Childhood screening for type 1 diabetes comparing automated multiplex Antibody Detection by Agglutination-PCR (ADAP) with single plex islet autoantibody radiobinding assays.

BACKGROUND: Two or more autoantibodies against either insulin (IAA), glutamic acid decarboxylase (GADA), islet antigen-2 (IA-2A) or zinc transporter 8 (ZnT8A) denote stage 1 (normoglycemia) or stage 2 (dysglycemia) type 1 diabetes prior to stage 3 type 1 diabetes. Automated multiplex Antibody Detection by Agglutination-PCR (ADAP) assays in two laboratories were compared to single plex radiobinding assays (RBA) to define threshold levels for diagnostic specificity and sensitivity. METHODS: IAA, GADA, IA-2A and ZnT8A were analysed in 1504 (54% females) population based controls (PBC), 456 (55% females) doctor's office controls (DOC) and 535 (41% females) blood donor controls (BDC) as well as in 2300 (48% females) patients newly diagnosed (1-10 years of age) with stage 3 type 1 diabetes. The thresholds for autoantibody positivity were computed in 100 10-fold cross-validations to separate patients from controls either by maximizing the χ2-statistics (chisq) or using the 98th percentile of specificity (Spec98). Mean and 95% CI for threshold, sensitivity and specificity are presented. FINDINGS: The ADAP ROC curves of the four autoantibodies showed comparable AUC in the two ADAP laboratories and were higher than RBA. Detection of two or more autoantibodies using chisq showed 0.97 (0.95, 0.99) sensitivity and 0.94 (0.91, 0.97) specificity in ADAP compared to 0.90 (0.88, 0.95) sensitivity and 0.97 (0.94, 0.98) specificity in RBA. Using Spec98, ADAP showed 0.92 (0.89, 0.95) sensitivity and 0.99 (0.98, 1.00) specificity compared to 0.89 (0.77, 0.86) sensitivity and 1.00 (0.99, 1.00) specificity in the RBA. The diagnostic sensitivity and specificity were higher in PBC compared to DOC and BDC. INTERPRETATION: ADAP was comparable in two laboratories, both comparable to or better than RBA, to define threshold levels for two or more autoantibodies to stage type 1 diabetes. FUNDING: Supported by The Leona M. and Harry B. Helmsley Charitable Trust (grant number 2009-04078), the Swedish Foundation for Strategic Research (Dnr IRC15-0067) and the Swedish Research Council, Strategic Research Area (Dnr 2009-1039). AL was supported by the DiaUnion collaborative study, co-financed by EU Interreg ÖKS, Capital Region of Denmark, Region Skåne and the Novo Nordisk Foundation.

Significant Association of Serum Albumin With the Severity of Coronary Microvascular Dysfunction Using Dynamic CZT-SPECT.

OBJECTIVE: Both low serum albumin (SA) concentration and coronary microvascular dysfunction (CMD) are risk factors for the development of heart failure (HF). We hypothesized that SA concentration is associated with myocardial flow reserve (MFR) and implicated in pathophysiological mechanism of HF. METHODS: We retrospectively studied 454 patients undergoing dynamic cardiac cadmium-zinc-telluride myocardial perfusion imaging from April 2018 to February 2020. The population was categorized into three groups according to SA level (g/dL): Group 1: >4, Group 2: 3.5-4, and Group 3: <3.5. Myocardial blood flow (MBF) and myocardial flow reserve (MFR, defined as stress/rest MBF ratio) were compared. RESULTS: The mean age of the whole cohort was 66.2 years, and 65.2% were men. As SA decreased, stress MBF (mL min-1 g-1) and MFR decreased (MBF: 3.29 ± 1.03, MFR: 3.46 ± 1.33 in Group 1, MBF: 2.95 ± 1.13, MFR: 2.51 ± 0.93 in Group 2, and MBF: 2.64 ± 1.16, MFR: 1.90 ± 0.50 in Group 3), whereas rest MBF (mL min-1 g-1) increased (MBF: 1.05 ± 0.42 in Group 1, 1.27 ± 0.56 in Group 2, and 1.41 ± 0.61 in Group 3). After adjusting for covariates, compared with Group 1, the odds ratios for impaired MFR (defined as MFR < 2.5) were 3.57 (95% CI: 2.32-5.48) for Group 2 and 34.9 (95% CI: 13.23-92.14) for Group 3. The results would be similar if only regional MFR were assessed. The risk prediction for CMD using SA was acceptable, with an AUC of 0.76. CONCLUSION: Low SA concentration was associated with the severity of CMD in both global and regional MFR as well as MBF.

CalScope: methodology and lessons learned for conducting a remote statewide SARS-CoV-2 seroprevalence study in California using an at-home dried blood spot collection kit and online survey.

BACKGROUND: To describe the methodology for conducting the CalScope study, a remote, population-based survey launched by the California Department of Public Health (CDPH) to estimate SARS-CoV-2 seroprevalence and understand COVID-19 disease burden in California. METHODS: Between April 2021 and August 2022, 666,857 randomly selected households were invited by mail to complete an online survey and at-home test kit for up to one adult and one child. A gift card was given for each completed survey and test kit. Multiple customized REDCap databases were used to create a data system which provided task automation and scalable data management through API integrations. Support infrastructure was developed to manage follow-up for participant questions and a communications plan was used for outreach through local partners. RESULTS: Across 3 waves, 32,671 out of 666,857 (4.9%) households registered, 6.3% by phone using an interactive voice response (IVR) system and 95.7% in English. Overall, 25,488 (78.0%) households completed surveys, while 23,396 (71.6%) households returned blood samples for testing. Support requests (n = 5,807) received through the web-based form (36.3%), by email (34.1%), and voicemail (29.7%) were mostly concerned with the test kit (31.6%), test result (26.8%), and gift card (21.3%). CONCLUSIONS: Ensuring a well-integrated and scalable data system, responsive support infrastructure for participant follow-up, and appropriate academic and local health department partnerships for study management and communication allowed for successful rollout of a large population-based survey. Remote data collection utilizing online surveys and at-home test kits can complement routine surveillance data for a state health department.

Stacking architecture for collimated backlight using cylindrical lens sheet with linear light sources or edge-lit/direct-lit BLU.

Highly collimated and directional backlights are essential for realizing advanced display technologies such as autostereoscopic 3D displays. Previously reported collimated backlights, either edge-lit or direct-lit, in general still suffer unsatisfactory form factors, directivity, uniformity, or crosstalk etc. In this work, we report a simple stacking architecture for the highly collimated and uniform backlights, by combining linear light source arrays and carefully designed cylindrical lens arrays. Experiments were conducted to validate the design and simulation, using the conventional edge-lit backlight or the direct-lit mini-LED (mLED) arrays as light sources, the NiFe (stainless steel) barrier sheets, and cylindrical lens arrays fabricated by molding. Highly collimated backlights with small angular divergence of ±1.45°âˆ¼±2.61°, decent uniformity of 93-96%, and minimal larger-angle sidelobes in emission patterns were achieved with controlled divergence of the light source and optimization of lens designs. The architecture reported here provides a convenient way to convert available backlight sources into a highly collimated backlight, and the use of optically reflective barrier also helps recycle light energy and enhance the luminance. The results of this work are believed to provide a facile approach for display technologies requiring highly collimated backlights.

Accelerating Antimicrobial Peptide Discovery for WHO Priority Pathogens through Predictive and Interpretable Machine Learning Models.

The escalating menace of multidrug-resistant (MDR) pathogens necessitates a paradigm shift from conventional antibiotics to innovative alternatives. Antimicrobial peptides (AMPs) emerge as a compelling contender in this arena. Employing in silico methodologies, we can usher in a new era of AMP discovery, streamlining the identification process from vast candidate sequences, thereby optimizing laboratory screening expenditures. Here, we unveil cutting-edge machine learning (ML) models that are both predictive and interpretable, tailored for the identification of potent AMPs targeting World Health Organization's (WHO) high-priority pathogens. Furthermore, we have developed ML models that consider the hemolysis of human erythrocytes, emphasizing their therapeutic potential. Anchored in the nuanced physical-chemical attributes gleaned from the three-dimensional (3D) helical conformations of AMPs, our optimized models have demonstrated commendable performance-boasting an accuracy exceeding 75% when evaluated against both low-sequence-identified peptides and recently unveiled AMPs. As a testament to their efficacy, we deployed these models to prioritize peptide sequences stemming from PEM-2 and subsequently probed the bioactivity of our algorithm-predicted peptides vis-à-vis WHO's priority pathogens. Intriguingly, several of these new AMPs outperformed the native PEM-2 in their antimicrobial prowess, thereby underscoring the robustness of our modeling approach. To elucidate ML model outcomes, we probe via Shapley Additive exPlanations (SHAP) values, uncovering intricate mechanisms guiding diverse actions against bacteria. Our state-of-the-art predictive models expedite the design of new AMPs, offering a robust countermeasure to antibiotic resistance. Our prediction tool is available to the public at https://ai-meta.chem.ncu.edu.tw/amp-meta.

Preclinical systolic dysfunction relating to ankle-brachial index among high-risk PAD population with preserved left ventricular ejection fraction.

Peripheral artery disease (PAD) shares common clinical risk factors, for example, endothelial dysfunction, with preserved ejection fraction (LVEF) heart failure (HFpEF). Whether PAD is associated with preclinical systolic dysfunction and higher HF risk among individuals presenting preserved LVEF remains uncertain. We retrospectively included outpatients with at least one known or established cardiovascular (CV) risk factor with LVEF ≥ 50%. Patients were categorized into high risk and low risk of developing PAD (PAD vs Non-PAD) by ankle-brachial index (ABI) (≤ 0.90 or > 1.4) and further stratified based on their history of HFpEF (HFpEF vs. Non-HFpEF), resulting in the formation of four distinct strata. Preclinical systolic dysfunction was defined using dedicated speckle-tracking algorithm. A total of 2130 consecutive patients were enrolled in the study, with a median follow-up of 4.4 years. The analysis revealed a higher prevalence of high risk of developing PAD in patients with HFpEF compared to those without HFpEF (25.1% vs. 9.4%). Both high risk of developing PAD and HFpEF were independently associated with preclinical systolic dysfunction (global longitudinal strain, GLS ≥ - 18%) (odds ratio, OR: 1.38; 95% confidence interval, CI: 1.03-1.86). In comparison to patients at low risk of developing PAD without HFpEF (Non-PAD/Non-HFpEF group), those categorized as having a high risk of developing PAD with HFpEF (PAD/HFpEF group) exhibited the most impaired GLS and a heightened susceptibility to heart failure hospitalization (hazard ratio, HR: 6.51; 95% CI: 4.43-9.55), a twofold increased risk of all-cause mortality (HR: 2.01; 95% CI: 1.17-3.38), cardiovascular mortality (HR: 2.44; 95% CI: 1.08-5.51), and non-cardiovascular mortality (HR: 1.78; 95% CI: 0.82-3.84). A high risk of developing PAD was strongly linked to impaired preclinical systolic function and an increased likelihood for subsequent hospitalization for HF, all-cause mortality, CV mortality and non-CV mortality. There is a clear need for preventive strategies aimed at reducing hospitalizations for HF and mortality in this high-risk population.

Advances in risk predictive performance of pre-symptomatic type 1 diabetes via the multiplex Antibody-Detection-by-Agglutination-PCR assay.

Introduction: Achieving early diagnosis of pre-symptomatic type 1 diabetes is critical to reduce potentially life-threatening diabetic ketoacidosis (DKA) at symptom onset, link patients to FDA approved therapeutics that can delay disease progression and support novel interventional drugs development. The presence of two or more islet autoantibodies in pre-symptomatic type 1 diabetes patients indicates high-risk of progression to clinical manifestation. Method: Herein, we characterized the capability of multiplex ADAP assay to predict type 1 diabetes progression. We obtained retrospective coded sera from a cohort of 48 progressors and 44 non-progressors from the NIDDK DPT-1 study. Result: The multiplex ADAP assay and radiobinding assays had positive predictive value (PPV)/negative predictive value (NPV) of 68%/92% and 67%/66% respectively. The improved NPV stemmed from 12 progressors tested positive for multiple islet autoantibodies by multiplex ADAP assay but not by RBA. Furthermore, 6 out of these 12 patients tested positive for multiple islet autoantibodies by RBA in subsequent sampling events with a median delay of 2.8 years compared to multiplex ADAP assay. Discussion: In summary, multiplex ADAP assay could be an ideal tool for type 1 diabetes risk testing due to its sample-sparing nature (4µL), non-radioactiveness, compatibility with widely available real-time qPCR instruments and favorable risk prediction capability.

Penalized Model-Based Unsupervised Phenomapping Unravels Distinctive HFrEF Phenotypes With Improved Outcomes Discrimination From Sacubitril/Valsartan Treatment Independent of MAGGIC Score.

Background The angiotensin receptor-neprilysin inhibitor (LCZ696) has emerged as a promising pharmacological intervention against renin-angiotensin system inhibitor in reduced ejection fraction heart failure (HFrEF). Whether the therapeutic benefits may vary among heterogeneous HFrEF subgroups remains unknown. Methods and Results This study comprised a pooled 2-center analysis including 1103 patients with symptomatic HFrEF with LCZ696 use and another 1103 independent HFrEF control cohort (with renin-angiotensin system inhibitor use) matched for age, sex, left ventricular ejection fraction, and comorbidity conditions. Three main distinct phenogroup clusterings were identified from unsupervised machine learning using 29 clinical variables: phenogroup 1 (youngest, relatively lower diabetes prevalence, highest glomerular filtration rate with largest left ventricular size and left ventricular wall stress); phenogroup 2 (oldest, lean, highest diabetes and vascular diseases prevalence, lowest highest glomerular filtration rate with smallest left ventricular size and mass), and phenogroup 3 (lowest clinical comorbidity with largest left ventricular mass and highest hypertrophy prevalence). During the median 1.74-year follow-up, phenogroup assignment provided improved prognostic discrimination beyond Meta-Analysis Global Group in Chronic Heart Failure risk score risk score (all net reclassification index P<0.05) with overall good calibrations. While phenogroup 1 showed overall best clinical outcomes, phenogroup 2 demonstrated highest cardiovascular death and worst renal end point, with phenogroup 3 having the highest all-cause death rate and HF hospitalization among groups, respectively. These findings were broadly consistent when compared with the renin-angiotensin system inhibitor control as reference group. Conclusions Phenomapping provided novel insights on unique characteristics and cardiac features among patients with HFrEF with sacubitril/valsartan treatment. These findings further showed potentiality in identifying potential sacubitril/valsartan responders and nonresponders with improved outcome discrimination among patients with HFrEF beyond clinical scoring.

Shadow of a Pandemic: Persistence of Prenatal SARS-CoV-2 Antibodies in Newborn Blood Spots.

To investigate COVID-19 surveillance among pregnant women, the California Genetic Disease Screening Program conducted a screening performance and seroprevalence evaluation of maternal SARS-CoV-2 antibodies detected in banked newborn dried blood spots (DBS). We obtained seropositive results for 2890 newborn DBS from cohorts in 2020 and 2021 using Enable Bioscience's Antibody Detection by Agglutination-PCR (ADAP) assay for SARS-CoV-2 antibodies. To infer maternal infection, we linked 312 women with a known laboratory-confirmed COVID-19 episode with their newborn's DBS SARS-CoV02 antibody result. Among 2890 newborns, we detected 453 (15.7%) with SARS-CoV-2 antibodies in their DBS. Monthly snapshot statewide seroprevalence among neonates was 12.2% (95% CI 10.3-14.1%, n =1156) in December 2020 and 33.3% (95% CI 29.1-37.4%, n = 26) in March 2021. The longest time recorded from COVID-19 infection to a seropositive neonatal result was 11.7 months among the 312 mothers who had an available SARS-CoV-2 PCR test result. Approximately 94% (153/163) of DBS were seropositive when a known maternal infection occurred earlier than 19 days before birth. The estimated relative sensitivity of DBS to identify prevalent maternal infection was 85.1%, specificity 98.5% and PPV 99.2% (n = 312); the sensitivity was lowest during the December 2021 surge when many infections occurred within 19 days of birth. Fifty pre-pandemic specimens (100% seronegative) and 23 twin-pair results (100% concordant) support an intrinsic specificity and PPV of ADAP approaching 100%. Maternal infection surveillance is limited by a time lag prior to delivery, especially during pandemic surges.

Characterization of antibodies to SARS-CoV-2 in lyophilized plasma prepared with amotosalen-UVA pathogen reduction.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected patients exhibit disease ranging from asymptomatic to severe pneumonia, multi-organ failure, and death. convalescent COVID plasma (CCP) from recovered patients with high levels of neutralizing antibodies has demonstrated therapeutic efficacy to reduce the morbidity of coronavirus disease 2019 (COVID-19) in some studies. The development of assays to characterize the activity of CCP to neutralize SARS-CoV-2 infectivity offers the possibility to improve potential therapeutic efficacy. Lyophilization of CCP may increase the availability of this therapy. We hypothesized that SARS-CoV-2 antibody profiles of pooled lyophilized pathogen-reduced CCP from COVID-19-recovered blood donors retains virus-neutralizing efficacy as reported for frozen pathogen-reduced CCP. METHODS: Pooled lyophilized pathogen-reduced plasma was prepared from recovered COVID plasma donors. Antibodies to SARS-CoV-2 were characterized in each donor plasma prior to pathogen reduction and lyophilization and after lyophilization of individual CCP, and in the lyophilized CCP pool. Several complimentary assays were used to characterize antibody levels, neutralizing capacity, and the spectrum of antigen reactivity. The mean values for individual plasma samples and the value in the pool were compared. RESULTS: The mean ratio for antibody binding to SARS-CoV-2 antigens before and after treatment was 0.95 ± 0.22 mean fluorescent intensity (MFI) units. Antibody activity to an array of influenza virus antigens demonstrated a mean activity ratio of 0.92 ± 0.12 MFI before and after treatment. CONCLUSIONS: The antibody activity in pooled pathogen-reduced lyophilized CCPs demonstrated minimal impact due to pathogen reduction treatment and lyophilization.

Personalized Management for Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome with multiple underlying mechanisms and comorbidities that leads to a variety of clinical phenotypes. The identification and characterization of these phenotypes are essential for better understanding the precise pathophysiology of HFpEF, identifying appropriate treatment strategies, and improving patient outcomes. Despite accumulating data showing the potentiality of artificial intelligence (AI)-based phenotyping using clinical, biomarker, and imaging information from multiple dimensions in HFpEF management, contemporary guidelines and consensus do not incorporate these in daily practice. In the future, further studies are required to authenticate and substantiate these findings in order to establish a more standardized approach for clinical implementation.

Impact of Selection Preference on Longer-Term Outcomes between Bioresorbable Vascular Scaffold versus Everolimus-Eluting Stent for True Lumen Tracking-Recanalized Chronic Total Occlusion.

Creation of sizable subintima during intervention for chronic total occlusions (CTO) could lead to the key selection preference of metallic stents rather than bioresorbable vascular scaffolds (BVS) and then possibly deviate the outcome comparisons in real-world studies. By including recanalized CTO with true lumen tracking, we tested if any selection preference remained and compared the outcomes between everolimus-eluting stent (EES) and BVS implantation.Among 211 consecutive CTO interventions with true lumen tracking from August 2014 to April 2018 when BVS was available, we compared the clinical and interventional features between 28 patients with BVS and 77 patients with EES implantation. With propensity score matching and a median follow-up of 50.5 (37.3-60.3) months, we further assessed 25 patients with BVS and 25 with EES for target vessel failure (TVF: cardiac death, target vessel myocardial infarction, and target lesion revascularization).Multivariate analyses showed that BVS was still favored in the presence of LAD CTO (odds ratio (OR) = 3.4, 95% confidence interval (CI) = 1.0-11.7) and an average scaffold/stent size ≥ 3 mm (OR = 10.5, 95% CI = 3.0-37.3). EES was preferred for lesions with a J-CTO score ≥ 3 (OR = 19.3, 95% CI = 3.4-110.8) and multivessel intervention necessary at index procedure (OR = 11.3, 95% CI = 1.9-67.3). With matched comparisons, the TVF-free survival of EES was better than that of BVS for CTO recanalization (P = 0.049 by log-rank test) at long-term follow-up.Even with true lumen tracking techniques, selection bias remained substantial when determining either device for CTO implantation. The matched comparison of outcomes suggested the unfavorable longer-term impacts of the first generation of BVS on CTO lesions.

Pulse Wave Analysis Predicts Invasive Hemodynamics in Pre-Capillary Pulmonary Hypertension.

Background: We tested the hypothesis that non-invasive pulse wave analysis (PWA)-derived systemic circulation variables can predict invasive hemodynamics of pulmonary circulation and the indicator of right heart function, N-terminal pro-brain natriuretic peptide (NT-proBNP), in patients with precapillary pulmonary hypertension (PH). Methods: This prospective study enrolled patients with group 1 and 4 PH who had complete PWA, NT-proBNP, and hemodynamics data. Risk assessment-based "hemodynamic score (HS)" and principal component analysis-based PWA variable grouping were determined/performed. Models of hierarchical multiple linear regression (HMLR) and receiver operating characteristic (ROC) curves were used to determine the relationships of PWA variables with HS and NT-proBNP and to predict the latter parameters. Results: Fifty-three PWAs were included. PWA variables were classified into 4 eigenvalue principal components (representing 90% configuration). Univariate analysis showed that left ventricular ejection time (LVET) was significantly negatively associated with HS and NT-proBNP levels. HMLR analysis showed that LVET was still significantly, negatively, and independently associated with HS (B = -0.006 [-0.010~-0.001]) and NT-proBNP (B = -13.47 [-21.20~-5.73]). ROC curve analysis showed that LVET > 306.9 msec and > 313.2 msec predicted the low-risk group of HS (AUC: 0.802; p = 0.001; sensitivity: 100%; and specificity: 59%) and low-to-intermediate risk levels of NT-proBNP (AUC: 0.831; p < 0.001; sensitivity: 100%; and specificity: 59%). Conclusions: The non-invasive PWA parameter, LVET, is an independent predictor of invasive right heart HS and NT-proBNP levels; it may serve as a novel biomarker of right ventricular function in patients with pre-capillary PH.

Early detection of myocardial ischemia in resting ECG: analysis by HHT.

BACKGROUND: Exercise electrocardiography (ECG) is a noninvasive test aiming at producing ischemic changes. However, resting ECG cannot be adopted in diagnosing myocardial ischemia till ST-segment depressions. Therefore, this study aimed to detect myocardial energy defects in resting ECG using the Hilbert-Huang transformation (HHT) in patients with angina pectoris. METHODS: Electrocardiographic recordings of positive exercise ECG by performing coronary imaging test (n = 26) and negative exercise ECG (n = 47) were collected. Based on the coronary stenoses severity, patients were divided into three categories: normal, < 50%, and ≥ 50%. During the resting phase of the exercise ECG, all 10-s ECG signals are decomposed by HHT. The RT intensity index, composed of the power spectral density of the P, QRS, and T components, is used to estimate the myocardial energy defect. RESULTS: After analyzing the resting ECG using HHT, the RT intensity index was significantly higher in patients with positive exercise ECG (27.96%) than in those with negative exercise ECG (22.30%) (p < 0.001). In patients with positive exercise ECG, the RT intensity index was gradually increasing with the severity of coronary stenoses: 25.25% (normal, n = 4), 27.14% (stenoses < 50%, n = 14), and 30.75% (stenoses ≥ 50%, n = 8). The RT intensity index of different coronary stenoses was significantly higher in patients with negative exercise ECG, except for the normal coronary imaging test. CONCLUSIONS: Patients with coronary stenoses had a higher RT index at the resting stage of exercise ECG. Resting ECG analyzed using HHT could be a method for the early detection of myocardial ischemia.

QRS Fragmentation in Preserved Ejection Fraction Heart Failure: Functional Insights, Pathological Correlates, and Prognosis.

Background Fragmented QRS (fQRS) morphology as a surrogate marker of the possible presence of myocardial scarring has been shown to confer a higher risk in patients with reduced ejection fraction heart failure. We aimed to investigate the pathophysiological correlates and prognostic implications of fQRS in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We consecutively studied 960 patients with HFpEF (76.4±12.7 years, men: 37.2%). fQRS was assessed using a body surface ECG during hospitalization. QRS morphology was available and classified into 3 categories among 960 subjects with HFpEF as non-fQRS, inferior fQRS, and anterior/lateral fQRS groups. Despite comparable clinical features in most baseline demographics among the 3 fQRS categories, anterior/lateral fQRS showed significantly higher B-type natriuretic peptide/troponin levels (both P<0.001), with both the inferior and anterior/lateral fQRS HFpEF groups demonstrating a higher degree of unfavorable cardiac remodeling, greater extent of myocardial perfusion defect, and slower coronary flow phenomenon (all P<0.05). Patients with anterior/lateral fQRS HFpEF exhibited significantly altered cardiac structure/function and more impaired diastolic indices (all P<0.05). During a median of 657 days follow-up, the presence of anterior/lateral fQRS conferred a doubled HF re-admission risk (adjusted hazard ratio 1.90, P<0.001), with both inferior and anterior/lateral fQRS having a higher risk of cardiovascular and all-cause death (all P<0.05) by using Cox regression models. Conclusions The presence of fQRS in HFpEF was associated with more extensive myocardial perfusion defects and worsened mechanics, which possibly denotes a more severe involvement of cardiac damage. Early recognition in such patients with HFpEF likely benefits from targeted therapeutic interventions.

The Removal, Excision, Sterilization, and Quarantine (RESQ) Method is a Feasible Alternative Treatment for Cardiac Implantable Electronic Device Infections.

Background: Current guidelines recommend that all infected cardiac implantable electronic devices (CIEDs) should be removed. However, financial or anatomical concerns can lead to management of infection with simple debridement, as opposed to complete removal. In this observational study, we report the outcomes of our modified procedure for this real-world dilemma. Methods and Results: The Quarantine (RESQ) method is characterized as follows: the removal (R) of all non-essential foreign materials, including old sutures and leads; the excision (E) of all non-viable, chronically inflamed, granulation, or scar tissue; the sterilization (S) of the remaining generator; and the quarantine (Q) of a new pocket in the sub-muscular layer for reimplantation. From a review of electronic medical records, 30 patients were selected and divided into three groups according to the intervention used: RESQ (n = 9) in group A, simple debridement (n = 16) in group B, and guideline-recommended replacement (n = 5) in group C. Patient baseline characteristics were similar between the groups. After analyzing the proportion of patients that were free from infection one year following their respective interventions, we found that group A performed better than group B (100% and 31.2% infection-free, respectively, p = 0.001), and was comparable to group C (both 100% infection-free, p = not applicable). Conclusions: The RESQ method is a feasible and beneficial alternative for selected patients with CIED infections who are unable to receive a generator replacement according to the recommended guideline.

The Autonomic Imbalance of Myocardial Ischemia during Exercise Stress Testing: Insight from Short-Term Heart Rate Variability Analysis.

Exercise stress testing (EST) has limited power in diagnosing obstructive coronary artery disease (CAD). The heart rate variability (HRV) analysis might increase the sensitivity of CAD detection. This study aimed to evaluate the correlation between short-term HRV and myocardial ischemia during EST, including the acceleration, maximum, and recovery stages of heart rate (HR). The HRV during EST from 19 healthy (RHC) subjects and 35 patients with CAD (25 patients with insignificant CAD (iCAD), and 10 patients with significant CAD (sCAD)) were compared. As a result, all HRV indices decreased at the maximum stage and no significant differences between iCAD and sCAD were found. The low-frequency power of heart rate signal (LF) of the RHC group recovered relatively quickly from the third to the sixth minutes after maximum HR, compared with that of the sCAD group. The relative changes of most HRV indices between maximum HR and recovery stage were lower in the sCAD group than in the RHC group, especially in LF, the standard deviation of all normal to normal intervals (SDNN), and the standard deviation in the long axis direction of the Poincaré plot analysis (SD2) indices (p < 0.05). The recovery slope of LF was significantly smaller in the sCAD group than in the RHC group (p = 0.02). The result suggests that monitoring short-term HRV during EST provides helpful insight into the cardiovascular autonomic imbalance in patients with significant CAD. The relative change of autonomic tone, especially the delayed sympathetic recovery, could be an additional marker for diagnosing myocardial ischemia.

Both epicardial and peri-aortic adipose tissue blunt heart rate recovery beyond body fat mass.

Background: Epicardial adipose tissue (EAT) as a marker of metabolic disorders has been shown to be closely associated with a variety of unfavorable cardiovascular events and cardiac arrhythmias. Data on regional-specific visceral adiposity outside the heart and its modulation on autonomic dysfunction, particularly heart rate recovery after exercise, remain obscure. Methods: We studied 156 consecutive subjects (mean age: 49.3 ± 8.0 years) who underwent annual health surveys and completed treadmill tests. Multi-detector computed tomography-based visceral adiposity, including EAT and peri-aortic fat (PAF) tissue, was quantified using dedicated software (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA). We further correlated EAT and PAF with blood pressure and heart rate (HR) recovery information from an exercise treadmill test. Metabolic abnormalities were scored by anthropometrics in combination with biochemical data. Results: Increased EAT and PAF were both associated with a smaller reduction in systolic blood pressure during the hyperventilation stage before exercise compared to supine status (ß-coefficient (coef.): -0.19 and -0.23, respectively, both p < 0.05). Both visceral adipose tissue mediated an inverted relationship with heart rate recovery at 3 (EAT: ß-coef.: -0.3; PAF: ß-coef.: -0.36) and 6 min (EAT: ß-coef.: -0.32; PAF: ß-coef.: -0.34) after peak exercise, even after adjusting for baseline clinical variables and body fat composition (all p < 0.05). Conclusion: Excessive visceral adiposity, whether proximal or distal to the heart, may modulate the autonomic response by lowering the rate of HR recovery from exercise after accounting for clinical metabolic index. Cardiac autonomic dysfunction may partly explain the increase in cardiovascular morbidity and mortality related to both visceral fats.

Characterization of pathogen-inactivated COVID-19 convalescent plasma and responses in transfused patients.

BACKGROUND: Efficacy of donated COVID-19 convalescent plasma (dCCP) is uncertain and may depend on antibody titers, neutralizing capacity, timing of administration, and patient characteristics. STUDY DESIGN AND METHODS: In a single-center hypothesis-generating prospective case-control study with 1:2 matched dCCP recipients to controls according to disease severity at day 1, hospitalized adults with COVID-19 pneumonia received 2 × 200 ml pathogen-reduced treated dCCP from 2 different donors. We evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in COVID-19 convalescent plasma donors and recipients using multiple antibody assays including a Coronavirus antigen microarray (COVAM), and binding and neutralizing antibody assays. Outcomes were dCCP characteristics, antibody responses, 28-day mortality, and dCCP -related adverse events in recipients. RESULTS: Eleven of 13 dCCPs (85%) contained neutralizing antibodies (nAb). PRT did not affect dCCP antibody activity. Fifteen CCP recipients and 30 controls (median age 64 and 65 years, respectively) were enrolled. dCCP recipients received 2 dCCPs from 2 different donors after a median of one hospital day and 11 days after symptom onset. One dCCP recipient (6.7%) and 6 controls (20%) died (p = 0.233). We observed no dCCP-related adverse events. Transfusion of unselected dCCP led to heterogeneous SARS CoV-2 antibody responses. COVAM clustered dCCPs in 4 distinct groups and showed endogenous immune responses to SARS-CoV-2 antigens over 14-21 days post dCCP in all except 4 immunosuppressed recipients. DISCUSSION: PRT did not impact dCCP anti-virus neutralizing activity. Transfusion of unselected dCCP did not impact survival and had no adverse effects. Variable dCCP antibodies and post-transfusion antibody responses indicate the need for controlled trials using well-characterized dCCP with informative assays.