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Background: Parkinson's disease (PD) is a neurodegenerative movement disorder with prodromal and highly prevalent gastrointestinal (GI) symptoms, especially constipation. Although PD models suggest gut-brain axis dysfunction, the mechanistic underpinnings and their correlation with GI symptoms are poorly understood., Aim: To examine the bidirectional gut-brain axis function in PD and correlate it with constipation severity, PD duration, and severity., Methods: Rectal sensory thresholds and afferent cortical evoked potentials (CEP) were assessed using a 4-ring EMG electrode probe. Efferent anal and rectal motor evoked potentials (MEPs) were obtained following transcranial and lumbosacral magnetic stimulation. Bowel symptoms were assessed by prospective stool diary. The CEP and MEP latencies, rectal sensory thresholds, and anorectal sensorimotor data were compared between PD subjects and age-adjusted healthy subjects., Key Results: Twenty-five PD subjects with constipation (F/M = 6/19) and 20 healthy subjects (F/M = 14/6) were enrolled. The first and pain sensation thresholds were higher in PD subjects than healthy subjects (p < 0.002) but lost significance after adjustment for age. Age-adjusted rectal CEP and right-sided cortico-anal MEP latencies were prolonged in PD subjects compared to healthy subjects (p < 0.04). Also, half (4 of 8) age-adjusted spino-anal and rectal MEP latencies in PD subjects were significantly longer. In multivariate linear analysis, first rectal sensation and right-sided MEP latencies showed moderate correlation with constipation severity., Conclusions & Inferences: Parkinson's disease is associated with significant bidirectional gut-brain axis dysfunction as evidenced by prolonged afferent and efferent neuronal signaling. Constipation severity in PD is correlated to abnormal rectal sensation and lateralized disturbance of efferent brain-gut signaling., (© 2023 John Wiley & Sons Ltd.)

Introduction: Fecal incontinence (FI) is characterized by both irregular and unpredictable bowel symptoms. An accurate history of symptoms is important for diagnosis and guiding management. Whether a patient's history of bowel symptoms is reliable or if there is recall bias is unknown., Aim: To evaluate the accuracy of FI symptoms based on patient's recall compared with a prospective stool diary., Methods: FI (Rome IV) patients completed a bowel questionnaire that included leakage episodes and stool consistency. Subsequently they completed a one-week FI stool diary. Agreement and correlation between historical recall and stool diary were compared., Results: One hundred patients participated. On average they reported 12 bowel movements (BMs) and five FI episodes per week. Fifty-two percent had completed under-graduation, 33% high school and 15% postgraduation. Using recall, 23% of patients accurately reported the number of FI episodes, whereas 41% underestimated and 36% overestimated its prevalence compared to the FI diary. Similarly, the concordance for the number of BMs was 30%, urgency was 54%, amount of stool leakage was 16%, and stool consistency was 12.5%. The concordance for nocturnal FI events, use of pads and lack of stool awareness were 63%, 75%, and 66.6% respectively., Conclusion: There is poor concordance for key bowel symptoms including the number of FI episodes as reported by FI patients, suggesting significant recall bias. Thus, historical recall of chronic FI symptoms may be less accurate. A prospective stool diary could provide more accurate information for the evaluation of FI patients., (© 2023 John Wiley & Sons Ltd.)

Introduction Catheter ablation (CA) of atrial fibrillation (AF) represents a mainstay in the treatment of this increasingly prevalent arrhythmia. Prospective clinical trials investigating the efficacy of CA may poorly represent real-world patient populations. However, many real-world clinical datasets possess missing data, which may impede their applicability in research. Thus, we sought to use ensemble modeling to address missing data and develop a model to estimate the probability of AF recurrence following CA. Methods We retrospectively analyzed clinical variables in 476 patients who underwent an initial CA of AF. Univariate and multivariate logistic regression was performed to determine those variables predictive of AF recurrence. A multivariate logistic model was created to estimate the probability of AF recurrence after CA. Missing data were addressed using ensemble modeling, and variable selection was performed using the aggregate of multiple models. Results After analysis, six variables remained in the model: AF during the post-procedural blanking period, coexistence of atrial flutter, end-stage renal disease, reduced left ventricular ejection fraction, prior failure of anti-arrhythmic drugs, and valvular heart disease. Predictive modeling was performed using these variables for 1000 randomly partitioned datasets (80% training, 20% testing) and 1000 random imputations for each partitioned dataset. The model predicted AF recurrence with an accuracy of 74.34 ± 3.99% (recall: 54.03 ± 8.15%; precision: 89.30 ± 4.21%; F1 score: 81.08 ± 3.65%).  Conclusion We successfully identified six clinical variables that, when modeled, predicted AF recurrence following CA with a high degree of classification accuracy. Application of this model to patients undergoing CA of AF may help identify those at risk of post-procedural AF recurrence., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2023, Horde et al.)

Naltrexone is an approved drug for management of alcohol use disorder (AUD), but data in patients with liver disease (LD) are limited. We aimed to evaluate the safety of naltrexone in those with LD. This is a retrospective cohort of adults with and without LD who were prescribed naltrexone for AUD from 2015 to 2019 in a safety-net setting. Naltrexone hepatic safety was determined by liver enzyme changes during and after compared to before naltrexone prescription as well as rates of subsequent hospitalization and death by Kaplan-Meier methods. Factors associated with hospitalization were examined by Cox regression. Of 160 patients prescribed naltrexone for AUD, 100 (63%) had LD and 47 (47%) of those with LD had cirrhosis (47% decompensated). The total cohort, LD, and cirrhosis groups had lower adjusted mean aspartate aminotransferase and alanine aminotransferase levels after versus before naltrexone prescription (p < 0.001). Two-year survival was 97.7% (95% confidence interval [CI], 84.6-99.7), 95.4% (95% CI, 82.8-98.8), 90.8% (95% CI, 73.5-97.0), and 81.3% (95% CI, 41.2-93.8) in those without LD, LD without cirrhosis, cirrhosis, and decompensated cirrhosis groups (p = 0.46), respectively. Alcohol-related 2-year hospitalization rates were 8.2% (95% CI, 2.7-24), 27.7% (95% CI, 16.6-44.0), 40.5% (95% CI, 24.8-61.6), and 41.7% (95% CI, 23.3-66.6) for the groups without LD, LD without cirrhosis, cirrhosis, and decompensated cirrhosis (p = 0.007), respectively. Independent predictors of subsequent hospitalization were LD, (hazard ratio [HR], 3.70; 95% CI, 1.19-11.51; p = 0.02), cirrhosis (HR, 5.16; 95% CI, 1.69-15.75), and shorter duration (≤30 days) of naltrexone prescription (HR, 2.50; 95% CI, 1.l2-5.20; p = 0.01). Conclusion: Naltrexone is safe to use in patients with underlying LD, including those with compensated cirrhosis. Although encouraging, more safety data are needed for those with decompensated cirrhosis., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Objectives: Despite the established role of the critical care pharmacist on the ICU multiprofessional team, critical care pharmacist workloads are likely not optimized in the ICU. Medication regimen complexity (as measured by the Medication Regimen Complexity-ICU [MRC-ICU] scoring tool) has been proposed as a potential metric to optimize critical care pharmacist workload but has lacked robust external validation. The purpose of this study was to test the hypothesis that MRC-ICU is related to both patient outcomes and pharmacist interventions in a diverse ICU population., Design: This was a multicenter, observational cohort study., Setting: Twenty-eight ICUs in the United States., Patients: Adult ICU patients., Interventions: Critical care pharmacist interventions (quantity and type) on the medication regimens of critically ill patients over a 4-week period were prospectively captured. MRC-ICU and patient outcomes (i.e., mortality and length of stay [LOS]) were recorded retrospectively., Measurements and Main Results: A total of 3,908 patients at 28 centers were included. Following analysis of variance, MRC-ICU was significantly associated with mortality (odds ratio, 1.09; 95% CI, 1.08-1.11; p < 0.01), ICU LOS (β coefficient, 0.41; 95% CI, 00.37-0.45; p < 0.01), total pharmacist interventions (β coefficient, 0.07; 95% CI, 0.04-0.09; p < 0.01), and a composite intensity score of pharmacist interventions (β coefficient, 0.19; 95% CI, 0.11-0.28; p < 0.01). In multivariable regression analysis, increased patient: pharmacist ratio (indicating more patients per clinician) was significantly associated with increased ICU LOS (β coefficient, 0.02; 0.00-0.04; p = 0.02) and reduced quantity (β coefficient, -0.03; 95% CI, -0.04 to -0.02; p < 0.01) and intensity of interventions (β coefficient, -0.05; 95% CI, -0.09 to -0.01)., Conclusions: Increased medication regimen complexity, defined by the MRC-ICU, is associated with increased mortality, LOS, intervention quantity, and intervention intensity. Further, these results suggest that increased pharmacist workload is associated with decreased care provided and worsened patient outcomes, which warrants further exploration into staffing models and patient outcomes., Competing Interests: Dr. Newsome has received research funding through the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Numbers UL1TR002378 and KL2TR002381. Dr. Rech’s institution received funding from Spero Pharmaceuticals; she received funding from Harm Reduction Therapeutics. Dr. DePriest received funding from Baxter. Dr. Flannery’s institution received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, the American Society of Nephrology, and La Jolla Pharmaceutical Company. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Rectal hyposensitivity (RH) is a well-known pathophysiological dysfunction in chronic constipation. Whether biofeedback training improves RH and restores bowel function is unknown., Aim: To investigate the efficacy of barostat-assisted sensory training (BAST) with syringe-assisted sensory training (SAST) in patients with RH in a randomized controlled trial., Methods: Patients with RH and chronic constipation (Rome III) were randomized to receive 6 biweekly sessions of BAST or SAST. Verbal/visual feedback was provided during repeated rectal distensions to improve defecation desire/urge and first sensations with either 10-cm balloon connected to barostat (BAST) or 4-cm balloon connected to syringe and manometry probe (SAST). Sensory thresholds, bowel symptoms, and therapist and patient's rating of treatments were compared. The primary outcome (responders) was the improvement in ≥2 sensory thresholds., Results: Sixty-six patients were enrolled: 32 received BAST, 34 received SAST, and 56 completed study. There were significantly more responders in BAST group than SAST (78% vs. 53%, p = 0.0320). Rectal sensation normalized in 81% with BAST compared to 56% with SAST (p = 0.0270). When compared to baseline, desire and urge to defecate thresholds and bowel satisfaction improved with BAST (p = 0.0013; p = 0.0002; p = 0.0001) and SAST (p = 0.0012; p = 0.0001; p < 0.0001) and number of complete spontaneous bowel movements with BAST (p = 0.0029) but without inter-group differences. Therapists rated BAST as superior to SAST (p < 0.0001), but patients rated both equally., Conclusions: Sensory biofeedback training was effective and significantly improved rectal sensation and constipation symptoms. Although both techniques were useful, the novel BAST was more efficacious and easier to administer for treating RH., (© 2021 John Wiley & Sons Ltd.)

Background: There is a lack of data surrounding the impact of coronavirus disease 2019 (COVID-19) among rural and urban communities. This study aims to determine whether there are differences in epidemiologic characteristics and clinical outcomes among individuals with COVID-19 among these communities., Methods: This was a retrospective analysis of 155 patients admitted to a single-center tertiary academic hospital located in Augusta, Georgia, with a large proportion of hospitalized patients transferred from or residing in rural and urban counties. Hospitalized adult patients were included in the study if they were admitted to AUMC between March 13, 2020, and June 25, 2020, and had a positive polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 regardless of the presence or absence of symptomatology. Demographics, admission data, and 30-day outcomes were examined overall and by geographical variation., Results: Urban patients were more likely to be admitted to the general medical floor ( P = .01), while rural patients were more likely to require an escalation in the level of care within 24 hours of admission ( P = .02). In contrast, of the patients who were discharged or expired at day 30, there were no statistically significant differences in either total hospital length of stay or intensive care unit length of stay between the populations., Conclusions: There may be many social determinants of health that limit a rural patient's ability to seek prompt medical care and contribute to decompensation within the first 24 hours of admission. This study provides insight into the differences in clinical course among patients admitted from different community settings and when accounting for comorbid conditions., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Translumbosacral neuromodulation therapy (TNT) improves symptoms of fecal incontinence (FI), but its mechanism of action is unknown. We tested the hypothesis that TNT at one or more frequency will significantly improve underlying pathophysiology of FI through modulation of ascending and/or descending signaling pathways in the gut and brain axis and anorectal sensorimotor function., Materials and Methods: We assessed afferent anorectal-cortical evoked potentials (CEP) following electrical stimulation of anorectum, efferent cortico-anorectal and lumbo-anorectal and sacro-anorectal motor evoked potentials (MEP) after transcranial and lumbosacral magnetic stimulations, and anorectal manometry before and after six weekly TNT sessions in FI subjects, randomized to 1, 5, or 15 Hz repetitive magnetic stimulations. Neurophysiology, anorectal sensorimotor function, and symptoms were compared to examine mechanistic effects. Co-primary measures were ano-cortical CEPs, cortico-anal MEPs, and lumbosacral-anal MEPs. Baseline and post-treatment data were compared with Wilcoxon signed-rank test and changes between the three frequencies with one-way ANOVA., Results: Thirty-three FI patients participated. After TNT, the afferent anal CEP latencies significantly decreased in the 1 Hz group compared to baseline (p = 0.0029) and 5 Hz or 15 Hz groups (p = 0.032). Cortico-anal MEPs were unchanged in all three groups. Bilateral lumbo-anal and sacro-anal MEP latencies significantly decreased with 1 Hz, lumbo-anal with 15 Hz, and sacro-anal with 5 Hz compared to baseline but without group differences. The 1 Hz group showed significant increase in anal squeeze sphincter pressure (p < 0.005) and maximum tolerable volume (p < 0.019) and demonstrated higher FI responder rate (p < 0.04) compared to the other two groups. The MEP responders were significantly correlated with FI responders (p = 0.006) in 1 Hz group., Conclusions: TNT significantly improves afferent ano-cortical signaling, efferent lumbo-anal and sacro-anal neuropathy and anorectal sensorimotor function. These neurobiologic effects were most prominent with 1 Hz frequency. TNT improves FI by modifying the underlying pathophysiology possibly through neuromodulation., (© 2021 International Neuromodulation Society.)

Introduction: Treatments for fecal incontinence (FI) remain unsatisfactory because they do not remedy the underlying multifactorial dysfunction(s) including anorectal neuropathy. The aim of this study was to investigate the optimal dose frequency, clinical effects, and safety of a novel treatment, translumbosacral neuromodulation therapy (TNT), aimed at improving neuropathy., Methods: Patients with FI were randomized to receive 6 sessions of weekly TNT treatments consisting of 600 repetitive magnetic stimulations over each of 2 lumbar and 2 sacral sites with either 1, 5, or 15 Hz frequency. Stool diaries, FI severity indices, anorectal neurophysiology and sensorimotor function, and quality of life were compared. Primary outcome measure was the change in FI episodes/week. Responders were patients with ≥50% decrease in weekly FI episodes., Results: Thirty-three patients with FI participated. FI episodes decreased significantly (∆ ±95% confidence interval, 4.2 ± 2.8 (1 Hz); 2 ± 1.7 (5 Hz); 3.4 ± 2.5 (15 Hz); P < 0.02) in all 3 groups when compared with baseline. The 1 Hz group showed a significantly higher (P = 0.04) responder rate (91 ± 9.1%) when compared with the 5 Hz group (36 ± 18.2%) or 15 Hz (55 ± 18.2%); no difference was found between the 5 and 15 Hz groups (P = 0.667). Anal neuropathy, squeeze pressure, and rectal capacity improved significantly only in the 1 Hz (P < 0.05) group compared with baseline, but not in other groups. Quality of life domains improved significantly (P < 0.05) with 1 and 5 Hz groups. No device-related serious adverse events were noted., Discussion: TNT significantly improves FI symptoms in the short term, and the 1 Hz frequency was overall better than 5 and 15 Hz. Both anorectal neuropathy and physiology significantly improved, demonstrating mechanistic improvement. TNT is a promising, novel, safe, efficacious, and noninvasive treatment for FI (see Visual Abstract, Supplementary Digital Content 3, http://links.lww.com/AJG/B598)., (Copyright © 2020 by The American College of Gastroenterology.)

Background: Linaclotide, a guanylate cyclase C agonist relieves irritable bowel syndrome with predominant constipation (IBS-C) symptoms, but how it improves pain in humans is unknown., Aims: To investigate the effects of linaclotide and placebo on the afferent and efferent gut-brain-gut signalling in IBS-C patients, in a randomised clinical trial., Methods: Patients with IBS-C (Rome III) and rectal hypersensitivity were randomised (2:1) to receive linaclotide (290 µg) or placebo for 10 weeks and undergo bi-directional gut and brain axis assessment using anorectal electrical stimulations and transcranial/transspinal-anorectal magnetic stimulations. Rectal sensations were examined by balloon distention. Assessments included abdominal pain, bowel symptoms and quality of life (QOL) scores. Primary outcomes were latencies of recto-cortical and cortico-rectal evoked potentials., Results: Thirty-nine patients participated; 26 received linaclotide and 13 received placebo. Rectal cortical evoked potentials latencies (milliseconds) were significantly prolonged with linaclotide compared to baseline (P1:Δ 19 ± 6, P < 0.005; N1:Δ 20 ± 7, P < 0.02) but not with placebo (P1:Δ 3 ± 5; N1:Δ 4.7 ± 5,P = 0.3) or between groups. The efferent cortico-anorectal and spino-anorectal latencies were unchanged. The maximum tolerable rectal volume (cc) increased significantly with linaclotide compared to baseline (P < 0.001) and placebo (Δ 29 ± 10 vs 4 ± 20, (P < 0.03). Abdominal pain decreased (P < 0.001) with linaclotide but not between groups. Complete spontaneous bowel movement frequency increased (P < 0.001), and IBS-QOL scores improved (P = 0.01) with linaclotide compared to baseline and placebo. There was no difference in overall responders between linaclotide and placebo (54% vs 23%, P = 0.13)., Conclusions: Linaclotide prolongs afferent gut-brain signalling from baseline but both afferent and efferent signalling were unaffected compared to placebo. Linaclotide significantly improves rectal hypersensitivity, IBS-C symptoms and QOL compared to placebo. These mechanisms may explain the effects of linaclotide on pain relief in IBS-C patients. ClinicalTrials.Gov: Registered at Clinical trials.gov no NCT02078323., (© 2020 John Wiley & Sons Ltd.)

Background: Among breast cancer survivors age > 50 years, deaths due to cardiovascular disease account for 35% of non-cancer related deaths. The increases in cardiovascular disease among breast cancer survivors is due to the cardiotoxic effects of breast cancer treatment and to overlapping risk factors for breast cancer and cardiovascular disease., Methods: We conducted a study of a sample of 164 breast cancer patients in order to examine the frequency of cardiovascular disease. The overall objective was to examine the frequency of high blood pressure, myocardial infarction, cardiomyopathy, congestive heart failure, stroke, and venous thrombosis/thromboembolism among women who have been diagnosed with stage I-IV breast cancer and who had completed primary therapy for the disease. Data were collected by postal survey and abstraction of electronic medical records., Results: A high percentage of the women (62.8%) had a reported history of high blood pressure. Fifty percent of the women had a reported history of high cholesterol. About 8.3% of the women were current smokers and 36.0% were former smokers. About 23.8% of the women had a reported history of diabetes. About 4.9% of the women had a reported history of congestive heart failure and 6.1% had a history of stroke., Discussion: Additional studies are needed of cardiovascular risk factors and adverse cardiovascular events among breast cancer survivors. Of particular concern is whether patients with hypertension, hypercholesterolemia, and diabetes are receiving appropriate therapy to reduce their cardiovascular risk and prevent morbidity and mortality from adverse cardiovascular events., Competing Interests: Conflicts of Interest None.

Background: Increasing efforts have been made in primary care settings to screen for a broad array of social determinants of health including inadequate food and nutrition, lack of education, unemployment, and inadequate housing, and to refer patients to community resources. Core tenets of primary care include integration with community resources., Methods: In the course of designing a randomized controlled trial of the effectiveness of a social determinants of health intervention aimed at adult, at-risk, African American primary care clinic patients, our research team developed a logic model to assist with the evaluation of the intervention., Results: In this article, we describe the logic model including elements of the intervention, mediator variables, and outcome variables., Conclusions: The proposed logic framework is likely to be helpful for planning, conducting, and evaluating social determinants of health interventions in primary care settings., Competing Interests: Conflicts of Interest: The author has no conflicts of interest to declare.

With the rapid development of high throughput technologies such as array and next generation sequencing (NGS), genome-wide, nucleotide-resolution epigenomic data are increasingly available. In recent years, there has been particular interest in data on DNA methylation and 3-dimensional (3D) chromosomal organization, which are believed to hold keys to understand biological mechanisms, such as transcription regulation, that are closely linked to human health and diseases. However, small sample size, complicated correlation structure, substantial noise, biases, and uncertainties, all present difficulties for performing statistical inference. In this review, we present an overview of the new technologies that are frequently utilized in studying DNA methylation and 3D chromosomal organization. We focus on reviewing recent developments in statistical methodologies designed for better interrogating epigenomic data, pointing out statistical challenges facing the field whenever appropriate.