TNF-NF-κB-p53 axis restricts in vivo survival of hPSC-derived dopamine neurons.

Ongoing, early-stage clinical trials illustrate the translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, an unresolved challenge is the extensive cell death following transplantation. Here, we performed a pooled CRISPR-Cas9 screen to enhance postmitotic dopamine neuron survival in vivo. We identified p53-mediated apoptotic cell death as a major contributor to dopamine neuron loss and uncovered a causal link of tumor necrosis factor alpha (TNF-α)-nuclear factor κB (NF-κB) signaling in limiting cell survival. As a translationally relevant strategy to purify postmitotic dopamine neurons, we identified cell surface markers that enable purification without the need for genetic reporters. Combining cell sorting and treatment with adalimumab, a clinically approved TNF-α inhibitor, enabled efficient engraftment of postmitotic dopamine neurons with extensive reinnervation and functional recovery in a preclinical PD mouse model. Thus, transient TNF-α inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic hPSC-derived dopamine neurons in PD.

TNF-NFkB-p53 axis restricts in vivo survival of hPSC-derived dopamine neuron.

Ongoing, first-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson's disease (PD). However, a major unresolved challenge in the field is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neurons in vivo . We identified p53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. As a translationally applicable strategy to purify postmitotic dopamine neurons, we performed a cell surface marker screen that enabled purification without the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved and widely used TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic human PSC-derived dopamine neurons in PD. Highlights: In vivo CRISPR-Cas9 screen identifies p53 limiting survival of grafted human dopamine neurons. TNFα-NFκB pathway mediates p53-dependent human dopamine neuron deathCell surface marker screen to enrich human dopamine neurons for translational use. FDA approved TNF-alpha inhibitor rescues in vivo dopamine neuron survival with in vivo function.

Biomedical discovery through the integrative biomedical knowledge hub (iBKH).

The abundance of biomedical knowledge gained from biological experiments and clinical practices is an invaluable resource for biomedicine. The emerging biomedical knowledge graphs (BKGs) provide an efficient and effective way to manage the abundant knowledge in biomedical and life science. In this study, we created a comprehensive BKG called the integrative Biomedical Knowledge Hub (iBKH) by harmonizing and integrating information from diverse biomedical resources. To make iBKH easily accessible for biomedical research, we developed a web-based, user-friendly graphical portal that allows fast and interactive knowledge retrieval. Additionally, we also implemented an efficient and scalable graph learning pipeline for discovering novel biomedical knowledge in iBKH. As a proof of concept, we performed our iBKH-based method for computational in-silico drug repurposing for Alzheimer's disease. The iBKH is publicly available.

Association of SARS-CoV-2 viral load at admission with in-hospital acute kidney injury: A retrospective cohort study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated Coronavirus Disease 2019 (COVID-19) is a public health emergency. Acute kidney injury (AKI) is a common complication in hospitalized patients with COVID-19 although mechanisms underlying AKI are yet unclear. There may be a direct effect of SARS-CoV-2 virus on the kidney; however, there is currently no data linking SARS-CoV-2 viral load (VL) to AKI. We explored the association of SARS-CoV-2 VL at admission to AKI in a large diverse cohort of hospitalized patients with COVID-19. METHODS AND FINDINGS: We included patients hospitalized between March 13th and May 19th, 2020 with SARS-CoV-2 in a large academic healthcare system in New York City (N = 1,049) with available VL at admission quantified by real-time RT-PCR. We extracted clinical and outcome data from our institutional electronic health records (EHRs). AKI was defined by KDIGO guidelines. We fit a Fine-Gray competing risks model (with death as a competing risk) using demographics, comorbidities, admission severity scores, and log10 transformed VL as covariates and generated adjusted hazard ratios (aHR) and 95% Confidence Intervals (CIs). VL was associated with an increased risk of AKI (aHR = 1.04, 95% CI: 1.01-1.08, p = 0.02) with a 4% increased hazard for each log10 VL change. Patients with a viral load in the top 50th percentile had an increased adjusted hazard of 1.27 (95% CI: 1.02-1.58, p = 0.03) for AKI as compared to those in the bottom 50th percentile. CONCLUSIONS: VL is weakly but significantly associated with in-hospital AKI after adjusting for confounders. This may indicate the role of VL in COVID-19 associated AKI. This data may inform future studies to discover the mechanistic basis of COVID-19 associated AKI.

Deep learning and the electrocardiogram: review of the current state-of-the-art.

In the recent decade, deep learning, a subset of artificial intelligence and machine learning, has been used to identify patterns in big healthcare datasets for disease phenotyping, event predictions, and complex decision making. Public datasets for electrocardiograms (ECGs) have existed since the 1980s and have been used for very specific tasks in cardiology, such as arrhythmia, ischemia, and cardiomyopathy detection. Recently, private institutions have begun curating large ECG databases that are orders of magnitude larger than the public databases for ingestion by deep learning models. These efforts have demonstrated not only improved performance and generalizability in these aforementioned tasks but also application to novel clinical scenarios. This review focuses on orienting the clinician towards fundamental tenets of deep learning, state-of-the-art prior to its use for ECG analysis, and current applications of deep learning on ECGs, as well as their limitations and future areas of improvement.

Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer's disease.

The evident genetic, pathological, and clinical heterogeneity of Alzheimer's disease (AD) poses challenges for traditional drug development. We conducted a computational drug repurposing screen for drugs to treat apolipoprotein (apo) E4-related AD. We first established apoE-genotype-dependent transcriptomic signatures of AD by analyzing publicly-available human brain database. We then queried these signatures against the Connectivity Map database containing transcriptomic perturbations of >1300 drugs to identify those that best reverse apoE-genotype-specific AD signatures. Bumetanide was identified as a top drug for apoE4 AD. Bumetanide treatment of apoE4 mice without or with Aß accumulation rescued electrophysiological, pathological, or cognitive deficits. Single-nucleus RNA-sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in apoE4-iPSC-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 in two electronic health record databases, suggesting effectiveness of bumetanide in preventing AD.

Molecular Imaging of Apoptosis in Atherosclerosis by Targeting Cell Membrane Phospholipid Asymmetry.

BACKGROUND: Apoptosis in atherosclerotic lesions contributes to plaque vulnerability by lipid core enlargement and fibrous cap attenuation. Apoptosis is associated with exteriorization of phosphatidylserine (PS) and phosphatidylethanolamine (PE) on the cell membrane. Although PS-avid radiolabeled annexin-V has been employed for molecular imaging of high-risk plaques, PE-targeted imaging in atherosclerosis has not been studied. OBJECTIVES: This study sought to evaluate the feasibility of molecular imaging with PE-avid radiolabeled duramycin in experimental atherosclerotic lesions in a rabbit model and compare duramycin targeting with radiolabeled annexin-V. METHODS: Of the 27 rabbits, 21 were fed high-cholesterol, high-fat diet for 16 weeks. Nine of the 21 rabbits received 99mTc-duramycin (test group), 6 received 99mTc-linear duramycin (duramycin without PE-binding capability, negative radiotracer control group), and 6 received 99mTc-annexin-V for radionuclide imaging. The remaining normal chow-fed 6 animals (disease control group) received 99mTc-duramycin. In vivo microSPECT/microCT imaging was performed, and the aortas were explanted for ex vivo imaging and for histological characterization of atherosclerosis. RESULTS: A significantly higher duramycin uptake was observed in the test group compared with that of disease control and negative radiotracer control animals; duramycin uptake was also significantly higher than the annexin-V uptake. Quantitative duramycin uptake, represented as the square root of percent injected dose per cm (√ID/cm) of abdominal aorta was >2-fold higher in atherosclerotic lesions in test group (0.08 ± 0.01%) than in comparable regions of disease control animals (0.039 ± 0.0061%, p = 3.70·10-8). Mean annexin uptake (0.060 ± 0.010%) was significantly lower than duramycin (p = 0.001). Duramycin uptake corresponded to the lesion severity and macrophage burden. The radiation burden to the kidneys was substantially lower with duramycin (0.49% ID/g) than annexin (5.48% ID/g; p = 4.00·10-4). CONCLUSIONS: Radiolabeled duramycin localizes in lipid-rich areas with high concentration of apoptotic macrophages in the experimental atherosclerosis model. Duramycin uptake in atherosclerotic lesions was significantly greater than annexin-V uptake and produced significantly lower radiation burden to nontarget organs.

Machine Learning to Predict Mortality and Critical Events in a Cohort of Patients With COVID-19 in New York City: Model Development and Validation.

BACKGROUND: COVID-19 has infected millions of people worldwide and is responsible for several hundred thousand fatalities. The COVID-19 pandemic has necessitated thoughtful resource allocation and early identification of high-risk patients. However, effective methods to meet these needs are lacking. OBJECTIVE: The aims of this study were to analyze the electronic health records (EHRs) of patients who tested positive for COVID-19 and were admitted to hospitals in the Mount Sinai Health System in New York City; to develop machine learning models for making predictions about the hospital course of the patients over clinically meaningful time horizons based on patient characteristics at admission; and to assess the performance of these models at multiple hospitals and time points. METHODS: We used Extreme Gradient Boosting (XGBoost) and baseline comparator models to predict in-hospital mortality and critical events at time windows of 3, 5, 7, and 10 days from admission. Our study population included harmonized EHR data from five hospitals in New York City for 4098 COVID-19-positive patients admitted from March 15 to May 22, 2020. The models were first trained on patients from a single hospital (n=1514) before or on May 1, externally validated on patients from four other hospitals (n=2201) before or on May 1, and prospectively validated on all patients after May 1 (n=383). Finally, we established model interpretability to identify and rank variables that drive model predictions. RESULTS: Upon cross-validation, the XGBoost classifier outperformed baseline models, with an area under the receiver operating characteristic curve (AUC-ROC) for mortality of 0.89 at 3 days, 0.85 at 5 and 7 days, and 0.84 at 10 days. XGBoost also performed well for critical event prediction, with an AUC-ROC of 0.80 at 3 days, 0.79 at 5 days, 0.80 at 7 days, and 0.81 at 10 days. In external validation, XGBoost achieved an AUC-ROC of 0.88 at 3 days, 0.86 at 5 days, 0.86 at 7 days, and 0.84 at 10 days for mortality prediction. Similarly, the unimputed XGBoost model achieved an AUC-ROC of 0.78 at 3 days, 0.79 at 5 days, 0.80 at 7 days, and 0.81 at 10 days. Trends in performance on prospective validation sets were similar. At 7 days, acute kidney injury on admission, elevated LDH, tachypnea, and hyperglycemia were the strongest drivers of critical event prediction, while higher age, anion gap, and C-reactive protein were the strongest drivers of mortality prediction. CONCLUSIONS: We externally and prospectively trained and validated machine learning models for mortality and critical events for patients with COVID-19 at different time horizons. These models identified at-risk patients and uncovered underlying relationships that predicted outcomes.

Prevalence and Impact of Myocardial Injury in Patients Hospitalized with COVID-19 Infection.

BACKGROUND: The degree of myocardial injury, reflected by troponin elevation, and associated outcomes among hospitalized patients with Coronavirus Disease (COVID-19) in the US are unknown. OBJECTIVES: To describe the degree of myocardial injury and associated outcomes in a large hospitalized cohort with laboratory-confirmed COVID-19. METHODS: Patients with COVID-19 admitted to one of five Mount Sinai Health System hospitals in New York City between February 27th and April 12th, 2020 with troponin-I (normal value <0.03ng/mL) measured within 24 hours of admission were included (n=2,736). Demographics, medical history, admission labs, and outcomes were captured from the hospital EHR. RESULTS: The median age was 66.4 years, with 59.6% men. Cardiovascular disease (CVD) including coronary artery disease, atrial fibrillation, and heart failure, was more prevalent in patients with higher troponin concentrations, as were hypertension and diabetes. A total of 506 (18.5%) patients died during hospitalization. Even small amounts of myocardial injury (e.g. troponin I 0.03-0.09ng/mL, n=455, 16.6%) were associated with death (adjusted HR: 1.77, 95% CI 1.39-2.26; P<0.001) while greater amounts (e.g. troponin I>0.09 ng/dL, n=530, 19.4%) were associated with more pronounced risk (adjusted HR 3.23, 95% CI 2.59-4.02). CONCLUSIONS: Myocardial injury is prevalent among patients hospitalized with COVID-19, and is associated with higher risk of mortality. Patients with CVD are more likely to have myocardial injury than patients without CVD. Troponin elevation likely reflects non-ischemic or secondary myocardial injury.

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection.

BACKGROUND: The degree of myocardial injury, as reflected by troponin elevation, and associated outcomes among U.S. hospitalized patients with coronavirus disease-2019 (COVID-19) are unknown. OBJECTIVES: The purpose of this study was to describe the degree of myocardial injury and associated outcomes in a large hospitalized cohort with laboratory-confirmed COVID-19. METHODS: Patients with COVID-19 admitted to 1 of 5 Mount Sinai Health System hospitals in New York City between February 27, 2020, and April 12, 2020, with troponin-I (normal value <0.03 ng/ml) measured within 24 h of admission were included (n = 2,736). Demographics, medical histories, admission laboratory results, and outcomes were captured from the hospitals' electronic health records. RESULTS: The median age was 66.4 years, with 59.6% men. Cardiovascular disease (CVD), including coronary artery disease, atrial fibrillation, and heart failure, was more prevalent in patients with higher troponin concentrations, as were hypertension and diabetes. A total of 506 (18.5%) patients died during hospitalization. In all, 985 (36%) patients had elevated troponin concentrations. After adjusting for disease severity and relevant clinical factors, even small amounts of myocardial injury (e.g., troponin I >0.03 to 0.09 ng/ml; n = 455; 16.6%) were significantly associated with death (adjusted hazard ratio: 1.75; 95% CI: 1.37 to 2.24; p < 0.001) while greater amounts (e.g., troponin I >0.09 ng/dl; n = 530; 19.4%) were significantly associated with higher risk (adjusted HR: 3.03; 95% CI: 2.42 to 3.80; p < 0.001). CONCLUSIONS: Myocardial injury is prevalent among patients hospitalized with COVID-19; however, troponin concentrations were generally present at low levels. Patients with CVD are more likely to have myocardial injury than patients without CVD. Troponin elevation among patients hospitalized with COVID-19 is associated with higher risk of mortality.

Derivation and validation of genome-wide polygenic score for urinary tract stone diagnosis.

Urinary tract stones have high heritability indicating a strong genetic component. However, genome-wide association studies (GWAS) have uncovered only a few genome wide significant single nucleotide polymorphisms (SNPs). Polygenic risk scores (PRS) sum cumulative effect of many SNPs and shed light on underlying genetic architecture. Using GWAS summary statistics from 361,141 participants in the United Kingdom Biobank, we generated a PRS and determined association with stone diagnosis in 28,877 participants in the Mount Sinai BioMe Biobank. In BioMe (1,071 cases and 27,806 controls), for every standard deviation increase, we observed a significant increment in adjusted odds ratio of a factor of 1.2 (95% confidence interval 1.13-1.26). In comparison, a risk score comprised of GWAS significant SNPs was not significantly associated with diagnosis. After stratifying individuals into low and high-risk categories on clinical risk factors, there was a significant increment in adjusted odds ratio of 1.3 (1.12-1.6) in the low- and 1.2 (1.1-1.2) in the high-risk group for every standard deviation increment in PRS. In a 14,348-participant validation cohort (Penn Medicine Biobank), every standard deviation increment was associated with a significant adjusted odds ratio of 1.1 (1.03 - 1.2). Thus, a genome-wide PRS is associated with urinary tract stones overall and in the absence of known clinical risk factors and illustrates their complex polygenic architecture.

Machine Learning in Cardiology-Ensuring Clinical Impact Lives Up to the Hype.

Despite substantial advances in the study, treatment, and prevention of cardiovascular disease, numerous challenges relating to optimally screening, diagnosing, and managing patients remain. Simultaneous improvements in computing power, data storage, and data analytics have led to the development of new techniques to address these challenges. One powerful tool to this end is machine learning (ML), which aims to algorithmically identify and represent structure within data. Machine learning's ability to efficiently analyze large and highly complex data sets make it a desirable investigative approach in modern biomedical research. Despite this potential and enormous public and private sector investment, few prospective studies have demonstrated improved clinical outcomes from this technology. This is particularly true in cardiology, despite its emphasis on objective, data-driven results. This threatens to stifle ML's growth and use in mainstream medicine. We outline the current state of ML in cardiology and outline methods through which impactful and sustainable ML research can occur. Following these steps can ensure ML reaches its potential as a transformative technology in medicine.

Sleep in the Natural Environment: A Pilot Study.

Sleep quality has been directly linked to cognitive function, quality of life, and a variety of serious diseases across many clinical domains. Standard methods for assessing sleep involve overnight studies in hospital settings, which are uncomfortable, expensive, not representative of real sleep, and difficult to conduct on a large scale. Recently, numerous commercial digital devices have been developed that record physiological data, such as movement, heart rate, and respiratory rate, which can act as a proxy for sleep quality in lieu of standard electroencephalogram recording equipment. The sleep-related output metrics from these devices include sleep staging and total sleep duration and are derived via proprietary algorithms that utilize a variety of these physiological recordings. Each device company makes different claims of accuracy and measures different features of sleep quality, and it is still unknown how well these devices correlate with one another and perform in a research setting. In this pilot study of 21 participants, we investigated whether sleep metric outputs from self-reported sleep metrics (SRSMs) and four sensors, specifically Fitbit Surge (a smart watch), Withings Aura (a sensor pad that is placed under a mattress), Hexoskin (a smart shirt), and Oura Ring (a smart ring), were related to known cognitive and psychological metrics, including the n-back test and Pittsburgh Sleep Quality Index (PSQI). We analyzed correlation between multiple device-related sleep metrics. Furthermore, we investigated relationships between these sleep metrics and cognitive scores across different timepoints and SRSM through univariate linear regressions. We found that correlations for sleep metrics between the devices across the sleep cycle were almost uniformly low, but still significant (P < 0.05). For cognitive scores, we found the Withings latency was statistically significant for afternoon and evening timepoints at P = 0.016 and P = 0.013. We did not find any significant associations between SRSMs and PSQI or cognitive scores. Additionally, Oura Ring's total sleep duration and efficiency in relation to the PSQI measure was statistically significant at P = 0.004 and P = 0.033, respectively. These findings can hopefully be used to guide future sensor-based sleep research.