Oral ENT-01 Targets Enteric Neurons to Treat Constipation in Parkinson Disease : A Randomized Controlled Trial.

BACKGROUND: Parkinson disease (PD) is associated with α-synuclein (αS) aggregation within enteric neurons. ENT-01 inhibits the formation of αS aggregates and improved constipation in an open-label study in patients with PD. OBJECTIVE: To evaluate the safety and efficacy of oral ENT-01 for constipation and neurologic symptoms in patients with PD and constipation. DESIGN: Randomized, placebo-controlled phase 2b study. (ClinicalTrials.gov: NCT03781791). SETTING: Outpatient. PATIENTS: 150 patients with PD and constipation. INTERVENTION: ENT-01 or placebo daily for up to 25 days. After baseline assessment of constipation severity, daily dosing was escalated to the prokinetic dose, the maximum dose (250 mg), or the tolerability limit, followed by a washout period. MEASUREMENTS: The primary efficacy end point was the number of complete spontaneous bowel movements (CSBMs) per week. Neurologic end points included dementia (assessed using the Mini-Mental State Examination [MMSE]) and psychosis (assessed using the Scale for the Assessment of Positive Symptoms adapted for PD [SAPS-PD]). RESULTS: The weekly CSBM rate increased from 0.7 to 3.2 in the ENT-01 group versus 0.7 to 1.2 in the placebo group (P < 0.001). Improvement in secondary end points included SBMs (P = 0.002), stool consistency (P < 0.001), ease of passage (P = 0.006), and laxative use (P = 0.041). In patients with dementia, MMSE scores improved by 3.4 points 6 weeks after treatment in the ENT-01 group (n = 14) versus 2.0 points in the placebo group (n = 14). Among patients with psychosis, SAPS-PD scores improved from 6.5 to 1.7 six weeks after treatment in the ENT-01 group (n = 5) and from 6.3 to 4.4 in the placebo group (n = 6). ENT-01 was well tolerated, with no deaths or drug-related serious adverse events. Adverse events were predominantly gastrointestinal, including nausea (34.4% [ENT-01] vs. 5.3% [placebo]; P < 0.001) and diarrhea (19.4% [ENT-01] vs. 5.3% [placebo]; P = 0.016). LIMITATION: Longer treatment periods need to be investigated in future studies. CONCLUSION: ENT-01 was safe and significantly improved constipation. PRIMARY FUNDING SOURCE: Enterin, Inc.

Clinical, biochemical, and hematological characteristics of community-dwelling adolescent and young adult males with anorexia nervosa.

OBJECTIVE: Data regarding clinical characteristics in males with AN are limited. We aimed to delineate clinical, biochemical, and hematological features in community-dwelling adolescent and young adult males with AN. METHOD: A retrospective chart review of electronic medical records from 2000 to 2016 was conducted for 53 males aged 10-23 years old; AN (n = 36) and healthy controls (n = 17) were similar for Tanner stage. RESULTS: Adolescent and young adult males with AN were diagnosed at a mean age of 15.9 ± 3.0 years. The most prevalent strategy for weight loss (following calorie restriction) was over-exercising. Labs demonstrated polycythemia, leukopenia, and thrombocytopenia, but no electrolyte abnormalities. Compared with healthy controls of similar Tanner stage, males with AN had lower total testosterone levels. A significant proportion of males with AN had traumatic bone fractures. DISCUSSION: Over-exercising is a common secondary weight loss strategy in males with AN. Testosterone levels are lower than in controls, but electrolyte abnormalities are rare. With enhanced provider awareness, diagnostic delays may be prevented.

Barriers and facilitators of implementing an antimicrobial stewardship intervention for urinary tract infection in a long-term care facility.

BACKGROUND: Fifty percent of antibiotic courses in long-term care facilities (LTCFs) are unnecessary, leading to increased risk of harm. Most studies to improve antibiotic prescribing in LTCFs showed modest and unsustained results. We aimed to identify facilitators, barriers and strategies in implementing a urinary tract infection (UTI)-focused antimicrobial stewardship (AS) intervention at a LTCF, with the secondary objective of exploring the pharmacist's potential roles. METHODS: The study used a qualitative descriptive design. Participants attended either a focus group or one-on-one interview. Data were analyzed inductively using a codebook modified in an iterative analytic process. Barrier and facilitator themes were mapped using the capability, opportunity, motivation and behaviour (COM-B) model. Similarly, themes were identified from the transcripts regarding the pharmacist's roles. RESULTS: Sixteen participants were interviewed. Most barriers and facilitators mapped to the opportunities domain of the COM-B model. The main barrier themes were lack of access, lack of knowledge, ineffective communication, lack of resources and external factors, while the main facilitator themes were education, effective collaboration, good communication, sufficient resources and access. For the pharmacist's role, the barrier themes were ineffective collaboration and communication. CONCLUSION: This study supports the importance of tailoring interventions to target factors underlying barriers to behaviour change. At this LTCF, an effective antimicrobial stewardship intervention should incorporate strategies to improve access, knowledge, communication and collaboration in its design, having sufficient resources and addressing external factors to optimize its success and long-term sustainability. Can Pharm J (Ott) 2021;154:xx-xx.

QTNet: Predicting Drug-Induced QT Prolongation With Artificial Intelligence-Enabled Electrocardiograms.

BACKGROUND: Prediction of drug-induced long QT syndrome (diLQTS) is of critical importance given its association with torsades de pointes. There is no reliable method for the outpatient prediction of diLQTS. OBJECTIVES: This study sought to evaluate the use of a convolutional neural network (CNN) applied to electrocardiograms (ECGs) to predict diLQTS in an outpatient population. METHODS: We identified all adult outpatients newly prescribed a QT-prolonging medication between January 1, 2003, and March 31, 2022, who had a 12-lead sinus ECG in the preceding 6 months. Using risk factor data and the ECG signal as inputs, the CNN QTNet was implemented in TensorFlow to predict diLQTS. RESULTS: Models were evaluated in a held-out test dataset of 44,386 patients (57% female) with a median age of 62 years. Compared with 3 other models relying on risk factors or ECG signal or baseline QTc alone, QTNet achieved the best (P < 0.001) performance with a mean area under the curve of 0.802 (95% CI: 0.786-0.818). In a survival analysis, QTNet also had the highest inverse probability of censorship-weighted area under the receiver-operating characteristic curve at day 2 (0.875; 95% CI: 0.848-0.904) and up to 6 months. In a subgroup analysis, QTNet performed best among males and patients ≤50 years or with baseline QTc <450 ms. In an external validation cohort of solely suburban outpatient practices, QTNet similarly maintained the highest predictive performance. CONCLUSIONS: An ECG-based CNN can accurately predict diLQTS in the outpatient setting while maintaining its predictive performance over time. In the outpatient setting, our model could identify higher-risk individuals who would benefit from closer monitoring.

Development and external validation of a dynamic risk score for early prediction of cardiogenic shock in cardiac intensive care units using machine learning.

AIMS: Myocardial infarction and heart failure are major cardiovascular diseases that affect millions of people in the USA with morbidity and mortality being highest among patients who develop cardiogenic shock. Early recognition of cardiogenic shock allows prompt implementation of treatment measures. Our objective is to develop a new dynamic risk score, called CShock, to improve early detection of cardiogenic shock in the cardiac intensive care unit (ICU). METHODS AND RESULTS: We developed and externally validated a deep learning-based risk stratification tool, called CShock, for patients admitted into the cardiac ICU with acute decompensated heart failure and/or myocardial infarction to predict the onset of cardiogenic shock. We prepared a cardiac ICU dataset using the Medical Information Mart for Intensive Care-III database by annotating with physician-adjudicated outcomes. This dataset which consisted of 1500 patients with 204 having cardiogenic/mixed shock was then used to train CShock. The features used to train the model for CShock included patient demographics, cardiac ICU admission diagnoses, routinely measured laboratory values and vital signs, and relevant features manually extracted from echocardiogram and left heart catheterization reports. We externally validated the risk model on the New York University (NYU) Langone Health cardiac ICU database which was also annotated with physician-adjudicated outcomes. The external validation cohort consisted of 131 patients with 25 patients experiencing cardiogenic/mixed shock. CShock achieved an area under the receiver operator characteristic curve (AUROC) of 0.821 (95% CI 0.792-0.850). CShock was externally validated in the more contemporary NYU cohort and achieved an AUROC of 0.800 (95% CI 0.717-0.884), demonstrating its generalizability in other cardiac ICUs. Having an elevated heart rate is most predictive of cardiogenic shock development based on Shapley values. The other top 10 predictors are having an admission diagnosis of myocardial infarction with ST-segment elevation, having an admission diagnosis of acute decompensated heart failure, Braden Scale, Glasgow Coma Scale, blood urea nitrogen, systolic blood pressure, serum chloride, serum sodium, and arterial blood pH. CONCLUSION: The novel CShock score has the potential to provide automated detection and early warning for cardiogenic shock and improve the outcomes for millions of patients who suffer from myocardial infarction and heart failure.

Do statins cause diabetes?

A wealth of evidence has established that cholesterol-lowering statin drugs, widely used for the prevention of cardiovascular disease, do increase the risk of new-onset diabetes, possibly by impairing pancreatic beta cell function and decreasing peripheral insulin sensitivity. Groups at particular risk include the elderly, women, and Asians. The diabetogenic effect of statins appear directly related to statin dose and the degree of attained cholesterol lowering. Statins can cause hyperinsulinemia even in the absence of hyperglycemia and the potential mitogenic effects and implications of prolonged hyperinsulinemia are discussed. Suggestions are made as to how physicians might avert the hyperinsulinemic and diabetogenic effects of statin therapy in clinical practice, and modulate the detrimental effects of these drugs on exercise performance. Finally, long-term studies are needed to determine if the deleterious hyperinsulinemic and diabetogenic effects of statin therapy undermine the beneficial cardiovascular disease risk outcomes in various segments of the population.

Nonfocal renal biopsies: adequacy and factors affecting a successful outcome.

PURPOSE: The purpose of this study was to evaluate factors affecting the success of ultrasound-guided core biopsy of kidneys and determine the optimum number of passes. METHODS: This retrospective study evaluated 484 nonfocal renal biopsies performed with 18-gauge side-notch biopsy needles. Number of biopsy passes, serum creatinine, body mass index, needle type, transplant age, kidney size, diabetic status, and operator were evaluated as predictors of the number of biopsy passes. RESULTS: Four hundred seventy-four biopsies (338 transplant, 136 native) were included with mean number of passes 2.87 (3.1 native vs 2.78 transplant; P = 0.002). Mean number of glomeruli yielded per pass was 6.9 (7.2 transplant vs 6.1 native; P = 0.0002) with 3 passes adequate for histological diagnosis in 84% of biopsies. Native kidney, increasing serum creatinine level, trainee biopsy operator, and use of a Temno needle were found to be independent predictors of having more than 3 biopsy passes on multivariate analysis. Age, sex, body mass index, diabetic status, and kidney size were not associated with the number of biopsy passes. CONCLUSIONS: The success of a nonfocal renal biopsy has many influencing variables, and in the absence of an on-site electron microscopy technologist to immediately evaluate biopsy samples, 3 passes with an 18-gauge needle would be adequate in 84% of kidneys to achieve a histological diagnosis, with 2 passes needed for transplant kidneys to meet the Banff 97 criteria.

Ulotaront, a Trace Amine-Associated Receptor 1/Serotonin 5-HT1A Agonist, in Patients With Parkinson Disease Psychosis: A Pilot Study.

Background and Objectives: Ulotaront (SEP-363856) is a trace amine-associated receptor 1 agonist with 5-HT1A receptor agonist activity currently in phase 3 clinical development for the treatment of schizophrenia. In this exploratory, flexibly dosed study, ulotaront was evaluated for the treatment of Parkinson disease psychosis (PDP). Methods: Patients with PDP requiring antipsychotic therapy were randomized, double-blind to ulotaront (25, 50, or 75 mg/d) or placebo. Mixed Model for Repeated Measures was used to assess change from baseline in the Scale for the Assessment of Positive Symptoms for Parkinson Disease (SAPS-PD) at 6 weeks (primary end point). Results: The efficacy analysis sample comprised 38 patients (ulotaront, n = 24; placebo, n = 14). SAPS-PD total scores were numerically reduced in ulotaront-treated vs placebo-treated patients from week 1 to week 6: Least squares mean (95% confidence interval) difference in change from baseline at week 6 was -1.1 (-6.5, 4.3, p = 0.681). PDP symptom complete remission (≥100% improvement [reduction] from baseline in SAPS-PD total score) was observed in 25% of ulotaront-treated vs 0% of placebo-treated patients. SAPS-PD and Neuropsychiatric Inventory hallucinations subscales were numerically reduced vs placebo, and SAPS-PD total scores were reduced in patients with greater cognitive impairment (baseline Mini-Mental State Examination [MMSE] scores ≤24). Ulotaront improved Scales for Outcomes in Parkinson Disease Sleep Scale - Daytime Sleepiness scores (p = 0.022). There was no worsening of Unified Parkinson Disease Rating Scale Part III motor score, MMSE, or vital signs. Adverse events (≥10%) with ulotaront vs placebo included hallucinations (24% vs 14%), confusional state (20% vs 14%), dizziness (16% vs 7%), nausea (12% vs 7%), and falls (12% vs 21%). Discussion: In this exploratory pilot study, ulotaront may decrease PDP symptoms without worsening motor function, particularly in patients with cognitive impairment. Trial Registration Information: ClinicalTrials.gov identifier: NCT02969369; submitted: November 17, 2016; study start date: December 31, 2016. Classification of Evidence: This Class II study was an exploratory pilot study that was underpowered to detect a statistically significant difference between ulotaront and placebo in the treatment of patients with Parkinson disease psychosis without worsening motor function.