Search

Background: Protein-bound solutes are poorly cleared by means of conventional hemodialysis because protein binding limits the "free" solute concentration driving diffusion. This study tested the modeled prediction that clearances of bound solutes could be increased by increasing the dialyzer mass transfer area coefficient (K(o)A) and dialysate flow (Q(d)) to greater than the levels used in conventional practice.Study Design: Pilot crossover trial.Setting& Participants: 6 stable long-term hemodialysis patients.Intervention: Study participants underwent an experimental dialysis treatment in which K(o)A and Q(d) were increased by using 2 dialyzers in series and supplying each dialyzer with a Q(d) of 800 mL/min by using 2 dialysis machines. Experimental clearances were compared with those during a conventional treatment with a single dialyzer and Q(d) of 800 mL/min supplied by 1 machine.Outcomes: Measured clearances of uremic solutes.Measurements: Clearances were measured for urea nitrogen and the bound solutes p-cresol sulfate, indoxyl sulfate, kynurenic acid, and hippurate.Results: Clearances for the bound solutes during conventional treatment were lower than for urea nitrogen (clearance values: urea nitrogen, 255 +/- 16 mL/min; p-cresol sulfate, 23 +/- 4 mL/min; indoxyl sulfate, 30 +/- 7 mL/min; kynurenic acid, 43 +/- 4 mL/min; and hippurate, 115 +/- 11 mL/min). Experimental treatment increased clearances of all solutes (clearance values: urea nitrogen, 318 +/- 19 mL/min; p-cresol sulfate, 37 +/- 6 mL/min; indoxyl sulfate, 46 +/- 8 mL/min; kynurenic acid, 73 +/- 7 mL/min; and hippurate, 165 +/- 17 mL/min). The magnitude of the increases in clearance was greater for bound solutes than for urea nitrogen (increase in clearance: urea nitrogen, 25% +/- 6%; p-cresol sulfate, 66% +/- 19%; indoxyl sulfate, 57% +/- 27%; kynurenic acid, 69% +/- 5%; and hippurate, 44% +/- 15%).Limitations: A longer term study would be required to determine whether increased dialytic clearance of bound solutes leads to a decrease in plasma solute levels.Conclusions: Dialytic clearance of protein-bound solutes can be increased by increasing K(o)A and Q(d) to greater than conventional levels. [ABSTRACT FROM AUTHOR]

Study Design: A comparative study of aggrecanases and aggrecan fragmentation profile in the human intervertebral disc at early and advanced stages of disc degeneration. Objective: To determine differences in the content of the aggrecanases and the profile of aggrecan fragmentation in early and advanced stages of disc degeneration using cadaveric human intervertebral discs. Summary Of Background Data: Aggrecanases and aggrecanase-generated aggrecan fragments have been found in human degenerated discs. However, the association between the grade of disc degeneration and the content of the aggrecanases and the profile of aggrecan fragments has not been well studied. Methods: A total of 108 cadaveric donor spines were assessed by MRI T2 imaging and graded based on the Thompson scale. Twelve donor spines (average age, 63 years), each specifically exhibiting 2 different stages (Grade 2 and Grade 4) of disc degeneration at different disc levels, were included in this study. After harvesting the preselected discs, tissue samples were obtained from the center of the nucleus pulposus (NP) and the middle zone of the anulus fibrosus (AF). The amount of the aggrecanases, specifically ADAMTS-4 and ADAMTS-5, and the pattern of aggrecan fragmentation in the isolated tissues were assessed by western blot using specific antibodies. Results: In both NP and the AF tissues, the amount of ADAMTS-4 detected was higher in disc tissues with a higher level of degeneration (Grade 4) than in Grade 2 disc tissues with a lower level of degeneration. However, the amount of ADAMTS-5 detected did not differ between the 2 disc tissue grades. The aggrecan fragmentation analysis of these samples demonstrated the presence of aggrecanase-mediated fragmentation in both groups; however, there was no apparent difference in the aggrecan fragmentation profile between discs at early and advanced stages of disc degeneration. Conclusion: Aggrecanases are involved in aggrecanolysis at both the early and advanced stages of disc degeneration. The aggrecan fragmentation profile analysis demonstrates the involvement of aggrecanases, as well as that of matrix metalloproteinases and/or cathepsins, during disc degeneration. [ABSTRACT FROM AUTHOR]

Aortic regurgitation (AR) is a common clinical disease associated with significant morbidity and mortality. Investigations based largely on non-invasive imaging are pivotal in discerning the severity of disease and its impact on the heart. Advances in technology have contributed to improved risk stratification and to our understanding of the pathophysiology of AR. Surgical aortic valve replacement is the predominant treatment. However, its use is limited to patients with an acceptable surgical risk profile. Transcatheter aortic valve implantation is an alternative treatment. However, this therapy remains in its infancy, and further data and experience are required. This review article on AR describes its prevalence, mechanisms, diagnosis and treatment.

Aim: The current study investigated the prospective relationships between parental monitoring, family conflict, and screen time across six screen time modalities in early adolescents in the USA., Methods: We utilised prospective cohort data of children (ages 10-14 years) from the Adolescent Brain Cognitive Development (ABCD) Study (years baseline to Year 2 of follow-up; 2016-2020; N = 10 757). Adjusted coefficients (B) and 95% confidence intervals (CIs) were estimated using mixed-effect models with robust standard errors., Results: A higher parental monitoring score was associated with less total screen time (B = -0.37, 95% CI -0.58, -0.16), with the strongest associations being with video games and YouTube videos. Conversely, a higher family conflict score was associated with more total screen time (B = 0.08, 95% CI 0.03, 0.12), with the strongest associations being with YouTube videos, video games, and watching television shows/movies in Years 1 and 2., Conclusion: The current study found that greater parental monitoring was associated with less screen time, while greater family conflict was linked to more screen time. These results may inform strategies to reduce screen time in adolescence, such as improving communication between parents and their children to strengthen family relationships., (© 2024 The Author(s). Acta Paediatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica.)

Background: KIT p.D816 mutation is strongly associated with systemic mastocytosis (SM). Next-generation sequencing (NGS) is now routinely performed in almost all bone marrow sample and KIT mutations are detected from patients who are not known or suspected to have SM. Therefore, we wanted to assess if KIT mutations in this patient population are associated with unsuspected SM., Methods: We searched NGS result in our institution with positive result for KIT mutation from patients with known/suspected myeloid neoplasms. Patients with previously documented history of systemic mastocytosis were excluded. Bone marrow biopsies from patients with KIT mutation were assessed with immunohistochemical stains for CD117 and mast cell tryptase (MST)., Results: Bone marrow biopsies were assessed with immunohistochemical stains for CD117 and mast cell tryptase (n = 49). Most patients had acute myeloid leukemia (AML, n = 38) or chronic myelomonocytic leukemia (CMML, n = 6). Immunohistochemical stains for CD117 and tryptase were performed in all 49 patients. A total of 4 patients (8.2%) showed mast cell nodules where spindled shaped mast cells were present, meeting the WHO criteria for SM. All four patients had KIT p.D816V mutation and had high mutant allelic frequency (∼ 50%) except one patient (1%)., Conclusion: We discovered approximately 8% of patients who had myeloid neoplasms with unexpected KIT mutations fulfilled the diagnostic criteria for systemic mastocytosis after additional immunohistochemical studies. Our data support that application of additional immunohistochemical studies is recommended to identify underrecognized SM when KIT mutations are found by molecular assays., Competing Interests: Disclosure CYO has received research funding from Blueprint Medicines., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Severe pure aortic regurgitation (AR) carries a high mortality and morbidity risk, and it is often undertreated because of the inherent surgical risk. Transcatheter heart valves (THVs) have been used off-label in this setting with overall suboptimal results. The dedicated "purpose-built" Jena Valve Trilogy (JVT, JenaValve Technology) showed an encouraging performance, although it has never been compared to other THVs., Objectives: The aim of our study was to assess the performance of the latest iteration of THVs used off-label in comparison to the purpose-built JVT in inoperable patients with severe AR., Methods: We performed a multicenter, retrospective registry with 18 participating centers worldwide collecting data on inoperable patients with severe AR of the native valve. A bicuspid aortic valve was the main exclusion criterion. The primary endpoints were technical and device success, 1-year all-cause mortality, and the composite of 1-year mortality and the heart failure rehospitalization rate., Results: Overall, 256 patients were enrolled. THVs used off-label were used in 168 cases (66%), whereas JVT was used in 88 (34%). JVT had higher technical (81% vs 98%; P < 0.001) and device success rates (73% vs 95%; P < 0.001), primarily driven by significantly lower incidences of THV embolization (15% vs 1.1%; P < 0.001), the need for a second valve (11% vs 1.1%; P = 0.004), and moderate residual AR (10% vs 1.1%; P = 0.007). The permanent pacemaker implantation rate was comparable and elevated for both groups (22% vs 24%; P = 0.70). Finally, no significant difference was observed at the 1-year follow-up in terms of mortality (HR: 0.99; P = 0.980) and the composite endpoint (HR: 1.5; P = 0.355)., Conclusions: The JVT platform has a better acute performance than other THVs when used off-label for inoperable patients with severe AR. A longer follow-up is conceivably needed to detect a possible impact on prognosis., Competing Interests: Funding Support and Author Disclosures This study has been performed at IRCCS Policlinico San Donato, a clinical research hospital partially funded by the Italian Ministry of Health. Dr Adam has received grants and personal fees from Medtronic; and has received personal fees from JenaValve, Edwards Lifesciences, and Boston Scientific. Dr Wienemann has received travel grants from JenaValve. Dr Panoulas has received consultancy fees for Medtronic; and has served as a proctor for Medtronic. Dr Taramasso has received consultancy fees from Abbott, Edwards Lifescience, Medtronic, Boston Scientific, Shenqi Medical, PiCardia, CoreMedic, CoreQuest, MEDIRA, Simulands, and VentriMend; and serves on the Advisory Boards for Abbott and HiD Imaging. Dr Baldus has received lecture fees from JenaValve; and has received lecture and speaker fees from Edwards Lifesciences. Dr Baumbach has received speaker/consultant fees from Medtronic, Biotronik, Meril, Sinomed, and Microport; and is a proctor for JenaValve. Dr Rudolph has received consultancy fees/speaker honoraria from Abbott, JenaValve, Edwards Lifesciences, and Medtronic. Dr Testa is a proctor/consultant for Abbott, Medtronic, Boston Scientific, and Meril; and has received speaker honoraria from Abbott, Medtronic, Boston Scientific, and Meril., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

We present 2 diagnostically challenging cases of pediatric/adolescent relapsed/refractory aggressive mature B-cell non-Hodgkin lymphoma (B-NHL) within the spectrum of Burkitt lymphoma and diffuse large B-cell lymphoma and illustrate the different therapeutic regimens that are employed for pediatric and adult cancer centers. Both cases displayed varying-sized lymphoma cells with occasional single prominent nucleoli and heterogeneous BCL2 expression. Cytogenetics revealed complex karyotypes with t(8:14)(q24.2;q32) and IGH::MYC rearrangement by FISH. Next generation sequencing revealed deleterious TP53 and MYC mutations. We concluded that both could be diagnosed as "DLBCL-NOS with MYC rearrangement" using the current pathologic classifications, 2022 International Consensus Classification (ICC) and World Health Organization Classifications of Haematolymphoid Tumors (WHO-HAEM5). This report illustrates diagnostic challenges and treatment dilemmas that may be encountered, particularly for adolescent and young adults (AYA)., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Aortic Stenosis (AS) is a common syndrome in older adults wherein the narrowing of the aortic valve impedes blood flow, resulting in advanced heart failure. 1 AS is associated with a high mortality rate (50 % at 6 months if left untreated), substantial symptom burden, and reduced quality of life. 1-3 Transcatheter aortic valve replacement (TAVR) was approved in 2012 as a less invasive alternative to surgical valve repair, offering a treatment for older frail patients. Although objective outcomes have been widely reported, 4 the perspectives of older adults undergoing the TAVR process have never been synthesized., Objectives: To contextualize the perspectives and experiences of older adults undergoing TAVR., Methods: An integrative review was conducted using Whittemore and Knafl's five-stage methodology. 5 Four electronic databases were searched in April 2023. Articles were included if a qualitative methodology was used to assess the perceptions of older adults (>65 years old) undergoing or recovering from TAVR., Results: Out of 4619 articles screened, 12 articles met the criteria, representing 353 individuals from 10 countries. Relevant themes included the need for an individualized care plan, caregiver and family support, communication and education, persistent psychosocial and physical symptoms, and the unique recovery journey., Conclusion: Older adults with AS undergoing TAVR generally perceive their procedure positively. Improved interdisciplinary and holistic management, open communication, symptom assessment, support, and education is needed., Competing Interests: Declaration of competing interest None., (Published by Elsevier Inc.)

Background: The outcome of patients with acute promyelocytic leukemia (APL) has improved significantly since the introduction of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) as APL therapies. The optimal therapy for APL relapse is believed to require autologous or allogeneic stem cell transplantation (SCT) based on historical experience., Study Aims: To evaluate the outcome of patients with relapsed APL before and after the era of ATRA-ATO., Patients and Methods: We reviewed 61 patients with relapsed APL treated from November 1991 to June 2023; 31 patients (51%) received modern therapy with the combination of ATRA and ATO with and without idarubicin and gemtuzumab ozogamicin (GO)., Results: Overall, 56 patients (92%) achieved CR after the first salvage therapy; 20 patients received SCT (10 autologous SCT;10 allogeneic SCT). With a median follow-up time of 138 months, the median survival durations were 32 months and 164 months with historical therapy vs. modern (ATRA-ATO) therapy (P = .035); the 5-year survival rates were 44% vs. 71%. With a 10-month landmark analysis, the median survival durations were 102 months vs. not reached, and the 5-year survival rates were 57% and 70% without SCT vs. with SCT (P = .193). The survival benefit with SCT was more prominent in the historical therapy era. However, patients who received the modern combination therapy of ATRA-ATO with and without idarubicin and GO had similar outcomes without vs. with SCT (P = .848)., Conclusion: The combination of ATRA-ATO (+/- GO and idarubicin) is a highly effective salvage therapy in relapsed APL. The use of SCT may not be needed after first relapse-second remission but may be considered in subsequent relapses., Competing Interests: Disclosure Koji Sasaki reports personal fees from Otsuka and Pfizer, outside the submitted work; research funding from Novartis; advisory boards from Novartis. Farhad Ravandi reports research funding from Amgen, Cyclacel LTD, Macrogenix, Menarini Ricerche, Selvita, and Xencor; and personal fees from Amgen, Macrogenix, and Xencor, all outside the submitted work. Guillermo Garcia-Manero reports grants or research support from Amphivena, Helsinn, Novartis, AbbVie, Bristol-Myers Squibb, Astex, Onconova, H3 Biomedicine, Merck, Curis, Janssen, Genentech, Forty Seven, and Aprea; and personal fees from Bristol-Myers Squibb, Astex, Helsinn, and Genentech outside the submitted work. Tapan Kadia reports research Funding from AbbVie, Amgen, BioLine Rx, Bristol‐Myers Squibb, Celgene, Jazz, and Pfizer; and personal fees from AbbVie, Amgen, Genentech, Jazz, Pfizer, Pharmacyclics, and Takeda, all outside the submitted work. Courtney DiNardo reports personal fees and honoraria from AbbVie, Agios, Celgene, Daiichi Sankyo, Jazz, Medimmune, and Syros, all outside the submitted work. Musa Yilmaz reports research funding from Pfizer and Daiichi-Sankyo. Nicholas Short reports research funding from Takeda Oncology; and personal fees from Amgen, AstraZeneca, and Takeda Oncology, all outside the submitted work. Gautam Borthakur reports research funding from AbbVie, Agensys, Arvinas, AstraZeneca, Bayer Healthcare AG, BioLine Rx, Bristol‐Myers Squibb, Cantargia AB, Cyclacel, Eli Lilly and Company, Esai, GlaxoSmithKline, Incyte, Merck, Novartix, Oncoceutics, Polaris, Tetralogic Pharmaceuticals, and XBiotech USA; and personal fees from Argenx, BioLine Rx, BioTheryX, FTC Therapeutics, NKarta, Strategia Therapeutics, and TPC Therapeutics, all outside the submitted work. Hagop Kantarjian reports research grants and honoraria from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis, Pfizer and Sanofi; honoraria from Actinium (Advisory Board), Adaptive Biotechnologies, Aptitude Health, BioAscend, Delta Fly, Janssen Global, Oxford Biomedical and Takeda Oncology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The purpose of this article was to analyze the concept of "the fighter in the intensive care unit (ICU)" per the scientific literature and the impact this mentality has on care administered in the ICU. A literature review and a concept analysis based on Rodger's evolutionary method were performed to identify surrogate terms, antecedents, attributes, and consequences pertaining to the "fighter" in the ICU. Thirteen articles with a focus on "the fighter" were included in this analysis. There is a strong desire to remain optimistic and maintain high spirits as a coping mechanism in the face of extreme prognostic uncertainty. Themes that emerged from the literature were the need to find inner strength and persist in the face of adversity. The concept of "the fighter in the ICU" can serve as either adaptive or maladaptive coping, depending on the larger clinical picture. Patient experiences in the ICU are fraught with physical and psychological distress. How the patient and family unit cope during this anxiety-provoking time is based on the individual. Maintaining optimism and identifying as a fighter can be healthy ways to adapt to the circumstances. This concept analysis highlights the importance of holistic care and instilling hope particularly as patients may be nearing the end of life., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 by The Hospice and Palliative Nurses Association. All rights reserved.)

Background: Social determinants of health (SDOH) may influence the clinical management of patients with heart failure. Further research is warranted on the relationship between SDOH and Ventricular Assist Device (VAD) therapy for heart failure., Objectives: The purpose of this integrative review was to synthesize the state of knowledge on the intersection of SDOH with VAD therapy., Methods: Guided by Whittemore and Knafl's methodology, this literature search captured three concepts of interest including VAD therapy, SDOH, and their domains of intersection with patient selection, decision-making, treatment outcome, and resource allocation. CINAHL, Embase, PsycINFO, PubMed, and Web of Science were searched in March 2023. Articles were included if they were peer-reviewed publications in English, published between 2006 and 2023, conducted in the United States, and examined VAD therapy in the context of adult patients (age ≥ 18 years)., Results: 22 quantitative studies meeting the inclusion criteria informed the conceptualization of SDOH using the Healthy People 2030 framework. Four themes captured how the identified SDOH intersected with different processes relating to VAD therapy: patient decision-making, healthcare access and resource allocation, patient selection, and treatment outcomes. Most studies addressed the intersection of SDOH with healthcare access and treatment outcomes., Conclusion: This review highlights substantial gaps in understanding how SDOH intersect with patient and patient selection for VAD. More research using mixed methods designs is warranted. On an institutional level, addressing bias and discrimination may have mitigated health disparities with treatment outcomes, but further research is needed for implementing system-wide change. Standardized assessment of SDOH is recommended throughout clinical practice from patient selection to outpatient VAD care., Competing Interests: Declaration of competing interest The 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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Extracellular volume fraction (ECV) is a marker for myocardial fibrosis and infiltration, can be quantified using cardiac computed tomography (ECV CT ), and has prognostic utility in several diseases. This study aims to map out regional differences in ECV CT to obtain greater insights into the pathophysiological mechanisms of ECV expansion and its clinical implications., Methods: Three prospective cohorts were included: patients with aortic stenosis (AS) and coexisting AS and transthyretin cardiac amyloidosis were referred for a transcatheter aortic valve replacement and had ECG-gated CT angiography and Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy to differentiate between the 2 cohorts. Controls had CT angiography and cardiac magnetic resonance demonstrating no significant coronary artery disease or infarction. Global and regional ECV CT was analyzed, and its association with mortality was assessed for patients with AS., Results: In 199 patients, controls (n=65; 66% male), AS (n=115), and coexisting AS and transthyretin cardiac amyloidosis (n=19) had a global ECV CT of 26.1 (25.0-27.8%) versus 29.1 (27.5-31.1%) versus 37.4 (32.5-46.6%), respectively; P <0.001. Across cohorts, ECV CT was higher at the base (versus apex), the inferoseptum (versus anterolateral wall), and the subendocardium (versus subepicardium); P <0.05 for all. Among patients with AS, epicardial ECV CT , rather than any other regional value or global ECV CT , was the strongest predictor of mortality at a median of 3.9 (max 6.3) years (adjusted hazard ratio, 1.21 [95% CI, 1.08-1.36]; P =0.002)., Conclusions: Regional differences in ECV CT suggest a predilection for fibrosis and amyloid infiltration at the base, subendocardium, inferior wall, and septum more than the anterior and lateral myocardium. ECV CT can predict long-term mortality with the subepicardium demonstrating the strongest discriminatory power., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03029026 and NCT03094143., Competing Interests: Disclosures Dr Treibel is funded by a BHF Intermediate Research Fellowship (FS/19/35/34374). E. Klotz is a consultant for Siemens Healthineers. Drs Moon and Treibel are directly and indirectly supported by the University College London Hospital (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre and Biomedical Research Unit at UCLH and Barts, respectively. Dr Pugliese has received research support from Siemens Healthineers, and acknowledges the support of the National Institute for Health and Care Research Barts Biomedical Research Centre (NIHR203330); a delivery partnership of Barts Health National Health Service (NHS) Trust, Queen Mary University of London, St George’s University Hospitals NHS Foundation Trust, and St George’s University of London. The other authors report no conflicts

Purpose: Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3 -mutated AML., Methods: This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3 -mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3 -mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II)., Results: Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3 -internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3 -ITD measurable residual disease <5 × 10 -5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort., Conclusion: The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3 -mutated AML. Myelosuppression was manageable with mitigative dosing strategies.

Objectives: Grading the severity of moderate mixed aortic stenosis and regurgitation (MAVD) is challenging and the disease poorly understood. Identifying markers of haemodynamic severity will improve risk stratification and potentially guide timely treatment. This study aims to identify prognostic haemodynamic markers in patients with moderate MAVD., Methods: Moderate MAVD was defined as coexisting moderate aortic stenosis (aortic valve area (AVA) 1.0-1.5 cm 2 ) and moderate aortic regurgitation (vena contracta (VC) 0.3-0.6 cm). Consecutive patients diagnosed between 2015 and 2019 were included from a multicentre registry. The primary composite outcome of death or heart failure hospitalisation was evaluated among these patients. Demographics, comorbidities, echocardiography and treatment data were assessed for their prognostic significance., Results: 207 patients with moderate MAVD were included, aged 78 (66-84) years, 56% male sex, AVA 1.2 (1.1-1.4) cm 2 and VC 0.4 (0.4-0.5) cm. Over a follow-up of 3.5 (2.5-4.7) years, the composite outcome was met in 89 patients (43%). Univariable associations with the primary outcome included older age, previous myocardial infarction, previous cerebrovascular event, atrial fibrillation, New York Heart Association >2, worse renal function, tricuspid regurgitation ≥2 and mitral regurgitation ≥2. Markers of biventricular systolic function, cardiac remodelling and transaortic valve haemodynamics demonstrated an inverse association with the primary composite outcome. In multivariable analysis, peak aortic jet velocity (Vmax) was independently and inversely associated with the composite outcome (HR: 0.63, 95% CI 0.43 to 0.93; p=0.021) in an adjusted model along with age (HR: 1.05, 95% CI 1.03 to 1.08; p<0.001), creatinine (HR: 1.002, 95% CI 1.001 to 1.003; p=0.005), previous cerebrovascular event (85% vs 42%; HR: 3.04, 95% CI 1.54 to 5.99; p=0.001) and left ventricular ejection fraction (LVEF) (HR: 0.97, 95% CI 0.95 to 0.99; p=0.007). Patients with Vmax ≤2.8 m/s and LVEF ≤50% (n=27) had the worst outcome compared with the rest of the population (72% vs 41%; HR: 3.87, 95% CI 2.20 to 6.80; p<0.001)., Conclusions: Patients with truly moderate MAVD have a high incidence of death and heart failure hospitalisation (43% at 3.5 (2.5-4.7) years). Within this group, a high-risk group characterised by disproportionately low aortic Vmax (≤2.8 m/s) and adverse remodelling (LVEF ≤50%) have the worst outcomes., Competing Interests: Competing interests: KPP has an unrestricted research grant from Edwards Lifesciences. TAT is directly and indirectly supported by the UCLH and Barts NIHR Biomedical Research Units. MJM has received grants and personal fees from Edwards Lifesciences and personal fees from Abbott Vascular., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ultrafiltration (UF) is a common practice during cardiopulmonary bypass (CPB) where it is used as a blood management strategy to reduce red blood cell (RBC) transfusion, minimize adverse effects of hemodilution, and reduce proinflammatory mediators. However, its clinical utilization has been shown to vary throughout the continents., Purpose: The purpose of this investigation was to assess the distribution of UF use across the United States., Data Collection: Data on UF use during cardiac surgery was obtained from a national (United States) perfusion database for adult cardiac procedures performed from January 2016 through December 2018., Study Sample: Four geographical regions were established: Northeast (NE), South (SO), Midwest (MW) and West (WE). The primary endpoint was the use of UF with secondary endpoints UF volume, CPB and anesthesia asanguineous volumes, intraoperative allogeneic RBC transfusion, nadir hematocrit and urine output (UO). 92,859 adult cardiac cases from 191 hospitals were reviewed., Results: The NE and the WE had similar usages of UF (59.9% and 59.7% respectively), which were higher than the MW and the SO (38.6% and 34.9%, p < .001). When UF was utilized, the median [IQR] volume removed was highest in the NE (1900 [1200-2800]mL), and similar in all other regions (WE 1500 [850-2400 mL, MW 1500 [900-2300]mL and SO 1500 [950-2200]mL, p < .001. Median total UO was lowest in the NE 400 [210,650]mL vs all other regions ( p < .001), and remained so when indexed by patient weight and operative time (NE-0.8 [0.5, 1.3]mL/kg/hour, MW-1.1 [0.7, 1.8] mL/kg/hour, SO-1.3 [0.8, 2.0]mL/kg/hour, WE-1.1 [0.7, 1.3]mL/kg/hour, p < .001. Intraoperative RBC transfusion rate was highest in the SO (21.3%) and WE (20.5%), while similar rates seen in the NE (16.2%) and MW (17.6%), p < .001., Conclusions: Across the United States there is geographic variation on the use of UF. Further research is warranted to investigate why these practice variations exist and to better understand and determine their reasons for use., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

In the Targeted therapy with a localised abluminal coated, low-dose sirolimus-eluting, biodegreadable polymer coronary stent (TARGET; NCT02520180) All Comers trial the biodegradable polymer (BP) sirolimus-eluting FIREHAWK stent was noninferior to the durable polymer (DP) everolimus-eluting XIENCE stent with respect to target lesion failure (TLF) at 1 and 5 years; however, the long-term safety and efficacy in the setting of acute coronary syndromes (ACS) are not known. We sought to assess the long-term outcomes in ACS versus chronic coronary syndromes (CCS) with BP sirolimus-eluting stent (SES) versus DP everolimus-eluting stent (EES). The TARGET AC study was a multicenter, open-label, noninferiority trial of all comer patients randomly allocated 1:1 to BP SES or DP EES (stratified by ST-elevation myocardial infarction and study site). In this predefined substudy, the outcomes were compared based on clinical presentation (ACS vs CCS) and treatment allocation. A total of 1,653 patients were enrolled (728 with ACS and 922 with CCS), with 94% completing the 5-year follow-up. The baseline characteristics were well-matched between the 2 stent types; however, co-morbidities were more prevalent in the CCS than in the ACS population. TLF (15.5% vs 17.7%, p = 0.24), patient-oriented outcomes (32.0% vs 34.4%, p = 0.31), and stent thrombosis (4.1% vs 3.3%, p = 0.40) were similar between patients with ACS and patients with CCS. In the ACS cohort, the outcomes at 5 years for BP SES versus DP EES were similar for TLF (16.0% vs 14.9%, p = 0.70), ischemia-driven target lesion revascularization (5.6% vs 8.3%, p = 0.17), and definite/probable stent thrombosis (2.7% vs 4.6%, p = 0.18). The same was true for the CCS cohort, with 5-year outcomes for BP SES versus DP EES for TLF (18.0% vs 17.4%, p = 0.82), ischemia-driven target lesion revascularization (6.4% vs 5.0%, p = 0.37), and definite/probable stent thrombosis (3.0% vs 1.8%, p = 0.26). In conclusion, in the TARGET AC trial, 1 in 3 patients had a major adverse event at 5 years, irrespective of CCS or ACS presentation. Long-term, the BP sirolimus-eluting FIREHAWK stent was as safe and effective as the DP everolimus-eluting XIENCE stent across the spectrum of clinical presentations., Competing Interests: Declaration of competing interest Dr. Lansky has received research grants from MicroPort, Sinomed, Abbott Vascular, and Abiomed-Johnson & Johnson and speaker fees from MicroPort and Shockwave Medical. Dr. van Royen has received speaker fees from Abbott Vascular, MicroPort, RainMed, and Bayer and research grants from Abbott, Biotronik, Philips, and Medtronic. Dr. Johnson has received research grants from Abbott Vascular and speaker fees from Abbott Vascular, Boston Scientific, MicroPort, Shockwave Medical, and Terumo. Dr. Anderson has received speaker fees from Shockwave Medical. Dr. Wijns has received research grants from MicroPort and is the co-founder of Argonauts Partners, an innovation facilitator. Dr. Baumbach has received research support from Abbott Vascular and speaker fees from Abbott Vascular, MicroPort, AstraZeneca, and Sinomed. The remaining authors have no competing interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: While salt sensitivity of blood pressure (SSBP) is a risk factor for hypertension, end-organ damage and death, most studies are conducted in western countries and in White people. We previously found that the prevalence of SSBP in Blacks living in Sub-Saharan Africa is as high as 75-80% like what has been reported in the west. Erythrocyte glycocalyx sensitivity to sodium (eGCSS), a marker of sodium-induced damage to the erythrocyte and vascular endothelial glycocalyx is thought to be related to blood pressure perturbations associated with salt intake. We hypothesized that SSBP correlates with eGCSS differently in men and women in Black people., Methods: We conducted a cross sectional study using data from our recent clinical trial from Livingstone University Teaching Hospital among 117 normotensive young adults. We used a "salt blood test" to determine eGCSS and an immediate pressor response to oral salt (IPROS) for the diagnosis of SSBP., Results: The proportion of males were equal to females and the median age (interquartile range) of the participants was 29 (22-45) years. The eGCSS scores were higher in salt-resistant females compared to salt-sensitive females and males. eGCSS correlated negatively with SSBP (AOR 0.98, 95% CI 0.97-0.99, p  = 0.008), however, this relationship was driven by female sex and abrogated by male sex. Although blood pressure elevations exhibited a sustained bimodal pattern in both sexes, in males, systolic and diastolic blood pressure never returned to baseline during the time course as it did in females., Conclusion: In this study, eGCSS correlated negatively with SSBP in black women but not in black men and the pressor response to dietary salt was significantly higher in men compared to women. These results suggest that women tend to have a higher disruption of the vascular endothelial glycocalyx by an acute salt load, implying that acute changes in blood pressure may not be driven directly by the endothelial glycocalyx. Our findings suggest a novel mechanism linking eGCSS and SSBP with potential implications for sex differences in salt-induced cardiovascular disease. Clinical trial registration : https://clinicaltrials.gov/, identifier [NCT04844255]., 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., (Copyright © 2024 Masenga, Hamooya, Patel and Kirabo.)

Recent advances in molecular diagnostics have markedly expanded our understanding of the genetic underpinnings of lymphomas and catalysed a transformation in not just how we classify lymphomas, but also how we treat, target, and monitor affected patients. Reflecting these advances, the World Health Organization Classification, International Consensus Classification, and National Comprehensive Cancer Network guidelines were recently updated to better integrate these molecular insights into clinical practice. We summarise here the molecular biomarkers of lymphomas with an emphasis on biomarkers that have well-supported prognostic and predictive utility, as well as emerging biomarkers that show promise for clinical practice. These biomarkers include: (1) diagnostic entity-defining genetic abnormalities [e.g., B-cell acute lymphoblastic leukaemia (B-ALL) with KMT2A rearrangement]; (2) molecular alterations that guide patients' prognoses (e.g., TP53 loss frequently conferring worse prognosis); (3) mutations that serve as the targets of, and often a source of acquired resistance to, small molecular inhibitors (e.g., ABL1 tyrosine kinase inhibitors for B-ALL BCR::ABL1, hindered by ABL1 kinase domain resistance mutations); (4) the growing incorporation of molecular measurable residual disease (MRD) in the management of lymphoma patients (e.g., molecular complete response and sequencing MRD-negative criteria in multiple myeloma). Altogether, our review spans the spectrum of lymphoma types, from the genetically defined subclasses of precursor B-cell lymphomas to the highly heterogeneous categories of small and large cell mature B-cell lymphomas, Hodgkin lymphomas, plasma cell neoplasms, and T/NK-cell lymphomas, and provides an expansive summary of our current understanding of their molecular pathology., (Copyright © 2024 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Engineering biosynthetic pathways to ribosomally synthesized and post-translationally modified peptides (RiPPs) offers several advantages for both in vivo and in vitro applications. Here we probe the ability of peptide cyclases to generate trimacrocycle microviridin analogs with non-native cross-links. The results demonstrate that diverse chemistries are tolerated by macrocyclases in the ATP-grasp family and allow for the construction of unique cyclic peptide architectures that retain protease inhibition activity. In addition, cocomplex structures of analogs bound to a model protease were determined, illustrating how changes in functional groups maintain peptide conformation and target binding.

Hypertension is the leading cause of cardiovascular disease in women, and sub-Saharan African (SSA) countries have some of the highest rates of hypertension in the world. Expanding knowledge of causes, management, and awareness of hypertension and its co-morbidities worldwide is an effective strategy to mitigate its harms, decrease morbidities and mortality, and improve individual quality of life. Hypertensive disorders of pregnancy (HDPs) are a particularly important subset of hypertension, as pregnancy is a major stress test of the cardiovascular system and can be the first instance in which cardiovascular disease is clinically apparent. In SSA, women experience a higher incidence of HDP compared with other African regions. However, the region has yet to adopt treatment and preventative strategies for HDP. This delay stems from insufficient awareness, lack of clinical screening for hypertension, and lack of prevention programs. In this brief literature review, we will address the long-term consequences of hypertension and HDP in women. We evaluate the effects of uncontrolled hypertension in SSA by including research on heart disease, stroke, kidney disease, peripheral arterial disease, and HDP. Limitations exist in the number of studies from SSA; therefore, we will use data from countries across the globe, comparing and contrasting approaches in similar and dissimilar populations. Our review highlights an urgent need to prioritize public health, clinical, and bench research to discover cost-effective preventative and treatment strategies that will improve the lives of women living with hypertension in SSA., Competing Interests: Disclosures None.

Introduction: This study was designed to measure the concentration and activity of urinary proteases that activate renal epithelial sodium channel (ENaC) mediated Na + transport in infants with congenital heart disease, a potential mechanism for fluid retention., Methods: Urine samples from infants undergoing cardiac surgery were collected at three time points: T1) pre-operatively, T2) 6-8 h after surgery, and T3) 24 h after diuretics. Urine was collected from five heathy infant controls. The urine was tested for four proteases and whole-cell patch-clamp testing was conducted in renal collecting duct M-1 cells to test whether patient urine increased Na + currents consistent with ENaC activation., Results: Heavy chain of plasminogen, furin, and prostasin were significantly higher in cardiac patients prior to surgery compared to controls. There was no difference in most proteases before and after surgery. Urine from cardiac patients produced a significantly greater increase in Na + inward currents compared to healthy controls., Conclusion: Urine from infants with congenital heart disease is richer in proteases and has the potential to increase activation of ENaC in the nephron to enhance Na + reabsorption, which may lead to fluid retention in this population., 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 author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Ortmann, Nandi, Li, Zheng and Patel.)

Introduction: Genomic profiling is performed in patients with advanced or metastatic cancer, in order to direct cancer treatment, often sequencing tumor-only, without a matched germline comparator. However, because many of the genes analyzed on tumor profiling overlap with those known to be associated with hereditary cancer predisposition syndromes (HCPS), tumor-only profiling can unknowingly uncover germline pathogenic (P) and likely pathogenic variants (LPV). In this study, we evaluated the number of patients with P/LPVs identified in BRCA1 and BRCA2 ( BRCA1/2 ) via tumor-only profiling, then determined the germline testing outcomes for those patients., Methods: A retrospective chart review was performed to identify patients with BRCA1/2 variants on tumor-only genomic profiling, and whether they had germline testing., Results: This study found that of 2923 patients with 36 tumor types who underwent tumor-only testing, 554 had a variant in BRCA1/2 (19.0%); 119 of the 554 patients (21.5%) had a P/LP BRCA1/2 variant, representing 4.1% of the overall population who underwent genomic profiling. Seventy-three (61.3%) of 119 patients with BRCA1/2 P/LPV on tumor-only testing did not undergo germline testing, 34 (28.6%) had already had germline testing before tumor-only testing, and 12 (10.1%) underwent germline testing after tumor-only testing. Twenty-eight germline BRCA1/2 P/LPVs were detected, 24 in those who had prior germline testing, and 4 among the 12 patients who had germline testing after tumor-only testing., Conclusion: Tumor-only testing is likely to identify P/LPVs in BRCA1/2 . Efforts to improve follow-up germline testing is needed to improve identification of germline BRCA1/2 alterations., Competing Interests: Conflict of Interest: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships may not relate to the subject matter of this manuscript. Ecaterina E. Ileana Dumbrava reports the following: Consulting: Catamaran Bio; Advisory Committee: BOLT Therapeutics; and Sponsored Research (to the institution): Bayer HealthCare Pharmaceuticals Inc., Immunocore LTD, Amgen, Aileron Therapeutics, Compugen LTD, TRACON Pharmaceuticals Inc., Unum Therapeutics, Immunomedics, BOLT Therapeutics, Aprea Therapeutics, Bellicum Pharmaceuticals, PMV Pharma, Triumvira, Seagen Inc, Mereo BioPharma 5 Inc., Sanofi, and Astex Therapetics. Ying Yuan reports the following: Consulting: AbbVie, Amgen, Bexion Pharmaceuticals, BeyondSpring Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals, Bristol Myers Squibb, GT Medical Technologies, Mirati Therapeutics, Servier Pharmaceuticals, Starpax Pharmaceuticals, and Vertex Pharmaceuticals; and Honoraria: Blueprint. Milind Javle reports the following: Advisory Committee: OrgiMed, More Health, EDO; Sponsored Research (self): QED, Novartis, and Meclun; Sponsored Research (to the institution): Lily and Arqule; Honoraria: Taiho, Seattle Genetics, Merck. Jordi Rodon Ahnert reports the following: Advisory Committee: Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceuticals/Klus Pharma, Spectrum Pharmaceuticals, Inc., Pfizer, Roche Pharmaceuticals, Ellipses Pharma, Certera, Bayer, Molecular Partners, NovellusDX, IONCTURA SA, Kisoji Biotechnology, Inc.; Sponsored Research (to the institution): Bayer, Novartis, Blueprint Medicines, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenniums, GlaxoSmithKline, Ipsen; Travel Reimbursement: ESMO, Department of Defense, Merck Sharp & Dohme, Louisiana State University, Kelun Pharmaceuticals/Klus Pharma, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, Bayer, WIN Consortium, Janssen, Molecular Partners; Other: European Journal of Cancer, VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline. Timothy A. Yap reports the following: Consulting: AstraZeneca, Almac, Aduro, Artios, Athena, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, GLG, Guidepoint, Ignyta, I-Mab, ImmuneSensor, Jansen, Merck, Pfizer, Repare, Roche, Schrodinger, Seattle Genetics, Varian, Zai Labs, and ZielBio; Sponsored Research (to the institution): AstraZeneca, Artios, Bayer, Beigene, BioNTech, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, Haihe, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Novartis, Pfizer, Repare, Ribon Therapeutics, Regeneron, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vivace. Banu Arun reports the following: Sponsored Research (to the institution): AstraZeneca; and Advisory Committee: AbbVie (non-paid steering committee member for BROCADE 3 study). Funda Meric-Bernstam reports the following: Consulting: AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, Daiichi Sankyo Co. Ltd., DebioPharm, Ecor1 Capital, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., GT Apeiron, Genentech Inc., Harbinger Health, IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, Menarini Group, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Protai Bio Ltd, Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, Zymeworks; Advisory Committee: Black Diamond, Biovica, Eisai, FogPharma, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Sanofi, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis; Sponsored Research (to the institution): Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., and Taiho Pharmaceutical Co.; Honoraria: Chugai Biopharmaceuticals; and Other (Travel Related): European Organisation for Research and Treatment of Cancer (EORTC), European Society for Medical Oncology (ESMO). The remaining authors have no disclosures.

Aims: Surgical ablation of atrial fibrillation (AF) has been demonstrated to be a safe procedure conducted concomitantly alongside cardiac surgery. However, there are conflicting guideline recommendations surrounding indications for surgical ablation. We conducted a systematic review of current recommendations on concomitant surgical AF ablation., Methods and Results: We identified publications from MEDLINE and EMBASE between January 2011 and December 2022 and additionally searched Guideline libraries and websites of relevant organizations in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Of 895 studies screened, 4 were rigorously developed (AGREE-II > 50%) and included. All guidelines agreed on the definitions of paroxysmal, persistent, and longstanding AF based on duration and refraction to current treatment modalities. In the Australia-New Zealand (CSANZ) and European (EACTS) guidelines, opportunistic screening for patients >65 years is recommended. The EACTS recommends systematic screening for those aged >75 or at high stroke risk (Class IIa, Level B). However, this was not recommended by American Heart Association or Society of Thoracic Surgeons guidelines. All guidelines identified surgical AF ablation during concomitant cardiac surgery as safe and recommended for consideration by a Heart Team with notable variation in recommendation strength and the specific indication (three guidelines fail to specify any indication for surgery). Only the STS recommended left atrial appendage occlusion (LAAO) alongside surgical ablation (Class IIa, Level C)., Conclusion: Disagreements exist in recommendations for specific indications for concomitant AF ablation and LAAO, with the decision subject to Heart Team assessment. Further evidence is needed to develop recommendations for specific indications for concomitant AF procedures and guidelines need to be made congruent., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: In 2011, the American Board of Medical Specialties established clinical informatics (CI) as a subspecialty in medicine, jointly administered by the American Board of Pathology and the American Board of Preventive Medicine. Subsequently, many institutions created CI fellowship training programs to meet the growing need for informaticists. Although many programs share similar features, there is considerable variation in program funding and administrative structures., Objectives: The aim of our study was to characterize CI fellowship program features, including governance structures, funding sources, and expenses., Methods: We created a cross-sectional online REDCap survey with 44 items requesting information on program administration, fellows, administrative support, funding sources, and expenses. We surveyed program directors of programs accredited by the Accreditation Council for Graduate Medical Education between 2014 and 2021., Results: We invited 54 program directors, of which 41 (76%) completed the survey. The average administrative support received was $27,732/year. Most programs (85.4%) were accredited to have two or more fellows per year. Programs were administratively housed under six departments: Internal Medicine (17; 41.5%), Pediatrics (7; 17.1%), Pathology (6; 14.6%), Family Medicine (6; 14.6%), Emergency Medicine (4; 9.8%), and Anesthesiology (1; 2.4%). Funding sources for CI fellowship program directors included: hospital or health systems (28.3%), clinical departments (28.3%), graduate medical education office (13.2%), biomedical informatics department (9.4%), hospital information technology (9.4%), research and grants (7.5%), and other sources (3.8%) that included philanthropy and external entities., Conclusion: CI fellowships have been established in leading academic and community health care systems across the country. Due to their unique training requirements, these programs require significant resources for education, administration, and recruitment. There continues to be considerable heterogeneity in funding models between programs. Our survey findings reinforce the need for reformed federal funding models for informatics practice and training., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: To determine sex differences in cholesterol and triglyceride levels among adolescents and young adults hospitalized for medical complications of eating disorders., Methods: A retrospective electronic medical record review of patients aged 9-25 years admitted to the University of California, San Francisco Eating Disorders Program for medical stabilization, between 2012 and 2020, was conducted. Non-fasting total cholesterol and triglycerides were collected; however, LDL and HDL levels were not available., Results: Among 83 males and 441 females, mean ± SD age was 15.5 ± 2.8 years, 64.1% had anorexia nervosa, and admission percent median body mass index was 87.3 ± 13.9. The proportion of males and females with high total cholesterol (13.3% vs. 18.1%, Cramer's V = 0.05, p = .28) and high triglyceride levels (9.6% vs. 8.1%, Cramer's V = 0.02, p = .63) did not differ. Mean total cholesterol levels were higher in females compared to males (F 169.6 ± 41.1 mg/dL vs. M 154.5 ± 45.1 mg/dL, Cohen's d = 0.36, p = .003), although a majority were within the normal range. In adjusted linear regression models, male (compared to female) sex (B = -14.40, 95% CI -24.54, -4.27) and higher percent median body mass index (B = -0.33, 95% CI -0.60, -0.06) were associated with lower total cholesterol levels in adjusted models (R 2  = 0.04)., Discussion: Building on prior work showing equally severe complications of eating disorders in males compared to females, we did not find sex differences in those presenting with high total cholesterol or triglycerides. Future research is needed to understand the pathophysiology and role of dyslipidemia in acute malnutrition, and the impact of nutritional rehabilitation and weight restoration., Public Significance: We found that the proportion of male and female adolescents and young adults hospitalized for medical complications of an eating disorder with high total cholesterol did not significantly differ. Although average total cholesterol levels were higher in female compared to male patients with eating disorders, a majority of these levels remained within the normal range. Patients with more severe malnutrition had a higher risk of elevated total cholesterol levels. Clinicians should consider monitoring cholesterol levels in young people hospitalized for restrictive eating disorders., (© 2023 The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.)

Background: Genomic profiling is needed to identify actionable alterations in non-small cell lung cancer (NSCLC). Panel-based testing such as next-generation sequencing (NGS) is often preferred to interrogate multiple alterations simultaneously. In this study, we evaluate the utility of an RNA-based NGS assay to detect genomic alterations in NSCLC cytology specimens and compare these results to fluorescence in situ hybridization (FISH) testing., Methods: A retrospective review was performed of 264 NSCLC cytology specimens that were concurrently tested for gene fusions by RNA-based NGS and ALK, RET, and/or ROS1 by FISH., Results: Genomic alterations were detected in 29 cases by NGS, including ALK, RET, ROS1, NTRK, NUTM1, and FGFR3 fusions and MET exon 14 skipping alterations. Of the 20 cases with ALK, RET, and ROS1 fusions detected by NGS, 16 (80%) were concordant with the corresponding FISH results. Three cases showed discordance, where EML4::ALK (n = 2) and SLC34A2::ROS1 (n = 1) fusions were not detected by the corresponding FISH assay; one case with EZR::ROS1 was inadequate for FISH. No gene fusions were detected in 181 cases by NGS and 54 cases failed testing. The concordance rates for detecting ALK, RET, and ROS1 fusions using NGS and FISH were 97%, 100%, and 99.5%, respectively., Conclusion: RNA-based NGS can be used to detect gene fusions in NSCLC cytology cases with high concordance with FISH results. However, RNA-based NGS may have high failure rates and therefore a low threshold for reflexing inadequate cases to an orthogonal testing method is essential for comprehensive genomic profiling., (© 2023 American Cancer Society.)

Epidermal growth factor receptor variant III (EGFRvIII, the deletion of exons 2-7) is a recurrent intragenic EGFR::EGFR .E1E8 fusion that occurs in high-grade gliomas. The presence of EGFRvIII in other solid tumors has not been well characterized. We retrospectively reviewed advanced malignant solid tumor cases tested by a custom hybrid capture 610-gene next-generation sequencing platform from 2021 to 2022. EGFRvIII was identified in 17 of 4331 (0.4%) cases, including 16 of 238 (7%) brain tumors and 1/301 (0.3%) breast tumors. EGFRvIII-positive brain tumors were all glioblastoma IDH-wildtype, most with concurrent TERT promoter mutation (14 of 16), EGFR amplification (13 of 16), and EGFR mutation (8 of 16). The only EGFRvIII-positive breast lesion was a sarcomatoid neoplasm in a young female patient. A separate breast case tested outside our institution with reported EGFRvIII was noted in a young female patient with a malignant phyllodes tumor with stromal overgrowth. Microscopically, both EGFRvIII-positive breast tumors showed high-grade sarcomatoid morphology with brisk mitotic activity. In summary, EGFRvIII is rare, occurring primarily in glioblastoma and rarely in breast sarcomatoid neoplasm, with no instances identified in other tumor types in our series. This select group of patients may benefit from chemotherapy and/or targeted anti-EGFR therapy.

Heart failure with preserved ejection fraction (HFpEF) is a heterogenous clinical syndrome characterized by diastolic dysfunction, concentric cardiac left ventricular (LV) hypertrophy, and myocardial fibrosis with preserved systolic function. However, the underlying mechanisms of HFpEF are not clear. We hypothesize that an enhanced central sympathetic drive is sufficient to induce LV dysfunction and HFpEF in rats. Male Sprague-Dawley rats were subjected to central infusion of either saline controls (saline) or angiotensin II (Ang II, 20 ng/min, i.c.v) via osmotic mini-pumps for 14 days to elicit enhanced sympathetic drive. Echocardiography and invasive cardiac catheterization were used to measure systolic and diastolic functions. Mean arterial pressure, heart rate, left ventricular end-diastolic pressure (LVEDP), and ± dP/dt changes in responses to isoproterenol (0.5 μg/kg, iv) were measured. Central infusion of Ang II resulted in increased sympatho-excitation with a consequent increase in blood pressure. Although the ejection fraction was comparable between the groups, there was a decrease in the E/A ratio (saline: 1.5 ± 0.2 vs Ang II: 1.2 ± 0.1). LVEDP was significantly increased in the Ang II-treated group (saline: 1.8 ± 0.2 vs Ang II: 4.6 ± 0.5). The increase in +dP/dt to isoproterenol was not significantly different between the groups, but the response in -dP/dt was significantly lower in Ang II-infused rats (saline: 11,765 ± 708 mmHg/s vs Ang II: 8,581 ± 661). Ang II-infused rats demonstrated an increased heart to body weight ratio, cardiomyocyte hypertrophy, and fibrosis. There were elevated levels of atrial natriuretic peptide and interleukin-6 in the Ang II-infused group. In conclusion, central infusion of Ang II in rats induces sympatho-excitation with concurrent diastolic dysfunction, pathological cardiac concentric hypertrophy, and cardiac fibrosis. This novel model of centrally mediated sympatho-excitation demonstrates characteristic diastolic dysfunction in rats, representing a potentially useful preclinical murine model of HFpEF to investigate various altered underlying mechanisms during HFpEF in future studies., 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 author(s) declared that they were editorial board members of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Nandi, Katsurada, Moulton, Zheng and Patel.)

Aims: Aortic stenosis is characterized by fibrosis and calcification of the valve, with a higher proportion of fibrosis observed in women. Stenotic bicuspid aortic valves progress more rapidly than tricuspid valves, which may also influence the relative composition of the valve. We aimed to investigate the influence of cusp morphology on quantitative aortic valve composition quantified from contrast-enhanced computed tomography angiography in severe aortic stenosis., Methods and Results: Patients undergoing transcatheter aortic valve implantation with bicuspid and tricuspid valves were propensity matched 1:1 by age, sex, and comorbidities. Computed tomography angiograms were analysed using semi-automated software to quantify the fibrotic and calcific scores (volume/valve annular area) and the fibro-calcific ratio (fibrotic score/calcific score). The study population (n = 140) was elderly (76 ± 10 years, 62% male) and had a peak aortic jet velocity of 4.1 ± 0.7 m/s. Compared with those with tricuspid valves (n = 70), patients with bicuspid valves (n = 70) had higher fibrotic scores [204 (interquartile range 118-267) vs. 144 (99-208) mm3/cm2, P = 0.006] with similar calcific scores (P = 0.614). Women had greater fibrotic scores than men in bicuspid [224 (181-307) vs. 169 (109-247) mm3/cm2, P = 0.042] but not tricuspid valves (P = 0.232). Men had greater calcific scores than women in both bicuspid [203 (124-355) vs. 130 (70-182) mm3/cm2, P = 0.008] and tricuspid [177 (136-249) vs. 100 (62-150) mm3/cm2, P = 0.004] valves. Among both valve types, women had a greater fibro-calcific ratio compared with men [tricuspid 1.86 (0.94-2.56) vs. 0.86 (0.54-1.24), P = 0.001 and bicuspid 1.78 (1.21-2.90) vs. 0.74 (0.44-1.53), P = 0.001]., Conclusions: In severe aortic stenosis, bicuspid valves have proportionately more fibrosis than tricuspid valves, especially in women., Competing Interests: Conflict of interest: K.P.P. and M.J.M. have received an unrestricted grant from Edwards Lifesciences. K.G. reports grants or contracts from the Foundation for Polish Science and Polish Society of Cardiology. D.D. received software royalties from Cedars-Sinai Medical Center outside of the current work and holds a patent (US8885905B2/WO2011069120A1, Method and System for Plaque Characterisation). M.C.W. reports a grant from the British Heart Foundation; declares payment or honoraria from Cannon Medical Systems; and reports leadership or fiduciary roles with the British Society of Cardiovascular Imaging, Society of Cardiovascular Computed Tomography, and European Society of Cardiovascular Radiology. M.R.D. reports consulting fees from Novartis, Jupiter Bioventures, and Silence Therapeutics and payment or honoraria from Pfizer and Novartis. D.E.N. reports a grant from the British Heart Foundation and Wellcome Trust., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Acute decompensated aortic stenosis (ADAS) is common and associated with higher mortality, acute kidney injury (AKI) and longer hospital length of stay (LoS) compared with electively treated stable AS. The aim of this study was to assess the impact of a dedicated pathway that reduces time to transcatheter aortic valve implantation (TAVI) in ADAS, hypothesizing that LoS can be reduced without compromising patient safety., Methods and Results: Using a prospective, open label, cluster design, patients from 5 referring centres were allocated to the ASessment and TReatment In Decompensated Aortic Stenosis (ASTRID-AS) pathway where the diagnosis, referral, investigations and treatment of ADAS were prioritised and expedited. 15 hospitals remained on the conventional pathway that followed the same process, albeit according to a waiting list. The primary efficacy endpoint was hospital LoS and the secondary safety endpoint, a composite of death or AKI at 30 days post-TAVI. 58 conventional patients and 25 ASTRID-AS patients were included in this study. Time to TAVI in the conventional vs. ASTRID-AS cohort was 22 (15-30) vs. 10 (6-12) days; P < 0.001, respectively. Length of hospital stay was 24 (18-33) vs. 13 (8-18) days; P < 0.001, respectively. 13.4 bed days were saved per patient using the ASTRID-AS pathway. Secondary safety endpoint occurred in 12 (20.7%) vs. 1 (4.0%) patients; P = 0.093, respectively. Procedural complications were similar between the two cohorts., Conclusion: A dedicated pathway for ADAS that shortens time to TAVI demonstrated reduced hospital LoS without compromising patient safety and a trend towards improving clinical outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The growing number of people living with dementia (PLWD) requires a coordinated clinical response to deliver pragmatic, evidence-based interventions in frontline care settings. However, infrastructure to support such a response is lacking. Moreover, there are too few researchers conducting rigorous embedded pragmatic clinical trials (ePCTs) to make the vision of high quality, widely accessible dementia care a reality. National Institute on Aging (NIA) Imbedded Pragmatic Alzheimer's disease and Related Dementias Clinical Trials (IMPACT) Collaboratory seeks to improve the pipeline of early career researchers qualified to lead ePCTs by funding career development awards. Even with support from the Collaboratory, awardees face practical and methodological challenges to success, recently exacerbated by the COVID-19 pandemic. We first describe the training opportunities and support network for the IMPACT CDA recipients. This report then describes the unique career development challenges faced by early-career researchers involved in ePCTs for dementia care. Topics addressed include challenges in establishing a laboratory, academic promotion, mentoring and professional development, and work-life balance. Concrete suggestions to address these challenges are offered for early-career investigators, their mentors, and their supporting institutions. While some of these challenges are faced by researchers in other fields, this report seeks to provide a roadmap for expanding the work of the IMPACT Collaboratory and initiating future efforts to recruit, train, and retain talented early-career researchers involved in ePCTs for dementia care., (© 2023 The American Geriatrics Society.)

DDX41 is the most frequently mutated gene in myeloid neoplasms associated with germline predisposition including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We analyzed 3795 patients with myeloid neoplasms and identified 151 (4%) with DDX41 variants and a diagnosis of AML (n = 96), MDS (n = 52), and chronic myelomonocytic leukemia (n = 3). The most frequent DDX41 variants were the somatic variant p.R525H, followed by the germline variants p.M1I and p.D140fs. Most neoplasms had a normal karyotype (59%) and the most frequent co-mutations were TP53 (16%) and ASXL1 (15%). 30% of patients had no concomitant mutations besides DDX41 mutation. Patients with myeloid malignancies and DDX41 variants responded well to therapy, with an overall response rate for patients with treatment naïve AML and MDS of 87% and 84%, respectively. The median overall survival (mOS) of patients with treatment-naïve AML or MDS was 49 and 71 months, respectively. Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively., (© 2023 Wiley Periodicals LLC.)

A variety of inducible protein degradation (IPD) systems have been developed as powerful tools for protein functional characterization. IPD systems provide a convenient mechanism for rapid inactivation of almost any target protein of interest. Auxin-inducible degradation (AID) is one of the most common IPD systems and has been established in diverse eukaryotic research model organisms. Thus far, IPD tools have not been developed for use in pathogenic fungal species. Here, we demonstrate that the original AID and the second generation, AID2, systems work efficiently and rapidly in the human pathogenic yeasts, Candida albicans and Candida glabrata . We developed a collection of plasmids that support AID system use in laboratory strains of these pathogens. These systems can induce >95% degradation of target proteins within minutes. In the case of AID2, maximal degradation was achieved at low nanomolar concentrations of the synthetic auxin analog 5-adamantyl-indole-3-acetic acid. Auxin-induced target degradation successfully phenocopied gene deletions in both species. The system should be readily adaptable to other fungal species and to clinical pathogen strains. Our results define the AID system as a powerful and convenient functional genomics tool for protein characterization in fungal pathogens. IMPORTANCE Life-threatening fungal infections are an escalating human health problem, complicated by limited treatment options and the evolution of drug resistant pathogen strains. Identification of new targets for therapeutics to combat invasive fungal infections, including those caused by Candida species, is an urgent need. In this report, we establish and validate an inducible protein degradation methodology in Candida albicans and Candida glabrata that provides a new tool for protein functional characterization in these, and likely other, fungal pathogen species. We expect this tool will ultimately be useful for the identification and characterization of promising drug targets and factors involved in virulence and drug resistance., Competing Interests: The authors declare no conflict of interest.

Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early-onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1-driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low-frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Oxidative stress is a deteriorating condition that arises due to an imbalance between the reactive oxygen species and the antioxidant system or defense of the body. The key reasons for the development of such conditions are malfunctioning of various cell organelles, such as mitochondria, endoplasmic reticulum, and Golgi complex, as well as physical and mental disturbances. The nervous system has a relatively high utilization of oxygen, thus making it particularly vulnerable to oxidative stress, which eventually leads to neuronal atrophy and death. This advances the development of neuroinflammation and neurodegeneration-associated disorders such as Alzheimer's disease, Parkinson's disease, epilepsy, dementia, and other memory disorders. It is imperative to treat such conditions as early as possible before they worsen and progress to irreversible damage. Oxidative damage can be negated by two mechanisms: improving the cellular defense system or providing exogenous antioxidants. Natural antioxidants can normally handle such oxidative stress, but they have limited efficacy. The valuable features of nanoparticles and/or nanomaterials, in combination with antioxidant features, offer innovative nanotheranostic tools as potential therapeutic modalities. Hence, this review aims to represent novel therapeutic approaches like utilizing nanoparticles with antioxidant properties and nanotheranostics as delivery systems for potential therapeutic applications in various neuroinflammation- and neurodegeneration-associated disease conditions.

Aortic regurgitation (AR) is associated with morbidity and premature mortality. Surgical aortic valve replacement is not an option for many patients due to an adverse surgical risk profile, whilst transcatheter aortic valve implantation with most available prostheses has demonstrated suboptimal implantation success and outcomes. The JenaValve Trilogy™ system provides an attractive solution for such patients as it utilizes clips that directly attach onto the native valve leaflets to anchor. Initially designed for transapical delivery, the current transfemoral delivery system is under investigation in the United States and approved for aortic stenosis and regurgitation in Europe. We present an expert review on the technical aspects of the Trilogy system, provide a guide for implantation, discuss the available evidence for the technology and provide illustrative case examples., (© 2023 The Authors. Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Acute decompensated aortic stenosis (ADAS) is common. The cumulative burden of ADAS from a clinical, health care resource, and financial perspective is unknown. This study sought to assess the national impact of ADAS compared with electively treated, stable patients with aortic stenosis (non-ADAS). Using the National Readmissions Database between 2016 and 2019, patients with ADAS and non-ADAS were identified using International Classification of Diseases, Tenth Revision codes. Patients with ADAS were propensity-matched to non-ADAS patients (1:2) using age, gender, and Charlson co-morbidity index. We compared in-hospital mortality, length of stay (LOS), health care-associated costs, and 90-day readmission data between the 2 cohorts. A total of 51,498 propensity-matched patients were included in this study: median age 75 years, 64% men. The in-hospital mortality for ADAS was higher than non-ADAS (2.8% vs 1.5%, p <0.0001). The LOS during the index admission was longer for ADAS (9 [5 to 13] vs 4 [2 to 6] days, p <0.0001). The health care-associated costs per patient was greater for ADAS ($55,450.0 [41,860.4 to 74,500.7] vs $43,405.7 [34,218.5 to 56,034.8], p <0.0001). Readmission to hospital within 90 days was more frequent in ADAS (21.1 vs 16.8%, p <0.001). The in-hospital mortality during readmission was higher with ADAS (3.9% vs 2.8%, p = 0.004). The readmission LOS was longer with ADAS (4 [2 to 7] vs 3 [2 to 6] days, p <0.0001). In conclusion, ADAS imposes a significant burden clinically and financially and on health care resources compared with non-ADAS during the index admission and 90-day follow-up. There is an urgent need to predict ADAS and optimize the timing of aortic valve replacement to reduce the incidence and the burden associated with ADAS., Competing Interests: Declaration of Competing Interest Drs. Patel and Mullen have an unrestricted grant from Edwards Lifesciences. The remaining authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare.