AI/ML Models to Predict the Severity of Drug-Induced Liver Injury for Small Molecules.

Drug-induced liver injury (DILI), believed to be a multifactorial toxicity, has been a leading cause of attrition of small molecules during discovery, clinical development, and postmarketing. Identification of DILI risk early reduces the costs and cycle times associated with drug development. In recent years, several groups have reported predictive models that use physicochemical properties or in vitro and in vivo assay endpoints; however, these approaches have not accounted for liver-expressed proteins and drug molecules. To address this gap, we have developed an integrated artificial intelligence/machine learning (AI/ML) model to predict DILI severity for small molecules using a combination of physicochemical properties and off-target interactions predicted in silico. We compiled a data set of 603 diverse compounds from public databases. Among them, 164 were categorized as Most DILI (M-DILI), 245 as Less DILI (L-DILI), and 194 as No DILI (N-DILI) by the FDA. Six machine learning methods were used to create a consensus model for predicting the DILI potential. These methods include k-nearest neighbor (k-NN), support vector machine (SVM), random forest (RF), Naïve Bayes (NB), artificial neural network (ANN), logistic regression (LR), weighted average ensemble learning (WA) and penalized logistic regression (PLR). Among the analyzed ML methods, SVM, RF, LR, WA, and PLR identified M-DILI and N-DILI compounds, achieving a receiver operating characteristic area under the curve of 0.88, sensitivity of 0.73, and specificity of 0.9. Approximately 43 off-targets, along with physicochemical properties (fsp3, log S, basicity, reactive functional groups, and predicted metabolites), were identified as significant factors in distinguishing between M-DILI and N-DILI compounds. The key off-targets that we identified include: PTGS1, PTGS2, SLC22A12, PPARγ, RXRA, CYP2C9, AKR1C3, MGLL, RET, AR, and ABCC4. The present AI/ML computational approach therefore demonstrates that the integration of physicochemical properties and predicted on- and off-target biological interactions can significantly improve DILI predictivity compared to chemical properties alone.

Utility of rapid atrial pacing before and after TAVR with balloon-expandable valve in predicting permanent pacemaker implantation.

BACKGROUND: High-grade or complete atrioventricular block (AVB) requiring permanent pacemaker (PPM) implantation is a known complication of transcatheter aortic valve replacement (TAVR). Wenckebach AVB induced by rapid atrial pacing (RAP) after TAVR was previously demonstrated in an observational analysis to be an independent predictor for PPM. We sought to investigate the utility of both pre- and post-TAVR RAP in predicting PPM implantation. METHODS: In a single-center, prospective study, 421 patients underwent TAVR with balloon-expandable valves (BEV) between April 2020 and August 2021. Intraprocedural RAP was performed in patients without a pre-existing pacemaker, atrial fibrillation/flutter, or intraprocedural complete AVB to assess for RAP-induced Wenckebach AVB. The primary outcome was PPM within 30 days after TAVR. RESULTS: RAP was performed in 253 patients, of whom 91.3% underwent post-TAVR RAP and 61.2% underwent pre-TAVR RAP. The overall PPM implantation rate at 30 days was 9.9%. Although there was a numerically higher rate of PPM at 30 days in patients with RAP-induced Wenckebach AVB, it did not reach statistical significance (13.3% vs. 8.4%, p = 0.23). In a multivariable analysis, RAP-induced Wenckebach was not an independent predictor for PPM implantation at 30 days after TAVR. PPM rates at 30 days were comparable in patients with or without pre-TAVR pacing-induced Wenckebach AVB (11.8% vs. 8.2%, p = 0.51) and post-TAVR pacing-induced Wenckebach AVB (10.2% vs. 5.8%, p = 0.25). CONCLUSION: In patients who underwent TAVR with BEV, there were no statistically significant differences in PPM implantation rates at 30 days regardless of the presence or absence of RAP-induced Wenckebach AVB. Due to conflicting results between the present study and the prior observational analysis, future studies with larger sample sizes are warranted to determine the role of RAP during TAVR as a risk-stratification tool for significant AVB requiring PPM after TAVR.

Shocked to death: a case report of cardiogenic shock and death following electrocardioversion for atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is prevalent, especially in patients with heart failure. Their prevalence increases with age and both conditions are interrelated. Electrocardioversion (ECV) is considered a safe and effective procedure and is among one of the recommended therapies to terminate AF back to normal sinus rhythm. Our study highlights one of the rare complications following ECV. A 71-year-old female with a history of atrial fibrillation underwent electrocardioversion and developed sudden onset of ventricular stunning resulting in refractory cardiogenic shock. She was treated with mechanical cardiac support including IABP and Impella. Both provided minimal support then rapid clinical deterioration happened leading to imminent death. CONCLUSION: Patients with atrial fibrillation and heart failure treated with electrocardioversion might develop refractory cardiogenic shock and death as a complication of this procedure.

In-hospital outcomes of TAVR patients with a bundle branch block: Insights from the National Inpatient Sample 2011-2018.

INTRODUCTION: Data on the outcomes following transcatheter aortic valve replacement (TAVR) in patients with a bundle branch block (BBB) remains limited. METHODS: We studied the outcomes of TAVR patients with a BBB from the National Inpatient Sample (NIS) database between 2011 and 2018 using ICD-9-CM and ICD-10-CM codes. RESULTS: Between 2011 and 2018, 194,237 patients underwent TAVR, where 1.7% (n = 3,232) had a right BBB (RBBB) and 13.7% (n = 26,689) had a left BBB (LBBB). Patients with a RBBB and LBBB had a higher rate of new permanent pacemaker (PPM) implantation (31.5% - RBBB, 15.7% LBBB vs. 10.2% - no BBB). RBBB was associated with a significantly longer median length of stay (5 days) and total hospitalization cost ($53,669) compared with LBBB (3 days and $47,552) and no BBB (3 days and $47,171). Trend analysis revealed lower rates of PPM implantation and reduced lengths of stay and costs across all comparison groups. CONCLUSION: In conclusion, patients undergoing TAVR with a BBB are associated with higher new rates of PPM implantation. RBBB is the strongest independent predictor for new PPM implantation following TAVR. Rates of new PPM implantation in TAVR patients with and without a BBB have improved over time including reductions in length of stay and hospital costs. Further study is needed to reduce the risks of PPM implantation in TAVR patients.

Outcomes of Cardiac Arrest and Cardiopulmonary Resuscitation in Patients With Left Ventricular Assist Device; an Insight From a National Inpatient Sample.

BACKGROUND: Outcomes of patients with implanted left ventricular assist device (LVAD) implantation experiencing a cardiac arrest (CA) are not well reported. We aimed at defining the in-hospital outcomes of patients with implanted LVAD experiencing a CA. METHODS: The national inpatient sample (NIS) was queried using ICD9/ICD10 codes for patients older than 18 years with implanted LVAD and CA between 2010-2018. We excluded patients with orthotropic heart transplantation, biventricular assist device (BiVAD) implantation and do not resuscitate (DNR) status. RESULTS: A total of 93,153 hospitalisations between 2010 and 2018 with implanted LVAD were identified. Only 578 of these hospitalisations had experienced CA and of those, 173 (33%) hospitalisations underwent cardiopulmonary resuscitation (CPR). The mean age of hospitalisations that experienced a CA was 60.61±14.85 for non-survivors and 56.23±17.33 for survivors (p=0.14). The in-hospital mortality was 60.8% in hospitalisations with CA and 74.33% in hospitalisations in whom CPR was performed. In an analysis comparing survivors with non-survivors, non-survivors had more diabetes mellitus (DM) (p=0.01), and ischaemic heart disease (IHD) (p=0.04). Age, female sex, peripheral vascular disease and history of coronary artery bypass graft (CABG) were independently associated with increased mortality in our cohort. Also, ventricular tachycardia (VT) and CPR were independently associated with in-hospital mortality. During the study period, there was a significantly decreasing trend in performing CPR in LVAD hospitalisations with CA. CONCLUSION: In conclusion, age, female sex, peripheral vascular disease, history of CABG, VT and CPR were independently associated with in-hospital mortality in LVAD hospitalisations who experienced CA.

Comparing Nasopharyngeal Swab and Early Morning Saliva for the Identification of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

BACKGROUND: The ideal severe acute respiratory syndrome coronavirus 2 (SARs-CoV-2) testing method would be accurate and also be patient-performed to reduce exposure to healthcare workers. The aim of this study was to compare patient-performed testing based on a morning saliva sample with the current standard testing method, healthcare worker-collected sampling via a nasopharyngeal swab (NPS). METHODS: This was a prospective single center study which recruited 217 asymptomatic adult male participants in a coronavirus disease 2019 (COVID-19) quarantine center who had tested positive for SARS-CoV-2 8-10 days prior to isolation. Paired NPS and saliva specimens were collected and processed within 5 hours of sample collection. Real time reverse transcription polymerase chain reaction (RT-PCR) targeting Envelope (E) and RNA-dependent RNA polymerase (RdRp) genes was performed and the results were compared. RESULTS: Overall, 160 of the 217 (74%) participants tested positive for COVID-19 based on saliva, NPS, or both testing methods. The detection rate for SARS-CoV-2 was higher in saliva compared to NPS testing (93.1%, 149/160 vs 52.5%, 84/160, P < .001). The concordance between the 2 tests was 45.6% (virus was detected in both saliva and NPS in 73/160), whereas 47.5% were discordant (87/160 tested positive for 1 whereas negative for the other). The cycle threshold (Ct) values for E and RdRp genes were significantly lower in saliva specimens compared to NP swab specimens. CONCLUSIONS: Our findings demonstrate that saliva is a better alternative specimen for detection of SARS-CoV-2. Taking into consideration, the simplicity of specimen collection, shortage of PPE and the transmissibility of the virus, saliva could enable self-collection for an accurate SARS-CoV-2 surveillance testing.

COVID-19 screening test by using random oropharyngeal saliva.

An optimal clinical specimen for accurate detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by minimizing the usage of consumables and reduce hazard exposure to healthcare workers is an urgent priority. The diagnostic performance of SARS-CoV-2 detection between healthcare worker-collected nasopharyngeal and oropharyngeal (NP + OP) swabs and patient performed self-collected random saliva was assessed. Paired NP + OP swabs and random saliva were collected and processed within 48 h of specimen collection from two cohort studies which recruited 562 asymptomatic adult candidates. Real-time reverse-transcription polymerase chain reaction targeting Open reading frame 1a (ORF1a) and nucleocapsid (N) genes was performed and the results were compared. Overall, 65 of 562 (28.1%) candidates tested positive for COVID-19 based on random saliva, NP + OP swabs, or both testing techniques. The detection rate of SARS-CoV-2 was higher in random saliva compared to NP + OP testing (92.3%; 60/65 vs. 73.8%; 48/65; p < .05). The estimated sensitivity and specificity of random saliva were higher than NP + OP swabs (95.0; 99.9 vs. 72.2; 99.4). The Ct  values of ORF1a and N genes were significantly lower in random saliva compared to NP + OP swabs specimens. Our findings demonstrate that random saliva is an alternative diagnostic specimen for the detection of SARS-CoV-2. Self-collected random oropharyngeal saliva is a valuable specimen that provides accurate SARS-CoV-2 surveillance testing of a community.

An Overview of Machine Learning and Big Data for Drug Toxicity Evaluation.

Drug toxicity evaluation is an essential process of drug development as it is reportedly responsible for the attrition of approximately 30% of drug candidates. The rapid increase in the number and types of large toxicology data sets together with the advances in computational methods may be used to improve many steps in drug safety evaluation. The development of in silico models to screen and understand mechanisms of drug toxicity may be particularly beneficial in the early stages of drug development where early toxicity assessment can most reduce expenses and labor time. To facilitate this, machine learning methods have been employed to evaluate drug toxicity but are often limited by small and less diverse data sets. Recent advances in machine learning methods together with the rapid increase in big toxicity data such as molecular descriptors, toxicogenomics, and high-throughput bioactivity data may help alleviate some of the current challenges. In this article, the most common machine learning methods used in toxicity assessment are reviewed together with examples of toxicity studies that have used machine learning methodology. Furthermore, a comprehensive overview of the different types of toxicity tools and data sets available to build in silico toxicity prediction models has been provided to give an overview of the current big toxicity data landscape and highlight opportunities and challenges related to them.

Adverse outcomes and short-term cost implications of bile duct injury during cholecystectomy.

BACKGROUND: Bile duct injury (BDI) is an uncommon but major complication of cholecystectomy that has a poorly defined magnitude of effect on hospital costs. This study sought to calculate the healthcare costs, length of stay, and discharge status associated with bile duct injury in patients undergoing cholecystectomy in the United States. METHODS: The Premier Healthcare Database, which comprises hospital-billing records from over 700 hospitals in the United States, was queried for all patients undergoing cholecystectomy between January 2010 and March 2018. BDI was defined by ICD-9-CM and ICD-10-CM codes. Patient demographics, clinical characteristics, and operative information were extracted. Hospital costs, length of stay, and discharge status were compared between BDI and non-BDI patients. Propensity score matching was used to minimize confounding factors. Multivariable regression models were used to estimate the association between BDI and the outcomes variables. RESULTS: A total of 1,168,288 cholecystectomies were identified. BDI occurred in 878 patients (0.08%). Laparoscopy was the most common approach (> 95%). The majority of BDI occurred during inpatient admissions (71.0%). BDI patients had higher index admission hospital costs ($18,771 vs. $12,345, p < 0.0001), increased rate of discharge to an institutional post-acute care facility (odds ratio 3.89, 95% CI 2.92-5.19, p < 0.0001), and increased risk of readmission within 30 days after discharge (odds ratio 1.86, 95% CI 1.52-2.28, p < 0.0001), compared to patients without BDI. Among inpatient cholecystectomies, BDI was associated with increased length of stay (8.6 days vs. 4.8 days, p < 0.0001). CONCLUSION: BDI is associated with significantly increased hospital costs, length of stay, 30-day readmission, and discharge to an institutional post-acute care facility.

Speckle tracking echocardiography can predict subclinical myocardial involvement in patients with sarcoidosis: A meta-analysis.

BACKGROUND: This meta-analysis aims to evaluate the utility of speckle tracking echocardiography (STE) as a tool to evaluate for cardiac sarcoidosis (CS) early in its course. Electrocardiography and echocardiography have limited sensitivity in this role, while advanced imaging modalities such as cardiac magnetic resonance (CMR) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) are limited by cost and availability. METHODS: We compiled English language articles that reported left ventricular global longitudinal strain (LVGLS) or global circumferential strain (GCS) in patients with confirmed extra-cardiac sarcoidosis versus healthy controls. Studies that exclusively included patients with probable or definite CS were excluded. Continuous data were pooled as a standard mean difference (SMD), comparing sarcoidosis group with healthy controls. A random-effect model was adopted in all analyses. Heterogeneity was assessed using Q and I2 statistics. RESULTS: Nine studies were included in our final analysis with an aggregate of 967 patients. LVGLS was significantly lower in the extra-cardiac sarcoidosis group as compared with controls, SMD -3.98, 95% confidence interval (CI): -5.32, -2.64, P < .001, also was significantly lower in patients who suffered major cardiac events (MCE), -3.89, 95% CI -6.14, -1.64, P < .001. GCS was significantly lower in the extra-cardiac sarcoidosis group as compared with controls, SMD: -3.33, 95% CI -4.71, -1.95, P < .001. CONCLUSION: LVGLS and GCS were significantly lower in extra-cardiac sarcoidosis patients despite not exhibiting any cardiac symptoms. LVGLS correlates with MCEs in CS. Further studies are required to investigate the role of STE in the early screening of CS.

Detection of Antimicrobial Resistance Genes Associated with Carbapenem Resistance from the Whole-Genome Sequence of Acinetobacter baumannii Isolates from Malaysia.

BACKGROUND: The spread of carbapenem-resistant A. baumannii (CrAb) is gaining worldwide attention. The spread of this pathogen is largely due to its ability to acquire various resistance genes of intrinsic and extrinsic origins that confer unpredictable susceptibility to ß-lactams. The aim of this study was to analyze ß-lactamase genetic compositions of CrAb in Malaysia. METHODS: Whole-genome sequencing (WGS) was carried out on 13 CrAb isolates from clinical samples in Malaysia from 2011 to 2016. RESULTS: Endotracheal aspirate was the dominant clinical sample source (n = 6), and only one isolate was obtained from wound swab. A total of 6 sequence types (STs) of the Oxford scheme were identified, including 4 reported STs and 2 novel STs. Eleven isolates were classified into clonal complex 92 (CC92/ICII), among which ST195 and ST208 were the most prevalent STs. All 13 CrAb isolates harbored multiple ß-lactamase genes. bla OXA-23 (n = 13) and bla OXA-66 (n = 11) were the dominant carbapenemase gene families found in these isolates. All isolates harbor bla ADC, bla OXA-51-like, and bla OXA-23-like genes. bla TEM (n = 7), bla NDM-1 (n = 3), bla CARB-8 (n = 1), and bla PER-3 (n = 1) are amongst other ß-lactamase genes found in this study. ISAba1 was found upstream to bla OXA-23 (n = 13), bla OXA-66 (n = 1), and bla ADC (n = 11). All bla NDM-1 isolates had ISAba125 (mobile genetic element) upstream to the genes. All isolates were positive for Tn2006/2008 and Tn2009 but were negative for Tn2007. CONCLUSION: Most of the isolates were grouped under the CC92 clonal complex which belongs to international clonal lineage 2. These findings predict that carriage of carbapenem-resistant genes possibly constitutes the underlying basis of high level of international clone II prevalence. Therefore, molecular surveillance and antimicrobial stewardship are essential in implementing policies to prevent and control the spread of CrAb in hospital settings.

Evaluation of a Rapid Kit for Detection of IgM against Leptospira in Human.

INTRODUCTION: Leptospirosis is an acute febrile illness, known for its protean clinical manifestations and the challenge in differentiating from other infectious diseases. Standardized confirmatory test is antibody dependent and not accessible by the suburban community. This study measures efficiency of an immune-chromatographic assay, Leptocheck WB, in detecting acute leptospirosis. METHODS: A total of 142 sera were used for kit evaluation. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated by comparing rapid kit results with gold standard laboratory, microscopic agglutination test (MAT). RESULTS: We found this rapid kit to have a sensitivity and specificity of 66.6% and 78.9%, respectively, whereas the PPV and NPV of the kit appeared to be 73.3% and 73.2%, respectively. DISCUSSION: Test efficiency of this rapid kit is reasonable. It is specific in detecting leptospiral antibody and assures clinician of accurate diagnosis by having higher PPV and NPV. It is prompt and efficient in comparison with conventional methods in assisting differential diagnosis. High sensitivity and specificity leptospirosis rapid test is indeed a crucial measure to assist the diagnosis of acute undifferentiated febrile illnesses.

A yoga intervention for type 2 diabetes risk reduction: a pilot randomized controlled trial.

BACKGROUND: Type 2 diabetes is a major health problem in many countries including India. Yoga may be an effective type 2 diabetes prevention strategy in India, particularly given its cultural familiarity. METHODS: This was a parallel, randomized controlled pilot study to collect feasibility and preliminary efficacy data on yoga for diabetes risk factors among people at high risk of diabetes. Primary outcomes included: changes in BMI, waist circumference, fasting blood glucose, postprandial blood glucose, insulin, insulin resistance, blood pressure, and cholesterol. We also looked at measures of psychological well-being including changes in depression, anxiety, positive and negative affect and perceived stress. Forty-one participants with elevated fasting blood glucose in Bangalore, India were randomized to either yoga (n = 21) or a walking control (n = 20). Participants were asked to either attend yoga classes or complete monitored walking 3-6 days per week for eight weeks. Randomization and allocation was performed using computer-generated random numbers and group assignments delivered in sealed, opaque envelopes generated by off-site study staff. Data were analyzed based on intention to treat. RESULTS: This study was feasible in terms of recruitment, retention and adherence. In addition, yoga participants had significantly greater reductions in weight, waist circumference and BMI versus control (weight -0.8 ± 2.1 vs. 1.4 ± 3.6, p = 0.02; waist circumference -4.2 ± 4.8 vs. 0.7 ± 4.2, p < 0.01; BMI -0.2 ± 0.8 vs. 0.6 ± 1.6, p = 0.05). There were no between group differences in fasting blood glucose, postprandial blood glucose, insulin resistance or any other factors related to diabetes risk or psychological well-being. There were significant reductions in systolic and diastolic blood pressure, total cholesterol, anxiety, depression, negative affect and perceived stress in both the yoga intervention and walking control over the course of the study. CONCLUSION: Among Indians with elevated fasting blood glucose, we found that participation in an 8-week yoga intervention was feasible and resulted in greater weight loss and reduction in waist circumference when compared to a walking control. Yoga offers a promising lifestyle intervention for decreasing weight-related type 2 diabetes risk factors and potentially increasing psychological well-being. TRIAL REGISTRATION: ClinicalTrials.gov Identified NCT00090506.

Safety Implications of Modulating Nuclear Receptors: A Comprehensive Analysis from Non-Clinical and Clinical Perspectives.

The unintended modulation of nuclear receptor (NR) activity by drugs can lead to toxicities amongst the endocrine, gastrointestinal, hepatic cardiovascular, and central nervous systems. While secondary pharmacology screening assays include NRs, safety risks due to unintended interactions of small molecule drugs with NRs remain poorly understood. To identify potential nonclinical and clinical safety effects resulting from functional interactions with 44 of the 48 human-expressed NRs, we conducted a systematic narrative review of the scientific literature, tissue expression data, and used curated databases (OFF-X™) (Off-X, Clarivate) to organize reported toxicities linked to the functional modulation of NRs in a tabular and machine-readable format. The top five NRs associated with the highest number of safety alerts from peer-reviewed journals, regulatory agency communications, congresses/conferences, clinical trial registries, and company communications were the Glucocorticoid Receptor (GR, 18,328), Androgen Receptor (AR, 18,219), Estrogen Receptor (ER, 12,028), Retinoic acid receptors (RAR, 10,450), and Pregnane X receptor (PXR, 8044). Toxicities associated with NR modulation include hepatotoxicity, cardiotoxicity, endocrine disruption, carcinogenicity, metabolic disorders, and neurotoxicity. These toxicities often arise from the dysregulation of receptors like Peroxisome proliferator-activated receptors (PPARα, PPARγ), the ER, PXR, AR, and GR. This dysregulation leads to various health issues, including liver enlargement, hepatocellular carcinoma, heart-related problems, hormonal imbalances, tumor growth, metabolic syndromes, and brain function impairment. Gene expression analysis using heatmaps for human and rat tissues complemented the functional modulation of NRs associated with the reported toxicities. Interestingly, certain NRs showed ubiquitous expression in tissues not previously linked to toxicities, suggesting the potential utilization of organ-specific NR interactions for therapeutic purposes.

The state of the art in secondary pharmacology and its impact on the safety of new medicines.

Secondary pharmacology screening of investigational small-molecule drugs for potentially adverse off-target activities has become standard practice in pharmaceutical research and development, and regulatory agencies are increasingly requesting data on activity against targets with recognized adverse effect relationships. However, the screening strategies and target panels used by pharmaceutical companies may vary substantially. To help identify commonalities and differences, as well as to highlight opportunities for further optimization of secondary pharmacology assessment, we conducted a broad-ranging survey across 18 companies under the auspices of the DruSafe leadership group of the International Consortium for Innovation and Quality in Pharmaceutical Development. Based on our analysis of this survey and discussions and additional research within the group, we present here an overview of the current state of the art in secondary pharmacology screening. We discuss best practices, including additional safety-associated targets not covered by most current screening panels, and present approaches for interpreting and reporting off-target activities. We also provide an assessment of the safety impact of secondary pharmacology screening, and a perspective on opportunities and challenges in this rapidly developing field.

QRS axis and the benefit of cardiac resynchronization therapy in patients with mildly symptomatic heart failure enrolled in MADIT-CRT.

BACKGROUND: Mildly symptomatic heart failure (HF) patients derive substantial clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D) as shown in MADIT-CRT. The presence of QRS axis deviation may influence response to CRT-D. The objective of this study was to determine whether QRS axis deviation will be associated with differential benefit from CRT-D. METHODS: Baseline electrocardiograms of 1,820 patients from MADIT-CRT were evaluated for left axis deviation (LAD: quantitative QRS axis -30 to -90) or right axis deviation (RAD: QRS axis 90-180) in left bundle branch block (LBBB), right bundle branch block (RBBB), and nonspecific interventricular conduction delay QRS morphologies. The primary endpoints were the first occurrence of a HF event or death and the separate occurrence of all-cause mortality as in MADIT-CRT. RESULTS: Among LBBB patients, those with LAD had a higher risk of primary events at 2 years than non-LAD patients (20% vs 16%; P = 0.024). The same was observed among RBBB patients (20% vs 10%; P = 0.05) but not in IVCD patients (22% vs 23%; P = NS). RAD did not convey any increased risk of the primary combined endpoint in any QRS morphology subgroup. When analyzing the benefit of CRT-D in the non-LBBB subgroups, there was no significant difference in hazard ratios for CRT-D versus ICD for either LAD or RAD. However, LBBB patients without LAD showed a trend toward greater benefit from CRT therapy than LBBB patients with LAD (HR for no LAD: 0.37, 95% CI: 0.26-0.53 and with LAD: 0.54, 95% CI: 0.36-0.79; P value for interaction = 0.18). CONCLUSIONS: LAD in non-LBBB patients (RBBB or IVCD) is not associated with an increased benefit from CRT. In LBBB patients, those without LAD seem to benefit more from CRT-D than those with LAD.

A 36-Year-Old Woman With an Unexpected Cause of Hypokalemia.

A 36-year-old woman complained of bilateral lower limb weakness for the last 3 days. She could move her upper limb, neck, and facial muscles and had no respiratory or swallowing difficulties. About 4 years ago, she complained of sudden weakness involving her lower limbs. Two years later, she had another episode involving only the right upper limb. In both cases, she was hypokalemic and received oral and intravenous potassium. She is a known diabetic and has polycystic ovary disease. Her blood pressure was 150/100 mm Hg, and body mass index was 29. Her serum potassium was 2 mEq/L, plasma renin 5 ng/dL, plasma aldosterone 0.63 µIU/mL, and aldosterone to plasma renin activity ratio 8. Cushing syndrome was considered a possibility. Subsequent analysis indicated a baseline cortisol level of 19.6 µg/dL at 8 Am. A screening overnight 1-mg dexamethasone suppression test (DST) showed 17 µg/dL cortisol. The low-dose DST revealed a cortisol level of 10.8 µg/dL. Adrenocorticotropin level was 196 pg/mL, and 24-hour urinary cortisol level was 1284 mg/dL. A high dose of 8-mg DST at 11 Pm to find the source of hypercortisolism performed yielded 15.9 µg/dL. Magnetic resonance imaging of the pituitary displayed a well-defined, heterogeneously enhanced mass lesion (15 × 13 × 11 mm) in the sella with mild suprasellar extension. Transsphenoidal resection and stereotactic radiosurgery were performed on the tumor with hormone replacement and glycemic control following surgery.

Artificial Intelligence/Machine Learning-Driven Small Molecule Repurposing via Off-Target Prediction and Transcriptomics.

The process of discovering small molecule drugs involves screening numerous compounds and optimizing the most promising ones, both in vitro and in vivo. However, approximately 90% of these optimized candidates fail during trials due to unexpected toxicity or insufficient efficacy. Current concepts with respect to drug-protein interactions suggest that each small molecule interacts with an average of 6-11 targets. This implies that approved drugs and even discontinued compounds could be repurposed by leveraging their interactions with unintended targets. Therefore, we developed a computational repurposing framework for small molecules, which combines artificial intelligence/machine learning (AI/ML)-based and chemical similarity-based target prediction methods with cross-species transcriptomics information. This repurposing methodology incorporates eight distinct target prediction methods, including three machine learning methods. By using multiple orthogonal methods for a "dataset" composed of 2766 FDA-approved drugs targeting multiple therapeutic target classes, we identified 27,371 off-target interactions involving 2013 protein targets (i.e., an average of around 10 interactions per drug). Relative to the drugs in the dataset, we identified 150,620 structurally similar compounds. The highest number of predicted interactions were for drugs targeting G protein-coupled receptors (GPCRs), enzymes, and kinases with 10,648, 4081, and 3678 interactions, respectively. Notably, 17,283 (63%) of the off-target interactions have been confirmed in vitro. Approximately 4000 interactions had an IC50 of <100 nM for 1105 FDA-approved drugs and 1661 interactions had an IC50 of <10 nM for 696 FDA-approved drugs. Together, the confirmation of numerous predicted interactions and the exploration of tissue-specific expression patterns in human and animal tissues offer insights into potential drug repurposing for new therapeutic applications.

Clopidogrel Vs Aspirin Monotherapy Following Dual Antiplatelet Therapy After Percutaneous Coronary Intervention: A Systematic Review and Meta-analysis.

Current guidelines recommend 6-12 months of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) followed by aspirin monotherapy indefinitely. We aimed to assess the efficacy and safety of clopidogrel vs aspirin in the post-PCI population after completing DAPT. We systematically searched 5 electronic databases to identify studies comparing clopidogrel with aspirin following completion of DAPT after PCI. We pooled outcomes for major adverse cardiac events (MACE), cardiac death, all-cause death, major bleeding, myocardial infarction (MI), and stroke. We included 5 studies with 13,850 patients, of whom 5601 (40.4%) received clopidogrel. Mean follow-up was 12-36 months. All patients received drug-eluting stents. Duration of DAPT before antiplatelet monotherapy was 1-18 months. Clopidogrel was associated with reductions in MACE (Risk ratio [RR] 0.77, 95% confidence interval [CI] 0.65-0.91), any stroke (RR 0.51; 95% confidence interval [CI] 0.35-0.76), ischemic stroke (RR 0.55; 95% CI 0.32-0.94), and hemorrhagic stroke (RR 0.24; 95% CI 0.09-0.68) when compared with aspirin. Cardiac death (RR 0.87; 95% CI 0.53-1.41), all-cause death (RR 1.06; 95% CI 0.81-1.39), major bleeding (RR 0.74; 95% CI 0.43-1.29), MI (RR 1.01; 95% CI 0.64-1.60), repeat revascularization (RR 0.88; 95% CI 0.71-1.09), target vessel revascularization (RR 0.76; 95% CI 0.52-1.13), and stent thrombosis (RR 0.96; 95% CI 0.35-2.59) were not significantly different among groups. Compared with aspirin, clopidogrel was associated with reductions in MACE and stroke (ischemic and hemorrhagic) following DAPT completion after PCI. There were no significant differences in mortality, major bleeding, MI, and repeat revascularization between groups.