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Introduction The authors tested the hypothesis that the EEG feature generalized polyspike train (GPT) is associated with drug-resistant idiopathic generalized epilepsy (IGE). Methods The authors conducted a single-center case-control study of patients with IGE who had outpatient EEGs performed between 2016 and 2020. The authors classified patients as drug-resistant or drug-responsive based on clinical review and in a masked manner reviewed EEG data for the presence and timing of GPT (a burst of generalized rhythmic spikes lasting less than 1 second) and other EEG features. A relationship between GPT and drug resistance was tested before and after controlling for EEG duration. The EEG duration needed to observe GPT was also calculated. Results One hundred three patients were included (70% drug-responsive and 30% drug-resistant patients). Generalized polyspike train was more prevalent in drug-resistant IGE (odds ratio, 3.8; 95% confidence interval, 1.3-11.4; P = 0.02). This finding persisted when controlling for EEG duration both with stratification and with survival analysis. A median of 6.5 hours (interquartile range, 0.5-12.7 hours) of EEG recording was required to capture the first occurrence of GPT. Conclusions The findings support the hypothesis that GPT is associated with drug-resistant IGE. Prolonged EEG recording is required to identify this feature. Thus, >24-hour EEG recording early in the evaluation of patients with IGE may facilitate prognostication.

AIMS: Targeting vascular inflammation represents a novel therapeutic approach to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) using canakinumab, a monoclonal antibody, reduces the incidence of cardiovascular events in patients after myocardial infarction (MI). The biological basis for these beneficial effects remains incompletely understood. We sought to explore the mechanisms of IL-1β-targeted therapies.METHODS AND RESULTS: In mice with early atherosclerosis (ApoE-/- mice on a high-cholesterol diet for six weeks), we found that three weeks of NLRP3-inflammasome inhibition or anti-IL-1β treatment (using either MCC950, an NLRP3 inflammasome inhibitor which blocks production and release of active IL-1β; or a murine analog of canakinumab) dampened accumulation of leukocytes in atherosclerotic aortas, which consequently resulted in slower progression of atherosclerosis. Causally, we found that endothelial cells from atherosclerotic aortas lowered expression of leukocyte chemoattractants and adhesion molecules upon NLRP3-inflammasome inhibition, indicating that NLRP3-inflammasome- and IL-1β-targeted therapies reduced blood leukocyte recruitment to atherosclerotic aortas. In accord, adoptive transfer experiments revealed that anti-IL-1β treatment mitigated blood myeloid cell uptake to atherosclerotic aortas. We further report that anti-IL-1β treatment and NLRP3-inflammasome inhibition reduced inflammatory leukocyte supply by decreasing proliferation of bone marrow hematopoietic stem and progenitor cells, demonstrating that suppression of IL-1β and the NLRP3-inflammasome lowered production of disease-propagating leukocytes. Using bone marrow reconstitution experiments, we observed that hematopoietic cell-specific NLRP3-inflammasome activity contributed to both enhanced recruitment and increased supply of blood inflammatory leukocytes. Further experiments that queried whether anti-IL-1β treatment reduced vascular inflammation also in post-MI accelerated atherosclerosis documented the operation of convergent mechanisms (reduced supply and uptake of inflammatory leukocytes). In line with our pre-clinical findings, post-MI patients on canakinumab treatment showed reduced blood monocyte numbers.CONCLUSIONS: Our murine and human data reveal that anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened vascular inflammation and progression of atherosclerosis through reduced blood inflammatory leukocyte 1) supply and 2) uptake into atherosclerotic aortas providing additional mechanistic insights into links between hematopoiesis and atherogenesis, and into the beneficial effects of NLRP3-inflammasome- and IL-1β-targeted therapies.TRANSLATIONAL PERSPECTIVE: Therapeutic targeting of vascular inflammation represents a promising avenue to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) reduces the incidence of cardiovascular events in patients with prior myocardial infarction. However, the mechanisms underlying these beneficial effects remain incompletely understood. This study explored how IL-1β and NLRP3-inflammasome suppression mitigated plaque progression. Our murine and human data reveal that pharmacological anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened inflammatory leukocyte accumulation in atherosclerotic aortas through 1) decreased blood inflammatory leukocyte supply and 2) reduced blood inflammatory leukocyte uptake into in atherosclerotic aortas. These data provide additional mechanistic insights into links between hematopoiesis and atherogenesis, and inform future anti-inflammatory interventions in patients with atherosclerosis.

Publisher Summary This chapter discusses the epidemiology and classification of traumatic peripheral nerve injuries, the effects of these injuries on nerve and muscle, and how electrodiagnosis is used to help classify the injury. Traumatic injury to peripheral nerves results in considerable disability across the world. In peacetime, peripheral nerve injuries result commonly from motor vehicle accident trauma and less commonly from penetrating trauma, such as falls and industrial accidents. If plexus and root injuries are also included, the incidence is about 5%. In the upper limb, the nerve injured most commonly is the radial nerve, followed by the ulnar and median nerves. Lower limb peripheral nerve injuries are less common, and the sciatic nerve is injured most frequently, followed by the peroneal and rarely the tibial or femoral nerves. Peripheral nerve injuries may be seen in isolation, but they also often accompany central nervous system (CNS) trauma. Peripheral nerve injuries have significant impact, as they impede the recovery of function and return to work. There is also a risk of secondary disability from falls, fractures, or other injuries.

Objectives Emerging evidence implicates atypical plasticity in the neurophysiology of autism spectrum disorder (ASD). Specifically, autistic people demonstrated hyperplasticity in response to theta-burst stimulation (TBS). We hypothesized that autistic adults would display hyperplasticity to TBS and that repetitive transcranial magnetic stimulation (rTMS) – which potentiates brain inhibitory mechanisms – would ‘stabilize’ hyperplasticity. Methods Using a randomized, cross-over design, plasticity was assessed using TBS in the left motor cortex (M1) in 31 autistic adults and 30 sex-, intelligence quotient-, and age-matched controls. Autistic adults (n = 29) were further randomized (1:1) to receive a single session of active (n = 14) or sham (n = 15) rTMS (6000 pulses at 20 Hz) over left M1 and plasticity was reassessed on the next day following rTMS. Results Both long-term potentiation (LTP) and long-term depression (LTD) were significantly increased in the ASD group, indicating hyperplasticity. Active, but not sham rTMS, attenuated LTD in autistic adults. Conclusions We provided further evidence for the presence of brain hyperplasticity in ASD. To our knowledge, this is the first study to show preliminary evidence that an excessive LTD in ASD can be ‘stabilized’ using rTMS. Such ‘stabilizing’ effect of rTMS on LTP was not observed, likely due to small sample size or a more specific ‘attenuating’ effect of rTMS on LTD, compared to LTP. Significance These findings indicate atypical brain inhibitory mechanisms behind hyperplasticity in ASD. Utilizing a larger sample, future replication studies could investigate therapeutic opportunities of ‘mechanism-driven’ rTMS.

Objective To investigate whether epileptiform discharge burden can identify those at risk for delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (SAH). Methods Retrospective analysis of 113 moderate to severe grade SAH patients who had continuous EEG (cEEG) recordings during their hospitalization. We calculated the burden of epileptiform discharges (ED), measured as number of ED per hour. Results We find that many SAH patients have an increase in ED burden during the first 3–10 days following rupture, the major risk period for DCI. However, those who develop DCI have a significantly higher hourly burden from days 3.5–6 after SAH vs. those who do not. ED burden is higher in DCI patients when assessed in relation to the onset of DCI (area under the receiver operator curve 0.72). Finally, specific trends of ED burden over time, assessed by group-based trajectory analysis, also help stratify DCI risk. Conclusions These results suggest that ED burden is a useful parameter for identifying those at higher risk of developing DCI after SAH. The higher burden rate associated with DCI supports the theory of metabolic supply-demand mismatch which contributes to this complication. Significance ED burden is a novel biomarker for predicting those at high risk of DCI.

To assess the utility of interictal magnetic and electric source imaging (MSI and ESI) using dipole clustering in magnetic resonance imaging (MRI)-negative patients with drug resistant epilepsy (DRE).We localized spikes in low-density (LD-EEG) and high-density (HD-EEG) electroencephalography as well as magnetoencephalography (MEG) recordings using dipoles from 11 pediatric patients. We computed each dipole's level of clustering and used it to discriminate between clustered and scattered dipoles. For each dipole, we computed the distance from seizure onset zone (SOZ) and irritative zone (IZ) defined by intracranial EEG. Finally, we assessed whether dipoles proximity to resection was predictive of outcome.LD-EEG had lower clusterness compared to HD-EEG and MEG (p 0.05). For all modalities, clustered dipoles showed higher proximity to SOZ and IZ than scattered (p 0.001). Resection percentage was higher in optimal vs. suboptimal outcome patients (p 0.001); their proximity to resection was correlated to outcome (p 0.001). No difference in resection percentage was seen for scattered dipoles between groups.MSI and ESI dipole clustering helps to localize the SOZ and IZ and facilitate the prognostic assessment of MRI-negative patients with DRE.Assessing the MSI and ESI clustering allows recognizing epileptogenic areas whose removal is associated with optimal outcome.

Atrial fibrillation (AF) is the most common cardiac arrhythmia with a high stroke and mortality rate. The video-assisted thoracoscopic radiofrequency pulmonary vein ablation is a treatment option for patients who fail catheter ablation. Randomized data comparing surgical versus catheter ablation are limited. We performed a meta-analysis of randomized control trials to explore the outcome efficacy between surgical and catheter radiofrequency pulmonary vein ablation in patients with AF.We comprehensively searched the databases of MEDLINE and EMBASE from inception to December 2020. Included studies were published randomized control trials that compared video-assisted thoracoscopic and catheter radiofrequency pulmonary vein ablation. Data from each study were combined using the fixed-effects, generic inverse variance method of DerSimonian, and Laird to calculate odds ratios and 95% confidence intervals.Six studies from November 2013 to 2020 were included in this meta-analysis involving 511 AF patients (79% paroxysmal) with 263 catheter ablation (mean age 56 ± 3 years) and 248 surgical ablations (mean age 52 ± 4 years). Catheter ablation was associated with increased atrial arrhythmias recurrence when compared to surgical ablation (pooled relative risk = 1.85, 95% confidence interval: 1.44-2.39, p .001, ICatheter ablation was associated with higher atrial arrhythmia recurrence when compared with surgical ablation. However, our study suggests that the benefit of surgical ablation in patients with persistent AF is unclear. More studies and alternative ablation strategies investigation in persistent AF are warranted.

Aims TASK-1 (K2P3.1) two-pore domain potassium channels are atrial-specific and significantly upregulated in atrial fibrillation (AF) patients, contributing to AF-related electrical remodelling. Inhibition of TASK-1 in cardiomyocytes of AF patients was shown to counteract AF-related action potential duration shortening. Doxapram was identified as a potent inhibitor of the TASK-1 channel. In the present study, we investigated the antiarrhythmic efficacy of doxapram in a porcine model of AF. Methods and results Doxapram successfully cardioverted pigs with artificially induced episodes of AF. We established a porcine model of persistent AF in domestic pigs via intermittent atrial burst stimulation using implanted pacemakers. All pigs underwent catheter-based electrophysiological investigations prior to and after 14 d of doxapram treatment. Pigs in the treatment group received intravenous administration of doxapram once per day. In doxapram-treated AF pigs, the AF burden was significantly reduced. After 14 d of treatment with doxapram, TASK-1 currents were still similar to values of sinus rhythm animals. Doxapram significantly suppressed AF episodes and normalized cellular electrophysiology by inhibition of the TASK-1 channel. Patch-clamp experiments on human atrial cardiomyocytes, isolated from patients with and without AF could reproduce the TASK-1 inhibitory effect of doxapram. Conclusions Repurposing doxapram might yield a promising new antiarrhythmic drug to treat AF in patients. Translational perspective Pharmacological suppression of atrial TASK 1 potassium currents prolongs atrial refractoriness with no effects on ventricular repolarization, resulting in atrial-specific class III antiarrhythmic effects. In our preclinical pilot study the respiratory stimulant doxapram was successfully administered for cardioversion of acute AF as well as rhythm control of persistent AF in a clinically relevant porcine animal model.

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): hospital resources Introduction Pacing impedance measurements are important in the surveillance of pacemaker and implantable cardioverter/defibrillator (ICD) devices. Whereas sudden changes in impedances can reflect lead fracture or isolation defects, gradually increasing impedances are thought to occur because of calcifications at the endomyocardial interface. In many cases, these leads are replaced prophylactically but this has not been studied systematically. Purpose We aimed to identify the outcome of right ventricular (RV) electrodes with high impedances that were left active in this single center study. Methods All patients in the electronic patient database were screened for impedances >1200Ohms. 41,201 individual recordings led to 219 individual patients. 161 patients were excluded from the analysis due to sudden impedance increase, temporarily high impedances or wrong entry. Of the remaining 58 patients, baseline characteristics as well as pacing impedance, sensing values, pacing thresholds, and shock impedance in case of ICDs were recorded. Results There were 17 pacemaker and 41 ICD patients, 68±15 years old, 69% were male. Glomerular filtration rate at baseline was 81±22 ml/min/1.73m2. Baseline RV impedance was 597±123Ohms. During follow-up impedances increased to 1875±682Ohms (p1000Ohms was 5,5 (3,4-7)years and median follow-up thereafter 3,8 years (1,6-6,6). During follow-up, no intervention was performed for 45 leads (78%). No events occurred. 13 leads (22%) were replaced , 9 prophylactically (mostly because of ICD advisory leads), 3 because of high pacing thresholds and high percentage pacing and one lead because of noise oversensing, probably unrelated as it occurred 7 years after impedance increase. Conclusions A watchful waiting strategy appears to be a safe option for patients with ICDs and pacemakers with low percentage pacing. As impedance increase cannot be used for surveillance for imminent lead fracture, other means such as short interval counts and non-sustained oversensing have to be employed and should be combined with remote monitoring.

PURPOSE Up to half of the children undergoing epilepsy surgery will continue to have seizures (szs) despite a cortical resection or ablation. Functional connectivity has shown promise in better identifying the epileptogenic zone. We hypothesized that cortical areas showing high information outflow during interictal epileptiform discharges are part of the epileptogenic zone. METHODS We identified 22 children with focal epilepsy who had undergone stereo electroencephalography, surgical resection or ablation, and had ≥1 year of postsurgical follow-up. The mean phase slope index, a directed measure of functional connectivity, was calculated for each electrode contact during interictal epileptiform discharges. The positive predictive value and negative predictive value for a sz-free outcome were calculated based on whether high information outflow brain regions were resected. RESULTS Resection of high outflow (z-score ≥ 1) and very high outflow (z-score ≥ 2) electrode contacts was associated with higher sz freedom (high outflow: χ2 statistic = 59.1; P < 0.001; very high outflow: χ2 statistic = 31.3; P < 0.001). The positive predictive value and negative predictive value for sz freedom based on resection at the electrode level increased at higher z-score thresholds with a peak positive predictive value of 0.86 and a peak negative predictive value of 0.9. CONCLUSIONS Better identification of the epileptogenic zone has the potential to improve epilepsy surgery outcomes. If the surgical plan can be modified to include these very high outflow areas, more children might achieve sz freedom. Conversely, if deficits from resecting these areas are unacceptable, ineffective surgeries could be avoided and alternative therapies offered.

Emerging research suggests that sleep contributes to racial disparities in cardiovascular disease (CVD). Racial/ethnic minorities are disproportionately affected by poor cardiovascular outcomes including obesity, hypertension and diabetes. Although circadian rhythms affect sleep patterns, few studies have examined disparities in circadian health or the contribution of circadian disparities to CVD. In this paper, we provide an overview of the relation between circadian health and CVD in the context of health disparities. We discuss (1) the current knowledge on racial disparities in circadian health; (2) social and environmental determinants of circadian health disparities; (3) the cardiovascular consequences of circadian disparities; and (4) future opportunities to advance the field of circadian disparities. In brief, our findings demonstrated that among a small literature, racial minorities (mainly African American) were more likely to have a shorter circadian period, delayed phase shifts, and were more likely to be shift workers, which are associated with CVD risk factors. Given racial minorities are disproportionately affected by CVD and CVD risk factors, it is important to further understand circadian health as an intervention target and support more research among racial minorities to understand circadian health in these populations.

Introduction: Intracranial aneurysms (IAs) are a common vascular pathology and are associated with a risk of rupture, which is often fatal. Aneurysm growth is considered a surrogate of rupture risk; therefore, the study aimed to develop and evaluate prediction models of future artificial intelligence (AI) growth based on baseline aneurysm morphology as a computer-aided treatment decision support.Materials and methods: Follow-up CT angiography (CTA) and magnetic resonance angiography (MRA) angiograms of 39 patients with 44 IAs were classified by an expert as growing and stable (25/19). From the angiograms vascular surface meshes were extracted and the aneurysm shape was characterized by established morphologic features and novel deep shape features. The features corresponding to the baseline aneurysms were used to predict future aneurysm growth using univariate thresholding, multivariate random forest and multi-layer perceptron (MLP) learning, and deep shape learning based on the PointNet++ model.Results: The proposed deep shape feature learning method achieved an accuracy of 0.82 (sensitivity = 0.96, specificity = 0.63), while the multivariate learning and univariate thresholding methods were inferior with an accuracy of up to 0.68 and 0.63, respectively.Conclusion: High-performing classification of future growing IAs renders the proposed deep shape features learning approach as the key enabling tool to manage rupture risk in the “no treatment” paradigm of patient follow-up imaging.

INTRODUCTION: Existing automated seizure detection algorithms report sensitivities between 43% and 77% and specificities between 56% and 90%. The algorithms suffer from false alarms when applied to neonatal EEG because of the high degree of nurse handling and rhythmic patting used to soothe neonates. Computer vision technology that quantifies movement in real time could distinguish artifactual motion and improve automated neonatal seizure detection algorithms. METHODS: The authors used video EEG recordings from 43 neonates undergoing monitoring for seizures as part of the NEOLEV2 clinical trial. The Persyst neonatal automated seizure detection algorithm ran in real time during study EEG acquisitions. Computer vision algorithms were applied to extract detailed accounts of artifactual movement of the neonate or people near the neonate though dense optical flow estimation. RESULTS: Using the methods mentioned above, 197 periods of patting activity were identified and quantified, of which 45 generated false-positive automated seizure detection events. A binary patting detection algorithm was trained with a subset of 470 event videos. This supervised detection algorithm was applied to a testing subset of 187 event videos with 8 false-positive events, which resulted in a 24% reduction in false-positive automated seizure detections and a 50% reduction in false-positive events caused by neonatal care patting, while maintaining 11 of 12 true-positive seizure detection events. CONCLUSIONS: This work presents a novel approach to improving automated seizure detection algorithms used during neonatal video EEG monitoring. This artifact detection mechanism can improve the ability of a seizure detector algorithm to distinguish between artifact and true seizure activity.

Objectives: Anti-interleukin-6 monoclonal antibody, tocilizumab, has produced mixed results in clinical trials for effectiveness against coronavirus disease 2019 (COVID-19). We conducted a retrospective cohort study to compare outcomes at 28 days of a cohort of patients with severe COVID-19 treated with tocilizumab and standard care, with those receiving standard care only. Materials and Methods: In this record-based retrospective cohort study, patients hospitalised with COVID-19 were classified into non-severe and severe disease as per institutional protocol. One cohort received tocilizumab with standard care and the second cohort received only standard care. Few patients also received high-dose steroids as ‘pulse’ steroids on initial clinical deterioration. Data were collected for the treatment given including oxygen interface, steroids, antimicrobials, duration of hospital stay in survivors, requirement of mechanical ventilation, and day of intubation from symptom onset. The primary outcome was to compare the all-cause mortality between the two groups. The effect of pulse steroid therapy on all-cause mortality was studied in the secondary outcome. Results: There was statistically significant mortality in the tocilizumab cohort as compared to standard care alone (HR 2.43, 95% CI 1.54–3.89). The need for mechanical ventilation was more in the tocilizumab cohort (85% vs. 18%, P < 0.001). Tocilizumab cohort had a delay in the day of intubation by a mean of 2.29 days from the day of symptom onset (P < 0.05). Pulse steroid administration showed increased all-cause mortality (HR 1.94, 95% CI 1.18–3.20) and risk of mechanical ventilation. Conclusion: Tocilizumab cohort showed higher mortality and need for mechanical ventilation in our study which contrasts the result of a few previous trials. Our study warrants the need for future clinical trials on this subject to ensure better treatment strategies in upcoming COVID-19 waves.

Aims The exploration of novel immunomodulatory interventions to improve outcome in heart failure (HF) is hampered by the complexity/redundancies of inflammatory pathways, which remain poorly understood. We thus aimed to investigate the associations between the activation of diverse immune processes and outcomes in patients with HF. Methods and results We measured 355 biomarkers in 2022 patients with worsening HF and an independent validation cohort (n = 1691) (BIOSTAT-CHF index and validation cohorts), and classified them according to their functions into biological processes based on the gene ontology classification. Principal component analyses were used to extract weighted scores per process. We investigated the association of these processes with all-cause mortality at 2-year follow-up. The contribution of each biomarker to the weighted score(s) of the processes was used to identify potential therapeutic targets. Mean age was 69 (±12.0) years and 537 (27%) patients were women. We identified 64 unique overrepresented immune-related processes representing 188 of 355 biomarkers. Of these processes, 19 were associated with all-cause mortality (10 positively and 9 negatively). Increased activation of ‘T-cell costimulation’ and ‘response to interferon-gamma/positive regulation of interferon-gamma production’ showed the most consistent positive and negative associations with all-cause mortality, respectively, after external validation. Within T-cell costimulation, inducible costimulator ligand, CD28, CD70, and tumour necrosis factor superfamily member-14 were identified as potential therapeutic targets. Conclusions We demonstrate the divergent protective and harmful effects of different immune processes in HF and suggest novel therapeutic targets. These findings constitute a rich knowledge base for informing future studies of inflammation in HF.

Acute lung injury (ALI) induced by bacteria lipopolysaccharide (LPS) is characterized by the upregulation of the apoptosis rate of tissue cells and aggravation of inflammatory response. Although many studies have focused on the pathogenesis of this disease, its mechanism remains unknown. This study examined the regulatory role of long non-coding RNA (lncRNA) LINC01194 in the progression of ALI through various bioinformatics analyses and experimental work, including ELISA assay, dual-luciferase reporter assay, biotinylated RNA pull-down assay, and Western blot analysis. The result showed that the LINC01194 was overexpressed in the ALI-induced mice model. We observed a significant upregulation of LINC01194 in LPS-treated mouse lung epithelial type II cells (MLE-12 cells) after 24 h of induction. Bioinformatics analysis, ELISA assay, quantitative reverse transcription polymerase chain reaction analysis, biotinylated RNA pull-down assay, apoptosis test, and Western blot analysis demonstrated that the LINC01194 could act as a microRNA (miR) miR-203a-3p sponge to activate the inflammatory response in LPS-induced ALI model through post-transcriptional upregulation of macrophage inflammatory protein (MIP-2). We showed that LINC01194 regulates the inflammatory response and apoptosis of LPS-induced mice and MLE-12 cells via the miR-203a-3p/MIP-2 axis. LINC01194 could be a potential biomarker for early diagnosis and the treatment of ALI.

Loss of functional pancreatic β-cell mass and increased β-cell apoptosis are fundamental to the pathophysiology of type 1 and type 2 diabetes. Pancreatic islet transplantation has the potential to cure type 1 diabetes but is often ineffective due to the death of the islet graft within the first few years after transplant. Therapeutic strategies to directly target pancreatic β-cell survival are needed to prevent and treat diabetes and to improve islet transplant outcomes. Reducing β-cell apoptosis is also a therapeutic strategy for type 2 diabetes. Cholecystokinin (CCK) is a peptide hormone typically produced in the gut after food intake, with positive effects on obesity and glucose metabolism in mouse models and human subjects. We have previously shown that pancreatic islets also produce CCK. The production of CCK within the islet promotes β-cell survival in rodent models of diabetes and aging. We demonstrate a direct effect of CCK to reduce cytokine-mediated apoptosis in a β-cell line and in isolated mouse islets in a receptor-dependent manner. However, whether CCK can protect human β-cells was previously unknown. Here, we report that CCK can also reduce cytokine-mediated apoptosis in isolated human islets and CCK treatment in vivo decreases β-cell apoptosis in human islets transplanted into the kidney capsule of diabetic NOD/SCID mice. Collectively, these data identify CCK as a novel therapy that can directly promote β-cell survival in human islets and has therapeutic potential to preserve β-cell mass in diabetes and as an adjunct therapy after transplant.

Metabolic syndrome (MetS) is a cluster of cardiovascular risk factors including central obesity, hypertension, insulin resistance, dyslipidemia, and hyperglyemia. MetS is found to be a positive predictor of cardiovascular morbidity and mortality. The present study was planned to test the efficacy of vitamin D3 supplementation as compared with cortisol inhibition on MetS parameters. Wistar rats were allocated into four groups: control, untreated MetS, and MetS treated with either vitamin D3 (10 µg/kg) or carbenoxolone (50 mg/kg). MetS was induced by combination of high-fat diet and oral fructose. After the induction period (8 weeks), MetS was confirmed, and treatment modalities started for a further 4 weeks. Compared with untreated MetS, vitamin D3- and carbenoxolone-treated rats showed significant reduction in blood pressure, body mass index, Lee index, waist circumference, retroperitoneal fat, and improvement of dyslipidemia. Meanwhile, treatment with carbenoxolone significantly lowered the elevated liver enzymes, and vitamin D3 resulted in improved insulin sensitivity, enhanced glucose uptake by muscles, and replenished glycogen content in the liver and muscles near control levels. In conclusion, although treatment with vitamin D3 or carbenoxolone reduced the risk factors associated with MetS, vitamin D3 was effective in ameliorating insulin resistance which is the hallmark of MetS.

BackgroundCalcific aortic valve disease (CAVD) is the most frequent pathogeny of aortic valve replacement in developed countries. Iron deposits are found in the intraleaflet hemorrhage (IH) areas of calcific aortic valves. Ferroptosis is a form of regulated cell death that involves metabolic dysfunction resulting from iron overload-dependent excessive lipid peroxidation. In this research, we attempted to clarify the role of ferroptosis in CAVD.MethodsThe level of ferroptosis in tissue and valvular interstitial cells (VICs) was assessed by the contents of 4-HNE, NADPH, ROS, and GSH, lipid peroxidation and mitochondrial morphology. The levels of calcification, iron accumulation and Slc7a11 expression in surgical aortic valve specimens were detected by Alizarin red or Von Kossa, Perl’s blue and immunohistochemical staining. The osteogenic differentiation of VICs was assessed by PCR and western blot analyses. Furthermore, RNA sequencing was used to detect potential differentially expressed genes between normal and osteogenic medium-treated (OM-treated) VICs.ResultsOur experiments demonstrated that ferroptosis occurred in the IH areas of calcific aortic valves. We also found that Slc7a11 was expressed at low levels in OM-treated VICs and IH areas. Finally, we demonstrated that iron promoted Slc7a11-deficient VICs osteogenic differentiation by aggravating ferroptosis in vitro.ConclusionIn conclusion, iron promotes Slc7a11-deficient VIC osteogenic differentiation by aggravating ferroptosis in vitro, thereby accelerating the progression of aortic valve calcification.StatementStatements and opinions expressed in the articles and communications herein are those of the author(s) and not necessarily those of the Editor(s), Society, or publisher, and the Editor(s), Society, and publisher disclaim any responsibility or liability for such material.Brief SummaryIn this work, two novel notions have been proposed. First, we reported that ferroptosis participated in the progression of CAVD. Second, this is the first cytology experiment of valvular interstitial cells (VICs) to clarify the mechanism by which intraleaflet hemorrhage aggravates calve calcification. This research provides new ideas and targets for alleviating the progression of CAVD, especially in patients who have calcified aortic valves without severe stenosis.

Fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance that results from an impaired collagen turnover. Peptidase D (PEPD) plays a vital role in collagen turnover by degrading proline-containing dipeptides. Nevertheless, its specific function and importance in AT is unknown. GWAS identified the rs731839 variant in the locus near PEPD that uncouples obesity from insulin resistance and dyslipidaemia, thus indicating that defective PEPD might impair AT remodelling and exacerbate metabolic complications. Here we show that in human and murine obesity, PEPD expression and activity decrease in AT, coupled to the release of PEPD systemically. Both events, in turn, are associated with the accumulation of fibrosis in AT and insulin resistance. Using pharmacologic and genetic animal models of PEPD down-regulation, we show that whereas dysfunctional PEPD activity provokes AT fibrosis, it is the PEPD secreted by AT the main contributor to inflammation, insulin resistance and metabolic dysfunction. Also, PEPD originated in inflammatory macrophages (Mɸ), plays an essential role promoting fibro-inflammatory responses via activation of EGFR in Mɸ and preadipocytes. Using genetic ablation of pepd in Mɸ that prevents obesity-induced PEPD release, also averts AT fibro-inflammation and obesity-associated metabolic dysfunctions. Taking advantage of factor analysis, we have identified the coupling of prolidase decreased activity and increased systemic levels of PEPD as the essential pathogenic triggers of AT fibrosis and insulin resistance. Thus, PEPD produced by Mɸ qualifies as a biomarker of AT fibro-inflammation and a therapeutic target for AT fibrosis and obesity-associated insulin resistance and type 2 diabetes.

Liver cirrhosis is an established high-risk factor for HCC and the majority of patients diagnosed with HCC have cirrhosis. However, HCC also arises in non-cirrhotic livers in approximately 20 %of all cases. HCC in non-cirrhotic patients is often clinically silent and surveillance is usually not recommended. HCC is often diagnosed at an advanced stage in these patients. Current information about HCC in patients with non-cirrhotic liver is limited. Here we review the current knowledge on epidemiology, clinical features and imaging features of those patiens.

Refractory epilepsy confers a considerable lifetime risk of sudden unexplained death in epilepsy (SUDEP). Mechanisms may overlap with sudden cardiac death (SCD), particularly regarding QTc prolongation. Guidelines in the United States do not mandate the use of electrocardiography (ECG) in diagnostic evaluation of seizures or epilepsy.The purpose of this study was to determine the frequency of ECG use and of QT prolongation, and whether QT prolongation predicts mortality in patients with seizures.We performed a retrospective cohort study including all patients seen at Mayo Clinic in Rochester, Minnesota, from January 1, 2000, to July 31, 2015, with index evaluation for seizure or epilepsy. Patients with an ECG were categorized by the presence of a prolonged QT interval with a primary endpoint of all-cause mortality after the 15-year observation period.Optimal cutoff QT intervals most predictive of mortality were identified. Median age was 40.0 years. An ECG was obtained in 18,222 patients (57.4%). After patients with confounding ECG findings were excluded, primary prolonged QT intervals were seen in 223 cases (1.4%), similar to the general population. Kaplan-Meier analysis demonstrated a significant increase in mortality (Cox hazard ratio [HR] 1.90; 95% confidence interval [CI] 1.76-2.05) for prolonged optimal cutoff QT, maintained after adjustments for age, Charlson comorbidity index, and sex (HR 1.48; 95% CI 1.37-1.59).Use of ECG in diagnostic workup of patients with seizures is poor. A prolonged optimal cutoff QTc interval predicts all-cause mortality in patients evaluated for seizure and those diagnosed with epilepsy. We advocate the routine use of a 12-lead ECG at index evaluation in patients with seizure or epilepsy.

Cardiac resynchronization therapy (CRT) reduces mortality and improves outcomes in appropriately selected patients with heart failure (HF); however, response may vary.We sought to correlate 6-month CRT response assessed by clinical composite score (CCS) and left ventricular end-systolic volume index (LVESVi) with longer-term mortality and HF-related hospitalizations.Individual patient data from 5 prospective CRT studies-Multicenter InSync Randomized Clinical Evaluation (MIRACLE), Multicenter InSync ICD Randomized Clinical Evaluation (MIRACLE ICD), InSync III Marquis, predictors of response to cardiac resynchronization therapy (PROSPECT), and Adaptive CRT-were pooled. Classification of CRT response status using CCS and LVESVi were made at 6 months. Kaplan-Meier analyses were used to assess time to mortality. Cox proportional hazards regression models were used to compute hazard ratios (HRs) for the 3 levels of CRT response: improved, stabilized, and worsened. Adjusted models controlled for baseline factors known to influence both CRT response and mortality. HF-related hospitalization was compared between CRT response categories using incidence rate ratios.Among a total of 1603 patients, 1426 and 1165 were evaluated in the CCS and LVESVi outcome assessments, respectively. Mortality was significantly lower for patients in the improved (CCS: HR 0.22; 95% confidence interval [CI] 0.15-0.31; LVESVi: HR 0.40; 95% CI 0.27-0.60) and stabilized (CCS: HR 0.38; 95% CI 0.24-0.61; LVESVi: HR 0.41; 95% CI 0.25-0.68) groups than in the worsened group for both measures after adjusting for potential confounders.Patients with a worsened CRT response status have a high mortality rate and HF-related hospitalizations. Stabilized patients have a more favorable prognosis than do worsened patients and thus should not be considered CRT nonresponders.

Intestinal fibrosis is considered an inevitable complication of Crohn’s disease (CD) that results in symptoms of obstruction and stricture formation. Endoscopic or surgical treatment is required to treat the majority of patients. Progress in the management of stricturing CD is hampered by the lack of effective antifibrotic therapy; however, this situation is likely to change because of recent advances in other fibrotic diseases of the lung, liver, and skin. In this review, we summarize data from randomized controlled trials (RCTs) of antifibrotic therapies in these conditions. Multiple compounds have been tested for antifibrotic effects in other organs. According to their mechanisms, they were categorized into growth factor modulators, inflammation modulators, 5-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, intracellular enzymes and kinases, renin-angiotensin system (RAS) modulators, and others. From our review of the results from the clinical trials and discussion of their implications in the gastrointestinal tract, we have identified several molecular candidates that could serve as potential therapies for intestinal fibrosis in CD.

Background Catheter ablation strategies for ventricular fibrillation (VF) and polymorphic ventricular tachycardia (PMVT) are not established when spontaneous triggers are rare or absent. Objective The purpose of this study was to report the feasibility and efficacy of a novel empiric ablation strategy of pacemapping to stored implantable cardioverter-defibrillator (ICD) template electrograms (SITE) of the clinical premature ventricular contraction (PVC) trigger. Methods Fifteen patients with drug-refractory VF/PMVT receiving defibrillator shocks without identifiable and mappable PVC triggers were prospectively analyzed. The protocol incorporated systematic pacemapping from known arrhythmogenic sites (moderator band/right ventricular [RV] papillary muscles, left conduction system/Purkinje network, outflow tracts) with real-time comparison between the paced ICD electrogram (EGM) morphology and SITE. Results Regions within the left Purkinje network yielded the best pacemap match for the SITE of the clinical PVC trigger in 55% of ablation targets (left posterior fascicle 6, left septal fascicle 1, left anterior fascicle 5), followed by the RV moderator band region in 14% (n = 3), RV papillary muscles in 13% (n = 3), periaortic region in 14% (n = 3), and left ventricular anterolateral papillary muscle in 4% (n = 1). Freedom from ICD therapies off antiarrhythmic drug (AAD) was 64% at 6 months and 48% at 12 months. Shock burden was reduced from 4 (2–6) to 0 (0–1) (P = .001), and use of AADs was reduced from 2 (1–2) to 0 (0–1) (P = .001). Conclusion In the absence of a mappable trigger, an empiric strategy of interrogating the Purkinje network, papillary muscles, and outflow tract regions by pacemap matching with SITE of the clinical PVC is feasible to guide ablation. A significant reduction in VF/PMVT therapy burden and AAD utilization was observed after a single procedure.

Although patients with systemic right ventricle (SRV) represent a significant proportion of patients with congenital heart disease (CHD) implanted with cardiac resynchronization therapy (CRT), there are limited and conflicting data in this specific patient group.We aimed to analyze outcomes of patients with SRV implanted with a CRT device.Data were analyzed from an observational, retrospective, multicenter cohort study including all patients with CHD implanted with a CRT device from 6 French centers from 2004 to 2020. Response to CRT was defined as an increase in systemic ventricular ejection fraction of ≥10% and/or an improvement in New York Heart Association functional class by at least 1 grade.A total of 85 patients with CHD were enrolled (mean age 39.8 ± 20.0 years; 55 [64.7%] males; 25 defibrillators [29.4%]), including 31 patients with SRV (36.5%) (mean age 43.9 ± 19.8 years; 16 [51.6%] males). The mean change in QRS duration after implantation was similar as compared with patients with systemic left ventricle (-46 ± 26 ms vs -35 ± 32 ms; P = .16). During a mean follow-up of 5.1 ± 3.5 years, late complications included 2 lead dysfunctions (6.5%), 3 CRT-related infections (9.7%), and 1 inappropriate implantable cardioverter-defibrillator shock (3.2%). The proportion of CRT responders at 6, 12, and 24 months were 82.6%, 80.0%, and 77.8% in patients with SRV vs 66.7%, 64.3%, and 69.6% in patients with systemic left ventricle (P = NS).In this multicenter cohort, one-third of patients with CHD implanted with a CRT device had SRV. CRT in patients with SRV was associated with a high rate of responders, comparable to that of patients with systemic left ventricle.

Individuals with evening chronotypes are prone to suffer chronodisruption and display worse lifestyle habits than morning-types, exhibiting higher cardiovascular diseases (CVD). However, it is unknown whether CVD patients, who are evening chronotypes, have higher cardiometabolic risk than morning-types. This study explored whether individual chronotypes were associated with cardiometabolic risk in patients from the CORDIOPREV study (n = 857). We also investigated whether potential associations were moderated by long-term consumption of two healthy diets (Mediterranean and Low-fat diets). This population was classified into chronotypes using the Morningness-Eveningness Questionnaire. Seven-day daily rhythms in wrist temperature (T), rest-activity (A) and position (P) were recorded in a subset of patients (n = 168), and an integrative variable TAP was determined. Metabolic Syndrome (MetS) was determined at baseline, and metabolic and inflammation markers were measured at baseline and yearly during the 4 years of follow-up. Differences in several lifestyle factors were analyzed according to chronotype. At all times, evening-types had higher triglycerides, C-reactive protein and homocysteine and lower high density lipoprotein cholesterol than morning-types (P < 0.05). Evening-types had a higher prevalence of MetS (OR 1.58 IC 95% [1.10 - 2.28], P = 0.01). Moreover, they were more sedentary, displayed less and delayed physical activity and ate and slept later. In addition, evening-types had lower amplitude, greater fragmentation, lower robustness and less stable circadian pattern at TAP (P < 0.01), all related to a less healthy circadian pattern. In conclusion, evening-types with CVD had higher cardiometabolic risk and less robust circadian-related rhythms than morning-types, regardless of the nutritional intervention.

Advances in our understanding of brain function, along with the development of neural interfaces that allow for the monitoring and activation of neurons, have paved the way for brain-machine interfaces (BMIs), which harness neural signals to reanimate the limbs via electrical activation of the muscles or to control extracorporeal devices, thereby bypassing the muscles and senses altogether. BMIs consist of reading out motor intent from the neuronal responses monitored in motor regions of the brain and executing intended movements with bionic limbs, reanimated limbs, or exoskeletons. BMIs also allow for the restoration of the sense of touch by electrically activating neurons in somatosensory regions of the brain, thereby evoking vivid tactile sensations and conveying feedback about object interactions. In this review, we discuss the neural mechanisms of motor control and somatosensation in able-bodied individuals and describe approaches to use neuronal responses as control signals for movement restoration and to activate residual sensory pathways to restore touch. Although the focus of the review is on intracortical approaches, we also describe alternative signal sources for control and noninvasive strategies for sensory restoration.

The aim of this study was to investigate the effect of Hibiscus sabdariffa tea on energy expenditure, satiety response and food intake. This is an open-label, crossover, randomized clinical trial that comprised 21 subjects (11 women, 10 men). The individuals were evaluated at acute moments (fasting and after eating standardized breakfast accompanied by water or H. sabdariffa tea). Resting energy expenditure was measured by indirect calorimetry, subjective satiety responses were evaluated with a visual analogue scale and food intake was assessed by using food records. The volunteers who drank the H. sabdariffa tea had lower perception of hunger (p = 0.002) and greater feeling of satiety (p = 0.01) and fullness (p = 0.009) compared to control. Men who ingested the H. sabdariffa tea had an increase in nitrogen energy expenditure (water: 1501 ± 290.7 kcal, H. sabdariffa tea: 1619 ± 288.9 kcal; p = 0.029). In comparison to control, men presented less perception of hunger (p = 0.003) and desire to eat (p = 0.016), increased satiety (p = 0.021) and fullness (p = 0.01), and women oxidized more fat (p = 0.034) when they drank H. sabdariffa tea. There was no difference between treatments regarding the energy and macronutrient intake from the first meal and throughout the day (p > 0.05) for all participants. The H. sabdariffa tea only affected energy expenditure and satiety responses in men. Clinical trial registry: ReBEC Platform of the Brazilian Clinical Trials Registry ( https://ensaiosclinicos.gov.br/ ) – RBR-5HZ86T. Novelty: H. sabdariffa tea promoted an increase in energy expenditure and caused less perception of hunger/desire to eat in men. H. sabdariffa tea intake increased postprandial fat oxidation in women.

BACKGROUND: The incidence of postoperative microcirculatory flow alterations and their effect on outcome have not been studied extensively. OBJECTIVE: This systematic review and meta-analysis were designed to investigate the presence of sublingual microcirculatory flow alterations during the immediate and early postoperative period and their correlation with complications and survival. METHODS: A systematic search of PubMed, Scopus, Embase, PubMed Central, and Google Scholar was conducted for relevant articles from January 2000 to March 2021. Eligibility criteria were randomized controlled and non-randomized trials. Case reports, case series, review papers, animal studies and non-English literature were excluded. The primary outcome was the assessment of sublingual microcirculatory alterations during the immediate and early postoperative period in adult patients undergoing surgery. Risk of bias was assessed with the Ottawa-Newcastle scale. Standard meta-analysis methods (random-effects models) were used to assess the difference in microcirculation variables. RESULTS: Thirteen studies were included. No statistically significant difference was found between preoperative and postoperative total vessel density (p = 0.084; Standardized Mean Difference (SMD): –0.029; 95%CI: –0.31 to 0.26; I2 = 22.55%). Perfused vessel density significantly decreased postoperatively (p = 0.035; SMD: 0.344; 95%CI: 0.02 to 0.66; I2 = 65.66%), while perfused boundary region significantly increased postoperatively (p = 0.031; SMD: –0.415; 95%CI: –0.79 to –0.03; I2 = 37.21%). Microvascular flow index significantly decreased postoperatively (p = 0.028; SMD: 0.587; 95%CI: 0.06 to 1.11; I2 = 86.09%), while no statistically significant difference was found between preoperative and postoperative proportion of perfused vessels (p = 0.089; SMD: 0.53; 95%CI: –0.08 to 1.14; I2 = 70.71%). The results of the non-cardiac surgery post-hoc analysis were comparable except that no statistically significant difference in perfused vessel density was found (p = 0.69; SMD: 0.07; 95%CI: –0.26 to 0.39; I2 = 0%). LIMITATIONS: The included studies investigate heterogeneous groups of surgical patients. There were no randomized controlled trials. CONCLUSIONS: Significant sublingual microcirculatory flow alterations are present during the immediate and early postoperative period. Further research is required to estimate the correlation of sublingual microcirculatory flow impairment with complications and survival.

INTRODUCTION: Essential thrombocythemia (ET) is an entity of classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), characterized by thrombocytosis with megakaryocytic hyperplasia where in the thrombocytes are increased with abnormal function. Thrombotic events are seen frequently and represent the main cause of morbidity and mortality in patients with MPNs, mainly polycythemia vera and ET. This study has aimed to research the effects of clonally increased thrombocytes on plasma viscosity (PV) levels among patients with ET and the relationship between PV and thromboembolism history, according to the hypotheses about the effects of PV in thromboembolic events among patients with ET. METHODS: A total of 55 patients were enrolled in the study group, 18 of who had been newly diagnosed with ET according to 2016 World Health Organization criteria and had not previously been treated. 37 of them had already been diagnosed with ET and had been treated. There were 47 healthy volunteers in the control group. 5 cc blood samples were taken from the patients into tubes including an anticoagulant to measure their PV levels. RESULTS: PV of the control group was found to be lower than in the study group and both each patient groups (p

OBJECTIVE: This study aimed to explore the clinical detection and prognosis of coagulation function in patients with liver failure and sepsis. METHODS: The plasma fibrinogen (FIB), factor II, factor VII, factor V, factor IV, antithrombin III (ATIII), platelet (PLT), mean PLT volume (MPV), D-dimer, prothrombin activity (PTA), and fibrin degradation product (FDP) levels and thromboelastogram values were detected in patients with liver failure complicated with sepsis and compared with those in the liver failure and liver cirrhosis groups. The patients with liver failure complicated with sepsis were analyzed by univariate and multivariate logistic regression, and the regression equation was established. RESULTS: The levels of FIB, factor II, factor VII, factor V, ATIII, PLT, MPV, D-dimer, and FDP in the patients with liver failure complicated with sepsis were compared with those in the control group patients, and the differences were statistically significant (p

Implantable loop recorders (ILRs) are effective in achieving symptom-rhythm correlation. Data on the diagnostic yield of ILRs, on nurse-led syncope clinics, and on nurse-led ILR implants are limited.We evaluated the safety and efficacy of our nurse-led syncope clinic and nurse-led ILR implants.A retrospective study of all consecutive patients undergoing nurse-led ILR implantations was performed between April 2016 and April 2018. Patients were referred from both nurse-led and physician-led clinics. Data were collected on baseline demographic characteristics, referral source, symptom-rhythm correlation, ILR findings, and subsequent changes to management. All ILRs were enrolled into remote monitoring with automatic arrhythmia detection, and all immediate (≤24 hours) ILR implant complications were recorded. Comparisons were made between nurse-led and physician-led clinics and subsequent outcomes.A total of 432 patients with an ILR were identified: 164 (38%) from nurse-led and 268 (62%) from physician-led clinics; 200 (46%) were women (mean age 66.5 ± 18.2 years; mean follow-up duration 28.9 ± 9.5 months). Primary ILR indications were syncope (n = 251 [58%]), presyncope (n = 33 [7%]), palpitation (n = 39 [9%]), cryptogenic stroke (n = 78 [18%]), and other reasons (n = 31 [7%]). No immediate ILR implant complications occurred. Overall, 156 patients (36%) had a change in management as a direct result of ILR findings, with no overall differences between nurse-led and physician-led clinics (35% vs 36%; P = .7). More patients had newly diagnosed atrial fibrillation in physician-led clinics (15% vs 7%; P = .01), and more patients had pacemaker implants for bradycardia in nurse-led clinics (23% vs 13%; P.01).Nurse-led ILR implantation was safe and effective. Nurse-led syncope clinics achieved good symptom-rhythm correlation with resultant significant changes to management in comparison to physician-led clinics. Larger prospective studies are needed to evaluate their longer-term impact.

Early in the pandemic, concern that cardiovascular effects would accompany COVID-19 was fueled by lessons from the first SARS epidemic, knowledge that the SARS-COV2 entry receptor (Angiotensin-converting enzyme 2, ACE2) is highly expressed in the heart, early reports of myocarditis, and first-hand accounts by physicians caring for those with severe COVID-19. Over 18 months, our understanding of the cardiovascular manifestations has expanded greatly, leaving more new questions than those conclusively answered. Cardiac involvement is common (∼ 20%) but not uniformly observed in those who require treatment in a hospitalized setting. Cardiac MRI studies raise the possibility of manifestations in those with minimal symptoms. Some appear to experience protracted cardiovascular symptoms as part of a larger syndrome of post-acute sequelae of COVID-19 (PASC). Instances of vaccine induced thrombosis and myocarditis are exceedingly rare but illustrate the need to monitor the cardiovascular safety of interventions that induce inflammation. Here, we will summarize the current understanding of potential cardiovascular manifestations of SARS-COV2. To provide proper context, paradigms of cardiovascular injury due to other inflammatory processes will also be discussed. Ongoing research and a deeper understanding COVID-19 may ultimately reveal new insight into the mechanistic underpinnings of cardiovascular disease. Thus, in this time of unprecedented suffering and risk to global health, there exists the opportunity that well conducted translational research of SARS-COV2 may provide health dividends that outlast the current pandemic.

Altered ventricular depolarization due to manifest accessory pathway conduction (ie, Wolff-Parkinson-White syndrome) leads to repolarization abnormalities that persist after pathway ablation. The term T-wave memory (TWM) has been applied to these changes, as the postablation T-wave vector "remembers" the pre-excited QRS vector. In adults, these abnormalities can be misinterpreted as ischemia leading to unnecessary interventions. To date, no comprehensive studies have evaluated this phenomenon in the pediatric population.The purpose of this study was to define TWM in the pediatric population, identify preablation risk factors, and delineate the timeline of recovery.Pre- and postablation electrocardiograms (ECGs) in patients ≤25 years were analyzed over a 5-year period. Frontal plane QTc interval, T-wave axis, QRST angle, and T-wave inversions were used to identify patients with TWM. Univariate analysis was performed to determine the association of preablation ECG features with the outcome of TWM.TWM was present in 42% of pediatric patients, with resolution occurring within 3 months of ablation. Preablation QRS axis0° was a strong predictor of TWM (odds ratio [OR] 15.2; 95% confidence interval [CI] 5.7-40), followed by posteroseptal pathway location (right posteroseptal-OR 8.9; 95% CI 4.2-18.8; left posteroseptal-OR 6.1; 95% CI 1.7-22.3). The degree of pre-excitation had a modest association with the development of TWM. No adverse events were observed.TWM is less common in children compared to adults, and normalization occurred within 3 months postablation. The most predictive features for the development of TWM include a leftward pre-excited QRS axis and posteroseptal pathway location.

Background Chronic kidney disease (CKD) is involved in a progressive deterioration in renal function over the years and is now a global public health problem. Currently, reducing the number of patients progressing to end-stage renal failure is urgently necessary. Hypertension and CKD interact with each other, and good control of blood pressure (BP) can improve CKD patients’ prognosis. With the current global trend for more strict BP control, the importance of BP management and the need for medication to achieve this strict goal are increasing. Calcium channel blockers (CCBs), which target voltage-dependent calcium channels, are frequently used in combination with renin–angiotensin–aldosterone system inhibitors for CKD patients because of their strong BP-lowering properties and relatively few adverse side effects. Calcium channels have several subtypes, including L, N, T, P/Q, and R, and three types of CCBs, L-type CCBs, L-/T-type CCBs, and L-/N-type CCBs, that are available. Nowadays, the new functions and effects of the CCBs are being elucidated. Conclusion We should use different types of CCBs properly depending on their pharmacological effects, such as the strength of antihypertensive effects and the organ protection effects, taking into account the pathophysiology of the patients. In this article, the role and the use of CCBs in CKD patients are reviewed.

The Brugada pattern manifests as a spontaneous variability of the electrocardiographic marker, suggesting a variability of the underlying electrical substrate.The purpose of this study was to investigate the response of the epicardial substrate of Brugada syndrome (BrS) to programmed ventricular stimulation and to Na blocker infusion.We investigated 6 patients (all male; mean age 54 ± 14 years) with BrS and recurrent ventricular fibrillation. Five had no type 1 BrS electrocardiogram pattern at admission. They underwent combined epicardial-endocardial mapping using multielectrode catheters. Changes in epicardial electrograms were evaluated during single endocardial extrastimulation and after low-dose ajmaline infusion (0.5 mg/kg in 5 minutes).All patients had a region in the anterior epicardial right ventricle with prolonged multicomponent electrograms. Single extrastimulation prolonged late epicardial components by 59 ± 31 ms and in 4 patients abolished epicardial components at some sites, without reactivation by surrounding activated sites. These localized blocks occurred at an initial coupling interval of 335 ± 58 ms and then expanded to other sites, being observed in up to 40% of epicardial sites. Ajmaline infusion prolonged electrogram duration in all and produced localized blocks in 62% of sites in the same patients as during extrastimulation. Epicardial conduction recovery after ajmaline occurred intermittently and at discontinuous sites and produced beat-to-beat changes in local repolarization, resulting in an area of marked electrical disparity. These changes were consistent with models based on microstructural alterations under critical propagation conditions.In BrS, localized functional conduction blocks occur at multiple epicardial sites and with variable patterns, without being reactivated from the surrounding sites.

Myotonic dystrophy type 1 (DM1) is the most common adult form of muscular dystrophy, presenting with a constellation of systemic findings secondary to a CTG triplet expansion of the noncoding region of the DMPK gene. Cardiac involvement is frequent, with conduction disease and supraventricular and ventricular arrhythmias being the most prevalent cardiac manifestations, often developing from a young age. The development of cardiac arrhythmias has been linked to increased morbidity and mortality, with sudden cardiac death well described. Strategies to mitigate risk of arrhythmic death have been developed. In this review, we outline the current knowledge on the pathophysiology of rhythm abnormalities in patients with myotonic dystrophy and summarize available knowledge on arrhythmic risk stratification. We also review management strategies from an electrophysiological perspective, attempting to underline the substantial unmet need to address residual arrhythmic risks for this population.

Synopsis We review the current data on epidemiology, the clinical significance, the pathophysiologic mechanisms, and the treatment of VAs in the setting of COVID-19. VAs prevail in 0.15-8% of in hospitalized patients, but only sustained and rapid tachyarrhythmias are purportedly associated with a significant increase in mortality. Multiple factors can elicit VAs, which are ultimately deemed to be a marker of severe systemic disease rather than a distinct cardiac condition. Even though the electrophysiologist plays a determinant role in the secondary prevention of VAs, a multidisciplinary approach is indispensable for primary prophylaxis and acute management.

The objective of the present study was to investigate the relationship between moderate-to-vigorous physical activity (MVPA) and arterial stiffness in pregnancy. Thirty-nine women participated in this study, resulting in 68 measurements in non-pregnant (NP; n = 21), first (TM1; n = 8), second (TM2; n = 20), and third trimesters (TM3; n = 19). Compliance, distensibility, elasticity, β-stiffness, and carotid to femoral (central) and carotid to finger (peripheral) pulse wave velocity (PWV) were assessed. MVPA was measured using accelerometry. Multilevel linear regressions adjusted for multiple tests per participant using random effects to generate β coefficients and 95% confidence intervals (CIs) were performed. Distensibility, elasticity, β-stiffness, and central- and peripheral-PWV did not differ between pregnant and non-pregnant assessments. Carotid artery compliance was higher in TM2 compared with NP. Central PWV (β coefficient: –0.14, 95% CI: –0.27, –0.02) decreased from early to mid-pregnancy and increased in late pregnancy. Meeting the MVPA guidelines was significantly associated with central-PWV (adjusted β coefficient: –0.34, 95% CI: –0.62, −0.06, p = 0.016), peripheral-PWV (adjusted β coefficient: –0.54, 95% CI: –0.91, –0.16, p = 0.005), and distensibility (adjusted β coefficient: –0.001, 95% CI: –0.002, –0.0001, p = 0.018), in pregnancy. These results suggest that MVPA may be associated with improved (i.e., reduced) arterial stiffness in pregnancy. Novelty: Central PWV, distensibility, compliance, elasticity, and β-stiffness, but not peripheral PWV, exhibited curvilinear relationships with gestational age Central and peripheral PWV were lower in pregnant women who met the physical activity guidelines of 150 minutes of moderate-to-vigorous physical activity per week

Synopsis Covid-19 is an acute respiratory disease of viral origin caused by Sars-Cov2. This disease is associated with a hypercoagulable state resulting in arterial and venous thrombotic events. The latter are more frequent, especially in patients who develop a severe form of the disease and are associated with an increased mortality rate. It is therefore essential to identify patients at higher risk in order to initiate antithrombotic therapy. Hospitalized patients treated with treatment-dose of anticoagulants had better outcomes than those treated with prophylactic-dose. However, several trials are ongoing to better define the therapeutic and prevention strategies for this insidious complication.

While looking for a “magic bullet” to treat COVID-19, the massive off-label use of several of drugs in COVID-19, including repurposed antimalarial drugs, immunosuppressive agents, anti-virals and antibacterial agents, have generated concerns in the early phase of the pandemic due a possible arrhythmogenic effects in relation to QTc interval prolongation. Indeed, some of these drugs have been historically associated to QT prolongation and Torsade de Point, a potentially lethal ventricular arrhythmia, and their first-time use on a very large scale has raised several concerns in the scientific community. The aim of this work is to summarize the underlying arrhythmogenic mechanisms related to the use of potentially QT prolonging drugs used during the pandemic to treat COVID-19.

The primary purpose of this study was to determine prevalence of the Male Athlete Triad (MAT) conditions: low energy availability (EA), low bone mineral density (BMD), and low testosterone in male collegiate athletes from different sports. Participants included 44 collegiate male athletes (age, 20.4 ± 0.2 years; body mass index, 25.3 ± 1.3 kg/m2) from 7 sports (cross country, soccer, basketball, wrestling, track, golf, and baseball). Resting metabolic rate, 3-day food intake, 7-day exercise energy expenditure, body composition, and reproductive and metabolic hormones were assessed. Of the total participants, 15% had low EA, 0% had low BMD, 28% had low total testosterone (TT), and 80% had low calculated free testosterone (cFT). There were no significant correlations between EA, BMD, TT, and cFT. Insulin and sex hormone binding globulin (SHBG) were below and on the upper end of the reference range for healthy male adults, respectively. Insulin was negatively correlated with total (r = –0.330, p = 0.043) and lumbar spine BMD z-scores (r = –0.413, p = 0.010). Low TT and low cFT were the most prevalent MAT conditions among all athletes. Further research should investigate the relationship between insulin and SHBG and the role of these hormones in the MAT. Novelty: Assessment of energy availability alone is not sufficient to identify physiological disturbances in collegiate male athletes. Low total and/or free testosterone may be present in some collegiate male athletes, regardless of BMD status. Low insulin and high SHBG concentration may portray the presence of conditions of the MAT in male collegiate athletes.

Up to 87% of patients hospitalized with coronavirus disease 2019 (COVID-19) experience chronic sequelae following infection. The long-term impact of COVID-19 infection on kidney function is largely unknown at this point in the COVID-19 pandemic. In this review, we highlight the current understanding of the pathophysiology of COVID-19-associated kidney injury and the impact COVID-19 may have on long-term kidney function. COVID-19-induced acute kidney injury may lead to tubular injury, endothelial injury, and glomerular injury. We highlight histopathologic correlates from large kidney biopsy and autopsy series. By conducting a comprehensive review of published literature to date, we summarize the rates of recovery from COVID-19-associated-AKI. Finally, we discuss how certain genetic differences, including APOL1 risk alleles (a risk factor for collapsing glomerulopathy), coupled with systemic healthcare disparities, may lead to a disproportionate burden of post-COVID-19-kidney function decline among racial and ethnic minority groups. We highlight the need for prospective studies to determine the true incidence of chronic kidney disease burden after COVID-19.

Background: Pathogenic/likely pathogenic (P/LP) variants in the KCNQ1-encoded Kv7.1 potassium channel cause type 1 long QT syndrome (LQT1). Despite the revamped 2015 American College of Medical Genetics (ACMG) variant interpretation guidelines, the burden of KCNQ1 variants of uncertain significance (VUS) in patients with LQTS remains ∼30%. Objective: The purpose of this study was to determine whether a phenotype-enhanced (PE) variant classification approach could reduce the VUS burden in LQTS genetic testing. Methods: Retrospective analysis was performed on 79 KCNQ1 missense variants in 356 patients from Mayo Clinic and an independent cohort of 42 variants in 225 patients from Amsterdam University Medical Center (UMC). Each variant was classified initially using the ACMG guidelines and then readjudicated using a PE-ACMG framework that incorporated the LQTS clinical diagnostic Schwartz score plus 4 “LQT1-defining features”: broad-based/slow upstroke T waves, syncope/seizure during exertion, swimming-associated events, and a maladaptive LQT1 treadmill stress test. Results: According to the ACMG guidelines, Mayo Clinic variants were classified as follows: 17 of 79 P variants (22%), 34 of 79 LP variants (43%), and 28 of 79 VUS (35%). Similarly, for Amsterdam UMC, the variant distribution was 9 of 42 P variants (22%), 14 of 42 LP variants (33%), and 19 of 42 variants VUS (45%). After PE-ACMG readjudication, the total VUS burden decreased significantly from 28 (35%) to 13 (16%) (P = .0007) for Mayo Clinic and from 19 (45%) to 12 (29%) (P = .02) for Amsterdam UMC. Conclusion: Phenotype-guided variant adjudication decreased significantly the VUS burden of LQT1 case–derived KCNQ1 missense variants in 2 independent cohorts. This study demonstrates the value of incorporating LQT1-specific phenotype/clinical data to aid in the interpretation of KCNQ1 missense variants identified during genetic testing for LQTS.

Background Risk stratification for sudden cardiac death (SCD) in cardiac sarcoidosis (CS) is challenging in patients without overt cardiac symptoms. Objective This study reports the incidence of ventricular arrhythmias (VA) and mortality after long-term monitoring with cardiovascular implantable electronic devices (CIED) in CS patients identified after systematic screening in patients with extra-cardiac sarcoidosis (ECS). Methods A retrospective study was performed in 547 predominantly Caucasian patients with ECS screened for cardiac involvement. If CS was diagnosed, risk stratification (high- versus low-risk) for SCD was performed by a multidisciplinary team. The primary endpoint was defined as sustained VA, appropriate implantable cardioverter defibrillator (ICD) therapy or cardiac death. Results In total, 105 patients were included with a mean follow-up of 33±16 months. An ICD was implanted in 17 high-risk patients (16.2%), while 80 low-risk patients (76.1%) received an implantable loop recorder (ILR). Eight low-risk patients (7.6%) did not receive a device. The primary endpoint occurred in 4.8% (n=5) with an overall annualized event rate of 1.7%. The annualized event rate was 9.8% in high-risk patients and 0.4% in low-risk patients. Nine low-risk patients received an ICD during follow-up; in 7 patients due to ILR recordings. None of these patients required ICD therapy. Conclusion Overall, the annualized event rate of VA and cardiac death in CS patients without overt cardiac symptoms at initial presentation was 1.7%, but the event rate increased to 10% in high-risk patients. In low-risk patients, long-term arrhythmia monitoring enabled early detection of clinically important arrhythmias, without showing impact on prognosis.