Citations

Background and Objectives: Knowledge of the incidence and time frames of the adverse events of patients presenting syncope at the ED is essential for developing effective management strategies. The aim of the present study was to perform a meta-analysis of the incidence and time frames of adverse events of syncope patients. Materials and Methods: We combined individual patients’ data from prospective observational studies including adult patients who presented syncope at the ED. We assessed the pooled rate of adverse events at 24 h, 72 h, 7–10 days, 1 month and 1 year after ED evaluation. Results: We included nine studies that enrolled 12,269 patients. The mean age varied between 53 and 73 years, with 42% to 57% females. The pooled rate of adverse events was 5.1% (95% CI 3.4% to 7.7%) at 24 h, 7.0% (95% CI 4.9% to 9.9%) at 72 h, 8.4% (95% CI 6.2% to 11.3%) at 7–10 days, 10.3% (95% CI 7.8% to 13.3%) at 1 month and 21.3% (95% CI 15.8% to 28.0%) at 1 year. The pooled death rate was 0.2% (95% CI 0.1% to 0.5%) at 24 h, 0.3% (95% CI 0.1% to 0.7%) at 72 h, 0.5% (95% CI 0.3% to 0.9%) at 7–10 days, 1% (95% CI 0.6% to 1.7%) at 1 month and 5.9% (95% CI 4.5% to 7.7%) at 1 year. The most common adverse event was arrhythmia, for which its rate was 3.1% (95% CI 2.0% to 4.9%) at 24 h, 4.8% (95% CI 3.5% to 6.7%) at 72 h, 5.8% (95% CI 4.2% to 7.9%) at 7–10 days, 6.9% (95% CI 5.3% to 9.1%) at 1 month and 9.9% (95% CI 5.5% to 17) at 1 year. Ventricular arrhythmia was rare. Conclusions: The risk of death or life-threatening adverse event is rare in patients presenting syncope at the ED. The most common adverse events are brady and supraventricular arrhythmias, which occur during the first 3 days. Prolonged ECG monitoring in the ED in a short stay unit with ECG monitoring facilities may, therefore, be beneficial.

Background Tumor-infiltrating lymphocytes (TILs), especially CD8+ TILs, can be used for predicting immunotherapy responsiveness and survival outcome. However, the evaluation of CD8+ TILs currently relies on histopathological methodology with high variability. We therefore aimed to develop a DNA methylation signature for CD8+ TILs (CD8+ MeTIL) that could evaluate immune response and prognosis in colorectal cancer (CRC). Methods A CD8+ MeTIL signature score was constructed by using CD8+ T cell-specific differentially methylated positions (DMPs) that were identified from Illumina EPIC methylation arrays. Immune cells, colon epithelial cells, and two CRC cohorts (n=282 and 335) were used to develop a PCR-based assay for quantitative analysis of DNA methylation at single-base resolution (QASM) to determine CD8 + MeTIL signature score. Results Three CD8+ T cell-specific DMPs were identified to construct the CD8+ MeTIL signature score, which showed a dramatic discriminability between CD8+ T cells and other cells. The QASM assay we developed for CD8+ MeTIL markers could measure CD8+ TILs distributions in a fully quantitative, accurate, and simple manner. The CD8+ MeTIL score determined by QASM assay showed a strong association with histopathology-based CD8+ TIL counts and a gene expression-based immune marker. Furthermore, the low CD8+ MeTIL score (enriched CD8+ TILs) was associated with MSI-H tumors and predicted better survival in CRC cohorts. Conclusions This study developed a quantitative DNA methylation-based signature that was reliable to evaluate CD8+ TILs and prognosis in CRC. This approach has the potential to be a tool for investigations on CD8+ TILs and a biomarker for therapeutic approaches, including immunotherapy.

Abstract Background Individuals who carry pathogenic mutations in DNA mismatch repair (MMR) genes have high risks of cancer, and small studies have suggested that these risks depend on the sex of the parent from whom the mutation was inherited. We have conducted the first large study of such a parent-of-origin effect (POE). Methods Our study was based on all MMR gene mutation carriers and their relatives in the Colon Cancer Family Registry, comprising 18,226 people. The POE was estimated as a hazard ratio (HR) using a segregation analysis approach that adjusted for ascertainment. HR = 1 corresponds to no POE and HR > 1 corresponds to higher risks for maternal mutations. Results For all MMR genes combined, the estimated POE HRs were 1.02 (95% confidence interval (CI) 0.75-1.39, p = 0.9) for male colorectal cancer, 1.12 (95% CI 0.81-1.54, p = 0.5) for female colorectal cancer and 0.84 (95% CI 0.52-1.36, p = 0.5) for endometrial cancer. Separate results for each MMR gene were similar. Conclusions Despite being well-powered, our study did not find any evidence that cancer risks for MMR gene mutation carriers depend on the parent-of-origin of the mutation. Based on current evidence, we don’t recommend that POEs be incorporated into the clinical guidelines or advice for such carriers. Key messages MMR gene mutations inherited from the maternal and paternal side confer similar risks of developing colorectal and endometrial cancer.

Background: The Acute Decompensated Heart Failure National Registry (ADHERE) Classification and Regression Tree (CART) algorithm is an accepted method to assess a heart failure (HF) patient’s risk of inpatient mortality based on the patient’s systolic blood pressure (≥115 vs. <115 mmHg), blood urea nitrogen (BUN; ≥43 vs. <43 mg/dL), and creatinine (≥2.75 vs. <2.75 mg/dL) at the time of admission. Whether the ADHERE CART algorithm identifies risk of longer term poor outcomes and is predictive in patients with systolic (EF < 50%) or diastolic (EF ≥ 50%) HF in the community is unclear. Methods: We identified all hospitalizations for a primary diagnosis of HF occurring between 2000-2013 in a community-based cohort living within 40 miles of Rochester, MN. Outcomes including length of stay, in-hospital mortality, 30 and 90 day post-discharge mortality and readmission for any cause at 30 and 90 days were compared across the ADHERE CART risk groups using logistic regression for the entire cohort and separately for systolic (EF < 50%) and diastolic (EF ≥ 50%) HF. Results: See Table. We examined 5,918 heart failure hospitalizations among 3,628 individual patients. Distribution of hospitalizations across the risk categories is shown in table. Length of stay, in-hospital mortality, 30 and 90 day mortality and 30 and 90 day readmission rates all increased with increasing ADHERE risk categories. Similar results were obtained separately for systolic and diastolic HF. Conclusion: The ADHERE CART algorithm is simple, uses data universally available on admission, and identifies groups that differ substantially in their post-discharge adverse outcomes regardless of HF type (systolic vs diastolic) in the community. The ADHERE CART algorithm may inform clinical decision regarding advanced HF treatments, end-of-life planning and care transition services in patients hospitalized for HF in the community.

Background : Lipid lowering therapy reduces mortality in patients with both ischemic and nonischemic cardiomyopathies and recently has been shown to decrease ICD shocks. Radiofrequency ablation (RFA) of recurrent VT in patients with an ICD also reduces shocks following intervention. It is unclear if statin therapy after VT RFA will further impact ICD shock rates. Methods : All patients from 1993–2005 who underwent a RFA procedure for recurrent VT at the Mayo Clinic with an ICD were included. Patient records were extracted for medical and procedural details and all ICD interrogations were reviewed for VT recurrence and therapies. Results: 63 patients (age 62±15 years) were followed over 3.9±3.6 years. Comorbid diseases included: coronary artery disease 37(58%, 34 prior myocardial infarction), ARVD/C 6(10%), nonischemic dilated cardiomyopathy 7(11%), moderate-severe valve disease 14(22%), hypertension 34(54%), and hyperlipidemia 35(56%). Ejection fraction was <0.35 in 34(56%). VT was induced in all patients (LV 55 (LVOT 1), RV 8 (RVOT 3) with multiple inducible VTs in 21(33%). VT was noninducible after RFA in 39(62%) patients. Dismissal medications included: statins 19(30%), beta blockers 40(66%), ACE/ARB 37(61%), diuretics 34(55%), and digoxin 23(37%). 5-year overall survival was 63%(95% CI 55–71). Age, diabetes, and renal insufficiency were associated with increased post ablation mortality, with no medication improving survival. 5-year survival free of ICD shocks was 31%(95% CI 24–38). Only statin therapy at discharge was associated with a decreased risk of ICD shocks [5(26%) versus 26(59%), p=0.020]. 7 additional patients received statins during follow-up, but not at discharge, of these 5(71%) had shocks. Conclusion : Statin use at discharge in patients with an ICD undergoing RFA for refractory VT significantly reduced recurrent ventricular arrhythmias and ICD shocks. Although the mechanism underlying the effects of statins on arrhythmic recurrence early after RFA requires further study, these data support aggressive therapy of the underlying substrate responsible for the VT.

Background: The hallmark of Long QT Syndrome (LQTS) is a prolongation of the ventricular electrical action potential caused by mutations involving key cardiac ion channels on the surface membrane of ventricular myocytes. Different mutations are associated with specific modes of arrhythmia initiation and distinct changes in cardiac rhythm prior to these events. We hypothesized that some LQTS-causing mutations might involve the sinus node, leading to aberrations in cardiac rhythm. To test this hypothesis, we examined the features of cardiac rhythm in 23 genotyped patients with LQTS and 14 matched controls (C) using Holter ECG data (6hrs). Methods: QRS-complexes were identified using custom software and verified by an experienced ECG reader; series of sinus beats were extracted and gaps in time series were linearly interpolated. The mean, max, and min heart rate (HR), the time (SD, SDNN, SDANN, RMSSD, pNN50) and frequency-domain (Total (TP), Very low (VLF), Low (LF), High (HF) frequency powers, and LF/HF) indices of heart rate variability (HRV) were calculated in each 5-min interval and over the entire recording. The short-long-short irregularity was examined using the novel multiscale rhythmogenetic analysis (MRA), which quantifies changes in the HRV indices during the transition from one time-scale window to another. Results: The maximum heart rate was slower in LQTS than in C (101±13 and 119±19bpm, p=0.001). The high-frequency power (HF) was lower in LQTS than in C (80±76 and 113±58ms 2 , p<0.05). However, the short-term irregularity (quantified by the difference in RMSSD between the 75ms and 2000ms time scales) was 4 times greater in LQTS compared to C (p=0.003). Inclusion or exclusion of two patents who were on β-blockers did not change the results. Conclusions: LQTS is associated with specific changes in cardiac rhythm, including: diminished acceleration capacity, decreased high-frequency power, and enhanced short-long-short irregularity. This suggests that LQTS involves channel modifications in the sinus node, which might contribute to arrhythmogenesis. Rhythm characterization in genetic sub-types of LQTS might improve arrhythmia risk stratification in this heterogeneous patient population.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Introduction Optivol (Medtronic Inc.) thoracic impedance (ZT) provides preemptive disease status information in heart failure (HF). It remains unclear how pulmonary‐capillary blood volume (Vc), lung volume (Lvol), and interstitial fluid influence ZT. Hypothesis Positional change and exercise result in increased Vc and/or lung interstitial fluid and ZT tracks fluctuation in these variables. Methods 12 HF patients (age 63±8yr, LVEF 41±14%) were recruited. Measures were taken at rest, exercise, recovery. This included: spirometry, ZT, diffusing capacity of the lungs for CO and NO (DLCO, DLNO), alveolar‐capillary conductance (Dm, interstitial fluid index), and Vc. Inspiratory capacity was obtained to provide consistent lung volumes for assessing ZT. Results Positional change (upright‐supine) resulted in an increased ZT (5±4%, p<0.01), while the change in Lvol (RV‐TLC) resulted in a 7±2 ohm swing in ZT (0.2±0.1ohm change/100ml change in Lvol). After 30min supine, Vc increased 28±39% (p<0.05) while Dm/Vc and Lvol decreased (29±11% and 17±3%, p<0.05). During exercise compared to baseline, Vc increased 56±44% (p<0.01), DmCO/Vc decreased 25±7% (p<0.05), and ZT did not change. During recovery measures normalized except DmCO/Vc. Conclusion Positional changes and fluctuations in Lvol influence ZT yet measures of lung fluid minimally impact this measure despite significant fluctuations.

Background Brugada syndrome is an inherited cardiac channelopathy associated with major arrhythmic events (MAEs). The presence of a positive family history of sudden cardiac death (SCD) as a risk predictor of MAE remains controversial. We aimed to examine the association between family history of SCD and MAEs stratified by age of SCD with a systematic review and meta‐analysis. Methods and Results We searched the databases of MEDLINE and EMBASE from January 1992 to January 2020. Data from each study were combined using the random‐effects model. Fitted metaregression was performed to evaluate the association between the age of SCD in families and the risk of MAE. Twenty‐two studies from 2004 to 2019 were included in this meta‐analysis involving 3386 patients with Brugada syndrome. The overall family history of SCD was not associated with increased risk of MAE in Brugada syndrome (pooled odds ratio [OR], 1.11; 95% CI, 0.82–1.51; P =0.489, I 2 =45.0%). However, a history of SCD in family members of age younger than 40 years of age did increase the risk of MAE by ≈2‐fold (pooled OR, 2.03; 95% CI, 1.11–3.73; P =0.022, I 2 =0.0%). When stratified by the age of cut point at 50, 45, 40, and 35 years old, a history of SCD in younger family member was significantly associated with a higher risk of MAE (pooled OR, 0.49, 1.30, 1.51, and 2.97, respectively; P =0.046). Conclusions A history of SCD among family members of age younger than 40 years was associated with a higher risk of MAE.

Introduction: Drug challenge testing is performed to unmask Type-1 Brugada pattern. The safety and prevalence of its complications during the test are unclear. We aimed to assess the relation of complications in patients with positive and negative results by a systematic review and meta-analysis. Hypothesis: The prevalence of arrhythmic complications is higher in patients with positive drug challenge testing. Methods: We comprehensively searched the databases of MEDLINE and EMBASE from inception to June 2020. Included studies were cohort studies that reported ventricular arrhythmia that required interventions (VAI) (sustained ventricular tachycardia [VT], polymorphic VT, ventricular fibrillation, appropriate implantable cardioverter defibrillator [ICD] shock, or sudden cardiac arrest) and ventricular arrhythmias that did not required interventions (VANI) (premature ventricular complexes and non-sustained VT) during drug challenge testing. Data were combined using the random-effects model. Results: Thirteen studies involving 2,688 patients (62.7% positive) were included. The overall prevalence of VAI and VANI were 3.7% (95% confidence interval [CI]: 1.8-5.7) and 0.5% (95% CI: 0.1-0.9), respectively. VAI were more common in positive when compared to negative test result patients (1.5% [95% CI: 0.6-2.4] and 0%, respectively) but the prevalence of VANI were similar (2.7% [95% CI: 0.8-4.6] and 2.6% [95% CI: 0.8-4.6], respectively). VAI in positive result patients were more common with flecainide followed by pilsicainide and ajmaline (2.4% [95% CI: -4.3 to 9.2], 2.2% [95% CI: 0.5-4.0], and 1.5% [95% CI: 0.6 to 2.4], respectively). Most of patients with VAI during drug challenge testing underwent ICD implantation (94%). VAI during drug challenge testing in positive result patients carries an increased risk of VAI during 8.6 ± 4.9 years follow-up (odds ratio 3.73, 95% CI: 1.77-7.86, p=0.001). Conclusions: VAI were more common in patients with positive drug challenge testing, more often occurring with positive flecainide challenge, and carries an increased risk of VAI over long-term follow-up in patients with positive drug challenge testing.