Citations

Abstract Heart failure (HF) is a major cause of hospitalization and mortality worldwide. Ventricular assist devices (VADs) represent an alternative to cardiac transplantation for advanced HF. The main FDA-approved VAD (HeartMate III, Abbott), while effective, requires major cardiac surgery to insert the inflow cannula into the cardiac apex, and is associated with numerous co-morbidities and re-hospitalizations related to continuous flow and an external drive line and power supply. Mi-VAD, Inc. aspires to improve outcomes and quality of life with a miniature, minimally invasive, pulsatile, transcutaneously-powered VAD that is implanted above the aortic valve and/or the pulmonary valve and offering a wide range of hemodynamic support suitable for both advanced-stage and less advanced HF. Through its unique placement, there is the potential for right ventricular and biventricular cardiac assist for patients with restrictive cardiomyopathy and HFpEF for whom current VAD therapy is ineffective. Mi-VAD, Inc. has achieved proof of concept with its prototype, providing pulsatile ECG gated cardiac assist up to 10L/minute. Following initial bench top performance testing and in vivo efficacy and safety studies future work will focus on the development of wireless charging capability and conducting GLP builds for verification, regulatory clearance and commercialization. Additional technical development will focus on AI-driven hemodynamic optimization using multimodal physiologic sensing towards patient-specific digital twin of the Mi-VAD platform.

ABSTRACT Background/Objectives Prospective applicants for pediatric dermatology fellowships often use program websites as a source of information. This study evaluated the content of pediatric dermatology fellowship websites to identify potential areas of improvement including website accessibility and information found on websites. In addition, this study also surveyed current pediatric dermatology fellows and program directors (PDs) to determine priorities in website content across different stakeholders. Methods Using the Society for Pediatric Dermatology's (SPD) list of fellowship programs, two independent evaluators assessed the same 40 total programs, with 29 of the same websites included for analysis, against 27 criteria across four domains. In addition, an electronic survey was disseminated via the SPD's mailing list to current pediatric dermatology fellows and fellowship PDs. Results On average between both evaluators, of the 29 included fellowship websites, 9 educational criteria were included 47.8% of the time across the websites, compared to 46.0% of 10 recruitment criteria, 30.7% of 5 social criteria, and 31.6% of 3 other criteria. Fellows were significantly more likely than PDs to consider several website components as highly valuable. Conclusions These findings reveal variable and incomplete content across pediatric dermatology fellowship websites, as well as differing expectations for fellowship websites between pediatric dermatology fellowship applicants and PDs, which may help provide suggestions to optimize future website development to enhance applicant engagement.

Objective The Accreditation Council for Graduate Medical Education (ACGME) introduced Milestones in 2013 to aid the assessment of residents and fellows within the framework of the six core competencies of practice. Feedback from program directors and trainees, clinical competency committee processes, and milestone reporting identified the need for modification. This study represents a consensus-driven educational quality improvement initiative which describes the development, revision process, and key features of Critical Care Anesthesiology (CCA) Milestones 2.0, and provides lessons learned in adapting competency-based assessment to a one-year subspecialty training program. Methods A Critical Care Anesthesiology (CCA) working group was convened by the ACGME in 2021 to revise the content, enhance relevance to training, clarify goals for program leadership, and develop supplemental resources to aid implementation. The group consisted of a diverse group of experienced educators and clinicians from CCA fellowship programs nationwide. A modified Delphi process, stakeholder feedback, Milestones performance data, and public comment were used to iteratively revise Milestones. In addition, a supplemental guide was developed to provide examples and resources to aid the Milestones assessment. Conclusion The Milestones 2.0 simplify the use, implementation, and interpretation of this competency framework for program directors, trainees, faculty, and the American Board of Anesthesiology. The resulting CCA Milestones 2.0 provide updated specialty-specific, competency-based behavioral anchors to guide the developmental progression of competencies and outcomes for CCA fellows and facilitate the design of curricula and the advancement of CCA training programs. Lessons learned in the development of the CCA Milestones 2.0 include the importance of simplification, behavioral specificity, and supplemental.

Background: Gender-based reimbursement disparities in orthopedic surgery remain poorly understood, particularly when accounting for practice composition and setting. The purpose of this study was to compare and evaluate gender-based differences in Medicare reimbursement and practice patterns among female and male orthopedic surgeons. Methods: A cross sectional analysis of public Medicare data from 2013 to 2021 was performed. Outcomes included annual Medicare payments, submitted charges, total services, service categories, and beneficiaries treated by orthopedic surgeons who bill Medicare. Univariate and multivariable analyses quantified differences in payment, practice volume and composition, geographic adjustment, and Current Procedural Terminology (CPT)-matched reimbursements. Results: A total of 29,357 orthopedic surgeons (27,442 men and 1,919 women) billed Medicare fee-for-service during the study period. Female surgeons, on average, submitted 48.3% fewer total charges and received 44.1% lower annual Medicare payments per surgeon compared with male surgeons. These differences persisted after multivariable regression adjusted for practice metrics and excluded top and bottom earners. Female surgeons also billed fewer services, treated fewer beneficiaries, and submitted fewer unique CPT codes. However, payment disparities persisted even after matching surgeons by volume of services, beneficiaries, and years in practice. Male surgeons performed higher volumes of all 10 highest-paying orthopedic CPT codes. In CPT matched analyses, female surgeons received lower reimbursement per service than male surgeons performing identical procedures. Conclusion: These findings suggest that the observed gender-based disparities in orthopedic surgery Medicare reimbursement cannot be explained by differences in volume, procedural mix, or geographic practice cost. Instead, they likely reflect a combination of structural and behavioral mechanisms described in prior literature that may influence how access to clinical opportunities, referrals, and reimbursement practices unfold in surgical practices. Variations in coding practices may represent an important focus for future investigation and targeted educational initiatives. Level of Evidence: Level III , Retrospective Cohort Study. See Instructions for Authors for a complete description of levels of evidence.

RELA-related disease is a rare, autosomal-dominant condition presenting with immune dysregulation and immunodeficiency. RELA encodes the p65 subunit, a component of the canonical NFκB pathway. The underlying pathogenesis, at least in part, involves impaired NFκB activation, increased susceptibility to TNFα-induced apoptosis, and hyperinflammation. To date, only a modest number of cases have been documented worldwide, and the full clinical and functional spectrum of disease remains incompletely defined. This study represents a large global cohort identified with RELA variants, comprising 40 patients from 30 institutions, expanding our previous report of a single large kindred (1). The clinical spectrum includes arthritis, mucocutaneous ulcers, uveitis, dermatitis, irritable bowel disease, recurrent infections, lymphopenia, hypogammaglobulinemia, recurrent fevers, and susceptibility to neoplasia. The patients represent 36 kindreds with 28 unique RELA variants, of which 15 are missense, 7 nonsense, and 6 frameshift variants. Fifteen are in the Rel homology domain, 7 in the transcriptional activation domain, and 6 in the C-terminal region proximal to TAD (Fig. 1). Functional studies assessed the canonical NFκB pathway in 27% of the cohort (n = 11; healthy controls = 40). Patient peripheral blood mononuclear cells (PBMCs) were used to quantify total and phosphorylated p65 (ph-p65, Ser529) by flow cytometry after stimulation with PMA (100 ng/ml) and ionomycin (1 uM). In 8 patients, we assessed the kinetics of IκBα degradation, required for p65 phosphorylation and nuclear translocation of p65/p50. All patients tested had decreased total p65, while 64% had decreased ph-p65 with altered phosphorylation kinetics. Nearly 45% had impaired IκBα degradation. One patient (P4) demonstrated increased IκBα degradation and ph-p65, while a related proband (P1) had decreased ph-p65. Additionally, P4 did not have the same mucocutaneous clinical phenotype as P1 despite sharing the same RELA variant. This could reflect the effect of other genetic modifiers, epigenetic, environmental, or stochastic variations, which could lead to variable expressivity and/or incomplete penetrance. All patients appeared to have haploinsufficiency, as none had normal levels of p65. This study expands the clinical and genetic spectrum of RELA-related disease and provides mechanistic insights into the impact of these variants on p65 phosphorylation and downstream function, resulting in variable expressivity. Figure 1. RelA protein structure. Represents unique variant locations and categories, key domains, and phosphorylation sites. Source: UniProt. Adapted from (2). BioRender.

ABSTRACT BACKGROUND Point-of-care (POC) high-sensitivity cardiac troponin (hs-cTn) testing has the potential to expedite decision-making and reduce emergency department (ED) length of stay for patients presenting with possible myocardial infarction (MI) by ensuring that results are consistently available when looked for by clinicians. We assessed the real-life effectiveness and safety of implementing POC hs-cTn testing in the ED. METHODS We conducted a pragmatic, stepped-wedge cluster randomized trial. The control arm was usual care with an accelerated diagnostic pathway utilizing a single-sample rule-out step with a central laboratory hs-cTn assay. The intervention arm used the same pathway with a POC hs-cTnI. The primary effectiveness outcome was ED length of stay assessed using a generalized linear mixed model, and the safety outcome was 30-day MI or cardiac death. RESULTS Six sites participated with 59,980 ED presentations (44,747 individuals, 61±19 years, 49.5% female) from February 2023 to January 2025, in which 31,392 presentations were during the intervention arm. After adjustment for co-variates associated with length of stay, the intervention reduced length of stay by 13% (95% confidence intervals [CI], 9 to 16%. P<0.001), corresponding to a reduction of 47 minutes (95%CI, 33 to 61 minutes) from a mean length of stay in the control arm of 376 minutes. The 30-day MI or cardiac death rate was similar in the control and intervention arms (0.39% and 0.39% respectively, P=0.54). CONCLUSIONS Implementation of whole-blood hs-cTnI testing at the POC into an accelerated diagnostic pathway was safe and reduced length of stay in the ED compared with laboratory testing. (Australia New Zealand Clinical Trials Registry ACTRN12619001189112) Clinical Perspective What is new? Point-of-care troponin assays with good precision have become available and received regulatory approval as high-sensitivity assays. A pragmatic stepped-wedge cluster randomized trial implementing the validated Siemens VTLi high-sensitivity point-of-care assay into 6 emergency departments investigating ∼60,000 patients, was conducted to ascertain if the rapid turnaround time reduced lengths of stay. Introduction of the VTLi high-sensitivity point-of-care assay into clinical pathways reduced emergency department lengths of stay by an average 13% (47 minutes) without compromising safety. What are the clinical implications? Early decision-making using a point-of-care high-sensitivity troponin assay within a structured clinical pathway was safe. Faster turnaround means troponin results are consistently available when clinicians first seek them. This can facilitate earlier decisions and reduce patient length of stay.

Abstract Advances in biomarker technology, digital cognitive assessments, and amyloid‐targeting therapies have redefined the opportunities for accurate and early diagnosis and care of Alzheimer's disease (AD). These advances also create new possibilities for intervention before the onset of cognitive impairment. This paradigm shift has increased the focus on Stages 1 and 2 of AD, in which individuals are cognitively unimpaired but exhibit biological evidence of disease. While early identification of AD offers an opportunity to intervene early to delay progression and preserve quality of life, it also presents complex challenges related to communicating diagnostic results to patients and their families, contextualizing the cost effectiveness of early diagnosis and treatment, and implementation of and equitable access to treatments. Recent, successfully enrolled, preclinical AD trials highlight the complex strategies required to identify asymptomatic, biomarker‐positive individuals on a large scale, and demonstrate critical knowledge gaps in inclusion, follow‐up, and long‐term outcome measurement. The Spring 2025 Alzheimer's Association Research Roundtable (AARR) meeting brought together academics, clinicians, industry, and regulatory leaders to exchange perspectives on current challenges, key learnings, and potential strategies for identifying and treating individuals in very early stages of AD, effectively and safely. This paper presents key takeaways from the Spring 2025 AARR meeting. Highlights New criteria for Alzheimer's disease (AD) enable early identification of AD pathology. Blood tests and digital cognitive assessment tools may facilitate early and personalized care. Plasma biomarkers may be scalable in clinical settings but need confirmation or follow‐up assessments in those individuals with equivocal results. Early therapy shows best results in people with lower initial amyloid and tau burden.

Importance A greater proportion of older patients (age ≥65 years) are undergoing thyroidectomy amidst an aging population. Given the elusive results in the literature, clarifying whether older patients face different thyroidectomy safety profiles is crucial for optimizing risk assessment and patient counseling. Objective To evaluate the association between older age (age ≥65 years) and thyroidectomy safety by comparing endocrine-related complications, including recurrent laryngeal nerve injury, hypocalcemia, hematoma, and mortality in older compared with younger patients. Data Sources Ovid MEDLINE, CINAHL, Ovid Embase, and the Cochrane Library were systematically searched from inception to May 29, 2025; only English-language studies were included. Study Selection Cohort studies comparing thyroidectomy outcomes between older and younger patients and reporting endocrine-related complications were included. Two independent reviewers screened abstracts and full texts. Of 3192 studies identified, 11 met inclusion criteria. Data Extraction and Synthesis Two independent reviewers extracted data following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Risk of bias across studies was evaluated using the ROBINS-I (Risk of Bias in Nonrandomized Studies of Interventions) tool. Random-effects models were used to pool data. Main Outcomes and Measures Incidence of recurrent laryngeal nerve injury, hypocalcemia, and hematoma; odds ratios (ORs) with 95% CIs were calculated. Results The analysis included 11 studies with a total of 427 886 patients of whom 104 232 (24.4%) were older adults (≥65 years). Older adults had greater odds of overall recurrent laryngeal nerve injury (2.3% vs 1.0%; OR, 1.58; 95% CI, 1.15-2.16; I 2 = 76%), hematoma (2.4% vs 1.0%; OR, 2.32; 95% CI, 1.70-3.16; I 2 = 0%), and mortality at last follow-up (0.3% vs 0.01%; OR, 11.09; 95% CI, 1.77-69.52; I 2 = 90%) compared with younger patients. However, rates of overall hypocalcemia (OR, 0.80; 95% CI, 0.61-1.05; I 2 = 71%) and wound complications (OR, 1.38; 95% CI, 0.92-2.06; I 2 = 0%) were similar. Conclusions and Relevance This systematic review and meta-analysis found that thyroidectomy is safe in older patients, with only small absolute increases in recurrent laryngeal nerve injury, hematoma, and mortality despite statistical significance. These findings support individualized counseling and perioperative planning while acknowledging the overall safety of thyroidectomy in this population.

Abstract Background Icotrokinra is the first targeted oral peptide that selectively blocks the IL-23 receptor (IL-23R) and precisely inhibits the IL-23 pathway. In ANTHEM-UC—a Phase 2b, randomised, double-blind, placebo (PBO)-controlled, dose-ranging study in adults with moderately to severely active ulcerative colitis (UC)—all doses of icotrokinra achieved the primary endpoint of clinical response and delivered clinically meaningful improvements across key secondary endpoints at Week (W)12,1 which were maintained or improved at W28.2 Here we report the impact of icotrokinra on systemic and tissue biomarkers of inflammatory burden in UC. Methods Participants were randomised (1:1:1:1) to receive once-daily icotrokinra 100 mg, 200 mg, 400 mg, or PBO. Clinical inflammatory biomarkers, C-reactive protein (CRP) and faecal calprotectin (FCP), along with serum IL-23 pathway biomarkers (IL-22, IL-17A, and IL-17F) were used to determine the impact of icotrokinra on systemic inflammation. Gene expression changes in colonic biopsies were used to confirm tissue IL-23 pathway engagement and dampening of tissue inflammation with icotrokinra. Results At the W12 primary timepoint, all doses of icotrokinra attenuated levels of serum CRP and FCP (Figure 1). All doses of icotrokinra, but not PBO, markedly reduced serum levels of IL-22, IL-17A, and IL-17F at W12 relative to baseline. Greater reductions in these serum biomarkers of IL-23 pathway activation were observed with the 200 mg and 400 mg doses relative to the 100 mg dose (Figure 1, nominal p &lt; 0.05). All doses of icotrokinra, but not PBO, markedly reduced expression of gene sets associated with the IL-23–driven inflammation in tissue at W12 relative to baseline (Figure 2, nominal p &lt; 0.0001). With icotrokinra treatment, the tissue transcriptome more closely resembled that of healthy individuals, with decreased expression of gene sets associated with UC-relevant inflammatory cell types and increased expression of genes characteristic of healthy epithelial cells. Importantly, dampening of systemic and tissue inflammation with icotrokinra was sustained at W28 (Figures 1 & 2). Conclusion We show for the first time that blocking the IL-23R can inhibit IL-23-mediated inflammatory signaling in UC patients. Icotrokinra treatment induced a sustained (W28) reduction in systemic and tissue biomarkers of inflammatory burden in UC. Furthermore, icotrokinra induced transcriptional changes that are consistent with dampening of IL-23–driven inflammation and normalization of the tissue transcriptome. While all once-daily doses of icotrokinra attenuated systemic and tissue inflammation, greater reduction of systemic inflammatory burden was observed with the 200 mg and 400 mg doses of icotrokinra. References: 1. Abreu MT, et al. United European Gastroenterol J. 2025 10;13(suppl 8):172-3. 2. Jairath V, et al. Am J Gastroenterol. 2025 120;10(suppl 2):S312. Conflict of interest: Louis, Edouard: Education and Research Grants for my department: Abbvie, Takeda, Janssen, Pfizer, Fresenius-Kabi, Celltrion, EG pharma, Sandoz, Falk Personal Fees for conferences, advisory boards and consultancy: Abbvie, Takeda, Ferring, Pfizer, Janssen, Lilly, Galapagos, Celltrion, Arena, BMS, Falk, Biokuris, Fresenius-Kabi, Thabor Jairath, Vipul: Consulting fees from AbbVie, Alimentiv, Amgen, Anaptys Bio, Asahi Kasei, Asieris, Astra Zeneca, Attovia, Blackbird Labs, Bristol Myers Squibb, Boehringer Ingleheim, Biomebank, Caldera, Calluna, Catalytic Health, Celltrion, Ensho, Enthera, Exeliome Biosciences, Ferring, Fresenius Kabi, Gilead, Granite Bio, GSK, Johnson & Johnson, Lilly, Merck, Mountainfield, MRM Health, Nxera, Organon, OSE Immunotherapeutics, Pendopharm, Pioneering Medicine, Pfizer, Prometheus, Roche/Genentech, Sanofi, SCOPE, Shattuck Labs, Sorriso, Spyre, Synedgen, Takeda, Teva, Tillotts, Union Therapeutics, Ventus, Ventyx, Vividion, Xencor, Zealand Pharma. Siegmund, Britta: Consultant for AbbVie, Abivax, Boehringer Ingelheim, Bristol Myers Squibb, Dr. Falk Pharma, Eli Lilly, Endpoint Health, Galapagos, Johnson & Johnson, Materia Prima, MSD, Pfizer, Takeda, Wedbush Securities speaker for AbbVie, AlfaSigma, Bristol Myers Squibb, CED Service GmbH, Dr. Falk Pharma, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MD Education, MSD, Pfizer, Tr1xBio grant from Pfizer. Kannan, Arun K: Employee and shareholder of Johnson & Johnson Zeeman, Martha: Employee and shareholder of Johnson & Johnson Hart, Amy: Employee and shareholder of Johnson & Johnson Strawn, David: Employee and shareholder of Johnson & Johnson Venkat, Swati: Employee and shareholder of Johnson & Johnson Tomsho, Lynn: Employee and shareholder of Johnson & Johnson Mcrae, Bradford: Employee and shareholder of Johnson & Johnson Ruane, Darren: Employee and shareholder of Johnson & Johnson Surace, Lindsey: Employee and shareholder of Johnson & Johnson Erondu, Ngozi: Employee and shareholder of Johnson & Johnson Zhan, Joyce: Employee and shareholder of Johnson & Johnson Chen, Minhu: I have received speaker honoraria from Takeda China, Xian Janssen, and AbbVie China, as well as research funding from Takeda (China). Chachu, Karen: Advisory board for Johnson & Johnson consultant for OptumRx Matsuoka, Katsuyoshi: Grant: Abbvie Inc., Mochida Pharmaceutical Co., Ltd., ZERIA Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., JIMRO Co., Ltd. Personal Fees: Mitsubishi Tanabe Pharma, Janssen Pharmaceutical K.K., Abbvie Inc., EA Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., ZERIA Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc., Kyorin Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Kissei Pharmaceutical Co., Ltd., Gilead Sciences, Celltrion Healthcare, Bristol-Myers Squibb Limdi, Jimmy: Speaker/consultancy fees from AbbVie, Abivax, Arena, BioHit, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Galapagos, Johnson & Johnson, MSD, Pfizer, Takeda research support from Galapagos, Takeda Rydzewska, Grazyna: Speaker and consultant fees from AbbVie, AlfaSigma, AstraZeneca, Bayer, Biocodex, Bristol Myers Squibb, Ferring, Johnson & Johnson, Lilly, PRO.MED.Pl, Recordati, Sanprobi, SOBI, Takeda travel/accommodation meeting expenses from AbbVie, Ferring, Takeda Abreu, Maria Teresa: Grant/Research Support: Janssen, Prometheus Bioscience, Takeda Consultant: Janssen, Prometheus Bioscience, Takeda Gilead, Eli Lilly, AbbVie Inc., Bristol Myers, Imedex, Loftus Jr, Edward V: Consultant/advisory board member for AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly and Company, Genentech, Gilead Sciences, Johnson & Johnson, Pfizer, Takeda, UCB.