Multiplatform-Integrated Identification of Melatonin Targets for a Triad of Psychosocial-Sleep/Circadian-Cardiometabolic Disorders.

Several psychosocial, sleep/circadian, and cardiometabolic disorders have intricately interconnected pathologies involving melatonin disruption. Therefore, we hypothesize that melatonin could be a therapeutic target for treating potential comorbid diseases associated with this triad of psychosocial-sleep/circadian-cardiometabolic disorders. We investigated melatonin's target prediction and tractability for this triad of disorders. The melatonin's target prediction for the proposed psychosocial-sleep/circadian-cardiometabolic disorder triad was investigated using databases from Europe PMC, ChEMBL, Open Targets Genetics, Phenodigm, and PheWAS. The association scores for melatonin receptors MT1 and MT2 with this disorder triad were explored for evidence of target-disease predictions. The potential of melatonin as a tractable target in managing the disorder triad was investigated using supervised machine learning to identify melatonin activities in cardiovascular, neuronal, and metabolic assays at the cell, tissue, and organism levels in a curated ChEMBL database. Target-disease visualization was done by graphs created using "igraph" library-based scripts and displayed using the Gephi ForceAtlas algorithm. The combined Europe PMC (data type: text mining), ChEMBL (data type: drugs), Open Targets Genetics Portal (data type: genetic associations), PhenoDigm (data type: animal models), and PheWAS (data type: genetic associations) databases yielded types and varying levels of evidence for melatonin-disease triad correlations. Of the investigated databases, 235 association scores of melatonin receptors with the targeted diseases were greater than 0.2; to classify the evidence per disease class: 37% listed psychosocial disorders, 9% sleep/circadian disorders, and 54% cardiometabolic disorders. Using supervised machine learning, 546 cardiovascular, neuronal, or metabolic experimental assays with predicted or measured melatonin activity scores were identified in the ChEMBL curated database. Of 248 registered trials, 144 phase I to IV trials for melatonin or agonists have been completed, of which 33.3% were for psychosocial disorders, 59.7% were for sleep/circadian disorders, and 6.9% were for cardiometabolic disorders. Melatonin's druggability was evidenced by evaluating target prediction and tractability for the triad of psychosocial-sleep/circadian-cardiometabolic disorders. While melatonin research and development in sleep/circadian and psychosocial disorders is more advanced, as evidenced by melatonin association scores, substantial evidence on melatonin discovery in cardiovascular and metabolic disorders supports continued R&D in cardiometabolic disorders, as evidenced by melatonin activity scores. A multiplatform analysis provided an integrative assessment of the target-disease investigations that may justify further translational research.

Bang the gavel: animal experimentation on trial-an interdisciplinary mock trial at the school of health sciences.

Active learning activities offer opportunities for medical students to facilitate the retention of knowledge and develop soft skills. We aimed to create a guide for an interdisciplinary mock trial learning activity within the medical curriculum of the College of Medicine, Anhembi Morumbi University-Laureate International Universities, Sao Paulo, Brazil. We designed an "Animal Experimentation Mock Trial" in which students are coached to search for scientific, legal, and ethical arguments pro and contra animal experimentation in medical research. The mock trial is prepared and staged with student teams to play the 1) presiding judge, 2) the plaintiff's attorney and expert witnesses contra animal research, 3) the defense attorney and expert witnesses pro animal research, and 4) the jury. The plaintiff and defense teams made presentations, and between each presentation the jury put questions to presenters (cross-examination). The jury team gave two evaluation scores after the plaintiff's presentation and then after the defense presentation. The formal feedback for this active learning activity indicated that students expressed satisfaction with the teaching strategies employed in the course. The mock trial with the lesson plan provides a learning mean to exemplify the complex relationship between animal experimentation, medical evidence, ethics, and law/regulations. This mock trial helps medical students to develop their soft skills, such as the ability to collaborate and also to recognize the limits of their own knowledge, important for professional development. The importance of interdisciplinary discussions is demonstrated by increasing the awareness of the multidisciplinary aspect of animal research.

Cardioprotective Melatonin: Translating from Proof-of-Concept Studies to Therapeutic Use.

In this review we summarized the actual clinical data for a cardioprotective therapeutic role of melatonin, listed melatonin and its agonists in different stages of development, and evaluated the melatonin cardiovascular target tractability and prediction using machine learning on ChEMBL. To date, most clinical trials investigating a cardioprotective therapeutic role of melatonin are in phase 2a. Selective melatonin receptor agonists Tasimelteon, Ramelteon, and combined melatonergic-serotonin Agomelatine, and other agonists with registered structures in CHEMBL were not yet investigated as cardioprotective or cardiovascular drugs. As drug-able for these therapeutic targets, melatonin receptor agonists have the benefit over melatonin of well-characterized pharmacologic profiles and extensive safety data. Recent reports of the X-ray crystal structures of MT1 and MT2 receptors shall lead to the development of highly selective melatonin receptor agonists. Predictive models using machine learning could help to identify cardiovascular targets for melatonin. Selecting ChEMBL scores > 4.5 in cardiovascular assays, and melatonin scores > 4, we obtained 284 records from 162 cardiovascular assays carried out with 80 molecules with predicted or measured melatonin activity. Melatonin activities (agonistic or antagonistic) found in these experimental cardiovascular assays and models include arrhythmias, coronary and large vessel contractility, and hypertension. Preclinical proof-of-concept and early clinical studies (phase 2a) suggest a cardioprotective benefit from melatonin in various heart diseases. However, larger phase 3 randomized interventional studies are necessary to establish melatonin and its agonists' actions as cardioprotective therapeutic agents.

High-frequency chest wall oscillation devices: An umbrella review and bibliometric analysis.

INTRODUCTION: High-frequency chest wall oscillation (HFCWO) devices are used to improve airway clearance in various respiratory conditions. This study comprehensively assesses the evidence on efficacy and safety and identifies trends in scientific publications and patents across geographic regions. METHODS: This study utilized an integrated approach, combining bibliographic and bibliometric research with artificial intelligence (AI) tools. Four databases - PubMed, Europe Pubmed Central, Cochrane Database of Systematic Reviews, and CINAHL - were searched for systematic reviews on the effectiveness of treatment options for HFCWO. The AMSTAR-2 tool was used to evaluate the risk of bias in systematic reviews. Bibliographic research synthesized the evidence following PRISMA and Cochrane guidelines. The Dimensions platform was used for bibliometric analysis to provide insights into the global landscape. AI tools with prompt engineering tools Chain-of-Thoughts (CoT) and Tree of Thoughts (ToT) were used to enhance data extraction capabilities. RESULTS: The umbrella review identified 12 systematic reviews supporting the effectiveness of HFCWO in improving pulmonary function parameters, sputum characteristics, dyspnea, health scores, and quality of life in conditions including cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease (COPD), or neuromuscular diseases, with varying evidence of certainty. Eight of the twelve reviews had a moderate to high AMSTAR-2 confidence level, while several studies lacked sufficient descriptions of methods, treatment regimens, outcome measures, and adverse effects. Despite the absence of adverse events, the overall evidence quality between studies is evaluated as low to very low. Bibliometric analysis found a significant increase in global interest over the past two decades, with 230 research publications, 137 patents, and 56 clinical trials. CONCLUSIONS: The study highlights the potential of HFCWO devices in respiratory care but demands more robust evidence. The increasing interest in airway clearance devices highlights the necessity for HFCWO mechanism and safety research, underlining its therapeutic relevance in respiratory medicine. The interdisciplinary integration of AI tools and prompt engineering contributes to a nuanced understanding of the available evidence.

High and low pitch sound stimuli effects on heart-brain coupling.

This study aimed to explore the influence of sound stimulation on heart rate and the potential coupling between cardiac and cerebral activities. Thirty-one participants underwent exposure to periods of silence and two distinct continuous, non-repetitive pure tone stimuli: low pitch (110 Hz) and high pitch (880 Hz). Electroencephalography (EEG) data from electrodes F3, F4, F7, F8, Fp1, Fp2, T3, T4, T5, and T6 were recorded, along with R-R interval data for heart rate. Heart-brain connectivity was assessed using wavelet coherence between heart rate variability (HRV) and EEG envelopes (EEGE). Heart rates were significantly lower during high and low-pitch sound periods than in silence (p < 0.002). HRV-EEGE coherence was significantly lower during high-pitch intervals than silence and low-pitch sound intervals (p < 0.048), specifically between the EEG Beta band and the low-frequency HRV range. These results imply a differential involvement of the frontal and temporal brain regions in response to varying auditory stimuli. Our findings highlight the essential nature of discerning the complex interrelations between sound frequencies and their implications for heart-brain connectivity. Such insights could have ramifications for conditions like seizures and sleep disturbances. A deeper exploration is warranted to decipher specific sound stimuli's potential advantages or drawbacks in diverse clinical scenarios.

Evidence for the druggability of aldosterone targets in heart failure: A bioinformatics and data science-driven decision-making approach.

BACKGROUND: Aldosterone plays a key role in the neurohormonal drive of heart failure. Systematic prioritization of drug targets using bioinformatics and database-driven decision-making can provide a competitive advantage in therapeutic R&D. This study investigated the evidence on the druggability of these aldosterone targets in heart failure. METHODS: The target disease predictability of mineralocorticoid receptors (MR) and aldosterone synthase (AS) in cardiac failure was evaluated using Open Targets target-disease association scores. The Open Targets database collections were downloaded to MongoDB and queried according to the desired aggregation level, and the results were retrieved from the Europe PMC (data type: text mining), ChEMBL (data type: drugs), Open Targets Genetics Portal (data type: genetic associations), and IMPC (data type: genetic associations) databases. The target tractability of MR and AS in the cardiovascular system was investigated by computing activity scores in a curated ChEMBL database using supervised machine learning. RESULTS: The medians of the association scores of the MR and AS groups were similar, indicating a comparable predictability of the target disease. The median of the MR activity scores group was significantly lower than that of AS, indicating that AS has higher target tractability than MR [Hodges-Lehmann difference 0.62 (95%CI 0.53-0.70, p < 0.0001]. The cumulative distributions of the overall multiplatform association scores of cardiac diseases with MR were considerably higher than with AS, indicating more advanced investigations on a wider range of disorders evaluated for MR (Kolmogorov-Smirnov D = 0.36, p = 0.0009). In curated ChEMBL, MR had a higher cumulative distribution of activity scores in experimental cardiovascular assays than AS (Kolmogorov-Smirnov D = 0.23, p < 0.0001). Documented clinical trials for MR in heart failures surfaced in database searches, none for AS. CONCLUSIONS: Although its clinical development has lagged behind that of MR, our findings indicate that AS is a promising therapeutic target for the treatment of cardiac failure. The multiplatform-integrated identification used in this study allowed us to comprehensively explore the available scientific evidence on MR and AS for heart failure therapy.

Sexual Dimorphism in the Expression of Cardiac and Hippocampal Renin-Angiotensin and Kallikrein-Kinin Systems in Offspring from Mice Exposed to Alcohol during Gestation.

Prenatal alcohol exposure (PAE) impairs fetal development. Alcohol consumption was shown to modulate the renin-angiotensin system (RAS). This study aimed to analyze the effects of PAE on the expression of the renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) peptide systems in the hippocampus and heart of mice of both sexes. C57Bl/6 mice were exposed to alcohol during pregnancy at a concentration of 10% (v/v). On postnatal day 45 (PN45), mouse hippocampi and left ventricles (LV) were collected and processed for messenger RNA (mRNA) expression of components of the RAS and KKS. In PAE animals, more pronounced expression of AT1 and ACE mRNAs in males and a restored AT2 mRNA expression in females were observed in both tissues. In LV, increased AT2, ACE2, and B2 mRNA expressions were also observed in PAE females. Furthermore, high levels of H2O2 were observed in males from the PAE group in both tissues. Taken together, our results suggest that modulation of the expression of these peptidergic systems in PAE females may make them less susceptible to the effects of alcohol.

"Involve Me and I Learn": Active Learning in a Hybrid Medical Biochemistry First Year Course on an American-Style MD Program in the UAE.

Perceived as a subject with abstract jargon, requiring extensive memorization of complex metabolic pathways, chemical structures, and names, students lose sight of the significance of biochemistry on their MD journey (Afshar M, Han Z. Teaching and learning medical biochemistry: Perspectives from a student and an educator. Med Sci Educ. 2014;24:339-41.). A disconnect between what is taught in the classroom and its application to clinical settings arises through over emphasis on the need to pass board exams, documented to be a poor measure of core competencies. Employing active learning strategies with meaningful activities with clinical applications, centered around the curriculum, cognitively engages students and is a deviation from the didactic way in which biochemistry is traditionally taught.

Quantitative cardiac autonomic outcomes of hydrotherapy in women during the first stage of labor.

Introduction: Most hydrotherapy studies during childbirth report findings related to pain using a widespread set of subjective measures. In this study, ECG biomarkers as quantitative cardiac autonomic outcomes were used to assess the effects of warm shower hydrotherapy on laboring women during the first stage of labor. Methods: This was a prospective single-blind cohort study on stage I delivering women. Their cardiac autonomic function was assessed using heart rate variability (HRV) measures during a deep breathing test using point-of-care testing comprised of an HRV scanner system with wireless ECG enabling real-time data analysis and visualization. Labor pain and anxiety were assessed using the Visual Analog Scale for Pain (VASP) and the Beck Anxiety Inventory (BAI). A total of 105 pregnant women in the first stage of labor who received warm shower hydrotherapy, intravenous analgesia (scopolamine + sodium dipyrone), or spinal anesthetic (bupivacaine + morphine) were enrolled. Results: In women during the first stage of labor, parasympathetic modulation reflected through RMSSD (root mean square of successive RR interval differences) was significantly reduced by hydrotherapy and intravenous analgesia (before vs. after mean rank diff. 35.73 and 65.93, respectively, p < 0.05). Overall HRV (SDNN, standard deviation of RR intervals) was significantly decreased only by intravenous analgesia (before vs. after mean rank diff. 65.43, p < 0.001). Mean heart rate was significantly increased by intravenous analgesia, while spinal anesthesia reduced it, and hydrotherapy did not alter it (before vs. after mean rank diff. -49.35*, 70.38*, -24.20 NS , respectively, *p < 0.05, NS not significant). Conclusion: This study demonstrates that warm shower therapy may impact the sympathovagal balance via parasympathetic withdrawal in women during the initial stage of labor. The findings of this study provide quantitative support for using warm shower hydrotherapy during labor via point-of-care testing. The dependability of hydrotherapy as a non-pharmacological treatment is linked to the completion of more clinical research demonstrating quantitative evidence via outcome biomarkers to support indications on stress and birth progress.

Urinary Angiotensinogen-Melatonin Ratio in Gestational Diabetes and Preeclampsia.

Background: A large research portfolio indicates that an activated renal renin-angiotensin system or a deficit on melatonin is associated with several cardiovascular pathologies. In this observational clinical study, we hypothesized that alterations in urinary melatonin or angiotensinogen levels may be altered in two common conditions, preeclampsia and gestational diabetes. Our study's primary objective was to assess melatonin and angiotensinogen as novel disease biomarkers detectable and quantifiable in the urine of pregnant women with or without pregnancy complications. Methods: This was a concurrent cohort study of pregnant women with selected obstetric pathologies (gestational diabetes, preeclampsia, hypertension and obesity with hypertension). A group of healthy controls was also included. Urinary 6-sulfatoxymelatonin and angiotensinogen were measured by sensitive and specific ELISAs in first morning void urine samples. The patients were included in the cohort consecutively, and the diagnosis was blinded at the level of urine collection. Urinary 6-sulfatoxymelatonin and angiotensinogen levels were investigated in the patients included in the cohort. Results: Urinary levels of angiotensinogen were significantly higher in the gestational diabetes [angiotensinogen/creatinine ratio median (25th, 75th): 0.11 (0.07, 0.18)] and preeclampsia [0.08 (0.06, 0.18)] groups than in those with healthy pregnancy [0.05(0.04, 0.06]; 6-sulfatoxymelatonin levels were significantly lower in the gestational diabetes [ug/h: median (25th, 75th): 0.12(0.08, 0.17)] and preeclampsia [0.12 (0.09, 0.15)] groups than in those with healthy pregnancy [0.20 (0.15, 0.27]. Neither morning void protein/creatinine ratio nor 24-h urine protein estimate were significantly different between the study groups. Conclusion: These results suggest that urinary angiotensinogen levels may indicate an intrarenal RAS activation while melatonin production appears to be defective in gestational diabetes or hypertension. An angiotensinogen/melatonin ratio is suggested as an early biomarker for identification of gestational diabetes or hypertension. This report provides a basis for the potential use of melatonin for the treatment of preeclampsia. A prospective study in a larger number of patients to determine the operative characteristics of these markers as potential diagnostic tests is justified.