Continuous Urine Output-Based Alert Identifies Cardiac Surgery-associated Acute Kidney Injury Earlier Than Serum Creatinine: A Prospective and Retrospective Observational Study.

OBJECTIVE(S): Acute kidney injury (AKI) is defined and staged by reduced urine output (UO) and increased serum creatinine (SCr). UO is typically measured manually and documented in the electronic health record, making early and reliable detection of oliguria-based AKI and electronic data extraction challenging. The authors investigated the diagnostic performance of continuous UO, enabled by active drain line clearance-based alerts (Accuryn AKI Alert), compared with AKI stage 2 SCr criteria and their associations with length of stay, need for continuous renal replacement therapy, and 30-day mortality. DESIGN: This study was a prospective and retrospective observational study. SETTING: Nine tertiary centers participated. PARTICIPANTS: Cardiac surgery patients were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 522 patients were analyzed. AKI stages 1, 2, and 3 were diagnosed in 32.18%, 30.46%, and 3.64% of patients based on UO, compared with 33.72%, 4.60%, and 3.26% of patients using SCr, respectively. Continuous UO-based alerts diagnosed stage ≥1 AKI 33.6 (IQR =15.43, 95.68) hours before stage ≥2 identified by SCr criteria. A SCr-based diagnosis of AKI stage ≥2 has been designated a Hospital Harm by the Centers for Medicare & Medicaid Services. Using this criterion as a benchmark, AKI alerts had a discriminative power of 0.78. The AKI Alert for stage 1 was significantly associated with increased intensive care unit and hospital length of stay and continuous renal replacement therapy, and stage ≥2 alerts were associated with mortality. CONCLUSIONS: AKI Alert, based on continuous UO and enabled by active drain line clearance, detected AKI stages 1 and 2 before SCr criteria. Early AKI detection allows for early kidney optimization, potentially improving patient outcomes.

Intra-abdominal hypertension in cardiac surgery patients: a multicenter observational sub-study of the Accuryn registry.

Intra-abdominal hypertension (IAH) is frequently present in the critically ill and is associated with increased morbidity and mortality. Conventionally, intermittent 'spot-check' manual measurements of bladder pressure in those perceived as high risk are used as surrogates for intra-abdominal pressure (IAP). True patterns of IAH remain unknown. We explored the incidence of IAH in cardiac surgery patients and describe the intra-and postoperative course of IAP using a novel, high frequency, automated bladder pressure measurement system. Sub-analysis of a prospective, multicenter, observational study (NCT04669548) conducted in three large academic medical centers. Continuous urinary output (CUO) and IAP measurements were observed using the Accuryn Monitoring System (Potrero Medical, Hayward, CA). Data collected included demographics, hemodynamic support, and high-frequency IAP and CUO. One Hundred Thirty-Seven cardiac surgery patients were analyzed intraoperatively and followed 48 h postoperatively in the intensive care unit. Median age was 66.4 [58.3, 72.0] years, and 61% were men. Median Foley catheter dwell time was 56.0 [46.8, 77.5] hours, and median baseline IAP was 6.3 [4.0, 8.1] mmHg. 93% (128/137) of patients were in IAH grade I, 82% (113/137) in grade II, 39% (53/137) in grade III, and 5% (7/137) in grade IV for at least 12 cumulative hours. For maximum consecutive duration of IAH, 84% (115/137) of patients spent at least 12 h in grade I, 62% (85/137) in grade II, 18% (25/137) in grade III, and 2% (3/137) in grade IV IAH. During the first 48 h after cardiac surgery, IAH is common and persistent. Improved and automated monitoring of IAP will increase the detection of IAH-which normally would remain undetected using traditional intermittent monitoring methods.

A Retrospective, Observational Study of Catheter-Associated Urinary Tract Infection Events Post-Implementation of a Novel Urinary Catheter System with Active Drain Line Clearance and Automated Intra-Abdominal Pressure Monitoring.

Objective: A quality improvement study to assess catheter-associated urinary tract infection (CAUTI) rate post-implementation of a bladder catheter with integrated active drain line urine clearance and automated intra-abdominal pressure monitoring in a burn intensive care unit (ICU). DESIGN: Eight-year retrospective before and after study (2015−2022). Setting: A single American Burn Association-verified Burn Center with 14 inpatient beds. Patients: Patients meeting criteria for admission to a Burn Center. Methods: Retrospective cohort study following the implementation of a novel urine output monitoring system with integrated drain line and urine clearance. Data from a 48-month (from January 2015−December 2018) historical control (period 1) were compared to data from a 28-month (from January 2020 to April 2022) post-implementation period (period 2). Pre- and post-implementation CAUTI event incidences were compared. Patients were transferred from outside hospitals with gravity bladder. A distinction in the chart between catheter types was impossible. Charts were reviewed to characterize patients with CAUTI events. Results: A total of 42 CAUTIs in 2243 patients were identified using the National Health and Safety Network (NHSN) definition during the analyzed period. There were 40 CAUTI events in period 1 and two CAUTIs in period 2. The incidence of CAUTI events pre-implementation was 0.030 (mean of 10 CAUTI events per year) compared to 0.002 (mean of 1 CAUTI event per year) post-implementation of an automatic drain line clearing UO monitoring system showing a significant reduction in CAUTI events (p < 0.01, risk ratio novel vs. gravity bladder catheter 0.071, 95% confidence interval: 0.017−0.294). Conclusions: CAUTIs were reduced in the period following the implementation of a novel urinary catheter system with an integrated active drain line and urine clearance in burn patients.

Soldiers' Heart: A Prospective Study of Cardiac Remodeling in Soldiers Undergoing Progressive Intensity Exercise Training.

PURPOSE: Most studies reporting cardiac changes with exercise have been cross sectional. The few available longitudinal studies have lacked standardization for environmental confounders. We prospectively assessed the relationship between increasing exercise intensity and cardiac remodeling in a highly standardized cohort of healthy young army soldiers. METHODS: Sixty-three male army recruits (22 ± 3 yr) underwent a 12-wk moderate-intensity mixed strength and endurance exercise program, followed by a further 15-wk high-intensity exercise program, with highly controlled exercise, diet, and sleep patterns. Fitness (multistage fitness test), anthropometry, and 2D echocardiography were assessed. RESULTS: Moderate-intensity exercise was associated with increased fitness and decreased body fat % (both P < 0.01). There was no significant incremental change in these parameters after high-intensity exercise. By contrast, both moderate- and high-intensity exercises were associated with dose-dependent increases in left atrial and left ventricular (LV) volumes, LV mass, and right ventricular (RV) size (all P < 0.01). At the end of high-intensity training, 51% had a dilated LV and 59% had a dilated RV compared with published normal ranges. Almost all had normal LV systolic function and strain before and after exercise training. A small number of soldiers had mildly decreased RV systolic function at baseline and after moderate-intensity exercise (3% and 6%, respectively). CONCLUSIONS: We describe "soldiers' heart," which is characterized by balanced chamber dilatation, normal LV mass, and largely normal systolic function and myocardial strain. This prospective and highly controlled longitudinal study also found that increasing intensity exercise was associated with increasing chamber dimensions, which paralleled an increase in fitness after moderate-intensity exercise. After high-intensity exercise, however, cardiac chamber size continued to increase, but fitness did not increase further.

Moderate- and High-Intensity Exercise Improves Lipoprotein Profile and Cholesterol Efflux Capacity in Healthy Young Men.

Background Exercise is associated with a reduced risk of cardiovascular disease. Increased high-density lipoprotein cholesterol (HDL-C) levels are thought to contribute to these benefits, but much of the research in this area has been limited by lack of well-controlled subject selection and exercise interventions. We sought to study the effect of moderate and high-intensity exercise on HDL function, lipid/lipoprotein profile, and other cardiometabolic parameters in a homogeneous population where exercise, daily routine, sleep patterns, and living conditions were carefully controlled. Methods and Results Male Army recruits (n=115, age 22±0.3 years) completed a 12-week moderate-intensity exercise program. A subset of 51 subsequently completed a 15-week high-intensity exercise program. Fitness increased and body fat decreased after moderate- and high-intensity exercise (P<0.001). Moderate-intensity exercise increased HDL-C and apolipoprotein A-I levels (6.6%, 11.6% respectively), and decreased low-density lipoprotein cholesterol and apolipoprotein B levels (7.2%, 4.9% respectively) (all P<0.01). HDL-C and apolipoprotein A-I levels further increased by 8.2% (P<0.001) and 6.3% (P<0.05) after high-intensity exercise. Moderate-intensity exercise increased ABCA-1 (ATP-binding cassette transporter A1) mediated cholesterol efflux by 13.5% (P<0.001), which was sustained after high-intensity exercise. In a selected subset the ability of HDLs to inhibit ICAM-1 (intercellular adhesion molecule-1) expression decreased after the high (P<0.001) but not the moderate-intensity exercise program. Conclusions When controlling for exercise patterns, diet, and sleep, moderate-intensity exercise improved HDL function, lipid/lipoprotein profile, fitness, and body composition. A sequential moderate followed by high-intensity exercise program showed sustained or incremental benefits in these parameters. Improved HDL function may be part of the mechanism by which exercise reduces cardiovascular disease risk.

The Effects of Exercise on Plaque Volume and Composition in a Mouse Model of Early and Late Life Atherosclerosis.

Background: Exercise is associated with a less atherogenic lipid profile; however, there is limited research on the effect of exercise on atherosclerotic plaque composition and markers of plaque stability. Methods: A total of 110 apolipoprotein (apo)E -/- mice were placed on a chow diet and randomly assigned to control or exercise for a period of 10 weeks, commencing either at 12 weeks of age (the early-stage atherosclerosis, EA group) or at 40 weeks of age (the late-stage atherosclerosis, LA group). At the end of the exercise period, blood was assayed for lipids. Histologic analysis of the aortic sinus was undertaken to assess plaque size and composition that includes macrophage content, monocyte chemoattractant protein (MCP)-1, matrix metalloproteinase-2 (MMP-2), and tissue inhibitors of metalloproteinase 1 and 2 (TIMP-1 and 2). Results: A total of 103 mice (38 EA, 65 LA) completed the protocol. In the EA group, exercise reduced plasma total cholesterol (TC) (-16%), free cholesterol (-13%), triglyceride (TG) (-35%), and phospholipid (-27%) levels, when compared to sedentary control mice (p < 0.01). In the EA group, exercise also significantly reduced plaque stenosis (-25%, p < 0.01), and there were higher levels of elastin (3-fold increase, p < 0.0001) and collagen (11-fold increase, p < 0.0001) in plaques, compared to control mice. There was an increase in plaque MMP-2 content in the exercise group (13% increase, p < 0.05) but no significant difference in macrophage or MCP-1 content. In the LA group, exercise reduced plaque stenosis (-18%, p < 0.05), but there was no significant difference in plaque composition. There was no difference in macrophage, MCP-1, or MMP-2 content in the LA groups. TIMP-1 was lower with exercise in both the EA and LA groups (-59%, p < 0.01 and -51%, p < 0.01 respectively); however, there was no difference in TIMP-2 levels. Conclusion: A 10-week exercise period reduces atherosclerotic plaque stenosis when commenced at both early- and late-stage atherosclerosis. Intervening earlier with exercise had a greater beneficial effect on lipids and plaque composition than when starting exercise at a later disease stage.

Effectiveness of a multi-modal hospital-wide doctor mental health and wellness intervention.

BACKGROUND: Doctors report high rates of workplace stress and are at increased risk of mental health disorders. However, there are few real-world studies evaluating the effectiveness of interventions aimed at addressing workplace risk factors and improving doctors' mental health in a hospital setting. This study was conducted over two years (2017-2019) to assess the effects of a multi-modal intervention on working conditions doctors' mental health and help-seeking for mental health problems in two Australian teaching hospitals. METHODS: The multimodal intervention consisted of organisational changes, such as reducing unrostered overtime, as well as strategies for individual doctors, such as mental health training programs. Hospital-based doctors at all career stages were eligible to participate in two cross-sectional surveys. 279 doctors completed the baseline survey (19.2% response rate) and 344 doctors completed the follow-up survey (31.3% response rate). A range of workplace risk and protective factors, mental health (psychological distress and suicidal ideation) and help-seeking outcomes were assessed. RESULTS: There were significant improvements in key workplace protective factors, with small effects found for doctors' job satisfaction, stress, work-life balance and perceived workplace support and a significant reduction in workplace risk factors including a moderate reduction in reported bullying behaviour between baseline to follow-up (job satisfaction p < 0.05, all other outcomes p < 0.01). However, no significant changes in doctors' mental health or help-seeking outcomes were found over the intervention period. CONCLUSION: Following the implementation of individual and organisational-level strategies in two Australian tertiary hospitals, doctors reported a reduction in some key workplace stressors, but no significant changes to their mental health or help-seeking for mental health problems. Further research is warranted, particularly to determine if these workplace changes will lead to improved mental health outcomes for doctors once maintained for a longer period.

Serial Echocardiographic Follow-up of Structural Heart Interventions Performed During Pacific Partnership Interventional Cardiology Subject Matter Exchanges From 2015 to 2017 in Da Nang, Vietnam.

INTRODUCTION: The U.S. Navy Medicine has a long history of conducting global health missions that foster international diplomacy through medical knowledge exchange with a goal of increasing partner nation's health care capacity. Pacific Partnership is an annual U.S. Navy-sponsored joint operation that enhances medical collaboration with participating nations throughout the Indo-Asia-Pacific region. Since 2015, a U.S. Navy Cardiology team has conducted a structural heart disease interventional workshop focused on congenital heart disease with the cardiologists at the Da Nang General Hospital, Da Nang, Vietnam. Herein, we describe the multinational collaborative project including the patient registry we developed to monitor the short- and long-term outcomes of structural heart disease interventions preformed during Pacific Partnership 2015 and 2016. MATERIALS AND METHODS: Our team developed a sustainable procedural registry with the goal of following the long-term outcomes of cardiac interventions for congenital heart disease in Vietnamese patients. Specifically, the registry was designed to record the changes in symptoms referable to the cardiovascular system and for device placement-associated complications for devices placed in 2015 and 2016 and has been updated annually thereafter. RESULTS: Twelve patients (age range, 7 months to 31 years) underwent successful atrial septal defect closure in 2015 without procedural complications. The follow-up rate was 75% at 1 year and 67% at 2 years, and all devices were in appropriate position with no complications identified. Fifteen patients (age range, 20-66 years) underwent successful atrial septal defect closure in 2016. The follow-up rate was 62.5% at 1 year, and all devices were in appropriate position with no complications identified. Three patients (age range, 5-25 months) underwent successful device closure of the patent ductus arteriosus in 2015 without complications. The follow-up rate was 67% in 2016 and again in 2017. Six patients (age range, 9-74 years) underwent successful patent ductus arteriosus closure in 2016 without complications. The follow-up rate was 67% in 2017, and all devices were in appropriate position with no device-related complications identified. CONCLUSIONS: The development of a patient registry during these missions allowed for the longitudinal monitoring of outcomes for cardiac interventions. Notably, treated patients experienced symptomatic improvement without significant long-term procedural complications. Following patients longitudinally across medical missions is of recognized importance but remains a difficult objective to achieve for a multitude of factors including administrative and financial burdens on both the medical systems and the patients of host nations. Despite these limitations, longitudinal follow-up of patient care facilitated by a patient registry has a vital role in monitoring the quality of care provided and should be an integral part of all future global medical missions.

Effect of chronic exercise in healthy young male adults: a metabolomic analysis.

AIMS: To examine the metabolic adaptation to an 80-day exercise intervention in healthy young male adults where lifestyle factors such as diet, sleep, and physical activities are controlled. METHODS AND RESULTS: This study involved cross-sectional analysis before and after an 80-day aerobic and strength exercise intervention in 52 young, adult, male, newly enlisted soldiers in 2015. Plasma metabolomic analyses were performed using liquid chromatography, tandem mass spectrometry. Data analyses were performed between March and August 2019. We analysed changes in metabolomic profiles at the end of an 80-day exercise intervention compared to baseline, and the association of metabolite changes with changes in clinical parameters. Global metabolism was dramatically shifted after the exercise training programme. Fatty acids and ketone body substrates, key fuels used by exercising muscle, were dramatically decreased in plasma in response to increased aerobic fitness. There were highly significant changes across many classes of metabolic substrates including lipids, ketone bodies, arginine metabolites, endocannabinoids, nucleotides, markers of proteolysis, products of fatty acid oxidation, microbiome-derived metabolites, markers of redox stress, and substrates of coagulation. For statistical analyses, a paired t-test was used and Bonferroni-adjusted P-value of <0.0004 was considered to be statistically significant. The metabolite dimethylguanidino valeric acid (DMGV) (recently shown to predict lack of metabolic response to exercise) tracked maladaptive metabolic changes to exercise; those with increases in DMGV levels had increases in several cardiovascular risk factors; changes in DMGV levels were significantly positively correlated with increases in body fat (P = 0.049), total and LDL cholesterol (P = 0.003 and P = 0.007), and systolic blood pressure (P = 0.006). This study was approved by the Departments of Defence and Veterans' Affairs Human Research Ethics Committee and written informed consent was obtained from each subject. CONCLUSION: For the first time, the true magnitude and extent of metabolic adaptation to chronic exercise training are revealed in this carefully designed study, which can be leveraged for novel therapeutic strategies in cardiometabolic disease. Extending the recent report of DMGV's predictive utility in sedentary, overweight individuals, we found that it is also a useful marker of poor metabolic response to exercise in young, healthy, fit males.

Efficient Propagation of Circulating Tumor Cells: A First Step for Probing Tumor Metastasis.

Circulating tumor cells (CTCs) represent a unique population of cells that can be used to investigate the mechanistic underpinnings of metastasis. Unfortunately, current technologies designed for the isolation and capture of CTCs are inefficient. Existing literature for in vitro CTC cultures report low (6-20%) success rates. Here, we describe a new method for the isolation and culture of CTCs. Once optimized, we employed the method on 12 individual metastatic breast cancer patients and successfully established CTC cultures from all 12 samples. We demonstrate that cells propagated were of breast and epithelial origin. RNA-sequencing and pathway analysis demonstrated that CTC cultures were distinct from cells obtained from healthy donors. Finally, we observed that CTC cultures that were associated with CD45+ leukocytes demonstrated higher viability. The presence of CD45+ leukocytes significantly enhanced culture survival and suggests a re-evaluation of the methods for CTC isolation and propagation. Routine access to CTCs is a valuable resource for identifying genetic and molecular markers of metastasis, personalizing the treatment of metastatic cancer patients and developing new therapeutics to selectively target metastatic cells.

Multiplexed (18-Plex) Measurement of Signaling Targets and Cytotoxic T Cells in Trastuzumab-Treated Patients using Imaging Mass Cytometry.

PURPOSE: Imaging mass cytometry (IMC) uses metal-conjugated antibodies to provide multidimensional, objective measurement of protein targets. We used this high-throughput platform to perform an 18-plex assessment of HER2 ICD/ECD, cytotoxic T-cell infiltration and other structural and signaling proteins in a cohort of patients treated with trastuzumab to discover associations with trastuzumab benefit. EXPERIMENTAL DESIGN: An antibody panel for detection of 18 targets (pan-cytokeratin, HER2 ICD, HER2 ECD, CD8, vimentin, cytokeratin 7, ß-catenin, HER3, MET, EGFR, ERK 1-2, MEK 1-2, PTEN, PI3K p110 α, Akt, mTOR, Ki67, and Histone H3) was used with a selection of trastuzumab-treated patients from the Hellenic Cooperative Oncology Group 10/05 trial (n = 180), and identified a case-control series. RESULTS: Patients that recurred after adjuvant treatment with trastuzumab trended toward a decreased fraction of HER2 ECD pixels over threshold compared with cases without recurrence (P = 0.057). After exclusion of the lowest HER2 expressers, 5-year recurrence events were associated with reduced total extracellular domain (ECD)/intracellular domain (ICD) ratio intensity in tumor (P = 0.044). These observations are consistent with our previous work using quantitative immunofluorescence, but represent the proof on identical cell content. We also describe the association of the ECD of HER2 with CD8 T-cell infiltration on the same slide. CONCLUSIONS: The proximity of CD8 cells as a function of the expression of the ECD of HER2 provides further evidence for the role of the immune system in the mechanism of action of trastuzumab.

Algorithm 971: An Implementation of a Randomized Algorithm for Principal Component Analysis.

Recent years have witnessed intense development of randomized methods for low-rank approximation. These methods target principal component analysis and the calculation of truncated singular value decompositions. The present article presents an essentially black-box, foolproof implementation for Mathworks' MATLAB, a popular software platform for numerical computation. As illustrated via several tests, the randomized algorithms for low-rank approximation outperform or at least match the classical deterministic techniques (such as Lanczos iterations run to convergence) in basically all respects: accuracy, computational efficiency (both speed and memory usage), ease-of-use, parallelizability, and reliability. However, the classical procedures remain the methods of choice for estimating spectral norms and are far superior for calculating the least singular values and corresponding singular vectors (or singular subspaces).

Ritornello: high fidelity control-free chromatin immunoprecipitation peak calling.

With the advent of next generation high-throughput DNA sequencing technologies, omics experiments have become the mainstay for studying diverse biological effects on a genome wide scale. Chromatin immunoprecipitation (ChIP-seq) is the omics technique that enables genome wide localization of transcription factor (TF) binding or epigenetic modification events. Since the inception of ChIP-seq in 2007, many methods have been developed to infer ChIP-target binding loci from the resultant reads after mapping them to a reference genome. However, interpreting these data has proven challenging, and as such these algorithms have several shortcomings, including susceptibility to false positives due to artifactual peaks, poor localization of binding sites and the requirement for a total DNA input control which increases the cost of performing these experiments. We present Ritornello, a new approach for finding TF-binding sites in ChIP-seq, with roots in digital signal processing that addresses all of these problems. We show that Ritornello generally performs equally or better than the peak callers tested and recommended by the ENCODE consortium, but in contrast, Ritornello does not require a matched total DNA input control to avoid false positives, effectively decreasing the sequencing cost to perform ChIP-seq. Ritornello is freely available at https://github.com/KlugerLab/Ritornello.

Gating mass cytometry data by deep learning.

MOTIVATION: Mass cytometry or CyTOF is an emerging technology for high-dimensional multiparameter single cell analysis that overcomes many limitations of fluorescence-based flow cytometry. New methods for analyzing CyTOF data attempt to improve automation, scalability, performance and interpretation of data generated in large studies. Assigning individual cells into discrete groups of cell types (gating) involves time-consuming sequential manual steps, untenable for larger studies. RESULTS: We introduce DeepCyTOF, a standardization approach for gating, based on deep learning techniques. DeepCyTOF requires labeled cells from only a single sample. It is based on domain adaptation principles and is a generalization of previous work that allows us to calibrate between a target distribution and a source distribution in an unsupervised manner. We show that DeepCyTOF is highly concordant (98%) with cell classification obtained by individual manual gating of each sample when applied to a collection of 16 biological replicates of primary immune blood cells, even when measured across several instruments. Further, DeepCyTOF achieves very high accuracy on the semi-automated gating challenge of the FlowCAP-I competition as well as two CyTOF datasets generated from primary immune blood cells: (i) 14 subjects with a history of infection with West Nile virus (WNV), (ii) 34 healthy subjects of different ages. We conclude that deep learning in general, and DeepCyTOF specifically, offers a powerful computational approach for semi-automated gating of CyTOF and flow cytometry data. AVAILABILITY AND IMPLEMENTATION: Our codes and data are publicly available at https://github.com/KlugerLab/deepcytof.git. CONTACT: yuval.kluger@yale.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The Utility of Cardiac Magnetic Resonance Imaging in the Diagnosis of Cardiac Sarcoidosis.

BACKGROUND: Autopsy reports suggest that cardiac sarcoidosis occurs in 20 to 25% of patients with pulmonary sarcoidosis, yet the clinical ante-mortem diagnosis is made in only 5% of cases. Current diagnostic algorithms are complex and lack sensitivity. Cardiac Magnetic Resonance imaging (CMR) provides an opportunity to detect myocardial involvement in sarcoidosis. The aim of this study is to determine the prevalence and clinical significance of late gadolinium enhancement (LGE) on CMR in patients with sarcoidosis. METHODS: Consecutive patients with biopsy-proven sarcoidosis undergoing CMR were retrospectively evaluated for cardiac sarcoidosis. Medical records were correlated with CMR. RESULTS: Forty-six patients were evaluated. Late gadolinium enhancement was present in 22%, indicating myocardial involvement, and 70% had corresponding hyper-intense T2 signal indicating active inflammation. Late gadolinium enhancement was 18%+/-9.7% of overall left ventricular (LV) mass and most commonly located in the basal to mid septum. There was no association between LGE and cardiovascular symptoms or pulmonary stage. Eighty per cent of patients with LGE did not fulfill conventional diagnostic criteria for cardiac sarcoidosis. However, LGE was associated with clinically significant arrhythmia (p<0.01) and a lower LVEF (p=0.04). CONCLUSIONS: Using CMR, we identified a higher prevalence of cardiac sarcoidosis than previously reported clinical studies, a prevalence which is more consistent with autopsy data. The presence of LGE was highly correlated with clinically significant arrhythmias and lower LVEF.

Removal of batch effects using distribution-matching residual networks.

MOTIVATION: Sources of variability in experimentally derived data include measurement error in addition to the physical phenomena of interest. This measurement error is a combination of systematic components, originating from the measuring instrument and random measurement errors. Several novel biological technologies, such as mass cytometry and single-cell RNA-seq (scRNA-seq), are plagued with systematic errors that may severely affect statistical analysis if the data are not properly calibrated. RESULTS: We propose a novel deep learning approach for removing systematic batch effects. Our method is based on a residual neural network, trained to minimize the Maximum Mean Discrepancy between the multivariate distributions of two replicates, measured in different batches. We apply our method to mass cytometry and scRNA-seq datasets, and demonstrate that it effectively attenuates batch effects. AVAILABILITY AND IMPLEMENTATION: our codes and data are publicly available at https://github.com/ushaham/BatchEffectRemoval.git. CONTACT: yuval.kluger@yale.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Maintenance of water uptake and reduced water loss contribute to water stress tolerance of Spiraea alba Du Roi and Spiraea tomentosa L.

Two primarily eastern US native shrubs, Spiraea alba Du Roi and Spiraea tomentosa L., are typically found growing in wet areas, often with standing water. Both species have potential for use in the landscape, but little is known of their environmental requirements, including their adaptation to water stress. Two geographic accessions of each species were evaluated for their response to water stress under greenhouse conditions. Above-ground biomass, water relations and gas exchange were measured in well-watered and water stress treatments. In both species, water stress resulted in reduced growth, transpiration and pre-dawn water potential. However, both species also exhibited the ability to osmotically adjust to lower soil water content, resulting in maintained midday leaf turgor potential in all accessions. Net CO2 assimilation was reduced only in one accession of S. alba, primarily due to large reductions in stomatal conductance. S. tomentosa lost a larger proportion of leaves than S. alba in response to water stress. The primary water stress tolerance strategies of S. alba and S. tomentosa appear to be the maintenance of water uptake and reduced water loss.

Arpeggio: harmonic compression of ChIP-seq data reveals protein-chromatin interaction signatures.

Researchers generating new genome-wide data in an exploratory sequencing study can gain biological insights by comparing their data with well-annotated data sets possessing similar genomic patterns. Data compression techniques are needed for efficient comparisons of a new genomic experiment with large repositories of publicly available profiles. Furthermore, data representations that allow comparisons of genomic signals from different platforms and across species enhance our ability to leverage these large repositories. Here, we present a signal processing approach that characterizes protein-chromatin interaction patterns at length scales of several kilobases. This allows us to efficiently compare numerous chromatin-immunoprecipitation sequencing (ChIP-seq) data sets consisting of many types of DNA-binding proteins collected from a variety of cells, conditions and organisms. Importantly, these interaction patterns broadly reflect the biological properties of the binding events. To generate these profiles, termed Arpeggio profiles, we applied harmonic deconvolution techniques to the autocorrelation profiles of the ChIP-seq signals. We used 806 publicly available ChIP-seq experiments and showed that Arpeggio profiles with similar spectral densities shared biological properties. Arpeggio profiles of ChIP-seq data sets revealed characteristics that are not easily detected by standard peak finders. They also allowed us to relate sequencing data sets from different genomes, experimental platforms and protocols. Arpeggio is freely available at http://sourceforge.net/p/arpeggio/wiki/Home/.