DNA methylation rates scale with maximum lifespan across mammals.

DNA methylation rates have previously been found to broadly correlate with maximum lifespan in mammals, yet no precise relationship has been observed. We developed a statistically robust framework to compare methylation rates at conserved age-related sites across mammals. We found that methylation rates negatively scale with maximum lifespan in both blood and skin. The emergence of explicit scaling suggests that methylation rates are, or are linked to, an evolutionary constraint on maximum lifespan acting across diverse mammalian lineages.

Region-based epigenetic clock design improves RRBS-based age prediction.

Recent studies suggest that epigenetic rejuvenation can be achieved using drugs that mimic calorie restriction and techniques such as reprogramming-induced rejuvenation. To effectively test rejuvenation in vivo, mouse models are the safest alternative. However, we have found that the recent epigenetic clocks developed for mouse reduced-representation bisulphite sequencing (RRBS) data have significantly poor performance when applied to external datasets. We show that the sites captured and the coverage of key CpGs required for age prediction vary greatly between datasets, which likely contributes to the lack of transferability in RRBS clocks. To mitigate these coverage issues in RRBS-based age prediction, we present two novel design strategies that use average methylation over large regions rather than individual CpGs, whereby regions are defined by sliding windows (e.g. 5 kb), or density-based clustering of CpGs. We observe improved correlation and error in our regional blood clocks (RegBCs) compared to published individual-CpG-based techniques when applied to external datasets. The RegBCs are also more robust when applied to low coverage data and detect a negative age acceleration in mice undergoing calorie restriction. Our RegBCs offer a proof of principle that age prediction of RRBS datasets can be improved by accounting for multiple CpGs over a region, which negates the lack of read depth currently hindering individual-CpG-based approaches.

Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects.

Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Because mutations in HSPCs often drive leukemia, we hypothesized that HSPC fitness substantially contributes to transformation from CHIP to leukemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12 years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals. We found that gene-specific fitness differences can outweigh inter-individual variation and, therefore, could form the basis for personalized clinical management.

Unskilled shooters improve both accuracy and grouping shot having as reference skilled shooters cortical area: An EEG and tDCS study.

Transcranial direct current stimulation (tDCS) has been used as a non-invasive method for enhanced motor and cognitive abilities. However, no previous study has investigated if the tDCS application in unskilled shooters on cortical sites, selected based on the cortical activity of skilled shooters, improves the accuracy and shot grouping. Sixty participants were selected, which included 10 skilled shooters and 50 unskilled shooters. After we identified the right dorsolateral prefrontal cortex (DLPFC) as the area with the highest activity in skilled shooters, we applied anodal tDCS over the right DLPFC in the unskilled shooters under two conditions: sham-tDCS (placebo) and real-tDCS (anodal tDCS). We also analyzed electroencephalography. Our results indicated that anodal tDCS application enhanced the shot accuracy (p = 0.001). Furthermore, the beta power in the EEG recording was higher in the left DLPFC, left and right parietal cortex (p = 0,001) after applying anodal tDCS, while the low-gamma power was higher in the right DLPFC in sham-tDCS (p = 0.001) and right parietal cortex after anodal-tDCS (p = 0.001). Our findings indicate that anodal tDCS can improve accuracy and shot grouping when applied over the unskilled shooters' right DLPFC. Furthermore, beta and low-gamma bands are influenced by anodal tDCS over the right DLPFC, which may be predictive of skill improvement.

Gelatinous Abdomen: A Rare Case of Pseudomyxoma Peritonei Arising from Metastatic Gastric Adenocarcinoma.

Pseudomyxoma peritonei (PMP) is a rare condition that is typically associated with appendicular adenocarcinoma. Other origins are rarely reported. Here, we report a rare case of abdominal PMP, which originated as gastric adenocarcinoma. The prognosis of the patient consisted of pathological diagnosis, with samples from exploratory laparotomy, radiological visualization, abdominal computed tomography (CT), and abdominal magnetic resonance imaging (MRI). We employed the standard treatment protocol for our patient, which was essentially surgical, applying a cytoreductive technique, in an attempt to remove all visible evidence of the disease, plus intraperitoneal chemotherapy.

His bundle pacing, learning curve, procedure characteristics, safety, and feasibility: Insights from a large international observational study.

BACKGROUND: His-bundle pacing (HBP) provides physiological ventricular activation. Observational studies have demonstrated the techniques' feasibility; however, data have come from a limited number of centers. OBJECTIVES: We set out to explore the contemporary global practice in HBP focusing on the learning curve, procedural characteristics, and outcomes. METHODS: This is a retrospective, multicenter observational study of patients undergoing attempted HBP at seven centers. Pacing indication, fluoroscopy time, HBP thresholds, and lead reintervention and deactivation rates were recorded. Where centers had systematically recorded implant success rates from the outset, these were collated. RESULTS: A total of 529 patients underwent attempted HBP during the study period (2014-19) with a mean follow-up of 217 ± 303 days. Most implants were for bradycardia indications. In the three centers with the systematic collation of all attempts, the overall implant success rate was 81%, which improved to 87% after completion of 40 cases. All seven centers reported data on successful implants. The mean fluoroscopy time was 11.7 ± 12.0 minutes, the His-bundle capture threshold at implant was 1.4 ± 0.9 V at 0.8 ± 0.3 ms, and it was 1.3 ± 1.2 V at 0.9 ± 0.2 ms at last device check. HBP lead reintervention or deactivation (for lead displacement or rise in threshold) occurred in 7.5% of successful implants. There was evidence of a learning curve: fluoroscopy time and HBP capture threshold reduced with greater experience, plateauing after approximately 30-50 cases. CONCLUSION: We found that it is feasible to establish a successful HBP program, using the currently available implantation tools. For physicians who are experienced at pacemaker implantation, the steepest part of the learning curve appears to be over the first 30-50 cases.

Neuroplasticity in visual impairments.

The visual acuity loss enables the brain to access new pathways in the quest to overcome the visual limitation and this is wellknown as neuroplasticity which have mechanisms to cortical reorganization. In this review, we related the evidences about the neuroplasticity as well as cortical anatomical differences and functional repercussions in visual impairments. We performed a systematic review of PUBMED database, without date or status publication restrictions. The findings demonstrate that the visual impairment produce a compensatory sensorial effect, in which non-visual areas are related to both cross (visual congenital) and multimodal (late blind) neuroplasticity.

Investigation of alpha band of the electroencephalogram before and after a task of proprioceptive neuromuscular facilitation.

The proprioceptive neuromuscular facilitation (PNF) sets up a feature of treatment developed with the objective to facilitate and improve the motor performance. The aim of this study was to investigate in healthy female individuals the effects of electrophysiological of a diagonal of the PNF upper limb. The sample consisted of 30 female participants aged between 18 to 28 years, randomly divided into 3 groups (G1, G2, and G3). The three groups had 2 moments of electroencephalographic signal detection, before and after the task. The statistical neurophysiological design allowed the analysis of the relative power of alpha band in three leads (Fz, F7, and F8). Thus, a three-way mixed factorial analysis of variance (ANOVA) was performed to investigate the factor inter subjects (groups) and intrasubjects (areas and moments), a two-way ANOVA to investigate the interactions between the three factors, and a one-way ANOVA to analyze separately the factors time and area. A P≤0.05 was considered as significance level. The results showed significant increase of alpha band in the three groups analyzed, being more evident to the G2 group. Therefore, the PNF can be considered favorable also in relation to the cortical behavior, reinforcing its use in rehabilitation processes, especially in the clinical practice of physiotherapy.

His-bundle pacing versus biventricular pacing in cardiac resynchronization therapy patients: A crossover design comparison.

BACKGROUND: Cardiac resynchronization therapy (CRT) typically is attempted with biventricular pacing (BiVP). One-third of patients are nonresponders. His-bundle pacing (HBP) has been evaluated as an alternative means of effecting CRT because it generates truly physiologic ventricular activation, as evidenced in part by the morphologic identity between normally conducted and paced QRS complexes. OBJECTIVE: The purpose of this study was to assess the feasibility of, and clinical response to, permanent HBP as an alternative to BiVP in CRT-indicated patients. METHODS: Patients were implanted with a right atrial pacing lead, defibrillation lead, left ventricular (LV) lead via the coronary sinus, and HBP lead. His and LV leads were plugged into the LV port via a Y-adapter. After successful implant, patients were randomized in single patient-blinded fashion to either HBP or BiVP. After 6 months, patients were crossed over to the other pacing modality and followed for another 6 months. Quality-of-life assessments, echocardiographic measurements, New York Heart Association classification, and 6-minute hall walk test were obtained at baseline and at each 6-month follow-up. RESULTS: Twenty-nine patients were enrolled; 21 (72%) demonstrated electrical resynchronization (QRS narrowing) at implant. Twelve patients completed the crossover analysis at 1 year. Clinical outcomes (quality of life, New York Heart Association functional class, 6-minute hall walk test, LV ejection fraction) were significantly improved for both pacing modes compared with baseline measures. CONCLUSION: In this crossover comparison between HBP and BiVP, HBP was found to effect an equivalent CRT response. QRS narrowing was observed in 21 of 29 patients, suggesting this approach may be feasible in more patients with left bundle branch block than previously assumed.

Predictors of pacemaker dependence and pacemaker dependence as a predictor of mortality in patients with implantable cardioverter defibrillator.

BACKGROUND: The prevalence, predictors, and survival for the development of pacemaker dependence (PD) in patients implanted with an implantable cardioverter defibrillator (ICD) are unknown. METHODS: This was a retrospective analysis of 1,550 consecutive patients with ICD implantation at a single center from 1996 to 2008 with a mean of 4.2 ± 3.4 years. Patients with implant intrinsic heart rates less than 40 beats/min (n = 48) and cardiac resynchronization therapy (n = 444) were excluded leaving 1,058 patients in this study. PD was defined as an intrinsic rhythm <40 beats/min after inhibiting the pacemaker, <50 beats/min with transient symptoms of dizziness relieved by resumption of pacing and right ventricle pacing despite algorithms to promote intrinsic conduction at the 3 monthly follow-up ICD clinic visits. Multivariate regression and Cox proportional hazard models were used for analysis. RESULTS: The mean age was 64 ± 13 years; 79% were male with a primary indication for the ICD in 57%. PD occurred in 142 (13.4%) of patients, with a mean time to PD of 2.6 ± 1.9 years. PD was associated with a 48% increased odds for mortality versus non-PD ICD patients during the mean follow-up time of 4.2 ± 3.4 years (adjusted odds ratio = 1.48 [95% confidence interval 1.080-2.042]; P = 0.015). Older age, a history of atrial fibrillation, amiodarone use, and secondary prevention were the strongest predictors for the development of PD. CONCLUSIONS: In this single-center ICD cohort, the development of PD was not uncommon and was associated with decreased survival.

CRT-D Therapy in Patients with Decompensated NYHA Class-Four CHF.

Background. ACC-HRS Guidelines for Cardiac Resynchronization Therapy ICD implantation (CRT-D) do not include patients with advanced nonambulatory NYHA class-four CHF due to an expectation of limited survival. There is little data available from these large multicenter randomized studies to support or refute this claim. Purpose. We evaluated the outcomes of patients with advanced nonambulatory NYHA class-four CHF who received CRT-D devices as an attempt to improve the clinical status and promote hospital discharge. Methods. Sixteen (of our six hundred and seventy CRT-D patients) were classified as advanced nonambulatory NYHA Class four inotrope/vasodilator/diuretic-dependent patients. These patients were analyzed retrospectively for weaning success to oral medications, hospital discharge, hemodynamic stability, and survival over eighteen months. Results. Thirteen of sixteen patients were discharged to home within two weeks of implantation. The survival to hospital discharge, as well as at six, twelve, and eighteen months was positive (ninety-four percent, seventy-five percent, sixty-nine percent, sixty-nine percent, resp.). The groups showed significant improvements in systolic blood pressure, renal function, left ventricular ejection fraction, and CHF class. Conclusion. CRT-D in advanced nonambulatory NYHA four patients proved feasible and beneficial. These findings suggest that the strategy merits further study.

Electrical resynchronization induced by direct His-bundle pacing.

BACKGROUND: Biventricular pacing (BiV) to effect cardiac resynchronization therapy can be technically difficult and fails to elicit a clinical response in 30% to 40% of patients. Direct His-bundle pacing (DHBP) theoretically could obviate some of these problems. Although DHBP is capable of narrowing the QRS in some patients, the consistency with which this can be achieved has not been characterized. OBJECTIVE: The purpose of this study was to restore His-Purkinje functionality in consecutive patients undergoing de novo clinically mandated cardiac resynchronization therapy. METHODS: DHBP was temporarily implemented at the time of implantation of a permanent BiV system in patients referred for cardiac resynchronization therapy. Native conduction, DHBP, and BiV QRS duration were compared. All patients presenting for BiV cardiac resynchronization therapy were eligible for the study. Ten patients were studied. RESULTS: DHBP was successfully implemented in all 10 patients. In 7 of 10 patients, DHBP narrowed the QRS significantly compared with native conduction and BiV (mean QRS duration: native 171 +/- 13 ms, DHBP 148 +/- 11 ms, BiV 158 +/- 21, P <.0001). QRS narrowing with DHBP was specifically attributable to capture of latent His-Purkinje tissue. DHBP lead implantation time (16 minutes) was shorter than standard left ventricular lead implantation time (42 minutes). CONCLUSION: DHBP was readily implemented in patients with standard indications for BiV cardiac resynchronization therapy. In most patients studied, DHBP resulted in a significantly narrower QRS compared with native conduction. DHBP may offer a physiologic alternative to BiV for cardiac resynchronization therapy.

Six-month follow-up of patients with in-hospital thrombocytopenia during heparin-based anticoagulation (from the Complications After Thrombocytopenia Caused by Heparin [CATCH] registry).

Thrombocytopenia is a predictor of adverse outcomes in patients with acute coronary syndromes and in critically ill patients. The Complications After Thrombocytopenia Caused by Heparin (CATCH) registry was designed to explore the incidence, management, and clinical consequences of in-hospital thrombocytopenia occurring during heparin-based anticoagulation in diverse clinical settings. We conducted a prospective observational study of 37 United States hospitals participating in the CATCH registry to assess the relation of in-hospital thrombocytopenia to long-term outcomes. A total of 2,104 patients at increased risk of developing in-hospital thrombocytopenia or thrombosis were identified, and the 6-month mortality and rehospitalization rates were determined. Thrombocytopenia was not a significant predictor of 6-month mortality. In an adjusted model for in-hospital death in this cohort, thrombocytopenia had an odds ratio of 3.59 (95% confidence interval 2.24 to 5.77). The postdischarge mortality rate at 6 months was 9.7%. No significant difference was observed in the long-term mortality between patients who developed thrombocytopenia and those who did not. Thrombocytopenia was a weak, but statistically significant, predictor of a composite of mortality and rehospitalization at 6 months (hazards ratio 0.80, 95% confidence interval 0.65 to 0.98, p = 0.03). In conclusion, the 6-month mortality rate among heparin-treated patients with thrombocytopenia is high, although the risk independently related to thrombocytopenia appears to be restricted to the acute hospital phase.

Contribution of bleeding and thromboembolic events to in-hospital mortality among patients with thrombocytopenia treated with heparin.

In a population of patients experiencing thrombocytopenia while treated with heparin, bleeding and thromboses are well-appreciated complications, but their relative contributions to mortality have been less well described. In this population, the aims of this study were (1) to identify the independent predictors of bleeding and (2) to compare the incidence and the strength of association of bleeding and of new thromboses to in-hospital mortality. The independent predictors of bleeding and in-hospital mortality were identified using multivariate logistic regression models on the 1,478 patients who developed thrombocytopenia after their enrollment in the Complications After Thrombocytopenia Caused by Heparin (CATCH) study. The independent predictors of bleeding were chronic hematologic disorders, intra-aortic balloon pump, congestive heart failure, and platelet count nadir <120 x 10(9)/L. Although bleeding (n = 141 [10%]) and thromboembolic complications (n = 135 [9%]) were equally prevalent, the former was less strongly associated than the latter with in-hospital mortality (odds ratio 1.75, 95% confidence interval 1.01 to 3.03, and odds ratio 2.77, 95% confidence interval 1.67 to 4.61, respectively). In conclusion, medical management should be directed mainly at the prevention of thromboembolic complications, while additionally considering the risk for bleeding.

Evaluation and management of thrombocytopenia and suspected heparin-induced thrombocytopenia in hospitalized patients: The Complications After Thrombocytopenia Caused by Heparin (CATCH) registry.

BACKGROUND: Thrombocytopenia and heparin-induced thrombocytopenia (HIT) are potentially devastating paradoxical side effects of heparin therapy. We explored the evaluation, management, and clinical consequences of thrombocytopenia occurring during heparin therapy in diverse clinical settings. METHODS: CATCH was a prospective observational study that enrolled 3,536 patients in 48 US hospitals. Data were collected on 3 strata: patients receiving any form of heparin for > or =96 hours (n = 2,420); cardiac care unit (CCU) patients treated with heparin who developed thrombocytopenia (n = 1,090); patients who had an HIT assay performed (n = 449). RESULTS: Thrombocytopenia occurred in 36.4% of patients in the prolonged heparin stratum and was associated with an increased risk of death or thromboembolic complication (OR 1.5, 95% CI 1.2-1.9). Among a subset of patients whose clinical presentation suggested they were at high risk for HIT, suspicion for HIT was uncommon (prolonged heparin stratum 19.8%, CCU stratum 37.6%) and often did not arise until > or =1 day after patients developed thrombocytopenia. Often patients were not evaluated for HIT until after they had had a thromboembolic complication (prolonged heparin stratum 43.8%, CCU stratum 61%). Even after HIT was suspected, patients often continued to receive heparin. Direct thrombin inhibitor use was infrequent (prolonged heparin stratum 29.4%, CCU stratum 35.6%). Among the few patients who underwent evaluation, HIT was confirmed in 46.7% of the prolonged heparin stratum and 31.4% of the CCU stratum. CONCLUSIONS: Thrombocytopenia is common among patients receiving heparin, and it is associated with substantial risk for catastrophic complications. Despite the high risk for HIT in this population, recognition, evaluation, and appropriate treatment are infrequent and delayed.