Half-Life and Clearance of Cardiac Troponin I and Troponin T in Humans.

BACKGROUND: Cardiac troponin (cTn) is key in diagnosing myocardial infarction (MI). After MI, the clinically observed half-life of cTn has been reported to be 7 to 20 hours, but this estimate reflects the combined elimination and simultaneous release of cTn from cardiomyocytes. More precise timing of myocardial injuries necessitates separation of these 2 components. We used a novel method for determination of isolated cTn elimination kinetics in humans. METHODS: Patients with MI were included within 24 hours after revascularization and underwent plasmapheresis to obtain plasma with a high cTn concentration. After at least 3 weeks, patients returned for an autologous plasma retransfusion followed by blood sampling for 8 hours. cTn was measured with 5 different high-sensitivity cTn assays. RESULTS: Of 25 included patients, 20 participants (mean age, 64.5 years; SD, 8.2 years; 4 women [20%]) received a retransfusion after a median of 5.8 weeks (interquartile range, 5.0-6.9 weeks) after MI. After retransfusion of a median of 620 mL (range, 180-679 mL) autologous plasma, the concentration of cTn in participants' blood increased 4 to 445 times above the upper reference level of the 5 high-sensitivity cTn assays. The median elimination half-life ranged from 134.1 minutes (95% CI, 117.8-168.0) for the Elecsys high-sensitivity cTnT assay to 239.7 minutes (95% CI, 153.7-295.1) for the Vitros high-sensitivity cTnI assay. The median clearance of cTnI ranged from 40.3 mL/min (95% CI, 32.0-44.9) to 52.7 mL/min (95% CI, 42.2-57.8). The clearance of cTnT was 77.0 mL/min (95% CI, 45.2-95.0). CONCLUSIONS: This novel method showed that the elimination half-life of cTnI and cTnT was 5 to 16 hours shorter than previously reported. This indicates a considerably longer duration of cardiomyocyte cTn release after MI than previously thought. Improved knowledge of timing of myocardial injury may call for changes in the management of MI and other disorders with myocardial injury.

Expanded utility of the R package, qgg, with applications within genomic medicine.

SUMMARY: Here, we present an expanded utility of the R package qgg for genetic analyses of complex traits and diseases. One of the major updates of the package is, that it now includes Bayesian linear regression modeling procedures, which provide a unified framework for mapping of genetic variants, estimation of heritability and genomic prediction from either individual level data or from genome-wide association study summary data. With this release, the qgg package now provides a wealth of the commonly used methods in analysis of complex traits and diseases, without the need to switch between software and data formats. AVAILABILITY AND IMPLEMENTATION: The methodologies are implemented in the publicly available R software package, qgg, using fast and memory efficient algorithms in C++ and is available on CRAN or as a developer version at our GitHub page (https://github.com/psoerensen/qgg). Notes on the implemented statistical genetic models, tutorials and example scripts are available at our GitHub page https://psoerensen.github.io/qgg/.

Diurnal variation in genetic parameters for locomotor activity in Drosophila melanogaster assessed under natural thermal conditions.

In nature, organisms are exposed to variable and occasionally stressful environmental conditions. Responses to diurnal and seasonal fluctuations, such as temperature and food accessibility, involve adaptive behavioural and physiological changes. While much work has been done on understanding the genetic architecture and evolutionary potential of stress tolerance traits under constant thermal conditions, there has been less focus on the quantitative genetic background in variable environments. In this study, we use the Drosophila Genetic Reference Panel (DGRP) to investigate the locomotor activity, a key behavioural trait, under variable natural thermal conditions during the summer in a temperate environment. Male flies from 100 DGRP lines were exposed to natural thermal and light conditions in Drosophila activity monitors across three experimental days. We found that activity was highly temperature and time dependent and varied between lines both within and between days. Furthermore, we observed variation in genetic and environmental variance components, with low to moderate estimates of the heritability for locomotor activity, consistently peaking in the afternoons. Moreover, we showed that the estimated genetic correlations of locomotor activity between two time points decreased, as the absolute differences in ambient temperature increased. In conclusion, we find that the genetic background for locomotor activity is environment specific, and we conclude that more variable and unpredictable future temperatures will likely have a strong impact on the evolutionary trajectories of behavioural traits in ectotherms.

Single center outcomes after temporary mechanical circulatory assist device prior to Heartmate 3 implantation - a retrospective cohort study.

Objectives. Temporary mechanical circulatory support (TMCS) has become a component in the therapeutic strategy for treatment of cardiogenic shock as a bridge-to-decision. TMCS can facilitate recovery of cardiopulmonary function, end-organ function, and potentially reduce the surgical risk of left ventricular assist device (LVAD) implantation. Despite the improvements of hemodynamics and end-organ function, post-LVAD operative morbidity might be increased in these high-risk patients. The aim of the study was to compare outcomes after Heartmate 3 (HM3) implantation in patients with and without TMCS prior to HM3 implant. Methods. In this retrospective cohort study of all HM3 patients in the period between November 2015 and October 2021, patients with and without prior TMCS were compared. Patients' demographics, baseline clinical characteristics, laboratory tests, intraoperative variables, postoperative outcomes, and adverse events were collected from patient records. Results. The TMCS group showed an improvement in hemodynamics prior to LVAD implantation. Median TMCS duration was 19.5 (14-26) days. However, the TMCS group were more coagulopathic, had more wound infections, neurological complications, and more patients were on dialysis compared with patient without TMCS prior to HM3 implantation. Survival four years after HM3 implantation was 80 and 82% in the TMCS (N = 22) and non-TMCS group (N = 41), respectively. Conclusion. Patients on TMCS had an acceptable short and long-term survival and comparable to patients receiving HM3 without prior TMCS. However, they had a more complicated postoperative course.

Extreme olfactory sensitivity of silver and bighead carp to overlapping suites of 21-carbon steroids suggests that these species, and likely all other Cyprinoidei, employ them as pheromones.

Although well established that several fishes including goldfish in the suborder Cypinoidei within the family Cypriniformes use the maturation-inducing steroid 17,20ß-dihydroxy-pregn-4-ene-3-one (17,20ßP) and its metabolites as a priming pheromone which they detect with sensitivity and specificity, it is unclear whether and how other Cypriniformes might have evolved to do so. This study examined this question in the family Xenocyprididae. Using electro-olfactogram recording we tested the olfactory sensitivity of silver (Hypophthalmichthys molitrix) and bighead carp (H. nobilis) to a range of 213 steroids in 21 mixtures at 10-9M. While silver carp detected 6 of 21 mixtures, bighead carp detected 5 (p< 0.05). Silver carp were sensitive to 13 21-carbon steroids in these mixtures including 17,20ßP while bighead carp detected 9, including 8 detected by silver carp. This assortment of steroids overlapped that detected by goldfish (family Cyprinidae) but no non-Cyprinoid, suggesting common evolutionary origin and function with differences characteristic of species-specificity.

Low soil Moisture Slows Uptake and Elimination Rates of Phenanthrene in Springtails.

This study investigated the influence of soil water status on the toxicokinetics of phenanthrene in the springtail Folsomia candida allowing estimation of uptake and elimination rates at two contrasting soil water potentials. Fitting a three-phase model to the observations showed that uptake rate (ku) was almost two times higher in moist soil (-2 kPa) than in dry soil (-360 kPa). During the first days of the exposure, elimination rate (ke) was not significantly different in moist and dry soil, but after eight days ke had increased significantly more in moist soil than in dry soil. Our results confirm the general notion that the exposure route via soil pore water is important. Understanding the significance of soil moisture in exposure and effects of contaminants on soil invertebrates is crucial for assessing the ecological risks associated with soil pollution in a changing climate.

Short-term outcomes after heart transplantation using donor hearts preserved with ex vivo perfusion.

The standard Conventional Cold Storage (CCS) during heart transplantation procurement is associated with time-dependent ischemic injury to the graft, which is a significant independent risk factor for post-transplant early morbidity and mortality - especially when cold ischemic time exceeds four hours. Since 2018, Rigshospitalet (Copenhagen, Denmark) has been utilising ex vivo perfusion (Organ Care System, OCS) in selected cases. The objective of this study was to compare the short-term clinical outcomes of patients transplanted with OCS compared to CCS. Methods: This retrospective single-centre study was based on consecutive patients undergoing a heart transplant between January 2018 and April 2021. Patients were selected for the OCS group when the cold ischemic time was expected to exceed four hours. The primary outcome measure was six-month event-free survival. Results: In total, 48 patients were included in the study; nine were transplanted with an OCS heart. The two groups had no significant differences in baseline characteristics. Six-month event-free survival was 77.8% [95% CI: 54.9-100%] in the OCS group and 79.5% [95% CI: 67.8-93.2%] in the CCS group (p = 0.91). While the OCS group had a median out-of-body time that was 183 min longer (p < 0.0001), the cold ischemic time was reduced by 51 min (p = 0.007). Conclusion: In a Scandinavian setting, our data confirms that utilising OCS in heart procurement allows for a longer out-of-body time and a reduced cold ischemic time without negatively affecting safety or early post-transplant outcomes.

Use of prone position ventilation in patients with COVID-19 induced severe ARDS supported with V-V ECMO: A danish cohort study with focus on adverse events.

INTRODUCTION: Prone position ventilation (PPV) of patients with adult respiratory distress syndrome (ARDS) supported with veno-venous extracorporeal membrane oxygenation (V-V ECMO) may improve oxygenation and alveolar recruitment and is recommended when extensive dorsal consolidations are present, but only few data regarding adverse events (AE) related to PPV in this group of patients have been published. METHODS: Nationwide retrospective analysis of 68 COVID-19 patients admitted from March 2020 - December 2021 with severe ARDS and need of V-V ECMO support. The number of patients treated with PPV, number of PPV-events, timing, the time spent in prone position, number and causes of AE are reported. Causes to stop the PPV regimen and risk factors for AE were explored. RESULTS: 44 out of 68 patients were treated with PPV, and 220 PPV events are evaluated. AE were identified in 99 out of 220 (45%) PPV events and occurred among 31 patients (71%). 1 fatal PPV related AE was registered. Acute supination occurred in 19 events (9%). Causes to stop the PPV regimen were almost equally distributed between effect (weaned from ECMO), no effect, death (of other reasons) and AE. Frequent causes of AE were pressures sores and ulcers, hypoxia, airway related and ECMO circuit related. Most AE occurred during patients first or second PPV event. CONCLUSIONS: PPV treatment was found to carry a high incidence of PPV related AE in these patients. Causes and preventive measures to reduce occurrence of PPV related AE during V-V ECMO support need further exploration.

Effects of electrokinetic and ultrasonication pre-treatment and two-step anaerobic digestion of biowastes on the nitrogen fertiliser value by injection or surface banding to cereal crops.

Biogas production from anaerobic digestion (AD) of biowastes is restricted by the recalcitrant nature of many substrates, and this may also reduce the fertiliser value of the produced digestate. The degradability of substrates can potentially be enhanced by physico-chemical pre-treatments before AD, and/or the degradation can be increased by a longer digestion time. In this study, we evaluated the effects of electrokinetic (high voltage) and ultrasonication pre-treatments of biowastes in a two-step AD process on nitrogen fertiliser replacement value (NFRV) of digestates obtained from two biogas plants with contrasting hydraulic retention time (HRT) in the primary AD step. The fertiliser value was tested by direct injection to spring barley and surface-banding to winter wheat, and the ammonium N was 15N-labelled to evaluate ammonia losses. The electrokinetic pre-treatment step significantly (p < 0.05) increased the NH4+-N/total N in the digestates before the second AD step but had an insignificant effect on the fertiliser value in winter wheat and spring barley. Ultrasonication pre-treatment had also no significant effect on the fertiliser value. The two-step AD significantly (p < 0.001) increased 15N recoveries and mineral fertiliser equivalence of labelled ammonium-N in winter wheat and reduced ammonia losses, with a significant effect (p < 0.001) observed in digestates sourced from a shorter HRT biogas reactor. The fertiliser equivalence of labelled ammonium-N in the digestates was 80-88% after injection, indicating relatively low N immobilisation with all the digestates. NFRV in the crops was mainly explained by the NH4+-N/total N ratio, C/N ratio and dry matter content of the digestates. The findings suggest that electrokinetic and ultrasonication pre-treatments combined with a second AD step have no considerable impact on the fertiliser value of digestates, whereas a second AD step significantly reduced ammonia losses after application by surface-banding in winter wheat.

Mercury contamination of two e-waste recycling sites in Ghana: an investigation into mercury pollution at Dagomba Line (Kumasi) and Agbogbloshie (Accra).

This study investigated mercury pollution at two e-waste recycling sites in Ghana-Dagomba Line in Kumasi and Agbogbloshie in Accra. A total of 129 soil samples taken at 100 m and 50 m resolutions, respectively, for Dagomba Line and Agbogbloshie, were analysed for mercury using a Zeeman atomic absorption spectrometry. Mercury concentrations from the recycling sites (ranging from 0.11 to 7.57 mg/kg Dagomba Line, and 0.01-4.36 mg/kg at Agbogbloshie) were significantly higher than that of the surrounding areas (0.01-0.17 mg/kg in Kumasi and 0.01-2.18 mg/kg in Accra) and unpolluted control sites (0.05 mg/kg in Kumasi and 0.02 mg/kg in Accra). The dismantling sites at both locations had the highest mercury concentrations. Furthermore, the concentrations were significantly higher at the Dagomba Line site in Kumasi than at Agbogbloshie, even though the Dagomba Line site is relatively recent. The mercury concentrations at both sites exceeded the pollution prevention and abatement level of 0.1 mg/kg. However, the estimated human health risk showed no potential human health effects. Moreover, the mercury concentrations in water and sediment (0.12-7.69 ng/L and 0.02-0.28 ng/L for Dagomba Line and Agbogbloshie, respectively) were below the US EPA standards. Findings from this study show that e-waste recycling can contaminate the topsoil with mercury, irrespective of the scale of the activity.

Gastrocolic Reflex Is Delayed and Diminished in Adults with Type 1 Diabetes.

BACKGROUND: Constipation is a prevalent gastrointestinal complication in diabetes. The pathophysiology may include neural dysfunction and impaired gastrocolic reflex; however, investigation of the latter has been limited in diabetes. Using the wireless motility capsule, we investigated whether the gastrocolic reflex was impaired in adults with type 1 diabetes compared to healthy. METHODS: One hundred and four adults with type 1 diabetes underwent investigation with the wireless motility capsule and recorded sleep cycle, eating habits, and bowel movements in a diary. Colonic motility index, contraction amplitudes, time-to-peak, peak motility, and colonic transit time were investigated directly in response to a meal. Diagnosis of peripheral (nerve conduction) and autonomic (orthostatic hypotension) polyneuropathy was verified. RESULTS: In comparison with health, people with diabetes had at the time of ingestion decreased motility index and contraction amplitudes (p < 0.001), prolonged time-to-peak (p = 0.01), and borderline decreased peak motility (p = 0.06), which taken together indicate impaired coordination of the gastrocolic reflex. These features were most prominent in those with concomitant peripheral or autonomic neuropathy. Additionally, they were associated with prolonged colonic transit time (p > 0.01). CONCLUSIONS: In type 1 diabetes, the gastrocolic reflex was delayed and diminished and further associated with the presence of neuropathy and constipation. These results suggest that impaired reflex is part of the underlying pathogenesis in the development of constipation.

qgg: an R package for large-scale quantitative genetic analyses.

SUMMARY: Here, we present the R package qgg, which provides an environment for large-scale genetic analyses of quantitative traits and diseases. The qgg package provides an infrastructure for efficient processing of large-scale genetic data and functions for estimating genetic parameters, and performing single and multiple marker association analyses and genomic-based predictions of phenotypes. AVAILABILITY AND IMPLEMENTATION: The qgg package is freely available. For the latest updates, user guides and example scripts, consult the main page http://psoerensen.github.io/qgg. The current release is available from CRAN (https://CRAN.R-project.org/package=qgg) for all major operating systems. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Mechanical circulatory support for refractory out-of-hospital cardiac arrest: a Danish nationwide multicenter study.

BACKGROUND: Mechanical circulatory support (MCS) with either extracorporeal membrane oxygenation or Impella has shown potential as a salvage therapy for patients with refractory out-of-hospital cardiac arrest (OHCA). The objective of this study was to describe the gradual implementation, survival and adherence to the national consensus with respect to use of MCS for OHCA in Denmark, and to identify factors associated with outcome. METHODS: This retrospective, observational cohort study included patients receiving MCS for OHCA at all tertiary cardiac arrest centers (n = 4) in Denmark between July 2011 and December 2020. Logistic regression and Kaplan-Meier survival analysis were used to determine association with outcome. Outcome was presented as survival to hospital discharge with good neurological outcome, 30-day survival and predictors of 30-day mortality. RESULTS: A total of 259 patients were included in the study. Thirty-day survival was 26%. Sixty-five (25%) survived to hospital discharge and a good neurological outcome (Glasgow-Pittsburgh Cerebral Performance Categories 1-2) was observed in 94% of these patients. Strict adherence to the national consensus showed a 30-day survival rate of 30% compared with 22% in patients violating one or more criteria. Adding criteria to the national consensus such as signs of life during cardiopulmonary resuscitation (CPR), pre-hospital low-flow < 100 min, pH > 6.8 and lactate < 15 mmol/L increased the survival rate to 48%, but would exclude 58% of the survivors from the current cohort. Logistic regression identified asystole (RR 1.36, 95% CI 1.18-1.57), pulseless electrical activity (RR 1.20, 95% CI 1.03-1.41), initial pH < 6.8 (RR 1.28, 95% CI 1.12-1.46) and lactate levels > 15 mmol/L (RR 1.16, 95% CI 1.16-1.53) as factors associated with increased risk of 30-day mortality. Patients presenting signs of life during CPR had reduced risk of 30-day mortality (RR 0.63, 95% CI 0.52-0.76). CONCLUSIONS: A high survival rate with a good neurological outcome was observed in this Danish population of patients treated with MCS for OHCA. Stringent patient selection for MCS may produce higher survival rates but potentially withholds life-saving treatment in a significant proportion of survivors.

Gross alpha and beta measurements in drinkable water from seven major geographical regions of China and the associated cancer risks.

In this study, human health risk derived from radioactive pollution in drinking water of China was assessed based on gross alpha and beta. Considering the presence of numerous data under the detection limits, the left-censored handling methods were employed to deal with the non-detected values in gross alpha and beta radioactive concentrations. Results show that concentrations of gross alpha and beta range from 4.98 × 10-4 Bq/L to 0.49 Bq/L with a mean value of 0.029 Bq/L and 5.00 × 10-3 Bq/L to 1.26 Bq/L with a mean value of 0.091 Bq/L, respectively. With the average effective dose being 1.41 × 10-2 mSv/y, the annual cancer risk due to radioactive pollution in Chinese drinking water is 7.75 × 10-7 /y. This study aimed to provide an easier method to quantify the radioactive pollution in drinking water and give a scientific basis for making policy decisions on radioactive pollution management.

Association between vectorcardiographic QRS area and incident heart failure diagnosis and mortality among patients with left bundle branch block: A register-based cohort study.

BACKGROUND: QRS duration and morphology including left bundle branch block (LBBB) are the most widely used electrocardiogram (ECG) markers for assessing ventricular dyssynchrony and predicting heart failure (HF). However, the vectorcardiographic QRS area may more accurately identify delayed left ventricular activation and HF development. OBJECTIVE: We investigated the association between QRS area and incident HF risk in patients with LBBB. METHODS: By crosslinking data from Danish nationwide registries, we identified patients with a first-time digital LBBB ECG between 2001 and 2015. The vectorcardiographic QRS area was derived from a 12­lead ECG using the Kors transformation method and grouped into quartiles. The endpoint was a composite of HF diagnosis, filled prescriptions for loop diuretics, or death from HF. Cause-specific multivariable Cox regression was used to compute hazard ratios(HR) with 95% confidence intervals(CI). RESULTS: We included 3316 patients with LBBB free from prior HF-related events (median age, 72 years; male, 40%). QRS area quartiles comprised Q1, 36-98 µVs; Q2, 99-119 µVs; Q3, 120-145 µVs; and Q4, 146-295 µVs. During a 5-year follow-up, 31% of patients reached the composite endpoint, with a rate of 39% in the highest quartile Q4. A QRS area in quartile Q4 was associated with increased hazard of the composite endpoint (HR:1.48, 95%CI:1.22-1.80) compared with Q1. CONCLUSIONS: Among primary care patients with newly discovered LBBB, a large vectorcardiographic QRS area (146-295 µVs) was associated with an increased risk of incident HF diagnosis, filling prescriptions for loop diuretics, or dying from HF within 5-years.

Application of the health risk assessment of acetochlor in the development of water quality criteria.

Acetochlor is a widely used herbicide in agricultural production. Studies have shown that acetochlor has obvious environmental hormone effects, and long-term exposure may pose a threat to human health. To quantify the hazards of acetochlor in drinking water, a health risk assessment of acetochlor was conducted in major cities of China based on the data of acetochlor residue concentrations in drinking water. The approach of the Species Sensitivity Distributions (SSD) method is used to extrapolate from animal testing data to reflect worst case human toxicity. Results show that hazard quotients related to acetochlor residues in drinking water for different age groups range from 1.94 × 10-4 to 6.13 × 10-4, so, there are no indication of human risk. Compared to the total estimated hazard quotient from oral intake of acetochlor, the chronic exposure imputed to acetochlor residues in drinking water in China accounts for 0.4%. This paper recommends 0.02 mg/L to be the maximum acetochlor residue concentration level in drinking water and source water criteria.

Lead one ratio in left bundle branch block predicts poor cardiac resynchronization therapy response.

BACKGROUND: A low electrocardiogram (ECG) lead one ratio (LOR) of the maximum positive/negative QRS amplitudes is associated with lower left ventricular ejection fraction (LVEF) and worse outcomes in left bundle branch block (LBBB); however, the impact of LOR on cardiac resynchronization therapy (CRT) outcomes is unknown. We compared clinical outcomes and echocardiographic changes after CRT implantation by LOR. METHODS: Consecutive CRT-defibrillator recipients with LBBB implanted between 2006 and 2015 at Duke University Medical Center were included (N = 496). Time to heart transplant, left ventricular assist device (LVAD) implantation, or death was compared among patients with LOR <12 vs ≥12 using Cox-proportional hazard models. Changes in LVEF and LV volumes after CRT were compared by LOR. RESULTS: Baseline ECG LOR <12 was associated with an adjusted hazard ratio (HR) of 1.69 (95% CI: 1.12-2.40, P = .01) for heart transplant, LVAD, or death. Patients with LOR <12 had less reduction of LV end diastolic volume (ΔLVEDV -4 ± 21 vs -13 ± 23%, P = .04) and LV end systolic volume (ΔLVESV -9 ± 27 vs -22 ± 26%, P = .03) after CRT. In patients with QRS duration (QRSd) ≥150 ms, LOR <12 was associated with an adjusted HR of 2.01 (95% CI 1.21-3.35, P = .008) for heart transplant, LVAD, or death, compared with LOR ≥12. CONCLUSIONS: Baseline ECG LOR <12 portends worse outcomes after CRT implantation in patients with LBBB, specifically among those with QRSd ≥150 ms. This ECG ratio may identify patients with a class I indication for CRT implantation at high risk for poor postimplantation outcomes.

Concomitant changes in ventricular depolarization and repolarization and long-term outcomes of biventricular pacing.

BACKGROUND: Biventricular (BiV) pacing increases transmural repolarization heterogeneity due to epicardial to endocardial conduction from the left ventricular (LV) lead. However, limited evidence is available on concomitant changes in ventricular depolarization and repolarization and long-term outcomes of BiV pacing. Therefore, we investigated associations of BiV pacing-induced concomitant changes in ventricular depolarization and repolarization with mortality (i.e., LV assist device, heart transplantation, or all-cause mortality) and sustained ventricular arrhythmia endpoints. METHODS: Consecutive BiV-defibrillator recipients with digital preimplantation and postimplantation electrocardiograms recorded between 2006 and 2015 at Duke University Medical Center were included. We calculated changes in QRS duration and corrected JT (JTc) interval and split them by median values. For simplicity, these variables were named QRSdecreased (≤ -12 ms), QRSincreased (> -12 ms), JTcdecreased (≤22 ms), and JTcincreased (> 22 ms) and subsequently used to construct four mutually exclusive groups. RESULTS: We included 528 patients (median age, 68 years; male, 69%). No correlation between changes in QRS duration and JTc interval was observed (P = .295). Compared to QRSdecreased /JTcincreased , increased risk of the composite mortality endpoint was associated with QRSdecreased /JTcdecreased (hazard ratio [HR] = 1.62; 95% confidence interval [CI] = 1.09-2.43), QRSincreased /JTcdecreased (HR = 1.86; 95% CI = 1.27-2.71), and QRSincreased /JTcincreased (HR = 2.25; 95% CI = 1.52-3.35). No QRS/JTc group was associated with excess sustained ventricular arrhythmia risk (P = .400). CONCLUSION: Among BiV-defibrillator recipients, QRSdecreased /JTcincreased was associated with the most favorable long-term survival free of LV assist device, heart transplantation, and sustained ventricular arrhythmias. Our findings suggest that improved electrical resynchronization may be achieved by assessing concomitant changes in ventricular depolarization and repolarization.

Non-invasively quantified changes in left ventricular activation predict outcomes in patients undergoing cardiac resynchronization therapy.

BACKGROUND: Changes in left ventricular (LV) activation after cardiac resynchronization therapy (CRT) influence survival but are difficult to quantify noninvasively. METHODS AND RESULTS: We studied 527 CRT patients to assess whether noninvasive quantification of changes in LV activation, defined by change (Δ) in QRS area (QRSA), can predict outcomes after CRT. The study outcome was time until LV assist device(LVAD), cardiac transplant, or death. The three-dimensional QRSA was measured from clinical 12 lead ECGs which were transformed into vectorcardiograms using the Kors method. QRSA was calculated as (QRSx2 + QRSy2 + QRSz2 )1/2 ; ΔQRSA was calculated as post-QRSA minus pre-QRSA, where a negative value represents a reduction in LV activation delay. Kaplan-Meier plots and multivariable Cox proportional hazards models were used to relate ΔQRSA area with outcomes after stratifying the population into quartiles of ΔQRSA. The median baseline QRSA of 93.6 µVs decreased to 59.7 µVs after CRT. Progressive reductions in QRSA with CRT were associated with a lower rate of LVAD, transplant, or death across patient quartiles (P < .001). In Cox regression analyses, ΔQRSA was associated with outcomes independent of QRS morphology and other clinical variables (Q1[greatest decrease] vs Q4[smallest change=reference], HR 0.45, CI, 0.30-0.70, P < .001). There was no interaction between ΔQRSA and QRS morphology. CONCLUSIONS: CRT induced ΔQRSA was associated with clinically meaningful changes in event-free survival. ΔQRSA may be a novel target to guide lead implantation and device optimization.

Strong impact of thermal environment on the quantitative genetic basis of a key stress tolerance trait.

Most organisms experience variable and sometimes suboptimal environments in their lifetime. While stressful environmental conditions are normally viewed as a strong selective force, they can also impact directly on the genetic basis of traits such as through environment-dependent gene action. Here, we used the Drosophila melanogaster Genetic Reference Panel to investigate the impact of developmental temperature on variance components and evolutionary potential of cold tolerance. We reared 166 lines at five temperatures and assessed cold tolerance of adult male flies from each line and environment. We show (1) that the expression of genetic variation for cold tolerance is highly dependent on developmental temperature, (2) that the genetic correlation of cold tolerance between environments decreases as developmental temperatures become more distinct, (3) that the correlation between cold tolerance at individual developmental temperatures and plasticity for cold tolerance differs across developmental temperatures, and even switches sign across the thermal developmental gradient, and (4) that evolvability decrease with increasing developmental temperatures. Our results show that the quantitative genetic basis of low temperature tolerance is environment specific. This conclusion is important for the understanding of evolution in variable thermal environments and for designing experiments aimed at pinpointing candidate genes and performing functional analyses of thermal resistance.