Citations

AbstractIntroductionAlthough prior studies indicate that a QTc > 500 ms on a single baseline 12‐lead electrocardiogram (ECG) is associated with significantly increased risk of arrhythmic events in long QT syndrome (LQTS), less is known about the risk of persistent QT prolongation. We sought to determine QTc persistence and its prognostic effect on breakthrough cardiac events (BCEs) among pediatric patients treated for LQTS.MethodsWe performed a retrospective analysis of 433 patients with LQTS evaluated, risk‐stratified, and undergoing active guideline‐based LQTS treatment between 1999 and 2019. BCEs were defined as arrhythmogenic syncope/seizure, sudden cardiac arrest (SCA), appropriate VF‐terminating ICD shock, and sudden cardiac death (SCD).ResultsDuring the median follow‐up of 5.5 years (interquartile range [IQR] = 3–9), 32 (7%) patients experienced a total of 129 BCEs. A maximum QTc threshold of 520 ms and median QTc threshold of 490 ms were determined to be strong predictors for BCEs. A landmark analysis controlling for age, sex, genotype, and symptomatic status demonstrated models utilizing both the median QTc and maximum QTc demonstrated the highest discriminatory value (c‐statistic = 0.93–0.95). Patients in the high‐risk group (median QTc > 490 ms and maximum QTc > 520 ms) had a significantly lower BCE free survival (70%–81%) when compared to patients in both medium‐risk (93%–97%) and low‐risk (98%–99%) groups.ConclusionsThe risk of BCE among patients treated for LQTS increases not only based upon their maximum QTc, but also their median QTc (persistence of QTc prolongation). Patients with a maximum QTc > 520 ms and median QTc > 490 ms over serial 12‐lead ECGs are at the highest risk of BCE while on guideline‐directed medical therapy.

Objective: To investigate the longitudinal effects of COVID-19 on major vascular structures and parameters and clinical outcomes. Design: Observational prospective trial. Setting: Post-COVID-19 research clinic established by University of Louisville Division of Infectious Diseases. Participants: The study population consisted of 72 post-COVID-19 individuals and 11 non-COVID-19 infected participants in the control group. The participants were recruited from adult hospitals and from the community. The enrollment started in October 2020 and follow-up periods were at 3, 6, and 12 months from their initial COVID-19 diagnosis. Interventions: The participants were interviewed for medical and COVID-19 infection history. Samples of white blood cell (WBC), C-reactive protein (CRP), and D-dimer were taken at each visit. Certified sonographers performed vascular ultrasound on the study participants. Measurements and Main Results: Median intima-media thickness (IMT) was increased in mild/asymptomatic (0.80 mm) and severe/critical (0.90 mm) groups when compared with controls (0.60 mm; P < .001 for both groups). In the asymptomatic/mild group, 6-month median IMT (0.88 mm) was increased, compared with the 3-month group (0.75 mm), with P = .026. Increased age was associated with decreased mean arterial blood velocities (cm/s): common carotid ( r = −0.236, P = .032), internal carotid ( r = −0.208, P = .048), and subclavian artery mean velocity ( r = −0.357, P = .003). We did not find any instance of deep vein thrombosis. Median D-dimer, CRP, and WBC in the control group differed from asymptomatic/mild COVID-19 group ( P = .026, .011, and .003, respectively). Moreover, WBC in the asymptomatic/mild group and moderate COVID-19 group differed from severe/critical group ( P = .025 and P = .027, respectively); CRP also differed between asymptomatic/mild group and severe/critical group ( P = .014). Conclusions: There were differences in intima-media lumen thickness (IMT), arterial velocities, and inflammatory markers in post-COVID-19 patients. There was no instance of deep vein thrombosis in this post-COVID-19 study cohort. The increased IMT might infer atherosclerosis, which has shown to increase cardiovascular risks. It is not yet known whether the increase in IMT due to COVID should be treated in the same way as non-COVID-19 atherosclerosis—through statins, for example—or whether regular cardiovascular risk reduction would be useful. Clinical trial and mechanistic studies should be performed to further our understanding of COVID-19-related vascular pathologies.

Objective Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. Design Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). Result We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. Conclusion Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.

AbstractExpiratory central airway collapse (ECAC) comprising excessive central airway collapse (EDAC) and tracheobronchomalacia. Treatment is challenging for severe cases that are not candidates for surgical management. We report a case of severe ECAC successfully managed with continuous positive airway pressure (CPAP) therapy. A 75‐year‐old female patient status post right pneumonectomy, presented with chronic cough. Dynamic bronchoscopy evaluation showed severe EDAC which improved with intraprocedural noninvasive positive pressure (NIPPV) therapy. Due to patients' comorbidities, she was not a candidate to surgical tracheobronchoplasty. Therefore, we attempted pneumatic stenting with long‐term CPAP therapy resulting in improvement of symptoms and functional capacity. The long‐term efficacy of pneumatic stenting has not been clearly established yet. Literature review of management of ECAC with NIPPV consist primarily of case reports and there is only one clinical trial being conducted to assess the efficacy of CPAP therapy in ECAC. While NIPPV arises as a sufficient alternative for management of severe ECAC, larger scale studies are needed to prove the real efficacy of NIPPV in this setting.

OBJECTIVE This study aimed to provide data on extended outcomes in primary clival chordomas, focusing on progression-free survival (PFS) and overall survival (OS). METHODS A retrospective single-center analysis was conducted on patients with clival chordoma treated between 1987 and 2022 using surgery, stereotactic radiosurgery, or proton radiation therapy (PRT). RESULTS The study included 100 patients (median age 44 years, 51% male). Surgery was performed using the endoscopic endonasal approach in 71 patients (71%). Gross-total resection (GTR) or near-total resection (NTR) was attained in 39 patients (39%). Postoperatively, new cranial nerve deficits occurred in 7%, CSF leak in 4%, and meningitis in none of the patients. Radiation therapy was performed in 79 patients (79%), with PRT in 50 patients (50%) as the primary treatment. During the median follow-up period of 73 (interquartile range [IQR] 38–132) months, 41 recurrences (41%) and 31 deaths (31%) were confirmed. Patients with GTR/NTR had a median PFS of 41 (IQR 24–70) months. Patients with subtotal resection or biopsy had a median PFS of 38 (IQR 16–97) months. The median PFS of patients who received radiation therapy was 43 (IQR 26–86) months, while that of patients who did not receive radiation therapy was 18 (IQR 5–62) months. The Kaplan-Meier method showed that patients with GTR/NTR (p = 0.007) and those who received radiation therapy (p < 0.001) had longer PFS than their counterparts. The PFS rates following primary treatment at 5, 10, 15, and 20 years were 51%, 25%, 17%, and 7%, respectively. The OS rates at the same intervals were 84%, 60%, 42%, and 34%, respectively. Multivariate Cox regression analysis showed that age < 44 years (p = 0.02), greater extent of resection (EOR; p = 0.03), and radiation therapy (p < 0.001) were associated with lower recurrence rates. Another multivariate analysis showed that age < 44 years (p = 0.01), greater EOR (p = 0.04), and freedom from recurrence (p = 0.02) were associated with lower mortality rates. Regarding pathology data, brachyury was positive in 98%, pan-cytokeratin in 93%, epithelial membrane antigen in 85%, and S100 in 74%. No immunohistochemical markers were associated with recurrence. CONCLUSIONS In this study, younger age, maximal safe resection, and radiation therapy were important factors for longer PFS in patients with primary clival chordomas. Preventing recurrences played a crucial role in achieving longer OS.

Abstract Artificial intelligence (AI) models based on deep learning of mammogram images have been developed for lesion detection and diagnosis as well as breast cancer (BC) risk. We and others have shown that these AI models, coupled with breast density, predict long-term breast cancer risk. Common germline genetic variation, in particular a polygenic risk score (PRS) that captures the cumulative impact of hundreds of common risk variants, has been shown associated with 3-fold increased BC risk. The BC-PRS may complement imaging risk factors to improve identification of women at high BC risk and better target prevention strategies. We evaluated the contribution of a BC-PRS to two imaging-based AI models (Transpara AI cancer detection system and Mirai 5-year risk) and breast density measures to long-term BC risk. We hypothesized that the BC-PRS will improve long-term risk prediction above AI and density measures. We examined this hypothesis within a cohort of 10,271 women enrolled to the Mayo Clinic Biobank between 2009 and 2015. Eligible women had no prior cancer, were ages 35 to 85, had a full-field digital screening mammogram within two years of enrollment and genotyping by Regeneron. Incident invasive and DCIS BC was identified through the Mayo tumor registry and follow-up questionnaires, and person years were calculated from date of mammogram through date of BC, last mammogram at Mayo or last questionnaire. We estimated Transpara AI malignancy score (1-10), 5-year Mirai risk and Volpara volumetric density measures (volumetric percent density, dense volume) on screening mammograms at enrollment and obtained clinical BI-RADS density. We calculated the BC-PRS using 268 SNPs (of the 313-SNP score) and the weighted sum of the SNPs using odds ratios from the largest BC GWAS of European ancestry to date. We performed cox proportional hazards regression adjusting for age and BMI to estimate hazard ratios (HRs), 95% confidence intervals (CI), and C-statistics (AUC) to describe the contribution of BC-PRS (per standard deviation (SD)) to the association of AI scores and breast density with BC risk. Likelihood ratio tests (LRT) and bootstrapping were used to compare model performance with vs. without inclusion of BC-PRS, at 10-years follow-up. Comparisons to the Tyrer-Cuzick model are ongoing. Over a median of 9.1 years (Interquartile range, 6.8 to 10.6), 446 incident BC were identified of which 285 invasive and 103 DCIS were confirmed by pathology report (60 were self-reported); 399 (256 invasive) occurred within 10 years and were used in primary analyses. Transpara score [HR per 1 unit=1.18 (1.14, 1.23), AUC=0.655 (0.628, 0.682)] and Mirai risk [HR per SD log risk=1.54 (1.43, 1.65), AUC=0.681 (0.655, 0.706)] were both associated with BC. All three breast density measures were also significantly associated with BC, including in models with AI scores (Table). Addition of the BC-PRS to models with AI scores and breast density improved both model fit (All PLRT &lt; 0.001; Table) and discrimination, with increases in AUC ranging from 0.033 to 0.034 for models with Transpara and density and 0.025 to 0.026 for models with Mirai and density (all P-values &lt; 0.001; Table). Analyses restricted to invasive BC showed identical results. But, the BC-PRS contribution at 5-year follow-up was attenuated. In this cohort study, we found BC-PRS contributed to long-term risk prediction of BC above imaging AI models and breast density. Imaging and genetic risk factors are complementary and may outperform existing risk models and provide more accurate risk assessment to aid in precision prevention strategies. Citation Format: Celine Vachon, Christopher Scott, Imon Banerjee, Ramon Correa Moderno, Dan Hursh, Matthew Jensen, Yvonne Wang, Kathleen Brandt, Karla Kerlikowske, Sandhya Pruthi, Fergus Couch, Stacey Winham. Contribution of a breast cancer polygenic risk score to mammography artificial intelligence models and breast density for long term breast cancer risk prediction [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS10-06.

Purpose: The purpose of this literature review is to guide speech-language pathologists (SLPs) on how to increase effective collaboration with interpreters and translators in order to enhance communication with clients and significant others from culturally and linguistically diverse backgrounds. Method: A review of definitions of interpretation and translations and practical guidance on certifications and collaborative practices within a health literacy framework approach is described. Strategies to build effective and ethical SLP–interpreter/translator working relationships are reviewed. Results: Findings emphasize the importance of interprofessional collaboration between SLPs and interpreters/translators. When working with professional interpreters/translators, SLPs application of a brief–intervention–debrief framework, use of plain language, and knowledge of local and national training and practice requirements, are identified as mechanisms to enhance effective and ethical collaboration. Conclusion: Effective collaboration with interpretation and translation services should be a key component of clinical practice to ensure that health information is clearly understood by clients and families.

Background: Acute cardiac injury (ACI) after COVID-19 has been linked with unfavorable clinical outcomes, but data on the clinical impact of elevated cardiac troponin on discharge during follow-up are scarce. Our objective is to elucidate the clinical outcome of patients with elevated troponin on discharge after surviving a COVID-19 hospitalization. Methods: We conducted an analysis in the prospective registry HOPE-2 (NCT04778020). Only patients discharged alive were selected for analysis, and all-cause death on follow-up was considered as the primary endpoint. As a secondary endpoint, we established any long-term COVID-19 symptoms. HOPE-2 stopped enrolling patients on 31 December 2021, with 9299 patients hospitalized with COVID-19, of which 1805 were deceased during the acute phase. Finally, 2382 patients alive on discharge underwent propensity score matching by relevant baseline variables in a 1:3 fashion, from 56 centers in 8 countries. Results: Patients with elevated troponin experienced significantly higher all-cause death during follow-up (log-rank = 27.23, p < 0.001), and had a higher chance of experiencing long-term COVID-19 cardiovascular symptoms. Specifically, fatigue and dyspnea (57.7% and 62.8%, with p-values of 0.009 and <0.001, respectively) are among the most common. Conclusions: After surviving the acute phase, patients with elevated troponin on discharge present increased mortality and long-term COVID-19 symptoms over time, which is clinically relevant in follow-up visits.

Introduction: Most of long QT syndrome (LQTS) is explained by pathogenic variants in KCNQ1 , KCNH2 , or SCN5A . However, ~10-20% of LQTS index cases remain genetically elusive following commercial genetic testing. Here, we identified and functionally characterized a novel LQTS genetic substrate in a multi-generational, “genotype negative” LQTS pedigree. Methods: The index case was a 40-year-old female with a history of syncope, seizures, ventricular fibrillation, and a family history of LQTS and sudden death. Although anticipated to have KCNH2- mediated LQT2, commercial genetic testing of all LQTS-causative genes was negative. Genome sequencing and variant analysis was performed on 6 affected family members. Patient-specific and CRISPR/Cas9 “gene-corrected” isogenic control induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) were generated. RT-PCR was used to determine the effects of the identified variant on splicing. Action potential duration (APD) and field potential duration (FPD) were measured using voltage-sensing dye (Fluovolt) and microelectrode array, respectively. Results: No ultra-rare, nonsynonymous heterozygous variants co-segregated among the 6 LQTS phenotype-positive individuals. Instead, a deep intronic KCNH2 variant (c.3331-316 G>T) was present in all affected individuals. RT-PCR analysis of patient-specific iPSC-CM-derived RNA revealed that c.3331-316 G>T creates a novel 89 base-pair exon residing between canonical exons 14 and 15 of KCNH2 that results in a frame-shift variant annotated as p.S1112Pfs*171. The APD 90 was significantly longer in p.S1112Pfs*171-iPSC-CMs (647 ± 12 ms, n=50) compared to isogenic control iPSC-CMs (412 ± 10 ms, n=50, p < 0.0001). Further, the FPD was significantly longer in p.S1112Pfs*171-iPSC-CMs (349 ± 8 ms, n=48) compared to isogenic control iPSC-CMs (209 ± 10 ms, n=20, p < 0.0001). Conclusions: A novel deep intronic KCNH2 variant was identified in a multi-generational genetically elusive LQTS pedigree. The patient-derived and isogenic control iPSC-CMs establish that the p.S1112Pfs*171-KCNH2 variant is the monogenetic cause for this family’s LQTS. As suggested by the phenotype, this family indeed has KCNH2 -mediated LQT2 albeit stemming from a deep intronic variant .