Proteomic Profile of the ICAM1 p.K56M HFpEF Risk Variant.

A common missense variant in ICAM1 among African American individuals (rs5491; pK56M) has been associated with risk of heart failure with preserved ejection fraction (HFpEF), but the pathways that lead to HFpEF among those with this variant are not clear. In this analysis of 92 circulating proteins and their associated networks, we identified 7 circulating inflammatory proteins associated with rs5491 among >600 African American individuals. Using weighted coexpression network analysis, 3 protein networks were identified, one of which was associated with rs5491. This protein network was most highly represented by members of the tumor necrosis receptor superfamily. The rs5491 variant demonstrated an inflammatory proteomic profile in a separate cohort of African American individuals. This analysis identifies inflammatory pathways that may drive HFpEF among African American individuals with the ICAM1 pK56M (rs5491) variant.

Endovascular Ablation of the Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction: The REBALANCE-HF Randomized Clinical Trial.

Importance: Greater splanchnic nerve ablation may improve hemodynamics in patients with heart failure and preserved ejection fraction (HFpEF). Objective: To explore the feasibility and safety of endovascular right-sided splanchnic nerve ablation for volume management (SAVM). Design, Setting, and Participants: This was a phase 2, double-blind, 1:1, sham-controlled, multicenter, randomized clinical trial conducted at 14 centers in the US and 1 center in the Republic of Georgia. Patients with HFpEF, left ventricular ejection fraction of 40% or greater, and invasively measured peak exercise pulmonary capillary wedge pressure (PCWP) of 25 mm Hg or greater were included. Study data were analyzed from May 2023 to June 2024. Intervention: SAVM vs sham control procedure. Main Outcomes and Measures: The primary efficacy end point was a reduction in legs-up and exercise PCWP at 1 month. The primary safety end point was serious device- or procedure-related adverse events at 1 month. Secondary efficacy end points included HF hospitalizations, changes in exercise function and health status through 12 months, and baseline to 1-month change in resting, legs-up, and 20-W exercise PCWP. Results: A total of 90 patients (median [range] age, 71 [47-90] years; 58 female [64.4%]) were randomized at 15 centers (44 SAVM vs 46 sham). There were no differences in adverse events between groups. The primary efficacy end point did not differ between SAVM or sham (mean between-group difference in PCWP, -0.03 mm Hg; 95% CI, -2.5 to 2.5 mm Hg; P = .95). There were also no differences in the secondary efficacy end points. There was no difference in the primary safety end point between the treatment (6.8% [3 of 44]) and sham (2.2% [1 of 46]) groups (difference, 4.6%; 95% CI, -6.1% to 15.4%; P = .36). There was no difference in the incidence of orthostatic hypotension between the treatment (11.4% [5 of 44]) and sham (6.5% [3 of 46]) groups (difference, 4.9%; 95% CI, -9.2% to 18.8%; P = .48). Conclusions and Relevance: Results show that SAVM was safe and technically feasible, but it did not reduce exercise PCWP at 1 month or improve clinical outcomes at 12 months in a broad population of patients with HFpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT04592445.

Newly diagnosed essential thrombocythemia leading to cardiogenic shock: a case report.

BACKGROUND: Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by uninhibited platelet production. It can present with vasomotor symptoms, and less commonly, severe thrombotic events such as myocardial infarction. ST-segment elevation myocardial infarction (STEMI) secondary to the hypercoagulable state in ET is a diagnostic challenge as the complication is rare, especially outside the typical demographics affected by ET such as the female and elderly populations. CASE PRESENTATION: Here we report a case of a 32-year-old male found to have STEMI and a markedly elevated platelet count. Angiography revealed occlusion of the left anterior descending and left circumflex arteries, requiring percutaneous intervention and Impella support. The patient was later diagnosed with essential thrombocythemia, treated with hydroxyurea and antiplatelet therapy, and discharged with a wearable cardioverter defibrillator. CONCLUSIONS: This case illustrates the potential for severe thrombotic complications such as STEMI due to ET. Severe thrombotic complications are less common manifestations of ET in general, particularly in young males. Recognition and diagnosis of ET are critical for the institution of appropriate therapy and prevention of STEMI and cardiogenic shock among other complications.

Robotic assisted versus conventional total knee arthroplasty: a systematic review and meta-analysis of randomised controlled trials.

The aim of this study is To compare robotic-assisted and conventional total knee arthroplasty (TKA) on both short- and long-term outcomes A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Cochrane, Scopus, and Web of Science databases were searched for relevant studies. The studies included were randomised controlled trials directly comparing robotic-assisted versus conventional TKA. The outcomes were pooled as mean difference (MD) or risk ratio (RR), with 95% confidence interval. RevMan software version 5.4 was used for performing the statistical analysis. Nine studies deemed eligible for inclusion. The data showed a significant favouring of robotic-assisted than the conventional TKA in mechanical alignment, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and femoral coronal plane outliers (MD = - 1.10, 95% CI [- 1.51, - 0.69], p < 0.00001), (MD = - 1.19, 95% CI [- 2.35, - 0.03], p = 0.04), and (RR = 0.49, 95% CI [0.30, 0.80], p = 0.004), respectively. On the other hand, conventional TKA was better in range of motion-flexion (long-term) than the robotic-assisted one (MD = - 3.02, 95% CI [- 3.68, - 2.37], p < 0.00001). There were no significant differences between them in knee society score-knee score, knee society score-function score, change in hospital for special surgery (HSS) knee rating scale, and change in range of motion-extension (MD = - 0.36, 95% CI [- 2.43, 1.70], p = 0.73), (MD = - 0.34, 95% CI [- 2.36, 1.68], p = 0.74), (MD = 0.78, 95% CI [- 0.84, 2.40], p = 0.34), and (MD = 0.16, 95% [- 1.32, 1.64], p = 0.83), respectively. Robotic-assisted TKA demonstrated better outcomes than conventional TKA in terms of mechanical alignment and WOMAC scores. However, the conventional TKA showed a better range of motion-flexion in the long term. More data are needed to assess long-term outcomes comprehensively.

Survey of Changes in Absolute Lymphocyte Counts and Peripheral Immune Repertoire Diversity after External Beam Radiotherapy.

Radiation-induced lymphopenia (RIL) is associated with worse outcomes in patients with multiple solid tumors. Hypofractionated radiation therapy (HFRT) reduces RIL compared with conventionally fractionated radiation therapy (CFRT). However, fractionation effects on immune repertoire (IR) diversity are unknown. RNA-based T- and B-cell receptor sequencing was performed on peripheral lymphocytes collected prospectively before radiation therapy and <4 weeks after the final radiation fraction. Patients received CFRT (≤3 Gy/day × ≥10 days ± chemotherapy, n = 13) or HFRT (≥5 Gy/day × ≤5 days, n = 10), per institutional standards of care. Immune repertoire diversity parameters analyzed were number of unique CDR3 receptors (uCDR3), Shannon entropy, and sample clonality (percentage of all receptors represented by the top 10 clones). RIL was severe with concurrent chemotherapy (median %Δ ALC -58.8%, -12.5%, and -28.6% in patients treated with CFRT and chemo, CFRT alone, and HFRT, respectively). CFRT and concurrent chemotherapy was associated with more severe diversity restriction in all examined parameters than either HFRT or CFRT alone. Increased immune repertoire diversity despite decreased ALC was more common in patients treated with HFRT than CFRT and significantly less common in patients treated with concurrent chemotherapy (P < 0.001). Radiation-induced changes in immune repertoire diversity are variably reflected in the peripheral ALC. Both HFRT and CFRT caused RIL, but HFRT was associated with improved immune repertoire diversity despite RIL. The addition of chemotherapy may potentiate radiation-induced restriction in immune repertoire diversity. As immune repertoire diversity is associated with response to immunotherapy, these findings may have implications for radiation therapy/chemotherapy/immunotherapy combinations. Further studies are required to understand the relationship between radiation, circulating lymphocyte populations, immune repertoire diversity and response to treatment.

Cardiac Myosin Inhibition in Heart Failure With Normal and Supranormal Ejection Fraction: Primary Results of the EMBARK-HFpEF Trial.

Importance: Patients with heart failure with preserved ejection fraction (HFpEF) who have left ventricular ejection fraction (LVEF) of 60% or greater have limited treatment options. Objective: To examine the effects of cardiac myosin inhibition with mavacamten in patients with HFpEF with LVEF of 60% or greater. Design, Setting, and Participants: The EMBARK-HFpEF trial was a phase 2a, open-label, single-arm, multicenter trial conducted from November 6, 2020, to February 26, 2024, at 20 sites in the US and Canada. Patients with symptomatic HFpEF (defined as a New York Heart Association [NYHA] functional class II or III), LVEF of 60% or greater, elevated N-terminal pro-B-type natriuretic peptide (NTproBNP), and left ventricular hypertrophy were eligible for inclusion. Intervention: Mavacamten treatment for 26 weeks, starting at 2.5 mg and potentially titrated up to 5 mg at week 14 based on prespecified LVEF and NTproBNP criteria. Main Outcomes and Measures: Primary efficacy end points (measured as the change from baseline to week 26) included NTproBNP and high-sensitivity troponin T (hsTnT); additional efficacy end points included changes in high-sensitivity troponin I (hsTnI), NYHA functional class, and echocardiographic parameters (resting and peak exercise). Safety end points included treatment-emergent adverse events and reductions in LVEF to less than 30%. Results: A total of 30 patients were enrolled and treated with mavacamten. Median (IQR) patient age was 76 (70-80) years, and 16 patients (53.3%) were female. From baseline to week 26, mavacamten was associated with reductions in NTproBNP (mean reduction, -26%; 95% CI, -44% to -4%; P = .04), hsTnT (mean reduction, -13%; 95% CI, -23% to -3%; P = .02), and hsTnI (mean reduction, -20%; 95% CI, -32% to -6%; P = .01). Cardiac biomarker values returned toward baseline levels 8 weeks after drug discontinuation. NYHA class improved in 10 of 24 patients (41.7%) who had evaluable NYHA class data at the end of treatment, and improvements in echocardiographic markers of LV diastolic function were observed. Mean LVEF decreased by 3.2 absolute percentage points (95% CI, 1.1-5.4; P = .005) during treatment. Mavacamten was interrupted in 3 patients (10% of the study population; 95% CI, 2.1%-26.5%) due to protocol prespecified criteria of LVEF less than 50% (n = 2) or a more than 20% relative decrease from baseline (n = 1; nadir LVEF, 58%), with LVEF recovery observed in all 3 patients. There were no deaths or instances of LVEF less than 30%; 1 patient had worsening heart failure deemed unrelated to the study drug. Conclusions and Relevance: In an open-label trial in patients with HFpEF with LVEF of 60% or greater, mavacamten was associated with improvements in biomarkers of cardiac wall stress and injury, with no sustained reductions in LVEF observed. Trial Registration: ClinicalTrials.gov Identifier: NCT04766892.

Clinical-transcriptional prioritization of the circulating proteome in human heart failure.

Given expanding studies in epidemiology and disease-oriented human studies offering hundreds of associations between the human "ome" and disease, prioritizing molecules relevant to disease mechanisms among this growing breadth is important. Here, we link the circulating proteome to human heart failure (HF) propensity (via echocardiographic phenotyping and clinical outcomes) across the lifespan, demonstrating key pathways of fibrosis, inflammation, metabolism, and hypertrophy. We observe a broad array of genes encoding proteins linked to HF phenotypes and outcomes in clinical populations dynamically expressed at a transcriptional level in human myocardium during HF and cardiac recovery (several in a cell-specific fashion). Many identified targets do not have wide precedent in large-scale genomic discovery or human studies, highlighting the complementary roles for proteomic and tissue transcriptomic discovery to focus epidemiological targets to those relevant in human myocardium for further interrogation.

Qualitative Study to Identify Strengths, Weakness, Opportunities, and Challenges of Family Adoption Programs among Students.

Background: National Medical Commission (NMC) in their recent notification included Family Adoption Program (FAP) in the undergraduate curriculum to provide a learning opportunity towards community-based health care to Indian medical graduates. This study is carried out to explore and know strengths, weaknesses, opportunities, and challenges of FAP. Materials and Methods: FAP were used to gather data using Focus Group Discussion (FGD) and in-depth interviews of the stakeholders of the program. FGD of students was conducted. In-depth interviews of families, Sarpanch, Panchayat members, ASHA workers of the village, faculties, and Head of the Department of Community Medicine were conducted. Data analysis was done by using deductive-inductive content analysis method using computer software NVivo. Results: Four main categories or themes were formed: strengths, weaknesses, opportunities, and challenges. Strengths include increased understanding about Community Medicine subject, beneficence to students, and community. Weakness includes difficulties in field with respect to time and availability and implementation of programs. Opportunities include early field exposure and FAP as a platform for primary healthcare. Challenges include competencies not aligned with phasewise curriculum and difficulties in adopting five families per student. Conclusions: The family adoption program needs to be adopted and implemented as a part of curriculum for MBBS students as there are many strengths and opportunities, while weaknesses and challenges need to be addressed.

Metabolomic profiling identifies novel metabolites associated with cardiac dysfunction.

Metabolic comorbidities, such as obesity and diabetes, are associated with subclinical alterations in both cardiac structure/function and natriuretic peptides prior to the onset of heart failure (HF). Despite this, the exact metabolic pathways of cardiac dysfunction which precede HF are not well-defined. Among older individuals without HF in the Multi-Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of 47 circulating metabolites measured by 1H-NMR with echocardiographic measures of cardiac structure and function. We then evaluated associations of significant metabolites with circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP). In a separate cohort, we evaluated differences between top metabolites in patients with HF with preserved ejection fraction (HFpEF) and comorbidity-matched controls. Genetic variants associated with top metabolites (mQTLs) were then related to echocardiographic measures and NT-proBNP. Among 3440 individuals with metabolic and echocardiographic data in MESA (62 ± 10 years, 52% female, 38% White), 10 metabolites broadly reflective of glucose and amino acid metabolism were associated with at least 1 measure of cardiac structure or function. Of these 10 metabolites, 4 (myo-inositol, glucose, dimethylsulfone, carnitine) were associated with higher NT-proBNP and 2 (d-mannose, acetone) were associated with lower NT-proBNP. In a separate cohort, patients with HFpEF had higher circulating myo-inositol levels compared with comorbidity-matched controls. Genetic analyses revealed that 1 of 6 known myo-inositol mQTLs conferred risk of higher NT-proBNP. In conclusion, metabolomic profiling identifies several novel metabolites associated with cardiac dysfunction in a cohort at high risk for HF, revealing pathways potentially relevant to future HF risk.

A literature review assessing the perioperative efficacy and safety of tranexamic acid in elective total hip and knee arthroplasty in UK practice.

Hip and knee arthroplasty are frequently associated with significant blood loss, often necessitating blood transfusions. A variety of methods are employed to minimise blood loss and consequently mitigate the necessity for transfusions. This review explores the incidence of blood loss in hip and knee arthroplasty alongside perioperative strategies aimed at its reduction in UK practice. Given the increasing prevalence of tranexamic acid utilisation, we systematically examine the extant literature concerning its application in patients undergoing hip and knee arthroplasty. Our analysis discerns a prevailing consensus within published studies favouring the implementation of tranexamic acid as a safe and efficacious measure for reducing blood loss during hip and knee arthroplasty procedures.

A Randomized, Multicenter Phase 3 Clinical Trial Evaluating Intracanalicular Dexamethasone Insert for the Treatment of Allergic Conjunctivitis.

Purpose: To evaluate the efficacy and safety of a dexamethasone intracanalicular insert (DEX) for treatment of allergic conjunctivitis (AC). Patients and Methods: In this multicenter, randomized, double-masked, placebo-controlled phase 3 study, adults (≥18 years) with AC were randomized 1:1 to DEX or placebo insert (PBO) placed bilaterally. Subjects underwent repetitive conjunctival allergen challenges (CAC) across 30 days and were assessed for changes in AC signs and symptoms. The primary endpoint was ocular itching score at 3, 5, and 7 minutes post-CAC at Day 8 (7 days post-insertion). This trial is registered on ClinicalTrials.gov (NCT04050865). Results: Ninety-six subjects were randomized (n=48 DEX, n=48 PBO). Compared to PBO, there were statistically significant treatment differences favoring DEX for the primary endpoint of mean ocular itching score at Day 8 (-0.86, -0.98, -0.96 at 3, 5, and 7 minutes post-CAC respectively; P<0.0001 for all). Treatment differences favored DEX for all 24 time points across 6 visits and were statistically significant (P<0.05) except for the first post-insertion (Day 7, 3 minutes). For the 18 time points at which conjunctival redness was assessed, DEX had lower scores than PBO (P<0.05 for all). The most common ocular adverse events (AEs) in DEX subjects were eye discharge and irritation. No serious AEs, elevated intraocular pressure, dacryocanaliculitis, or use of rescue medications were reported. Conclusion: Results of this study support the potential use of dexamethasone insert as a physician-administered, preservative-free treatment for AC, with significant improvements in ocular itching and conjunctival redness compared with placebo. The dexamethasone insert was generally safe with a favorable safety profile.

Nanocellulose in targeted drug delivery: A review of modifications and synergistic applications.

Nanocellulose, a versatile biopolymer renowned for its exceptional physicochemical attributes including lightweight, biocompatibility, biodegradability, and higher mechanical strength properties has captured significant attention in biomedical research. This renewable material, extracted from widely abundant biosources including plants, bacteria, and algae, exists in three primary forms: cellulose-based nanocrystals (CNCs), nanofibrils (CNFs), and bacterial nanocellulose (BNC). CNCs are characterized by their highly crystalline, needle-shaped structure, while CNFs possess a blend of amorphous and crystalline regions. BNC stands out as the purest form of nanocellulose. Chemical functionalization enables precise tuning of nanocellulose properties, enhancing its suitability for diverse biomedical applications. In drug delivery systems, nanocellulose's unique structure and surface chemistry offer opportunities for targeted delivery of active molecules. Surface-modified nanocellulose can effectively deliver drugs to specific sites, utilizing its inherent properties to control drug release kinetics and improve therapeutic outcomes. Despite these advantages, challenges such as achieving optimal drug loading capacity and ensuring sustained drug release remain. Future research aims to address these challenges and explore novel applications of nano-structured cellulose in targeted drug delivery, highlighting the continued evolution of this promising biomaterial in biomedicine. Furthermore, the review delves into the impact of chemical, physical, and enzymatic methods for CNC surface modifications, showcasing how these approaches enhance the functionalization of CNCs for targeted delivery of different compounds in biological systems.

Zein: Potential biopolymer in inflammatory bowel diseases.

Effectively managing inflammatory bowel disease (IBD) poses difficulties due to its persistent nature and unpredictable episodes of exacerbation. There is encouraging evidence that personalized medication delivery systems can improve therapy efficacy while reducing the negative effects of standard medicines. Zein, a protein produced from corn, has garnered interest as a possible means of delivering drugs for the treatment of IBD. This review delves into Zein-based drug delivery systems, showcasing its biodegradability, controlled release capabilities, and biocompatibility. Studies have shown that Zein-based nanoparticles, microcarriers, and core-shell microparticles have the capacity to increase medication stability, enhance targeting in the intestines, and decrease toxicity in animal models of IBD. The review highlights the promise of Zein in personalized therapy for IBD and urges more study to enhance its clinical use.

Identification and optimisation of perioperative factors for patients with von Willebrand disease undergoing elective total hip and knee arthroplasty.

Von Willebrand disease stands as the most prevalent bleeding disorder seen in both medical and surgical practice. Due to recurrent bleeding episodes within the joints, many patients endure arthropathy, leading to substantial pain and restricted function. Total joint arthroplasty emerges as a final option for managing such cases. Nevertheless, the existence of von Willebrand disease presents several challenges in this regard. This review aims to explore the perioperative strategies tailored for patients with von Willebrand disease undergoing elective total joint arthroplasty.

Innovative pharmacological approaches to hypertrophic cardiomyopathy: The emerging role of Aficamten.

Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy (LVH), which can lead to left ventricular outflow tract (LVOT) obstruction. Traditional treatments often provide limited symptom relief and may not adequately reduce the LVOT gradient. Myosin inhibitors, such as Aficamten , offer a new therapeutic approach by modulating myocardial contractility and improving symptoms. This paper evaluated the efficacy and safety of Aficamten in patients with symptomatic HCM. We conducted a comprehensive literature review of studies evaluating Aficamten for symptomatic HCM, including clinical trials and observational studies up to July 2024. Data on efficacy, safety, and patient outcomes were extracted and analyzed from a total of 10 studies involving 1,067 patients. Aficamten demonstrated substantial efficacy in reducing the LVOT gradient, with dose-dependent reductions ranging from 3.6 % to 48.6 %. It also improved symptoms, with 82.3 % of patients experiencing reduced left ventricular ejection fraction (LVEF) and notable improvements in New York Heart Association (NYHA) functional class. Exercise capacity was enhanced, as indicated by increased peak oxygen uptake. Safety profiles were generally favorable, though some serious adverse events, such as atrial fibrillation and cardiac dysfunction, were reported. Aficamten was well-tolerated overall, with manageable dose-dependent adverse effects. Aficamten represents a promising advance in the management of symptomatic HCM, offering significant reductions in LVOT gradient and improvement in symptoms and exercise capacity. Its safety profile is generally favorable, although ongoing monitoring is necessary to manage potential adverse effects. Future research should focus on long-term outcomes, comparative effectiveness, and real-world evidence.

Structural Snapshots of Proteus vulgaris Tryptophan Indole-Lyase Reveal Insights into the Catalytic Mechanism.

Tryptophan indole lyase (TIL; [E.C. 4.1.99.1]) is a bacterial pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyzes reversible ß-elimination of indole from L-tryptophan. The mechanism of elimination of indole from L-tryptophan starts with the formation of an external aldimine of the substrate and PLP, followed by deprotonation of the α-CH of the substrate, forming a resonance-stabilized quinonoid intermediate. Proton transfer to C3 of the indole ring and carbon-carbon bond cleavage of the quinonoid intermediate provide indole and aminoacrylate bound to PLP, which then releases indole, followed by iminopyruvate. We have now determined the X-ray crystal structures of TIL complexes with (3S)-dioxindolyl-l-alanine, an inhibitor, and with substrates L-tryptophan, 7-aza-L-tryptophan, and S-ethyl-l-cysteine (SEC) in the presence of benzimidazole (BZI), an isostere of the product indole. These structures show a mixture of gem-diamine, external aldimine, quinonoid, and aminoacrylate intermediates, in both open and closed active site conformations. In the closed conformations of L-tryptophan, (3S)-dioxindolyl-l-alanine, and 7-aza-L-tryptophan complexes, hydrogen bonds form between Asp-133 with N1 of the ligand heterocyclic ring and NE2 of His-458 in the small domain of TIL. This hydrogen bond also forms in the BZI complex with the aminoacrylate intermediates formed from both L-tryptophan and SEC. The closed quinonoid complex of 7-aza-L-tryptophan shows that the azaindole ring in the closed conformation is bent out of plane of the Cß-C3 bond by about 40°, putting it in a geometry that leads toward the transition-state geometry. Thus, both conformational dynamics and substrate activation play critical roles in the reaction mechanism of the TIL.

Acetaminophen for Patent Ductus Arteriosus and Risk of Mortality and Pulmonary Morbidity.

OBJECTIVE: Emerging data indicate that acetaminophen may adversely affect lung health. We examined whether acetaminophen compared with cyclooxygenase (COX) inhibitor alone for patent ductus arteriosus (PDA) is associated with mortality or respiratory morbidity in extremely preterm infants. METHODS: This is a retrospective cohort study using data from the National Institute of Child Health and Human Development Neonatal Research Network. Infants were born at 22 to 28 weeks' gestation or weighing 401 to 1000 g between 2016 and 2020 and received acetaminophen, ibuprofen, and/or indomethacin for PDA closure. The primary outcome was death or grade 2 to 3 bronchopulmonary dysplasia (BPD) at 36 weeks' postmenstrual age. Secondary outcomes included predischarge mortality and respiratory morbidities. Risk ratios were adjusted for baseline and early postnatal factors. Additional exploratory analyses were adjusted for later postnatal covariates. RESULTS: Of 1921 infants, 627 (32.6%) received acetaminophen and 1294 (67.3%) received COX inhibitor only. Multidrug therapy (42.9% vs 4.7%) and surgical or catheter PDA closure (26.5% vs 19.9%) were more common among acetaminophen-exposed infants. Death or grade 2 to 3 BPD at 36 weeks' postmenstrual age was similar between infants treated with acetaminophen versus COX inhibitor only (57.1% vs 58.3%; adjusted relative risk [aRR] 0.96, 95% confidence interval [CI] 0.87-1.06). Acetaminophen was associated with increased risk of predischarge mortality (13.3% vs 10.0%) when adjusting for perinatal and early postnatal factors (aRR 1.42, 95% CI 1.02-1.93), but not in exploratory analyses that included later postnatal factors (aRR 1.28, 95% CI 0.91-1.82). CONCLUSIONS: Treatment with acetaminophen versus COX inhibitor alone for PDA was not associated with the composite outcome of death or BPD in extremely preterm infants. Our results support further evaluation of whether acetaminophen for PDA increases mortality.

Immune cell profiling of the ICAM1 p.K56M heart failure with preserved ejection fraction risk variant.

AIMS: Intercellular adhesion molecule-1 (ICAM-1) facilitates inflammation via leucocyte recruitment and has been implicated in heart failure with preserved ejection fraction (HFpEF). Approximately 35% of African American individuals carry a copy of an ICAM1 missense variant (rs5491; p.K56M), which is associated with an increased risk of HFpEF. The pathways by which rs5491 increases HFpEF risk are not well defined. We evaluated the circulating immune cell profile of rs5491. METHODS: Among African American individuals in the Multi-Ethnic Study of Atherosclerosis, we evaluated the associations of rs5491 with 29 circulating peripheral blood mononuclear cell subsets. The top immune cells were then related to echocardiographic measures of structure and function. RESULTS: Among 502 individuals with immune cell profiling (mean age 63 years, 51% female), 191 individuals (38%) had at least one copy of rs5491. Each additional rs5491 allele was significantly associated with higher proportions of Tc17 CD8+ cytotoxic T cells (ß = 1.34, SE = 0.45, P = 9.5 × 10-5) and Tc2 CD8+ cytotoxic T cells (ß = 1.19, SE = 0.44, P = 0.00012). There were no other associations noted between rs5491 and the remaining immune cells. A higher proportion of Tc17 cells was significantly associated with a higher left ventricular ejection fraction, E/e' average and right ventricular systolic pressure (RVSP), while a higher proportion of Tc2 cells was significantly associated with a higher RVSP. CONCLUSIONS: The ICAM1 p.K56M variant (rs5491) carries a distinct and inflammatory T-cell subset profile. These cytotoxic T cells are in turn associated with alterations in cardiac function and adverse haemodynamics later in life, thus providing insight into pathways by which rs5491 may increase the risk of HFpEF.