yet well-targeted treatment of infiltrated tissue. We apply our method to preoperative multi-parametric magnetic resonance imaging (mpMRI) scans from a subset of 229 patients of a multi-institutional consortium (Radiomics Signatures for Precision Diagnostics) and test the model on subsequent scans with pathology-proven recurrence. Results: Leave-one-site-out cross-validation was used to train and evaluate the tumor infiltration prediction model using initial pre-surgical scans, comparing the generated prediction maps with follow-up mpMRI scans confirming recurrence through post-resection tissue analysis. Performance was measured by voxel-wised odds ratios (ORs) across six institutions: University of Pennsylvania (OR: 9.97), Ohio State University (OR: 14.03), Case Western Reserve University (OR: 8.13), New York University (OR: 16.43), Thomas Jefferson University (OR: 8.22), and Rio Hortega (OR: 19.48). Conclusions: The proposed model demonstrates that mpMRI analysis using deep learning can predict infiltration in the peri-tumoral brain region for GBM patients without needing to train a model using expert ROI drawings. Results for each institution demonstrate the model's generalizability and reproducibility.

Circulating inflammatory and immune response proteins and endometrial cancer risk: a nested case-control study and Mendelian randomization analyses.

BACKGROUND: Inflammation and immune dysregulation are hypothesized contributors to endometrial carcinogenesis; however, the precise underlying mechanisms remain unclear. METHODS: We measured pre-diagnostically 152 plasma protein biomarkers in 624 endometrial cancer case-control pairs nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Odds ratios (ORs) were estimated using conditional logistic regression, accounting for confounding and multiple comparisons. Proteins considered as associated with endometrial cancer risk were further tested in a two-sample Mendelian randomization (MR) analysis using summary data from the UK Biobank (n = 52,363) and the Endometrial Cancer Association Consortium (12,270 cases and 46,126 controls). FINDINGS: In the EPIC nested case-control study, IL-6 [OR per NPX (doubling of concentration) = 1.28 (95% confidence interval (CI) 1.03-1.57)], HGF [1.48 (1.06-2.07)], PIK3AP1 [1.22 (1.00-1.50)] and CLEC4G [1.52 (1.00-2.32)] were positively associated; HSD11B1 [0.67 (0.49-0.91)], SCF [0.68 (0.49-0.94)], and CCL25 [0.80 (0.65-0.99)] were inversely associated with endometrial cancer risk; all estimates had multiple comparisons adjusted P-value > 0.05. In complementary MR analysis, IL-6 [OR per inverse-rank normalized NPX = 1.19 (95% CI 1.04-1.36)] and HSD11B1 [0.91 (0.84-0.99)] were associated with endometrial cancer risk. INTERPRETATION: Altered IL-6 signalling and reduced glucocorticoid activity via HSD11B1 might play important roles in endometrial carcinogenesis. FUNDING: Funding for IIG_FULL_2021_008 was obtained from Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund International grant programme; Funding for INCA_15849 was obtained from Institut National du Cancer (INCa).

Educational Gaps in Dermatologic Diagnoses Among Otolaryngology Residents.

Otolaryngologists frequently serve as the first touchpoint for patients presenting with dermatologic conditions of the head and neck. This study aims to identify and quantify gaps in dermatologic training among otolaryngology residents, and to assess their diagnostic accuracy in comparison to dermatology residents. It comprised 14 multiple-choice questions focused on common dermatologic diagnoses related to the head and neck. Sixty-one dermatology and 36 otolaryngology residents participated in the study. Dermatology residents significantly outperformed otolaryngology residents, with average scores of 90% (SD = 8) compared to 71% (SD = 10) (P < .001). The observed effect size (Cohen's d = 2.010) significantly exceeded the expected effect size (0.603). Otolaryngology residents performed significantly lower on 7 out of the 14 questions. Analysis based on postgraduate year level showed no significant differences in scores within dermatology (P = .119) or otolaryngology (P = .402) residency programs.

Operative versus conservative management for inguinal hernia: a methodology scoping review of randomized controlled trials.

INTRODUCTION: There is a lack of consensus on the management of inguinal hernia with limited symptoms. To address this issue a systematic review of existing randomized clinical trials (RCTs) was performed to critically appraise all existing data on asymptomatic hernia management, focusing on generalizability. METHODS: A scoping review to identify all RCTs comparing surgical and conservative management of patients with inguinal hernias was undertaken. Medline, Embase, Cochrane and ClinicalTrials.gov databases were searched. Data collected included study characteristics and definitions of population, intervention/comparator, and outcomes; and limitations of each study were also extracted. The quality and generalizability of included RCTs were evaluated using Cochrane's ROB-2 and the PRECIS-2 tool, respectively. RESULTS: Searches returned 661 papers; 14 full-text papers were assessed and three RCTs were identified. All RCTs included only male patients with a mean age above 55 years. All RCTs included asymptomatic patients and two included those with minimal symptoms. Different definitions for 'minimally symptomatic' were used in RCTs and none provided details of what was meant by conservative treatment. Follow-up periods varied between studies (1, 2, 3 years). All RCTs had an overall high risk of bias. According to PRECIS-2, two RCTs were classified as pragmatic, and one was equally pragmatic and explanatory. DISCUSSION: This systematic review highlights a high risk of bias but a good generalizability of the findings from the RCTs conducted on minimally symptomatic inguinal hernia patients. To improve the guidelines for the management of this group of patients, more generalizable data are needed.

Correlation of HbA1c levels with CT-based body composition biomarkers in diabetes mellitus and metabolic syndrome.

Diabetes mellitus and metabolic syndrome are closely linked with visceral body composition, but clinical assessment is limited to external measurements and laboratory values including hemoglobin A1c (HbA1c). Modern deep learning and AI algorithms allow automated extraction of biomarkers for organ size, density, and body composition from routine computed tomography (CT) exams. Comparing visceral CT biomarkers across groups with differing glycemic control revealed significant, progressive CT biomarker changes with increasing HbA1c. For example, in the unenhanced female cohort, mean changes between normal and poorly-controlled diabetes showed: 53% increase in visceral adipose tissue area, 22% increase in kidney volume, 24% increase in liver volume, 6% decrease in liver density (hepatic steatosis), 16% increase in skeletal muscle area, and 21% decrease in skeletal muscle density (myosteatosis) (all p < 0.001). The multisystem changes of metabolic syndrome can be objectively and retrospectively measured using automated CT biomarkers, with implications for diabetes, metabolic syndrome, and GLP-1 agonists.

Biotransformation of 6:2/4:2 fluorotelomer alcohols by Dietzia aurantiaca J3: Enzymes and proteomics.

Per- and polyfluoroalkyl substances (PFAS) are recalcitrant synthetic organohalides known to negatively impact human health. Short-chain fluorotelomer alcohols are considered the precursor of various perfluorocarboxylic acids (PFCAs) in the environment. Their ongoing production and widespread detection motivate investigations of their biological transformation. Dietzia aurantiaca strain J3 was isolated from PFAS-contaminated landfill leachate using 6:2 fluorotelomer sulphonate (6:2 FTS) as a sulphur source. Resting cell experiments were used to test if strain J3 could transform fluorotelomer alcohols (6:2 and 4:2 FTOH). Strain J3 transformed fluorotelomer alcohols into PFCAs, polyfluorocarboxylic acids and transient intermediates. Over 6 days, 80 % and 58 % of 6:2 FTOH (0.1 mM) and 4:2 FTOH (0.12 mM) were degraded with 6.4 % and 14 % fluoride recovery respectively. Fluorotelomer unsaturated carboxylic acid (6:2 FTUCA) was the most abundant metabolite, accounting for 21 to 30 mol% of 6:2 FTOH (0.015 mM) applied on day zero. Glutathione (GSH) conjugates of 6:2/4:2 FTOH and 5:3 FTCA adducts were also structurally identified. Proteomics studies conducted to identify enzymes in the biotransformation pathway have revealed the role of various enzymes involved in ß oxidation. This is the first report of 6:2/4:2 FTOH glutathione conjugates and 5:3 FTCA adducts in prokaryotes, and the first study to explore the biotransformation of 4:2 FTOH by pure bacterial strain.

Outcomes of a Single Transverse Chest Roll for Prone Positioning Technique During Percutaneous Nephrolithotomy.

OBJECTIVE: To compare anesthetic parameters using a novel prone single transverse chest roll technique (STR) to the standard thoraco-pelvic dual transverse roll technique (DTR). METHODS: A retrospective review of 441 patients who underwent PCNL between 2018 and 2022 was performed. A total of 4 surgeons were included-surgeon 1 utilized the STR technique while surgeons 2, 3, and 4 used the DTR technique. Anesthetic parameters including end-tidal CO2 (ETCO2), mean arterial pressure (MAP), peak airway pressure (Ppeak), plateau airway pressure (Pplat), positive end-expiratory pressure (PEEP), oxygen saturation (SpO2), and tidal volume (TV) were compared between both groups at 0 (supine), 15-, 30-, and 60-minute post-intubation intervals. Mixed effects regression models with interaction and pairwise comparisons were made between both groups (P <.05). RESULTS: A total of 581 PCNLs were performed with 199 using STR and 382 using DTR. Surgery duration, ASA class, and age were similar amongst the STR and DTR groups. Estimated blood loss (59cc vs 83cc, P = .007) and length of stay (77 hrs vs 163 hrs, P = <.001) was significantly lower in the STR group. There was a significantly lower Ppeak, Pplat and TV in the STR compared to DTR group at 0, 15, 30, and 60 minutes (P <.001). CONCLUSION: Usage of a single transverse chest roll during prone PCNL appears to be a safe positioning method. STR patients had lower Ppeak and Pplat at all time points, which has been shown to be predictive of lower blood loss.

Kinematics-Based Predictions of External Loads during Handcycling.

The increased risk of cardiovascular disease in people with spinal cord injuries motivates work to identify exercise options that improve health outcomes without causing risk of musculoskeletal injury. Handcycling is an exercise mode that may be beneficial for wheelchair users, but further work is needed to establish appropriate guidelines and requires assessment of the external loads. The goal of this research was to predict the six-degree-of-freedom external loads during handcycling from data similar to those which can be measured from inertial measurement units (segment accelerations and velocities) using machine learning. Five neural network models and two ensemble models were compared against a statistical model. A temporal convolutional network (TCN) yielded the best predictions. Predictions of forces and moments in-plane with the crank were the most accurate (r = 0.95-0.97). The TCN model could predict external loads during activities of different intensities, making it viable for different exercise protocols. The ability to predict the loads associated with forward propulsion using wearable-type data enables the development of informed exercise guidelines.