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.

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.

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.

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.

"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.

Burnout and Cardiovascular Risk in Healthcare Professionals During the COVID-19 Pandemic.

Introduction: The objective of this study was to investigate the psychosocial and cardiovascular markers in healthcare professionals during the COVID-19 pandemic. Methods: This was a STROBE compliant, blended exploratory study. Residents, staff physicians, nurses, and auxiliary healthcare professionals from both inpatient and outpatient medicine services were recruited using a planned random probability sample. The Maslach Burnout Inventory (MBI), Fuster-BEWAT score (FBS), and socio-demographic factors, as well as sleep quality, were studied. The correlations between burnout severity and cardiovascular risk were examined using multivariable linear regression models adjusted for confounding variables, such as sociodemographic and anthropometric characteristics. Results: The regression analysis with FBS as the outcome showed a negative association between cardiovascular health and emotional exhaustion [Coef.(95%CI): -0.029 (-0.048, -0.01), p = 0.002]. The higher the emotional exhaustion the lower the cardiovascular health. Further, the model showed a positive association between personal accomplishment and cardiovascular health [Coef.(95%CI): 0.045 (0.007, 0.082), p = 0.02]. Emotional exhaustion was significantly positive correlated with REM sleep and light average (Spearman's rank correlation: 0.37 and 0.35, respectively, with P < 0.05). Conclusion: The data from this study show that healthcare practitioners who are with burnout and emotional exhaustion have an elevated cardiovascular risk, however, causality cannot be determined. As an adaptive response to stressful situations, REM sleep increases. The findings of this study may be relevant in creating preventive strategies for burnout and cardiovascular risk reduction or prevention. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [NCT04422418].

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.

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.

Health and Well-Being of Athletes During the Coronavirus Pandemic: A Scoping Review.

Background: The ongoing global pandemic has become the world's leading health problem, causing massive public fear and concern. Reports suggest that athletes are seeking mental health support, showing the pressures of boredom, and tension associated with their anticipated social isolation. The current study seeks to evaluate the evidence regarding the effects of the coronavirus pandemic on occupational stress in professional athletes. Method: A scoping review was conducted. A comprehensive search involving Embase and PubMed databases was conducted using a combination of the following key words: COVID-19, SARS-CoV-2, coronavirus, and athletes. In this study, articles were retained if they were original studies reporting on the impact of the pandemic on professional athletes. Results: Nine studies were identified as they investigated the impact of the pandemic on athletes. Most were observational and cross-sectional, and one was longitudinal. Outcome measures mainly investigated were level of depression, anxiety, and stress. Dependent variables were physical activity, nutrition, mental state, sleep quality, individual well-being, social identity, exclusivity, negative affectivity, alcohol consumption, psychological distress, and gambling habits. Conclusions: This review highlights the need for proactive engagement with professional athletes, coaches, trainers, and sports councils to facilitate understanding and awareness-raising, process optimization, and delivery of consistent training and psychosocial aid and occupational therapy programs that maintain the health and well-being of athletes while minimizing occupational stress during a pandemic.

Cross-Cultural Adaptation, Reliability, and Validity of a Brazilian of Short Version of the Posttraumatic Diagnostic Scale.

Background: A short version of the Posttraumatic Diagnostic Scale (PDS) comprising only re-experiencing symptom items has been recently validated on Japanese adults. This short-version-PDS had good psychometric properties among Japanese adults with and without posttraumatic stress disorder (PTSD). The aim of this study was to translate and culturally validate the short-version-PDS for the Brazilian sociolinguistic context. Methods: A translation of the short-version-PDS was performed based on established guidelines. We enrolled 53 patients with PTSD as a potential comorbidity. The translation and cross-cultural adaptation of the short-version-PDS included forward and back-translation by a Japanese Brazilian researcher and a certified translator; synthesis was achieved by consensus, backward translation, pilot test, and finalization. Content validity coefficient (CVC) was used to assess quality of adaptation. Internal consistency was calculated using Cronbach's alpha coefficient. Spearman correlations were between the new short-version-PDS and the Brazilian version of the posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), and a receiver operating characteristic (ROC) curve was used to determine the best cut-off values for the short-version-PDS. Results: The short-version-PDS was well accepted by all subjects, none of the questions were experienced as inappropriate, and all questions of the 3 items were judged important. Item 1 presented CVCt = 0.92; item 2 had a CVCt = 0.87 and item 3 had a CVCt = 0.95. The internal consistency of the final version as measured by Cronbach's alpha was 0.78. The short-version-PDS scale correlated positively with the DSM-5 scale with a Spearman rho of 0.64 (95%CI [0.4-0.8], p < 0.001). The receiver operating characteristic (ROC) curve value was 0.97 (95%CI [0.9-1.0], p < 0.001). The cut-off score for a maximum Youden Index of 0.8 to distinguish moderate from severe from slight PTSD was > 31.0 with sensitivity and specificity are 86.4 and 93.5%, respectively. Conclusions: This Brazilian Portuguese version of the short-version-PDS had good psychometric properties among Brazilian adults with and without PTSD. Transferability and generalizability of the cut-off scores should be further analyzed.

Prevalence and Determinants of Immediate and Long-Term PTSD Consequences of Coronavirus-Related (CoV-1 and CoV-2) Pandemics among Healthcare Professionals: A Systematic Review and Meta-Analysis.

BACKGROUND: The COVID-19 pandemic continues to rise. In order to control the COVID-19 pandemic, healthcare professionals have been subjected to increased exposure to work stress. In this systematic review, we aimed at investigating the prevalence and determinants of immediate and long-term post-traumatic stress disorder (PTSD) effects on healthcare professionals by the COVID-19 (SARS CoV-2) and SARS-2003 (SARS CoV-1) pandemics. METHODS: This systematic review was conducted according to the recommendations of the Protocols for Systemic Review and Meta-Analysis (PRISMA) statement. Only studies reporting the prevalence of PTSD (frequency, percentage) and related risk factors (adjusted odds ratio (OR)) in healthcare professionals (HCPs) during the SARS CoV-2 and SARS CoV-1 pandemics were included. The following databases were screened: Medline, Embase, PsychINFO, and Health Psychosocial Instrument (HaPI). RESULTS: Six of eight studies reported PTSD symptoms among healthcare professionals during the COVID-19 pandemic in China (three), Singapore (one), India (one), and the United States of America (USA) (two), while two studies reported symptoms during the SARS-2003 pandemic in China (one) and Singapore (one). Sample sizes ranged from 263 to 5062 with a combined total of 10,074 participants. All of the studies self-reported the level of exposure to coronaviruses (CoV-1 and CoV-2) and severity of PTSD. Seven studies reported the prevalence of immediate PTSD and determinants, while one study reported delayed-onset PTSD (3 years after CoV-1 pandemic). Determinants of immediate PTSD were reported for the CoV-2 pandemic, while those for long-term PTSD were reported for the CoV-1 pandemic. CONCLUSIONS: A comprehensive understanding of the prevalence and determinants of immediate or long-term pandemic PTSD for healthcare workers can improve prevention, diagnosis, and management. Rigorous research measuring the prevalence of PTSD and its associated risk factors (adjusted OR) for the CoV-2 pandemic are envisaged. Although strategies to resolve immediate PTSD are key, long-term PTSD must not be overlooked.

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.

Heart Rate Variability Indices as Possible Biomarkers for the Severity of Post-traumatic Stress Disorder Following Pregnancy Loss.

Background: Psychological distress, such as posttraumatic stress disorder (PTSD), is commonly evaluated using subjective questionnaires, a method prone to self-report bias. The study's working hypothesis was that levels of autonomic dysfunction determined by heart rate variability (HRV) measures are associated with the severity of PTSD in women following pregnancy loss. Methods: This was an observational prospective cohort study with 53 patients enrolled. The DSM-5 (Diagnostic and Statistical Manual of Mental Disorders) PTSD scale (PCL-5) was used to assess the severity of PTSD in women after pregnancy loss. The cardiac autonomic function was assessed using HRV measurements during a deep breathing test using an HRV scanner system with wireless ECG enabling real-time data analysis and visualization. HRV measures were: standard deviation (SD) of normal R-R wave intervals [SDNN, ms], square root of the mean of the sum of the squares of differences between adjacent normal R wave intervals [RMSSD, ms], and the number of all R-R intervals in which the change in consecutive normal sinus intervals exceeds 50 milliseconds divided by the total number of R-R intervals measured [pNN50 = (NN50/n-1)*100%] [pNN50%]. Results: The PCL-5 scores had a statistically significant association with HRV indices (SDNN; RMSSD, and pNN50%). Patients with PTSD had similar mean heart rate values as compared to patients without PTSD (PCL-5), but significantly higher SDNN [median[IQR, interquartile range]: 90.1 (69.1-112.1) vs. 52.5 (36.8-65.6)], RMSSD [59.4 (37.5-74.9) vs. 31.9 (19.3 - 44.0)], and PNN50% values [25.7 (16.4-37.7) vs. 10.6 (1.5-21.9)]. The SDNN of the deep breathing test HRV was effective at distinguishing between patients with PTSD and those without, with an AUC = 0.83 +/- 0.06 (95 % CI 0.94, p = 0.0001) of the ROC model. Conclusions: In this study, HRV indices as biomarkers of cardiac dysautonomia were found to be significantly related to the severity of PTSD symptoms in women after pregnancy loss.

Melatonin Therapy Improves Cardiac Autonomic Modulation in Pinealectomized Patients.

The purpose of this investigational study was to assess the effects of melatonin replacement therapy on cardiac autonomic modulation in pinealectomized patients. This was an open-label, single-arm, single-center, proof-of-concept study consisting of a screening period, a 3-month treatment period with melatonin (3 mg/day), and a 6-month washout period. The cardiac autonomic function was determined through heart rate variability (HRV) measures during polysomnography. Pinealectomized patients (n = 5) with confirmed absence of melatonin were included in this study. Melatonin treatment increased vagal-dominated HRV indices including root mean square of the successive R-R interval differences (RMSSD) (39.7 ms, 95% CI 2.0-77.4, p = 0.04), percentage of successive R-R intervals that differ by more than 50 ms (pNN50) (17.1%, 95% CI 9.1-25.1, p = 0.003), absolute power of the high-frequency band (HF power) (1,390 ms2, 95% CI 511.9-2,267, p = 0.01), and sympathetic HRV indices like standard deviation of normal R-R wave interval (SDNN) (57.6 ms, 95% CI 15.2-100.0, p = 0.02), and absolute power of the low-frequency band (LF power) (4,592 ms2, 95% CI 895.6-8,288, p = 0.03). These HRV indices returned to pretreatment values when melatonin treatment was discontinued. The HRV entropy-based regularity parameters were not altered in this study, suggesting that there were no significant alterations of the REM-NREM ratios between the time stages of the study. These data show that 3 months of melatonin treatment may induce an improvement in cardiac autonomic modulation in melatonin-non-proficient patients. ClinicalTrials.gov Identifier: NCT03885258.

Therapeutic Renin Inhibition in Diabetic Nephropathy-A Review of the Physiological Evidence.

The purpose of this systematic review was to investigate the scientific evidence to support the use of direct renin inhibitors (DRIs) in diabetic nephropathy (DN). MEDLINE was searched for articles reported until 2018. A standardized dataset was extracted from articles describing the effects of DRIs on plasma renin activity (PRA) in DN. A total of three clinical articles studying PRA as an outcome measure for DRIs use in DN were identified. These clinical studies were randomized controlled trials (RCTs): one double-blind crossover, one post hoc of a double-blind and placebo-controlled study, and one open-label and parallel-controlled study. Two studies reported a significant decrease of albuminuria associated with PRA reduction. One study had a DRI as monotherapy compared with placebo, and two studies had DRI as add-in to an angiotensin II (Ang II) receptor blocker (ARB). Of 10,393 patients with DN enrolled in five studies with DRI, 370 (3.6%) patients had PRA measured. Only one preclinical study was identified that determined PRA when investigating the effects of aliskiren in DN. Moreover, most of observational preclinical and clinical studies identified report on a low PRA or hyporeninemic hypoaldosteronism in DM. Renin inhibition has been suggested for DN, but proof-of-concept studies for this are scant. A small number of clinical and preclinical studies assessed the PRA effects of DRIs in DN. For a more successful translational research for DRIs, specific patient population responsive to the treatment should be identified, and PRA may remain a biomarker of choice for patient stratification.

Impact of COVID-19 Pandemic Burnout on Cardiovascular Risk in Healthcare Professionals Study Protocol: A Multicenter Exploratory Longitudinal Study.

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has created new and unpredictable challenges for healthcare systems. Healthcare professionals are heavily affected by this rapidly changing situation, especially frontline healthcare professionals who are directly engaged in the diagnosis, treatment, and care of patients with COVID-19 and may experience psychological burdens. The objective of this study is to explore the evolution of psychosocial, cardiovascular, and immune markers in healthcare professionals with different levels of exposure to the COVID-19 pandemic. Methods and Analysis: This is a STROBE compliant, blended, exploratory study involving online and onsite approaches that use wearable monitoring. A planned random probability sample of residents, staff physicians, nurses, and auxiliary healthcare professionals will be recruited. The study sample will be stratified by exposure to the COVID-19 pandemic. As a first step, recruitment will be conducted online, with e-consent and using e-surveys with Maslach Burnout Inventory, Fuster-BEWAT score, and sociodemographic characteristics. Onsite visits will be planned for the second step where participants will receive a wearable setup that will measure heart rate, actimetry, and sleep quality monitoring, which will be used together with blood sampling for immune biomarkers. Steps 1 and 2 will then be repeated at 2-3 months, and 6 months. Power BI and Tableau will be used for data visualization, while front-end data capture will be used for data collection using specific survey/questionnaires, which will enable data linkage between e-surveys, internet of things wearable devices, and clinical laboratory data. Clinical Trial Registration: ClinicalTrials.gov; Identifier: NCT04422418.

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.

Obesity and metabolic syndrome in children in Brazil: The challenge of lifestyle change.

The purpose of this observational study was to examine the prevalence of obesity in children of 6 to 8 years of age from primary public schools over a period of 6 years and the associated environmental and metabolic health risk factors.This was a cohort observational study to investigate the prevalence of obesity in children from 14 state primary schools in Vinhedo, Sao Paulo state. Environmental and metabolic health risk factors for obesity were investigated in a cross-sectional survey.This present study revealed 74.0% of children with obesity consumed fried foods and sweets at school, and 84.0% consumed snacks and soft drinks at home. This cohort reported to have engaged in physical activity for less than 3 hours per week at school (93.0%) and at home (85.0%). There was a high prevalence of increased waist circumference and insulin resistance among children with obesity (84.9% and 84.5%, respectively). The body mass index had a significant Spearman correlation with waist circumference, insulin resistance, and triglycerides.Childhood obesity was associated with a high prevalence of both environmental and metabolic risk factors. Also, the authors conclude that the lack of parents' awareness of childhood obesity and its risk factors represents a substantial barrier to lifestyle counseling.

Identification of insulin-regulated aminopeptidase (IRAP) in the rat pineal gland and the modulation of melatonin synthesis by angiotensin IV.

A local renin-angiotensin system (RAS) has been postulated in the pineal gland. In addition to angiotensin II (Ang II), other active metabolites have been described. In this study, we aimed to investigate a role for Ang IV in melatonin synthesis and the presence of its proposed (IRAP)/AT4 receptor (insulin-regulated aminopeptidase) in the pineal gland. The effect of Ang IV on melatonin synthesis was investigated in vitro using isolated pinealocytes. IRAP protein expression and activity were evaluated by Western blot and fluorimetry using Leu-4Me-ß-naphthylamide as a substrate. Melatonin was analyzed by HPLC, calcium content by confocal microscopy and cAMP by immunoassay. Ang IV significantly augmented the NE-induced melatonin synthesis to a similar degree as that achieved by Ang II. This Ang IV effect in pinealocytes appears to be mediated by an increase in the intracellular calcium content but not by cAMP. The (IRAP)/AT4 expression and activity were identified in the pineal gland, which were significantly higher in membrane fractions than in soluble fractions. Ang IV significantly reduced IRAP activity in the pineal membrane fractions. The main findings of the present study are as follows: (1) Ang IV potentiates NE-stimulated melatonin production in pinealocytes, (2) the (IRAP)/AT4 receptor is present in the rat pineal gland, and (3) Ang IV inhibits IRAP activity and increases pinealocytes [Ca2+]i. We conclude that Ang IV is an important component of RAS and modulates melatonin synthesis in the rat pineal gland.