Common genetic variation drives molecular heterogeneity in human iPSCs.

Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.

Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs.

This corrects the article DOI: 10.1038/nature22403.

Contrast associated nephropathy after intravenous administration: what is the magnitude of the problem?

Intravenous contrast media (CM) is often used in clinical practice to enhance CT scan imaging. For many years, contrast-induced nephropathy (CIN) was thought to be a common occurrence and to result in dire consequences. When treating patients with abnormal renal function, it is not unusual that clinicians postpone, cancel, or replace contrast-enhanced imaging with other, perhaps less informative tests. New studies however have challenged this paradigm and the true risk attributable to intravenous CM for the occurrence of CIN has become debatable. In this article, we review the latest relevant medical literature and aim to provide an evidence-based answer to questions surrounding the risk, outcomes, and potential mitigation strategies of CIN after intravenous CM administration.

A Review of Fluid Bolus in Critically Ill Patients After Initial Volume Expansion: Bayesian Probability Analysis and Case Studies.

Introduction Fluid resuscitation is a crucial intervention for the management of critically ill patients. However, after initial volume expansion, the advantages of fluid bolus administration remain controversial. Our aim was to investigate the probabilistic reasoning against fluid bolus administration in critically ill patients after initial volume expansion. We then applied this reasoning to two hypothetical case studies that evaluated the benefits and risks associated with a fluid bolus for each patient. Methods We analyzed data from 12 previously published studies, totaling 334 patients, on fluid responsiveness in critically ill patients. Owing to differences in these studies, we used a Monte Carlo simulation based on their parameters to improve our Bayesian prior, generate strong estimates, and address uncertainty. Using the established Bayesian prior for volume responsiveness, we scrutinized two hypothetical case studies employing Bayesian mathematical notation to assess the pre-test probability, posterior probability, and likelihood ratios in patients with septic shock. Results The Monte Carlo simulation yielded a mean response rate of 0.54 (SD = 0.026), suggesting that only approximately 54% of patients were responsive to fluid bolus administration. These results had an effective sample size of 17,204 and an R-hat value of 1, demonstrating the reliability of our results. In our Bayesian case studies, we demonstrate the low probabilities of volume and VO2 responsiveness over time using common bedside testing. Conclusion Our analysis shows that the pretest and posttest probabilities for volume responsiveness following initial fluid resuscitation are low. Additional bedside testing should be pursued before administering additional volume. This approach emphasizes the importance of evidence-based decision-making in the management of critically ill patients to optimize patient outcomes and minimize potential risks.

The Impact of Positive Fluid Balance on Sepsis Subtypes: A Causal Inference Study.

Introduction: Sepsis, the leading cause of death in hospitalized patients globally, was investigated in this study, examining the varying effects of positive fluid balance on sepsis subtypes through causal inference. Methods: In this study, data from the eICU database were utilized, extracting 35 features from sepsis patients. Fluid balance during ICU stay was the treatment, and ICU mortality was the primary outcome. Data preprocessing ensured linear assumptions for logistic regression. Binarized positive fluid balance with mortality was examined using DoWhy's logistic regression, while continuous data were analyzed with random forest T-learner. ATE served as the primary metric. Results: Results revealed that septic patients with higher fluid balance had worse mortality outcomes, with an ATE of 0.042 (95% CI: (0.034, 0.047)) using logistic regression and an ATE of 0.0340 (95% CI: (0.028-0.040)) using T-learner. In the pulmonary sepsis subtype, higher mortality was associated with increased fluid balance, showing an ATE of 0.047 (95% CI: (0.037, 0.055)) using logistic regression and an ATE of 0.28 (95% CI: (0.22, 0.34)) with T-learner. Conversely, urinary sepsis patients had improved mortality with higher fluid balance, presenting an ATE of -0.135 (95% CI: (-0.024, -0.0035)) using logistic regression and an ATE of -0.28 (95% CI: (-0.34, -0.22)) with T-learner. Conclusion: Our research implies that fluid balance impact on ICU mortality differs among sepsis subtypes. Positive fluid balance raises mortality in sepsis and pulmonary sepsis but may protect against urinary sepsis. Further trials are needed to confirm these findings.

Objective Methods of Assessing Fluid Status to Optimize Volume Management in Kidney Disease and Hypertension: The Importance of Ultrasound.

Fluid overload, a prevalent complication in patients with renal disease and hypertension, significantly impacts patient morbidity and mortality. The daily clinical challenges that clinicians face include how to identify fluid overload early enough in the course of the disease to prevent adverse outcomes and to guide and potentially reduce the intensity of the diuresis. Traditional methods for evaluating fluid status, such as pitting edema, pulmonary crackles, or chest radiography primarily assess extracellular fluid and do not accurately reflect intravascular volume status or venous congestion. This review explores the rationale, mechanism, and evidence behind more recent methods used to assess volume status, namely, lung ultrasound, inferior vena cava (IVC) ultrasound, venous excess ultrasound score, and basic and advanced cardiac echocardiographic techniques. These methods offer a more accurate and objective assessment of fluid status, providing real-time, non-invasive measures of intravascular volume and venous congestion. The methods we discuss are primarily used in inpatient settings, but, given the increased pervasiveness of ultrasound technology, some could soon expand to the outpatient setting.

Mapping interindividual dynamics of innate immune response at single-cell resolution.

Common genetic variants across individuals modulate the cellular response to pathogens and are implicated in diverse immune pathologies, yet how they dynamically alter the response upon infection is not well understood. Here, we triggered antiviral responses in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-sequencing. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), a statistical approach designed to identify nonlinear dynamic genetic effects across transcriptional trajectories of cells. This approach identified 1,275 expression quantitative trait loci (local false discovery rate 10%) that manifested during the responses, many of which were colocalized with susceptibility loci identified by genome-wide association studies of infectious and autoimmune diseases, including the OAS1 splicing quantitative trait locus in a COVID-19 susceptibility locus. In summary, our analytical approach provides a unique framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution.

Sepsis Management for the Nephrologist.

The definition of sepsis has evolved significantly over the past three decades. Today, sepsis is defined as a dysregulated host immune response to microbial invasion leading to end organ dysfunction. Septic shock is characterized by hypotension requiring vasopressors after adequate fluid resuscitation with elevated lactate. Early recognition and intervention remain hallmarks for sepsis management. We addressed the current literature and assimilated thought regarding optimum initial resuscitation of the patient with sepsis. A nuanced understanding of the physiology of lactate is provided in our review. Physiologic and practical knowledge of steroid and vasopressor therapy for sepsis is crucial and addressed. As blood purification may interest the nephrologist treating sepsis, we have also added a brief discussion of its status.

Mortality Prediction Using SaO2/FiO2 Ratio Based on eICU Database Analysis.

PURPOSE: PaO2 to FiO2 ratio (P/F) is used to assess the degree of hypoxemia adjusted for oxygen requirements. The Berlin definition of Acute Respiratory Distress Syndrome (ARDS) includes P/F as a diagnostic criterion. P/F is invasive and cost-prohibitive for resource-limited settings. SaO2/FiO2 (S/F) ratio has the advantages of being easy to calculate, noninvasive, continuous, cost-effective, and reliable, as well as lower infection exposure potential for staff, and avoids iatrogenic anemia. Previous work suggests that the SaO2/FiO2 ratio (S/F) correlates with P/F and can be used as a surrogate in ARDS. Quantitative correlation between S/F and P/F has been verified, but the data for the relative predictive ability for ICU mortality remains in question. We hypothesize that S/F is noninferior to P/F as a predictive feature for ICU mortality. Using a machine-learning approach, we hope to demonstrate the relative mortality predictive capacities of S/F and P/F. METHODS: We extracted data from the eICU Collaborative Research Database. The features age, gender, SaO2, PaO2, FIO2, admission diagnosis, Apache IV, mechanical ventilation (MV), and ICU mortality were extracted. Mortality was the dependent variable for our prediction models. Exploratory data analysis was performed in Python. Missing data was imputed with Sklearn Iterative Imputer. Random assignment of all the encounters, 80% to the training (n = 26690) and 20% to testing (n = 6741), was stratified by positive and negative classes to ensure a balanced distribution. We scaled the data using the Sklearn Standard Scaler. Categorical values were encoded using Target Encoding. We used a gradient boosting decision tree algorithm variant called XGBoost as our model. Model hyperparameters were tuned using the Sklearn RandomizedSearchCV with tenfold cross-validation. We used AUC as our metric for model performance. Feature importance was assessed using SHAP, ELI5 (permutation importance), and a built-in XGBoost feature importance method. We constructed partial dependence plots to illustrate the relationship between mortality probability and S/F values. RESULTS: The XGBoost hyperparameter optimized model had an AUC score of .85 on the test set. The hyperparameters selected to train the final models were as follows: colsample_bytree of 0.8, gamma of 1, max_depth of 3, subsample of 1, min_child_weight of 10, and scale_pos_weight of 3. The SHAP, ELI5, and XGBoost feature importance analysis demonstrates that the S/F ratio ranks as the strongest predictor for mortality amongst the physiologic variables. The partial dependence plots illustrate that mortality rises significantly above S/F values of 200. CONCLUSION: S/F was a stronger predictor of mortality than P/F based upon feature importance evaluation of our data. Our study is hypothesis-generating and a prospective evaluation is warranted. Take-Home Points. S/F ratio is a noninvasive continuous method of measuring hypoxemia as compared to P/F ratio. Our study shows that the S/F ratio is a better predictor of mortality than the more widely used P/F ratio to monitor and manage hypoxemia.

Critical Care Echocardiography: A Primer for the Nephrologist.

Critical care echocardiography (CCE) refers to the goal-directed use of transthoracic or transesophageal echocardiography and represents one of the most common applications of critical care ultrasound. CCE can be performed at the point of care, is easily repeated following changes in clinical status, and does not expose the patient to ionizing radiation. Nephrologists who participate in the care of patients in the intensive care unit will regularly encounter CCE as part of the decision-making and bedside management of ICU patients. The four primary indications for CCE are the characterization of shock, evaluation of preload tolerance, evaluation of volume responsiveness, and serial hemodynamic assessment to evaluate response to therapeutic interventions. This article provides an overview of the anatomical structures that are routinely assessed in basic CCE, describes how these findings are incorporated into the clinical assessment of critically ill patients, and introduces some common applications of advanced CCE.

Convolutional Neural Network Model for Intensive Care Unit Acute Kidney Injury Prediction.

INTRODUCTION: Acute kidney injury (AKI) is common among hospitalized patients and has a significant impact on morbidity and mortality. Although early prediction of AKI has the potential to reduce adverse patient outcomes, it remains a difficult condition to predict and diagnose. The purpose of this study was to evaluate the ability of a machine learning algorithm to predict for AKI as defined by Kidney Disease: Improving Global Outcomes (KDIGO) stage 2 or 3 up to 48 hours in advance of onset using convolutional neural networks (CNNs) and patient electronic health record (EHR) data. METHODS: A CNN prediction system was developed to use EHR data gathered during patients' stays to predict AKI up to 48 hours before onset. A total of 12,347 patient encounters were retrospectively analyzed from the Medical Information Mart for Intensive Care III (MIMIC-III) database. An XGBoost AKI prediction model and the sequential organ failure assessment (SOFA) scoring system were used as comparators. The outcome was AKI onset. The model was trained on routinely collected patient EHR data. Measurements included area under the receiver operating characteristic (AUROC) curve, positive predictive value (PPV), and a battery of additional performance metrics for advance prediction of AKI onset. RESULTS: On a hold-out test set, the algorithm attained an AUROC of 0.86 and PPV of 0.24, relative to a cohort AKI prevalence of 7.62%, for long-horizon AKI prediction at a 48-hour window before onset. CONCLUSION: A CNN machine learning-based AKI prediction model outperforms XGBoost and the SOFA scoring system, revealing superior performance in predicting AKI 48 hours before onset, without reliance on serum creatinine (SCr) measurements.

Pressure Regulated Volume Control (PRVC): Set it and forget it?

Pressure-regulated volume control (PRVC) is a mode of ventilation in which the ventilator attempts to achieve set tidal volume at lowest possible airway pressure. This mode of ventilation is being commonly used as the initial mode of ventilation in many intensive care units. We describe two cases where this adaptive mode of ventilation became maladaptive leading to patient-ventilator dyssynchrony.

Common Cognitive Biases in Nephrology Critical Care: A Plea for Metacognition.

The intensive care unit (ICU) is an incredibly complex environment, and ICU rounds are mentally taxing. The cognitive biases that tend to arise in mentally taxing environments such as the ICU pose a risk to patients. This review discusses 10 common cognitive biases and logical fallacies using examples in Nephrology Critical Care. Our objective is to promote metacognition (i.e., an awareness of one's cognition) among physicians. A state of metacognition is not a panacea, but aspiring for metacognition allows the critical care physician to improve chances for optimal patient outcomes.

The Use of Portal Vein Pulsatility to Differentiate Hypervolemic and Hypovolemic Hyponatremia.

Hypotonic hyponatremia is a common electrolyte disorder defined by a blood serum sodium value of less than 136 meq/L. A challenge in managing hyponatremia is accurately determining the etiology for the free water excess as management can markedly differ. Accurate diagnosis of the etiology of hypotonic hyponatremia requires precision in the determination of extracellular volume status. Determination of volume status has traditionally relied on physical examination, imaging modalities, and clinical gestalt, all of which are inaccurate. Portal vein pulsatility is an easy to perform bedside ultrasound imaging study which can be used as a marker for hypervolemia and venous congestion. We present 2 cases of hypervolemic hyponatremia in which portal vein pulsatility was used in the diagnosis and management and as a marker for efficacy of treatment.

Morphology and composition play distinct and complementary roles in the tolerance of plantar skin to mechanical load.

Plantar skin on the soles of the feet has a distinct morphology and composition that is thought to enhance its tolerance to mechanical loads, although the individual contributions of morphology and composition have never been quantified. Here, we combine multiscale mechanical testing and computational models of load bearing to quantify the mechanical environment of both plantar and nonplantar skin under load. We find that morphology and composition play distinct and complementary roles in plantar skin's load tolerance. More specifically, the thick stratum corneum provides protection from stress-based injuries such as skin tears and blisters, while epidermal and dermal compositions provide protection from deformation-based injuries such as pressure ulcers. This work provides insights into the roles of skin morphology and composition more generally and will inform the design of engineered skin substitutes as well as the etiology of skin injury.

Treatment of Cirrhosis-Associated Hyponatremia with Midodrine and Octreotide.

BACKGROUND: Hyponatremia in the setting of cirrhosis is a common electrolyte disorder with few therapeutic options. The free water retention is due to non-osmotic vasopressin secretion resulting from the cirrhosis-associated splanchnic vasodilatation. Therefore, vasoconstrictive therapy may correct this electrolyte abnormality. The aim of this study was to assess the efficacy of midodrine and octreotide as a therapeutic approach to increasing urinary electrolyte-free water clearance (EFWC) in the correction of cirrhosis-associated hyponatremia. METHODS: This observational study consisted of 10 patients with cirrhosis-associated hyponatremia. Hypovolemia was ruled out as the cause of the hyponatremia with a 48-h albumin challenge (25 g IV q6 h). Patients whose hyponatremia failed to improve with albumin challenge were started on midodrine and octreotide at 10 mg po tid and 100 µg sq tid, respectively, with rapid up-titration as tolerated to respective maximal doses of 15 mg tid and 200 µg tid within the first 24 h. We assessed urinary EFWC and serum sodium concentration before and 72 h after treatment. RESULTS: Pretreatment serum sodium levels ranged from 119 to 133 mmol/L. The mean pretreatment serum sodium concentration ± SEM was 124 mmol/L ± 1.6 vs 130 mmol/L ± 1.5 posttreatment (p = 0.00001). The mean pretreatment urinary EFWC ± SEM was 0.33 L ± 0.07 vs 0.82 L ± 0.11 posttreatment (p = 0.0003). CONCLUSION: Our data show a statistically significant increase in serum sodium concentration and urinary EFWC with the use of midodrine and octreotide in the treatment of cirrhosis-associated hyponatremia.

Late onset hydrocephalus in children with tuberculous meningitis.

Hydrocephalus is a known complication of tuberculous meningitis (TBM). It is almost always present in patients who have had the disease for four to six weeks. However, hydrocephalus can also develop later in the disease course as seen in our 3 patients. All 3 patients had multi-drug resistant (MDR) tuberculosis (TB) and developed hydrocephalus after variable time after starting second line anti-tuberculous therapy (ATT). A 7 years old girl had hydrocephalus at onset of TBM and was shunted but the hydrocephalus increased in size after 6 months of being on second line ATT in spite of a patent ventricular peritoneal (VP) shunt. Hydrocephalus responded to oral acetazolamide. Other 2 patients, a 2 years old girl and 3½ years old boy developed hydrocephalus after being on treatment for 14 months. Both required insertion of VP shunt. Thus, in patients with MDR-TB, hydrocephalus may develop as late onset phenomenon and a neurological examination would be essential in each visit to the hospital.

Successful Generation of Human Induced Pluripotent Stem Cell Lines from Blood Samples Held at Room Temperature for up to 48 hr.

The collection sites of human primary tissue samples and the receiving laboratories, where the human induced pluripotent stem cells (hIPSCs) are derived, are often not on the same site. Thus, the stability of samples prior to derivation constrains the distance between the collection site and the receiving laboratory. To investigate sample stability, we collected blood and held it at room temperature for 5, 24, or 48 hr before isolating peripheral blood mononuclear cells (PBMCs) and reprogramming into IPSCs. Additionally, PBMC samples at 5- and 48-hr time points were frozen in liquid nitrogen for 4 months and reprogrammed into IPSCs. hIPSC lines derived from all time points were pluripotent, displayed no marked difference in chromosomal aberration rates, and differentiated into three germ layers. Reprogramming efficiency at 24- and 48-hr time points was 3- and 10-fold lower, respectively, than at 5 hr; the freeze-thaw process of PBMCs resulted in no obvious change in reprogramming efficiency.

Carotid ultrasound identifies high risk subclinical atherosclerosis in adults with low framingham risk scores.

BACKGROUND: Worldwide, cardiovascular (CV) disease remains the most common cause of morbidity and mortality. Although effective in predicting CV risk in select populations, the Framingham risk score (FRS) fails to identify many young individuals who experience premature CV events. Accordingly, the aim of this study was to determine the prevalence of high-risk carotid intima-media thickness (CIMT) or plaque, a marker of atherosclerosis and predictor of CV events, in young asymptomatic individuals with low and intermediate FRS (<2% annualized event rate) using the carotid ultrasound protocol recommended by the American Society of Echocardiography and the Society of Vascular Medicine. METHODS: Individuals aged < or = 65 years not taking statins and without diabetes mellitus or histories of coronary artery disease underwent CIMT and plaque examination for primary prevention. Clinical variables including lipid values, family history of premature coronary artery disease, and FRS and subsequent pharmacotherapy recommendations were retrospectively collected for statistical analysis. RESULTS: Of 441 subjects (mean age, 49.7 + or - 7.9 years), 184 (42%; 95% confidence interval, 37.3%-46.5%) had high-risk carotid ultrasound findings (CIMT > or = 75th percentile adjusted for age, gender, and race or presence of plaque). Of those with the lowest FRS of < or =5% (n = 336) (mean age, 48.0 + or - 7.6 years; mean FRS, 2.5 + or - 1.5%), 127 (38%; 95% confidence interval, 32.6%-43.0%) had high-risk carotid ultrasound findings. For individuals with FRS < or = 5% and high-risk carotid ultrasound findings (n = 127; mean age, 47.3 + or - 8.1 years; mean FRS, 2.5 + or - 1.5%), lipid-lowering therapy was recommended by their treating physicians in 77 (61%). CONCLUSIONS: Thirty-eight percent of asymptomatic young to middle-aged individuals with FRS < or = 5% have abnormal carotid ultrasound findings associated with increased risk for CV events. Pharmacologic therapy for CV prevention was recommended in the majority of these individuals. The lack of radiation exposure, relatively low cost, and ability to detect early-stage atherosclerosis suggest that carotid ultrasound for CIMT and plaque detection should continue to be explored as a primary tool for CV risk stratification in young to middle-aged adults with low FRS.