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Macitentan is a dual endothelin receptor antagonist (ERA) approved for treating pulmonary arterial hypertension (PAH). SOPRANO evaluated the efficacy and safety of macitentan versus placebo in pulmonary hypertension (PH) patients after left ventricular assist device (LVAD) implantation. SOPRANO was a phase 2, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients with an LVAD implanted within the prior 90 days who had persistent PH (i.e., mean pulmonary arterial pressure ≥25 mmHg, pulmonary artery wedge pressure [PAWP] ≤18 mmHg, and pulmonary vascular resistance [PVR] >3 Wood units [WU]) were randomized (1:1) to macitentan 10 mg or placebo once daily for 12 weeks. The primary endpoint was change in PVR. Secondary endpoints included change in right-heart catheterization hemodynamic variables, N-terminal prohormone of brain natriuretic peptide levels, World Health Organization functional class, and safety/tolerability. Fifty-seven patients were randomized to macitentan ( n  = 28) or placebo ( n  = 29). A statistically significant reduction in PVR from baseline to Week 12 was observed with macitentan versus placebo (placebo-corrected geometric mean ratio, 0.74; 95% confidence interval, 0.58-0.94; p  = .0158). No statistically significant differences were observed in secondary endpoints. In a post-hoc analysis, 66.7% of patients receiving macitentan achieved PVR <3 WU versus 40.0% receiving placebo ( p  = .0383). Macitentan was generally well tolerated; adverse events were consistent with those in previous PAH studies with macitentan. In conclusion, macitentan showed promising tolerability and significantly reduced PVR in PH patients with persistently elevated PVR after LVAD implantation. ClinicalTrials. gov identifier: NCT02554903., Competing Interests: Robert P. Frantz is receiving grants and research support from United Therapeutics, Medtronic, and Gossamer Bio, and is scientific medical advisor to Altavant, ShouTi, Liquidia Corporation, Merck, Tenax Therapeutics, and Janssen Pharmaceutical Companies of Johnson & Johnson. His institution has received funding from Bayer and Gossamer Bio. Shashank S. Desai has served on the speakers’ bureau for Abbott. Gregory Ewald is on the speakers’ bureau and is a consultant with Abbott. Veronica Franco's institution receives research support from Acceleron/Merck, Gossamer, Janssen, United Therapeutics, Aerovate Therapeutics, Respira, and Cereno Scientific. Antoine Hage is receiving grants and research support from United Therapeutics, Lung LLC, Arena, Reata, and Bayer, and is a stockholder in Johnson & Johnson and Pfizer. Evelyn M. Horn's institution has received funding from Gossamer, Acceleron/Merck, Abbott, and Cereno Scientific. Stacy Mandras is a speaker and consultant for United Therapeutics and Bayer Pharmaceuticals. Myung H. Park is a scientific medical advisor with AstraZeneca. Ashwin K. Ravichandran is consulting/speaking for Abbott, Medtronic and speaking for United Therapeutics, Janssen, and Bayer; he personally receives no grants from these companies, but his institution does. Ronald Zolty is a consultant for Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, United Therapeutics, and Alnylam. Mark A. Rocco, Mona Selej, and Carol Zhao were employees of Actelion Pharmaceuticals US, Inc., South San Francisco, CA (at the time of manuscript development) and are current stockholders of Johnson & Johnson. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 Actelion Pharmaceuticals US, Inc. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Hemocompatibility-related adverse events affect patients after left ventricular assist device (LVAD) implantation but are hard to predict., Objectives: Dynamic risk modeling with a multistate model can predict risk of gastrointestinal bleeding (GIB), stroke, or death in ambulatory patients., Methods: This was a secondary analysis of the MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial. HeartMate 3 LVAD recipients who survived to hospital discharge and were followed for up to 2 years. A total of 145 variables were included in the multistate model with multivariate logistic regression. Model performance was assessed with the area under the curve in a holdout validation cohort. A risk stratification tool was created by dividing patients into categories of predicted risk using the final model variables and associated OR., Results: Among 2,056 LVAD patients, the median age was 59.4 years (20.4% women, 28.6% Black). At 2 years, the incidence of GIB, stroke, and death was 25.6%, 6.0%, and 12.3%, respectively. The multistate model included 39 total variables to predict risk of GIB (16 variables), stroke (10 variables), and death (19 variables). When ambulatory patients were classified according to their risk category, the 30-day observed event rate in the highest risk group for GIB, stroke, or death was 26.9%, 1.8%, and 4.8%, respectively. The multistate model predicted GIB, stroke, and death at any 30-day period with an area under the curve of 0.70, 0.69, and 0.86, respectively., Conclusions: The multistate model informs 30-day risk in ambulatory LVAD recipients and allows recalculation of risk as new patient-specific data become available. The model allows for accurate risk stratification that predicts impending adverse events and may guide clinical decision making. (MOMENTUM 3 IDE Clinical Study Protocol; NCT02224755)., Competing Interests: Funding Support and Author Disclosures Abbott is the sponsor of the MOMENTUM 3 studies. Abbott supported an investigator-initiated grant paid to the Inova Heart and Vascular Institute to support this effort; and Abbott has filed a U.S. provisional patent (U.S. Patent Application No. 63/421,450) for the work presented in the paper. Dr Shah is supported by National Institutes of Health K23 Career Development Award 1K23HL143179; has received consulting fees from Procyrion, Merck, and Natera; and grant support has been paid to his institution from Abbott, Roche, Merck, and Bayer. Dr Sayer has received consulting fees from Abbott. Dr Kanwar is on the medical advisory board for Abiomed, CorWave, and CareDx. Dr Cowger has served as a consultant for Abbott, Medtronic, Bioventrix, Endotronix, Bivacor, and Procyrion; and has received grant support and speaker fees from Abbott. Dr Pagani has served as an AD hoc scientific advisor without compensation for FineHeart, Medtronic, CH Biomedical, and Abbott; has served as medical monitor for Abiomed; is a member of the data safety monitoring board for Carmat and the National Heart, Lung, and Blood Institute PumpKIN clinical trial; and is Chair of the Society of Thoracic Surgeons Intermacs Task Force. Dr Mehra has received travel support and consulting fees, paid to Brigham and Women’s Hospital, from Abbott; has received fees for serving on a steering committee from Medtronic and Janssen (Johnson and Johnson); has received fees for serving on a data and safety monitoring board from Mesoblast; has received consulting fees from Natera, Paragonix, Moderna, Baim Institute of Clinical Research, and Broadview Ventures; and has received fees for serving as a scientific board member from NuPulseCV, Leviticus, and FineHeart. Dr Cleveland has received fees from Abbott and Medtronic. Dr Desai is on the Speakers Bureau for Abbott. Drs Lu, Hu, Connolly, and Kormos are employees of Abbott. Dr Uriel is a medical advisory board member for Livemetric, Levitcus, and Revamp; and receives grant support from Abbott, Abiomed, and Fire 1. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study is to compare 30-day perioperative outcomes following treatment of intertrochanteric (IT) fractures with intramedullary nail (IMN), total hip arthroplasty (THA), or hemiarthroplasty (HA)., Methods: Using the National Surgical Quality Improvement Program database, we conducted a retrospective cohort study of patients who had sustained an IT fracture treated with primary IMN, THA, or HA between 2017 and 2020. International Classification of Diseases, 10th Revision codes S72.141-S72.146, subtypes A through C, were used to identify eligible patients and were cross-referenced to primary Current Procedural Terminology codes, used to identify the following procedure types: 27245: IMN; 27130: THA; and 27236: HA. Revision cases and patients who underwent arthroplasty for osteoarthritis were excluded. Outcomes of interest included reoperation, readmission, operative time, length of stay, and major and minor complications. Multivariate regression was used to evaluate differences in postoperative outcomes between groups., Results: There were 29,809 IT fractures treated with IMN (94.6%), 1493 treated with HA (4.7%), and 217 treated with THA (0.70%). There was a statistically significant increase in 30-day reoperation rates (adjusted odds ratio [aOR] = 1.99 [95% confidence interval = 1.51, 2.63], P < .001) when combining all arthroplasty patients compared to IMN. There was no statistically significant difference in the overall complication rate between IMN (13.58%) and HA (14.60%, aOR = 1.09, P  = .315) or THA (11.98%, aOR = 1.00, P  = .998). When compared to IMN (0.12%), there was a statistically significantly decreased need for transfusion in the HA group (aOR = 0.71 [95% confidence interval = 0.61, 0.80], P < .001)., Conclusions: Primary HA is associated with an increased 30-day reoperation rate and decreased need for blood transfusion, but there were no other significant differences in postoperative morbidity identified among IMN, THA, and HA in the treatment of IT fractures. Given the challenges and inferior outcomes associated with conversion arthroplasty, the lack of significant difference in morbidity between the 3 groups suggests that primary arthroplasty may be a safe and viable treatment option in selected patients with IT fractures. Comparative studies with longer clinical follow-up will be necessary to establish the appropriate indications and further evaluate the clinical outcomes of primary arthroplasty in the treatment of IT fractures., (© 2024 The Authors.)

The process of Ag receptor diversity is initiated by RAGs consisting of RAG1 and RAG2 in developing lymphocytes. Besides its role as a sequence-specific nuclease during V(D)J recombination, RAGs can also act as a structure-specific nuclease leading to genome instability. Thus, regulation of RAG expression is essential to maintaining genome stability. Previously, the role of miR29c in the regulation of RAG1 was identified. In this article, we report the regulation of RAG1 by miR-29a in the lymphocytes of both mice (Mus musculus) and humans (Homo sapiens). The level of RAG1 could be modulated by overexpression of miR-29a and inhibition using anti-miRs. Argonaute2-immunoprecipitation and high-throughput sequencing of RNA isolated by crosslinking immunoprecipitation studies established the association of miR-29a and RAG1 with Argonaute proteins. We observed a negative correlation between miR-29a and RAG1 levels in mouse B and T cells and leukemia patients. Overexpression of pre-miR-29a in the bone marrow cells of mice led to the generation of mature miR-29a transcripts and reduced RAG1 expression, which led to a significant reduction in V(D)J recombination in pro-B cells. Importantly, our studies are consistent with the phenotype reported in miR-29a knockout mice, which showed impaired immunity and survival defects. Finally, we show that although both miR-29c and miR-29a can regulate RAG1 at mRNA and protein levels, miR-29a substantially impacts immunity and survival. Our results reveal that the repression of RAG1 activity by miR-29a in B cells of mice and humans is essential to maintain Ig diversity and prevent hematological malignancies resulting from aberrant RAG1 expression in lymphocytes., (Copyright © 2024 by The American Association of Immunologists, Inc.)

Aims: Despite significant morbidity and mortality, recent advances in cardiogenic shock (CS) management have been associated with increased survival. However, little is known regarding the management of patients who survive CS with heart failure (HF) with reduced left ventricular ejection fraction (LVEF, HFrEF), and the utilization of guideline-directed medical therapy (GDMT) in these patients has not been well described. To fill this gap, we investigated the use of GDMT during an admission for CS and short-term outcomes using the Inova single-centre shock registry., Methods: We investigated the implementation of GDMT for patients who survived an admission for CS with HFrEF using data from our single-centre shock registry from January 2017 to December 2019. Baseline characteristics, discharge clinical status, data on GDMT utilization and 30 day, 6 month and 12 month patient outcomes were collected by retrospective chart review., Results: Among 520 patients hospitalized for CS during the study period, 185 (35.6%) had HFrEF upon survival to discharge. The median age was 64 years [interquartile range (IQR) 56, 70], 72% (n = 133) were male, 22% (n = 40) were Black and 7% (n = 12) were Hispanic. Forty-one per cent of patients (n = 76) presented with shock related to acute myocardial infarction (AMI), while 59% (n = 109) had HF-related CS (HF-CS). The median length of hospital stay was 12 days (IQR 7, 18). At discharge, the proportions of patients on beta-blockers, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs)/angiotensin receptor/neprilysin inhibitors (ARNIs) and mineralocorticoid receptor antagonists (MRAs) were 78% (n = 144), 58% (n = 107) and 55% (n = 101), respectively. Utilization of three-drug GDMT was 33.0% (n = 61). Ten per cent of CS survivors with HFrEF (n = 19) were not prescribed any component of GDMT at discharge. Multivariable logistic regression adjusted for baseline GDMT use revealed that patients with lower LVEF and those who transferred to our centre from an outside hospital were more likely to experience GDMT addition (P < 0.05). Patients prescribed at least one additional class of GDMT during admission had higher odds of 6 month and 1 year survival (P < 0.01): On average, 6 month survival odds were 7.1 times greater [confidence interval (CI) 1.9, 28.5] and 1 year survival odds were 6.0 times greater than those who did not have at least one GDMT added (CI 1.9, 20.5)., Conclusions: Most patients who survived CS admission with HFrEF in this single-centre CS registry were not prescribed all classes or goal doses of GDMT at hospital discharge. These findings highlight an urgent need to augment multidisciplinary efforts to enhance the post-discharge medical management and outcomes of patients who survive CS with HFrEF., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Purpose: To systematically review the literature regarding the biomechanical properties of different repair techniques and fixation methods for vertically oriented meniscal tears., Methods: Human cadaveric studies evaluating the biomechanical properties of different repair techniques for vertically oriented meniscal tears were identified using the PubMed, EMBASE, and Cumulative Index to Nursing & Allied Health databases. Primary outcomes included load to failure, displacement, stiffness, peak contact pressure, and contact area of repaired menisci. Repair techniques from included studies were reclassified into a total of 19 distinct all-inside (AI), inside-out (IO), or outside-in (OI) techniques., Results: Sixteen studies were included (420 total menisci). Contact pressure and area were restored to intact-state values across all 5 compressive load studies at low knee flexion angles but not at greater knee flexion angles (i.e., >60°). There were no significant differences in contact pressure or area between AI, IO, and OI techniques across all studies. Some studies demonstrated statistically significant advantages in tensile properties with IO techniques when compared with AI techniques, whereas others found AI techniques to be superior. No studies directly compared tensile properties of OI techniques with those of AI or IO techniques. Vertical mattress suture configurations resulted in significantly greater load to failure and decreased displacement compared with horizontal mattress configurations in 67% of studies comparing the 2 techniques. There was no difference in the rate of tissue failure in AI (66.97%), IO (60.38%), or OI (66.67%, χ 2  = 0.83, P = .66) techniques., Conclusions: Contact mechanics are reliably restored after repair of vertical meniscal tears at low flexion angles but inconsistently restored at greater flexion angles, regardless of technique. Vertical mattress configurations outperformed horizontal mattress configurations under tensile load. There are conflicting data regarding the comparison of tensile properties between AI and IO techniques. Ultimately, neither AI, IO, nor OI repair demonstrated superior biomechanical properties in the present literature., Clinical Relevance: Several repair techniques demonstrate favorable biomechanical properties for vertical meniscal tears under tensile and compressive loads. Neither AI, IO, nor OI repair techniques demonstrate superior biomechanical properties at this time., Competing Interests: Disclosures The authors report the following potential conflicts of interest or sources of funding: J.C. reports other from the American Orthopaedic Society for Sports Medicine, AANA, and International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine; personal fees from Arthrex, Conmed Linvatec, Ossur, and Smith & Nephew, outside the submitted work. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Full ICMJE author disclosure forms are available for this article online, as supplementary material., (Copyright © 2024 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Background: Although internal medicine (IM) physicians accept public advocacy as a professional responsibility, there is little evidence that IM training programs teach advocacy skills. The prevalence and characteristics of public advocacy curricula in US IM residency programs are unknown., Objectives: To describe the prevalence and characteristics of curricula in US IM residencies addressing public advocacy for communities and populations; to describe barriers to the provision of such curricula., Design: Nationally representative, web-based, cross-sectional survey of IM residency program directors with membership in an academic professional association., Participants: A total of 276 IM residency program directors (61%) responded between August and December 2022., Main Measurements: Percentage of US IM residency programs that teach advocacy curricula; characteristics of advocacy curricula; perceptions of barriers to teaching advocacy., Key Results: More than half of respondents reported that their programs offer no advocacy curricula (148/276, 53.6%). Ninety-five programs (95/276, 34.4%) reported required advocacy curricula; 33 programs (33/276, 12%) provided curricula as elective only. The content, structure, and teaching methods of advocacy curricula in IM programs were heterogeneous; experiential learning in required curricula was low (23/95, 24.2%) compared to that in elective curricula (51/65, 78.5%). The most highly reported barriers to implementing or improving upon advocacy curricula (multiple responses allowed) were lack of faculty expertise in advocacy (200/276, 72%), inadequate faculty time (190/276, 69%), and limited curricular flexibility (148/276, 54%)., Conclusion: Over half of US IM residency programs offer no formal training in public advocacy skills and many reported lack of faculty expertise in public advocacy as a barrier. These findings suggest many IM residents are not taught how to advocate for communities and populations. Further, less than one-quarter of required curricula in public advocacy involves experiential learning., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Objective: The study aimed to characterize the experiences of primary caregivers of children with medical complexity (CMC) in engaging with other members of the child's caregiving network, thereby informing the design of health information technology (IT) for the caregiving network. Caregiving networks include friends, family, community members, and other trusted individuals who provide resources, information, health, or childcare., Materials and Methods: We performed a secondary analysis of two qualitative studies. Primary studies conducted semi-structured interviews (n = 50) with family caregivers of CMC. Interviews were held in the Midwest (n = 30) and the mid-Atlantic region (n = 20). Interviews were transcribed verbatim for thematic analysis. Emergent themes were mapped to implications for the design of future health IT., Results: Thematic analysis identified 8 themes characterizing a wide range of primary caregivers' experiences in constructing, managing, and ensuring high-quality care delivery across the caregiving network., Discussion: Findings evidence a critical need to create flexible and customizable tools designed to support hiring/training processes, coordinating daily care across the caregiving network, communicating changing needs and care updates across the caregiving network, and creating contingency plans for instances where caregivers are unavailable to provide care to the CMC. Informaticists should additionally design accessible platforms that allow primary caregivers to connect with and learn from other caregivers while minimizing exposure to sensitive or emotional content as indicated by the user., Conclusion: This article contributes to the design of health IT for CMC caregiving networks by uncovering previously underrecognized needs and experiences of CMC primary caregivers and drawing direct connections to design implications., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cardiogenic shock (CS) is a time-sensitive and hemodynamically complex syndrome with a broad spectrum of etiologies and clinical presentations. Despite contemporary therapies, CS continues to maintain high morbidity and mortality ranging from 35 to 50%. More recently, burgeoning observational research in this field aimed at enhancing the early recognition and characterization of the shock state through standardized team-based protocols, comprehensive hemodynamic profiling, and tailored and selective utilization of temporary mechanical circulatory support devices has been associated with improved outcomes. In this narrative review, we discuss the pathophysiology of CS, novel phenotypes, evolving definitions and staging systems, currently available pharmacologic and device-based therapies, standardized, team-based management protocols, and regionalized systems-of-care aimed at improving shock outcomes. We also explore opportunities for fertile investigation through randomized and non-randomized studies to address the prevailing knowledge gaps that will be critical to improving long-term outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor LC declared a past co-authorship with the authors CR, SD, MP., (© 2024 Mehta, Vavilin, Nguyen, Batchelor, Blumer, Cilia, Dewanjee, Desai, Desai, Flanagan, Isseh, Kennedy, Klein, Moukhachen, Psotka, Raja, Rosner, Shah, Tang, Truesdell, Tehrani and Sinha.)

One of the primary reasons behind the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL) is the deregulation of the transcription factor BCL11B . The exon 4 of BCL11B harbors several driver mutations, which abolishes its DNA-binding ability. The high frequency of C > T or G > A conversion in close vicinity of AID (Activation-induced cytidine deaminase)-hotspot motifs in the deregulated gene prompted us to investigate the role of AID in BCL11B mutagenesis. Our results reveal that AID is expressed in T-ALL patient-derived cells, binds to BCL11B fragile region (FR) in exon 4 of T cells in vivo, and generates a signature mutation pattern in this region. The mutation frequency in BCL11B FR could be modulated upon overexpression of the AID gene in the knockout background, further suggesting the involvement of AID in BCL11B mutagenesis. Importantly, various lines of experimentation reveal that BCL11B FR could fold into parallel G-quadruplex, triplex, and hairpin structures, which could act as a replication/transcription block, causing mutagenesis. Thus, our results suggest that AID binds to BCL11B exon 4 due to non-B DNA formation, causing U:G mismatches or replication blocks, which, when repaired erroneously, generates deleterious mutations, resulting in loss of functionality of BCL11B , and thus becomes the cause of T-ALL.