Citations

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Background: Patients with ccTGA have a high incidence of atrial arrhythmias and premature failure of the systemic right ventricle. We sought to better define this risk. Methods: A retrospective review of all clinical data for patients with ccTGA followed at a large tertiary care institution was performed. The primary outcome was a composite of death and cardiac transplantation. Results: A cohort of 165 patients (age 41±16 years, 53% male) were followed for 11±8 years; 41 patients died, 7 underwent cardiac transplantation, and 4 underwent VAD placement. Male sex (HR 2.7, p=0.002), older age (HR 1.04, p<0.001), clinical heart failure symptoms (HR 7, p<0.001), heart failure hospitalization (HR 4.9, p<0.001), syncope (HR 1.8, p=0.04) and pulmonary hypertension (HR 2.77, p<0.001) were significant predictors of the primary outcome. Atrial fibrillation (HR 3.5, p=0.002), atrial flutter (HR 3.05, p=0.04), and prolonged QRS duration (HR 1.01, p=0.004) on the first ECG, as well as right and left atrial enlargement (HR 4, p<0.001 and 3.7, p<0.003) and severe systemic AV valve regurgitation (HR 3.8, p=0.03) on the first echocardiogram were associated with poor outcomes. Atrial arrhythmias occurred in 110(67%) patients: atrial fibrillation in 75(45%), atrial flutter in 50(30%), and supraventricular tachycardia in 16(9.7%) patients. Arrhythmias were largely asymptomatic in 109(66%) patients, while 25(14.5%) experienced palpitations, dizziness or presyncope, and 10(6%) presented with decompensated heart failure. Cardioversion and antiarrhythmic therapy were utilized in 53(32%) patients. Surgical pulmonary vein isolation or atrial MAZE were performed in 15(9%) patients, cryoablation of the CTI in 3 patients, and surgical ablation of an accessory pathway in 2 patients. One or more catheter ablation procedures were also performed in 18(11%) patients. Conclusions: Atrial fibrillation and flutter, heart failure, prolonged QRS duration, systemic AV valve regurgitation and pulmonary hypertension predict worse outcomes in ccTGA. Although asymptomatic in a majority of patients, atrial arrhythmias are associated with significant morbidity and mortality. Whether a rhythm control strategy even in asymptomatic patients may improve outcomes remains unknown.

Introduction: Telestroke is an effective strategy to increase appropriate stroke treatments among patients in resource-limited environments. Despite the well-documented benefits of telestroke, there is limited literature regarding its utilization. The purposes of this study are: (1) determine the percentage of potential stroke patients who generate a telestroke consult in rural critical access hospitals (CAHs) and (2) validate an electronic medical record (EMR)-derived report as a stroke screen. Methods: This retrospective chart review analyzed patients presenting between September 1, 2020 and February 1, 2021 to three CAHs. Visits with triage complaints suggesting acute ischemic stroke (AIS)/transient ischemic attack (TIA) were pooled for analysis using an EMR-derived report. Patients with confirmed AIS/TIA at discharge over this period were used to validate the EMR tool. Results: The EMR report pooled 252 possible AIS/TIA visits out of 12,685 emergency department visits for analysis. It had a specificity of 98.78% and sensitivity of 58.06%. Of the 252 visits, 12.7% met telestroke criteria and 38.89% received telestroke evaluation. Among these, a definite diagnosis of AIS/TIA was made in 92.86%. Of the remaining population who met criteria but didn't undergo consultation, 61.11% were diagnosed with AIS/TIA at discharge. Conclusion: This study provides novel characterization of stroke presentations and telestroke in rural CAHs. The EMR-derived report is a reasonable tool to concentrate potential AIS/TIA cases for review and resource allocation but is not sensitive enough to detect stroke as a stand-alone tool. The majority (56%) of eligible patients did not undergo telestroke consultation. Future studies are critical to further understand reasons contributing to this.

Cellular senescence is emerging as a driver of idiopathic pulmonary fibrosis (IPF), a progressive and fatal disease with limited effective therapies. The senescence-associated secretory phenotype (SASP), involving the release of inflammatory cytokines and profibrotic growth factors by senescent cells, is thought to be a product of multiple cell types in IPF, including lung fibroblasts. NF-κB is a master regulator of the SASP, and its activity depends on the phosphorylation of p65/RelA. The purpose of this study was to assess the role of Pim-1 kinase as a driver of NF-κB-induced production of inflammatory cytokines from low-passage IPF fibroblast cultures displaying markers of senescence. Our results demonstrate that Pim-1 kinase phosphorylates p65/RelA, activating NF-κB activity and enhancing IL-6 production, which in turn amplifies the expression of PIM1, generating a positive feedback loop. In addition, targeting Pim-1 kinase with a small molecule inhibitor dramatically inhibited the expression of a broad array of cytokines and chemokines in IPF-derived fibroblasts. Furthermore, we provide evidence that Pim-1 overexpression in low-passage human lung fibroblasts is sufficient to drive premature senescence, in vitro. These findings highlight the therapeutic potential of targeting Pim-1 kinase to reprogram the secretome of senescent fibroblasts and halt IPF progression.

ImportanceThere is a knowledge gap about subcutaneous panniculitis-like T-cell lymphoma (SPTCL) owing to its rarity and diagnostic difficulty, resulting in an absence of well-documented large case series published to date.ObjectiveTo generate consensus knowledge by a joint multi-institutional review of SPTCL and related conditions.Design, Setting, and ParticipantsThis retrospective clinical and pathological review included cases initially diagnosed as SPTCL at 6 large US academic centers. All cases were reviewed by a group of pathologists, dermatologists, and oncologists with expertise in cutaneous lymphomas. Through a process of group consensus applying defined clinical and pathological diagnostic criteria, the cohort was classified as (1) SPTCL or (2) adipotropic lymphoproliferative disorder (ALPD) for similar cases with incomplete histopathological criteria for SPTCL designation.ExposuresCases of SPTCL diagnosed between 1998 and 2018.Main Outcomes and MeasuresThe main outcome was disease presentation and evolution, including response to therapy, disease progression, and development of hemophagocytic lymphohistiocytosis.ResultsThe cohort of 95 patients (median [range] age, 38 [2-81] years; female-to-male ratio, 2.7) included 75 cases of SPTCL and 20 cases of ALPD. The clinical presentation was similar for both groups with multiple (61 of 72 [85%]) or single (11 of 72 [15%]) tender nodules mostly involving extremities, occasionally resulting in lipoatrophy. Hemophagocytic lymphohistiocytosis (HLH) was only observed in SPTCL cases. With a mean follow-up of 56 months, 60 of 90 patients (67%) achieved complete remission with a median (range) of 3 (1-7) cumulative therapies. Relapse was common. None of the patients died of disease progression or HLH. Two patients with ALPD eventually progressed to SPTCL without associated systemic symptoms or HLH.Conclusions and RelevanceIn this case series of patients initially diagnosed as having SPTCL, results showed no evidence of systemic tumoral progression beyond the adipose tissue. The SPTCL experience in this study confirmed an indolent course and favorable response to a variety of treatments ranging from immune modulation to chemotherapy followed by hematopoietic stem cell transplantation. Morbidity was primarily associated with HLH.

Background: Patients with D-transposition of the great arteries and atrial switch have a high incidence of atrial arrhythmias. We sought to analyze the arrhythmia substrate, ablation strategies, and outcomes for catheter ablation in this population. Methods: An in-depth analysis of all clinical and procedural data in patients with D-transposition of the great arteries, atrial baffles, and atrial arrhythmia ablation was performed. Results: A cohort of 32 patients (72% male, mean age 38±7 years) underwent ablation for non-AV nodal reentrant tachycardia atrial arrhythmias, and 4 patients underwent AV nodal reentrant tachycardia ablation. Cavotricuspid isthmus flutter (CTI-flutter) was the most common arrhythmia, encountered in 75% of patients, followed by scar-related intraatrial reentrant tachycardia (non-CTI intraatrial reentrant tachycardia, 53%) and focal atrial tachycardia (focal atrial tachycardia, 6%). Among the 32 patients, 26 underwent 31 procedures at our institution. For patients with prior outside intervention, the index ablation at our institution revealed CTI-dependent flutter in 3/5 cases. However, redo ablation after an index ablation with demonstrated bidirectional CTI block revealed different/new arrhythmia substrates (80% non-CTI intraatrial reentrant tachycardia, 40% focal atrial tachycardia). Achieving bidirectional block across the CTI often required ablating on both sides of the baffle (retroaortic access, 81%; using a baffle leak, 11.5%; or transbaffle puncture, 7.7%). Combined approaches were necessary in 19% to reach the critical tissue. Acute procedural success was 81%, and recurrence was documented in 58% of patients. Despite recurrence, clinical arrhythmia burden was significantly reduced post-ablation ( P <0.001), with rare episodes, amenable to antiarrhythmic therapy. Redo ablation was required in 5 (19%) patients and uncovered new arrhythmia substrates. AV nodal reentrant tachycardia ablation also required transbaffle approaches in 3/4 patients. Conclusions: CTI-dependent flutter was the most common arrhythmia in patients with Dextro-Transposition of the Great Arteries and atrial switch. Transbaffle approaches were often necessary, and, provided that bidirectional CTI block was achieved at the index ablation, late recurrence was due to different arrhythmia mechanisms. Despite recurrence, ablation was associated with significant clinical improvement.

Abstract INTRODUCTION: Postoperative stress induced insulin resistance, and the resulting glycemic variability, is clearly associated with complication rates in cardiac surgery. Despite this, there is a paucity of data regarding the duration of stress induced hyperglycemia in cardiac surgery as well as the impact of specific strategies for carbohydrate loading in cardiac surgery patients. Prior work in colorectal and bariatric surgery has shown a significant reduction in glycemic events with the use of a low dose maltodextrin and citrulline loading strategy, but there is no data that the commonly recommended 50 gram supplements provides any impact on stress induced postoperative hyperglycemia. The aim of this study was to compare standard of care (SOC group) versus a three dose, 25 gram dose carbohydrate loading strategy (CL group) on the duration and severity of postoperative glycemic variability in both diabetic and non-diabetic cardiac surgery patients.METHODS: We compared CABG/AVR/MVR retrospective patients who received standard of care (SOC) to a prospective set of patients who were carbohydrate loaded (CL) with 3 preoperative doses of 25g maltodextrin/3g citrulline (G.E.D.TM, SOF Health, LLC).RESULTS: 152 patients total were included (SOC n=80, CL n= 72). 66 patients were diabetic. In both non-diabetic and diabetic patient populations, there was a statistically significant reduction in glycemic variability in G.E.D. groups for non- diabetics (27% reduction) and diabetics (40% reduction). The glycemic variability on POD 2 was not statistically different between treatment groups in non-diabetics (G.E.D. 25.2% vs SOC 24.7%) but approached significance in diabetics (G.E.D. 24.7% vs SOC 32.9%e). CONCLUSION: These are the first data demonstrating the reduction in post operative stress induced glycemic variability in cardiac surgery using a low dose carbohydrate loading regimen which includes the amino acid citrulline. The impact of surgical stress on glycemic variability appears to resolve by POD#2 in non-diabetics but may persist longer in diabetic patients. These data represent the first information regarding the benefits of a specific strategy for carbohydrate loading to reduces the stress induced component of post operative hyperglycemia in cardiac surgery.

Introduction: Atrial arrhythmias are common in patients with D-TGA and atrial switch. We sought to analyze the arrhythmia substrate and catheter ablation approaches and outcomes. Methods: We performed a retrospective review of all clinical and procedural data in patients with D-TGA followed at a large tertiary care center. Results: In a cohort of 152 patients (mean age 30±11 years), atrial tachycardia was present in 69(45%) patients. Ablations were performed in 39(26%) patients: macro-reentrant atrial flutter (N=37), atrial fibrillation (N=4), and focal automatic atrial tachycardia (N=3). Detailed electrophysiology study data was available for 34 patients. At first ablation (N=28), cavo-tricuspid isthmus dependent flutter (CTI, 23(82%)) was most common, followed by right atriotomy-related flutter (IART, 16(57%)) and focal atrial tachycardia (FAT, 1(3.5%)). Bidirectional CTI block often required ablation on both sides of the baffle to complete the isthmus line. Access to the pulmonary venous atrium was obtained in 82% of first-time ablations (via retrograde aortic access, 74%, baffle puncture, 6%, or baffle fenestration, 12%) and in 100% of redo procedures. The first ablation was acutely successful in 25 (89%) patients; the other 3 patients had either partial procedural success (1), failed ablation (1), or underwent an empirical ablation (1). Long-term arrhythmia recurrence occurred in 13(46%) after the first ablation and class III antiarrhythmic medications were utilized in 12 patients. At least one long-term recurrence occurred in 11(44%) patients. Importantly, clinical arrhythmia burden was significantly reduced post-ablation, with rare and short-limited episodes amenable to antiarrhythmic drugs or cardioversion. Repeat ablation was required in 3 cases. Long-term arrhythmia recurrence after a previously completed CTI line involved different arrhythmia mechanisms: scar-related reentry (80%) and automatic atrial tachycardia (40%). Conclusions: Atrial arrhythmia in patients with D-TGA often involves the CTI and atriotomy scars. Ablation of the CTI typically requires access to the pulmonary venous atrium to achieve bidirectional block. Despite late recurrence, the clinical arrhythmic burden is substantially improved.