Mental health and the effects on methylation of stress-related genes in front-line versus other health care professionals during the second wave of COVID-19 pandemic: an Italian pilot study.

Healthcare workers experienced high degree of stress during COVID-19. Purpose of the present article is to compare mental health (depressive and Post-Traumatic-Stress-Disorders-PTSD-symptoms) and epigenetics aspects (degree of methylation of stress-related genes) in front-line healthcare professionals versus healthcare working in non-COVID-19 wards. Sixty-eight healthcare workers were included in the study: 39 were working in COVID-19 wards (cases) and 29 in non-COVID wards (controls). From all participants, demographic and clinical information were collected by an ad-hoc questionnaire. Depressive and PTSD symptoms were evaluated by the Patient Health Questionnaire-9 (PHQ-9) and the Impact of Event Scale-Revised (IES-R), respectively. Methylation analyses of 9 promoter/regulatory regions of genes known to be implicated in depression/PTSD (ADCYAP1, BDNF, CRHR1, DRD2, IGF2, LSD1/KDM1A, NR3C1, OXTR, SLC6A4) were performed on DNA from blood samples by the MassARRAY EpiTYPER platform, with MassCleave settings. Controls showed more frequent lifetime history of anxiety/depression with respect to cases (χ2 = 5.72, p = 0.03). On the contrary, cases versus controls presented higher PHQ-9 (t = 2.13, p = 0.04), PHQ-9 sleep item (t = 2.26, p = 0.03), IES-R total (t = 2.17, p = 0.03), IES-R intrusion (t = 2.46, p = 0.02), IES-R avoidance (t = 1.99, p = 0.05) mean total scores. Methylation levels at CRHR1, DRD2 and LSD1 genes was significantly higher in cases with respect to controls (p < 0.01, p = 0.03 and p = 0.03, respectively). Frontline health professionals experienced more negative effects on mental health during COVID-19 pandemic than non-frontline healthcare workers. Methylation levels were increased in genes regulating HPA axis (CRHR1) and dopamine neurotransmission (DRD2 and LSD1), thus supporting the involvement of these biological processes in depression/PTSD and indicating that methylation of these genes can be modulated by stress conditions, such as working as healthcare front-line during COVID-19 pandemic.

The Interplay between Autonomic Nervous System and Inflammation across Systemic Autoimmune Diseases.

The autonomic nervous system (ANS) and the immune system are deeply interrelated. The ANS regulates both innate and adaptive immunity through the sympathetic and parasympathetic branches, and an imbalance in this system can determine an altered inflammatory response as typically observed in chronic conditions such as systemic autoimmune diseases. Rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis all show a dysfunction of the ANS that is mutually related to the increase in inflammation and cardiovascular risk. Moreover, an interaction between ANS and the gut microbiota has direct effects on inflammation homeostasis. Recently vagal stimulation techniques have emerged as an unprecedented possibility to reduce ANS dysfunction, especially in chronic diseases characterized by pain and a decreased quality of life as well as in chronic inflammation.

Targeting the Autonomic Nervous System for Risk Stratification, Outcome Prediction and Neuromodulation in Ischemic Stroke.

Ischemic stroke is a worldwide major cause of mortality and disability and has high costs in terms of health-related quality of life and expectancy as well as of social healthcare resources. In recent years, starting from the bidirectional relationship between autonomic nervous system (ANS) dysfunction and acute ischemic stroke (AIS), researchers have identified prognostic factors for risk stratification, prognosis of mid-term outcomes and response to recanalization therapy. In particular, the evaluation of the ANS function through the analysis of heart rate variability (HRV) appears to be a promising non-invasive and reliable tool for the management of patients with AIS. Furthermore, preclinical molecular studies on the pathophysiological mechanisms underlying the onset and progression of stroke damage have shown an extensive overlap with the activity of the vagus nerve. Evidence from the application of vagus nerve stimulation (VNS) on animal models of AIS and on patients with chronic ischemic stroke has highlighted the surprising therapeutic possibilities of neuromodulation. Preclinical molecular studies highlighted that the neuroprotective action of VNS results from anti-inflammatory, antioxidant and antiapoptotic mechanisms mediated by α7 nicotinic acetylcholine receptor. Given the proven safety of non-invasive VNS in the subacute phase, the ease of its use and its possible beneficial effect in hemorrhagic stroke as well, human studies with transcutaneous VNS should be less challenging than protocols that involve invasive VNS and could be the proof of concept that neuromodulation represents the very first therapeutic approach in the ultra-early management of stroke.

Cardiac autonomic dynamics during sleep are lost in patients with TIA and stroke.

Ischaemic stroke is accompanied by important alterations of cardiac autonomic control, which have an impact on stroke outcome. In sleep, cardiac autonomic control oscillates with a predominant sympathetic modulation during REM sleep. We aimed to assess cardiac autonomic control in different sleep stages in patients with ischaemic stroke. Forty-five patients enrolled in the prospective, multicentre SAS-CARE study but without significant sleep-disordered breathing (apnea-hypopnea index < 15/hr) and without atrial fibrillation were included in this analysis. The mean age was 56 years, 68% were male, 76% had a stroke (n = 34, mean National Institutes of Health Stroke Scale [NIHSS] score of 5, 11 involving the insula) and 24% (n = 11) had a transitory ischaemic attack. Cardiac autonomic control was evaluated using three different tools (spectral, symbolic and entropy analysis) according to sleep stages on short segments of 250 beats in all patients. Polysomnographic studies were performed within 7 days and 3 months after the ischaemic event. No significant differences in cardiac autonomic control between sleep stages were observed in the acute phase and after 3 months. Predominant vagal modulation and decreased sympathetic modulation were observed across all sleep stages in ischaemic stroke involving the insula. Patients with ischaemic stroke and transitory ischaemic attack present a loss of cardiac autonomic dynamics during sleep in the first 3 months after the ischaemic event. This change could represent an adaptive phenomenon, protecting the cardiovascular system from the instabilities of autonomic control, or a risk factor for stroke, which precedes the ischaemic event.

Particulate Air Pollution, Clock Gene Methylation, and Stroke: Effects on Stroke Severity and Disability.

Circadian rhythm disturbances have been consistently associated with the development of several diseases, particularly cardiovascular diseases (CVDs). A central clock in the brain maintains the daily rhythm in accordance with the external environment. At the molecular level, the clock is maintained by "clock genes", the regulation of which is mainly due to DNA methylation, a molecular mechanism of gene expression regulation, able to react to and be reprogrammed by environmental exposure such as exposure to particulate matter (PM). In 55 patients with a diagnosis of acute ischemic stroke, we showed that PM2.5 exposure experienced before the event influenced clock genes methylation (i.e., circadian locomotor output cycles protein kaput CLOCK, period 2 PER2, cryprochrome 1 CRY1, Neuronal PAS Domain Protein 2 NPAS2), possibly modulating the patient prognosis after the event, as cryptochrome 1 CRY1 and period 1 PER1 methylation levels were associated with the Rankin score. Moreover, if PM2.5 annual average was low, CRY1/CRY2 methylation levels were positively associated with the National Institutes of Health Stroke Scale (NIHSS) score, whereas they were negatively associated if PM2.5 exposure was high. Whether epigenetic changes in clock genes need to be considered as a prognostic marker of stroke or rather a causal agent in stroke development remains to be determined. Further studies are needed to determine the role of clock gene methylation in regulating the response to and recovery after a stroke event.

Acute particulate matter affects cardiovascular autonomic modulation and IFN-γ methylation in healthy volunteers.

AIMS: Air particulate matter (PM) is associated with increased cardiovascular morbidity and mortality. Altered autonomic functions play a key role in PM-induced cardiovascular disease. However, previous studies have not address the impact of PM on sympathetic and parasympathetic control of heart function, independently, and using controlled conditions, i.e., increasing titration of PM of known composition, in absence of other potential confounding factors. To fill this gap, here we used symbolic analysis that is capable of detecting non-mutual changes of the two autonomic branches, thus considering them as independent, and concentrations of PM as they could be measured at peak levels in Milan during a polluted winter day. METHODS AND RESULTS: In this randomized, cross-over study, we enrolled 12 healthy subjects who underwent two random sessions: inhalation of filtered air mixture or inhalation of filtered air containing particulate mixture (PM 10, PM 2.5, PM 1.0 and PM 0.5µm). ECG and respiration for autonomic analysis and blood sample for DNA Methylation were collected at baseline (T1), after air exposure (T2) and after 2h (T3). Spectral and symbolic analysis of heart rate variability (HRV) were performed for autonomic control of cardiac function, while alterations in DNA methylation of candidate genes were used to index pro-inflammatory modifications. In the PM expose group, autonomic analysis revealed a significant decrease of 2UV%, index of parasympathetic modulation (14% vs 9%, p = 0.0309), while DNA analysis showed a significant increase of interferon γ (IFN- γ) methylation, from T1 to T3. In a mixed model using T1, T2 and T3, fine and ultrafine PM fractions showed significant associations with IFN- γ methylation and parasympathetic modulation. CONCLUSIONS: Our study shows, for the first time, that in healthy subjects, acute exposure to PM affects parasympathetic control of heart function and it increases methylation of a pro-inflammatory gene (i.e. methylation of interferon γ). Thus, our study suggests that, even in absence of other co-factors and in otherwise healthy individuals, PM per se is sufficient to trigger parasympathetic dysautonomia, independently from changes in sympathetic control, and inflammation, in a dose-dependent manner.

Individualizing duration of antibiotic therapy in community-acquired pneumonia.

International experts suggest tailoring antibiotic duration in community-acquired pneumonia (CAP) according to patients' characteristics. We aimed to assess the effectiveness of an individualized approach to antibiotic duration based on time in which CAP patients reach clinical stability during hospitalization. In a multicenter, non-inferiority, randomized, controlled trial hospitalized adult patients with CAP reaching clinical stability within 5 days after hospitalization were randomized to a standard vs. individualized antibiotic duration. In the Individualized group, antibiotics were discontinued 48 h after the patient reached clinical stability, with at least five days of total antibiotic treatment. Early failure within 30 days was the primary composite outcome. 135 patients were randomized to the Standard group and 125 to the Individualized group. The trial was interrupted by the safety committee because of an apparent inferiority of the Individualized group over the Standard treatment: 14 (11.2%) patients in the Individualized group experienced early failure vs. 10 (7.4%) patients in the Standard group, p = 0.200, at the intention-to-treat analysis. 30-day mortality rate was four-time higher in the Individualized group than the Standard group. Shortening antibiotic duration according to patients' characteristics still remains an open question.

Captopril does not Potentiate Post-Exercise Hypotension: A Randomized Crossover Study.

To evaluate whether captopril (3×50 mg/day) potentiates post-resistance exercise hypotension (PREH) in hypertensives (HT), 12 HT men received captopril and placebo for 4 weeks each in a double-blinded, randomized-crossover design. On each therapy, subjects underwent 2 sessions: Control (C - rest) and Resistance Exercise (RE - 7 exercises, 3 sets to moderate fatigue, 50% of 1 RM -repetition maximum). Measurements were taken before and after 30-60 min (Post1) and 7 h (Post2), and ambulatory blood pressure (BP) was monitored for 24 h. There were no differences in PREH characteristics and mechanisms between the placebo and captopril periods. At Post1, systolic/diastolic BP decreased significantly and similarly after RE with both therapies (Placebo=-13±2/-9±1 mmHg vs. Captopril=-12±2/-10±1 mmHg, P<0.05). RE reduced cardiac output in some subjects and systemic vascular resistance in others. Heart rate and cardiac sympathetic modulation increased, while stroke volume and baroreflex sensitivity decreased after RE (Placebo: +13±2 bpm, +21±5 nu, -11±5 ml, -4±2 ms/mmHg; Captopril: +13±2 bpm, +35±4 nu, 17±5 ml, -3±1 ms/mmHg, P<0.05). At Post2, all variables returned to pre-intervention values. Ambulatory BP was similar between the sessions. Thus, captopril did not potentiate the magnitude and duration of PREH in HT men, and it did not influence PREH mechanisms.

Obstructive Sleep Apnea Syndrome (OSAS) and Cardiovascular System.

There is increasing evidence of a relationship between Obstructive Sleep Apnea (OSA) and cardiovascular diseases. The strong association between OSA and arterial hypertension, in particular in patients with resistant hypertension and/or a non-dipping profile, has been extensively reported. The relationship between OSA and high blood pressure (BP) has been found independent from a number of confounders, but several factors may affect this relationship, including age and sex. It is thus important to better assess pathophysiologic and clinical interactions between OSA and arterial hypertension, also aimed at optimizing treatment approaches in OSA and hypertensive patients with co-morbidities. Among possible mechanisms, cardiovascular autonomic control alterations, altered mechanics of ventilation, inflammation, endothelial dysfunction, and renin-angiotensin-aldosterone system should be considered with particular attention. Additionally, available studies also support the occurrence of a bidirectional association between OSA and cardiovascular alterations, in particular heart failure, stroke and cardiac arrhythmias, emphasizing that greater attention is needed to both identify and treat sleep apneas in patients with cardiovascular diseases. However, a number of aspects of such a relationship are still to be clarified, in particular with regard to gender differences, effect of sleep-related breathing disorders in childhood, and influence of OSA treatment on cardiovascular risk, and they may represent important targets for future studies.

Cardiovascular autonomic alterations in hospitalized patients with community-acquired pneumonia.

BACKGROUND: Alterations of cardiac autonomic control (CAC) are associated with poor outcomes in patients with infectious and non-infectious diseases. No evaluation of CAC in patients with community-acquired pneumonia (CAP) has been performed so far. The aim of the study was to assess CAC in patients with CAP and evaluate the impact of its alterations on disease severity and clinical outcomes in a multicenter, prospective, observational study. METHODS: Consecutive patients hospitalized for CAP were enrolled between 2011 and 2013 two university hospitals in Italy. CAC was assessed by linear spectral and non-linear symbolic analysis of heart rate variability. The presence of severe CAP was evaluated on hospital admission. The primary study outcome was time to clinical stability (TCS) during hospitalization. RESULTS: Among the 75 patients enrolled (median age: 75 years; 57 % males), a significantly lower total variability and reduction of sympathetic rhythmical component with predominant respiratory modulation was detected in comparison to controls. Among CAP patients affected by a severe CAP on admission, CAC showed a lower sympathetic modulation and predominant parasympathetic oscillatory rhythm. At the multivariate analysis, variables independently correlated with a TCS >7 days were total power, as marker of total variability, [OR (95 % CI): 0.997 (0.994-1.000), p = 0.0454] and sympathetic modulation [OR (95 % CI): 0.964 (0.932-0.998), p = 0.0367]. CONCLUSIONS: Loss of sympathetic rhythmical oscillation is associated with a more severe disease and worse early clinical outcome in hospitalized patients with CAP.

Predominant cardiac sympathetic modulation during wake and sleep in patients with Rett syndrome.

BACKGROUND: Rett syndrome (RTT) is a rare neurological disorder primarily associated with mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The syndrome is characterized by cognitive, social, and physical impairments, as well as sleep disorders and epilepsy. Notably, dysfunction of the autonomic nervous system is a key feature of the syndrome. Although Heart Rate Variability (HRV) has been used to investigate autonomic nervous system dysfunction in RTT during wakefulness, there is still a significant lack of information regarding the same during sleep. Therefore, our aim was to investigate cardiovascular autonomic modulation during sleep in subjects with RTT compared to an age-matched healthy control group (HC). METHOD: A complete overnight polysomnographic (PSG) recording was obtained from 11 patients with Rett syndrome (all females, 10 ± 4 years old) and 11 HC (all females, 11 ± 4 years old; p = 0.48). Electrocardiogram and breathing data were extracted from PSG and divided into wake, non-REM, and REM sleep stages. Cardiac autonomic control was assessed using symbolic non-linear heart rate variability analysis. The symbolic analysis identified three patterns: 0 V% (sympathetic), 2UV%, and 2LV% (vagal). RESULTS: The 0 V% was higher in the RTT group than in the HC group during wake, non-REM, and REM stages (p < 0.01), while the 2LV and 2UV% were lower during wake and sleep stages (p < 0.01). However, the 0 V% increased similarly from the wake to the REM stage in both RTT and HC groups. CONCLUSIONS: Therefore, the sympatho-vagal balance shifted towards sympathetic predominance and vagal withdrawal during wake and sleep in RTT, although cardiac autonomic dynamics were preserved during sleep.

The influence of inflammation and frailty in the aging continuum.

Inflammaging is a low-grade inflammatory state that can be considered an adaptive process aimed at stimulating appropriate anti-inflammatory response. Frailty is determined by the accumulation of molecular and cellular defects accumulated throughout life; therefore, an appropriate frailty computation could be a valuable tool for measuring biological age. This study aims to analyse the association between inflammatory markers and both chronological age "per se" and frailty. We studied 452 persons aged 43-114 years. A Frailty Index (FI) was computed considering a wide range of age-related signs, symptoms, disabilities, and diseases. Plasma concentrations of inflammatory cytokines and peripheral markers of neuroinflammation were analysed by next-generation ELISA. The mean age of the cohort was 79.7 (from 43 to 114) years and the median FI was 0.19 (from 0.00 to 0.75). The concentrations of most inflammatory markers increased significantly with chronological age, after adjustment for sex and FI. Interferon-γ was significantly affected only by FI, while interleukin (IL)-10 and IL-1ß were associated only with chronological age. In conclusion, we described different associations between inflammatory components and chronological vs. biological age. A better characterization of the molecular signature of aging could help to understand the complexity of this process.

The environmental cost of unwarranted variation in the use of magnetic resonance imaging and computed tomography scans.

BACKGROUND: Pollution is a major threat to global health, and there is growing interest on strategies to reduce emissions caused by health care systems. Unwarranted clinical variation, i.e. variation in the utilization of health services unexplained by differences in patient illness or preferences, may be an avoidable source of CO2 when related to overuse. Our objective was to evaluate the CO2 emissions attributable to unwarranted variation in the use of MRI and CT scans among countries of the G20-area. METHODS: We selected seven countries of the G20-area with available data on the use of CT and MRI scans from the organization for Economic Co-operation and Development repository. Each nation's annual electric energy expenditure per 1000 inhabitants for such exams (T-Enex-1000) was calculated and compared with the median and lowest value. Based on such differences we estimated the national energy and corresponding tons of CO2 that could be potentially avoided each year. RESULTS: With available data we found a significant variation in T-Enex-1000 (median value 1782 kWh, range 1200-3079 kWh) and estimated a significant amount of potentially avoidable emissions each year (range 2046-175120 tons of CO2). In practical terms such emissions would need, in the case of Germany, 71900 and 104210 acres of forest to be cleared from the atmosphere, which is 1.2 and 1.7 times the size of the largest German forest (Bavarian National Forest). CONCLUSION: Among countries with a similar rate of development, unwarranted clinical variation in the use of MRI and CT scan causes significant emissions of CO2.

Social Isolation: A Narrative Review on the Dangerous Liaison between the Autonomic Nervous System and Inflammation.

Social isolation and feelings of loneliness are related to higher mortality and morbidity. Evidence from studies conducted during space missions, in space analogs, and during the COVID-19 pandemic underline the possible role of the autonomic nervous system in mediating this relation. Indeed, the activation of the sympathetic branch of the autonomic nervous system enhances the cardiovascular response and activates the transcription of pro-inflammatory genes, which leads to a stimulation of inflammatory activation. This response is adaptive in the short term, in that it allows one to cope with a situation perceived as a threat, but in the long term it has detrimental effects on mental and physical health, leading to mood deflection and an increased risk of cardiovascular disease, as well as imbalances in immune system activation. The aim of this narrative review is to present the contributions from space studies and insights from the lockdown period on the relationship between social isolation and autonomic nervous system activation, focusing on cardiovascular impairment and immune imbalance. Knowing the pathophysiological mechanisms underlying this relationship is important as it enables us to structure effective countermeasures for the new challenges that lie ahead: the lengthening of space missions and Mars exploration, the specter of future pandemics, and the aging of the population.

An unusual case of pleural effusion.

CASE PRESENTATION: A 63-year-old man presented with fever, thoracalgia, weight loss, diffuse lymphadenopathy, and a massive pleural effusion. Extensive laboratory and radiologic investigations for possible autoimmune, infectious, hematologic, and neoplastic conditions all resulted negative. A lymph node biopsy showed a granulomatous necrotizing lymphadenitis, suspicious for tuberculosis. Although mycobacterium tuberculosis (MT) was never isolated and tuberculin skin test resulted negative, diagnosis of extrapulmonary tuberculosis was made and anti-tubercular therapy was started. Despite the strict adherence to 5 months of treatment, he returned to the emergency ward complaining of fever, chest pain and pleural effusion; total-body CT and PET scans demonstrated a progression of new disseminated nodular consolidations. DIAGNOSTIC WORK-UP: Microscopic and cultural search for MT and other micro-organisms resulted again negative on urine, stool, blood, pleural fluid, and spinal lesion biopsy. We therefore started considering alternative diagnosis for necrotizing granulomatosis, including multidrug-resistant tuberculosis, Wegener granulomatosis, Churg Strauss syndrome, necrobiotic nodules of rheumatoid arthritis, lymphomatoid granulomatosis and Necrotizing Sarcoid Granulomatosis (NSG). Having already rejected other autoimmune, hematological, and neoplastic disorders, NSG resulted the most consistent hypothesis. With an expert we thus re-examined histological specimens that were suggestive for an atypical presentation of sarcoidosis. Steroid therapy was initiated, achieving symptoms improvement. DISCUSSION: Sarcoidosis is a rare condition that can be challenging to diagnose, due to its variability in clinical presentation, often mimicking alternative conditions like disseminated tuberculosis. A high degree of suspicion and an experienced lab in anatomical pathology are essential for final diagnosis.

Advances in Non-Invasive Neuromodulation: Designing Closed-Loop Devices for Respiratory-Controlled Transcutaneous Vagus Nerve Stimulation.

Studies suggest non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) as a potential therapeutic option for various pathological conditions, such as epilepsy and depression. Exhalation-controlled taVNS, which synchronizes stimulation with internal body rhythms, holds promise for enhanced neuromodulation, but there is no closed-loop system in the literature capable of performing such integration in real time. In this context, the objective was to develop real-time signal processing techniques and an integrated closed-loop device with sensors to acquire physiological data. After a conditioning stage, the signal is processed and delivers synchronized electrical stimulation during the patient's expiratory phase. Additional modules were designed for processing, software-controlled selectors, remote and autonomous operation, improved analysis, and graphical visualization. The signal processing method effectively extracted respiratory cycles and successfully attenuated signal noise. Heart rate variability was assessed in real time, using linear statistical evaluation. The prototype feedback stimulator device was physically constructed. Respiratory peak detection achieved an accuracy of 90%, and the real-time processing resulted in a small delay of up to 150 ms in the detection of the expiratory phase. Thus, preliminary results show promising accuracy, indicating the need for additional tests to optimize real-time processing and the application of the prototype in clinical studies.

Transcutaneous auricular branch vagal nerve stimulation as a non-invasive add-on therapeutic approach for pain in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is an autoimmune disease with health-related quality of life (HRQoL) high impairment. Pain is of paramount importance to be targeted by therapeutical approaches. Our study aim was to perform an add-on device-based non-invasive neuromodulatory treatment through transcutaneous auricular vagal nerve stimulation (tVNS) in patients with SSc, assessing its effects on pain as primary endpoint and on inflammation, cardiovascular autonomic control and HRQoL. METHODS: Thirty-two patients with SSc were enrolled based on reported pain assessed through Numeric Rating Scale (NRS). Twenty-one (90% with limited cutaneous SSc) completed a randomised, cross-over, patient-blind trial, in which interventional and active control were used in random order for 4 weeks, interspersed with 4 weeks washout. NRS, Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) Item4 for pain interference, heart rate variability (HRV), serum cytokines and HRQoL questionnaires (Health Assessment Questionnaire, Patient Health Questionnaire-9, University of California, Los Angeles Gastrointestinal Tract, Pittsburgh Sleep Quality Index) were assessed at baseline, at T1 (after 1 month of tVNS or active control), at T2 (after washout) and at T3 (after 1 month of active control or tVNS). T-test for paired data and Wilcoxon signed-rank test for non-normally distributed parameters were performed to compare the effect of tVNS and active control. RESULTS: NRS pain was significantly reduced by tVNS and not by active control (Mean±SD: -27.7%±21.3% vs -7.7%±26.3%, p=0.002). Interleukin-6 was downregulated in tVNS versus active control (p=0.029). No significant differences were observed in tVNS versus active control for PROMIS-29 Item4, QoL scales and HRV with both spectral and symbolic analyses. CONCLUSION: tVNS demonstrated to be a safe and non-invasive add-on tool to reduce pain in SSc.

Remdesivir-induced bradycardia in patients hospitalized with SARS-CoV2 infection: a possible vagally-mediated mechanism.

Recently, case series studies on patients with SARS-CoV-2 infection reported an association between remdesivir (RDV) administration and incidental bradycardia. However, the phenomenon has not yet been described in detail. We conducted a retrospective case-control study to evaluate the occurrence of RDV-related bradycardia in patients hospitalized for SARS-CoV2 pneumoniae. We retrospectively evaluated 71 patients, hospitalized in six internal medicine wards of the Milan area, affected by mild-to-moderate COVID-19 who received RDV (RDV group) and 54 controls, matched for sex, age and disease severity on admission (CTR group). The mean heart rate value recorded during the first two days of hospitalization was considered as baseline heart rate (HRb). Heart rate values relative to the 5-days treatment and the 5-days post-treatment were extracted for RDV group, while heart rate values relative to 10 days of hospitalization were considered for the CTR group. ΔHR values were calculated as maximum HR drop versus HRb. Possible associations between ΔHR and clinical-demographic factors were assessed through regression analysis. The RDV group experienced a significantly higher incidence of bradycardia compared to the CTR group (56% vs 33%, OR 2.6, 95% CI 1.2-5.4, p value = 0.011). Moreover, the RDV group showed higher ΔHR values than the CTR group. The HR progressively decreased with daily administration of RDV, reaching the maximun drop on day six (-8.6±1.9 bpm). In RDV group, patients who experienced bradycardia had higher drop in HR, higher alanine aminotransferase (ALT) values at the baseline (bALT) and during the RDV administration period. ΔHR was positively associated with HRb (ß = 0.772, p < 0.001) and bALT (ß = 0.245, p = 0.005). In conclusion, our results confirmed a significant association between RDV administration and development of bradycardia. This effect was proportional to baseline HR and was associated with higher levels of baseline ALT, suggesting a possible interaction between RDV liver metabolism and a vagally-mediated effect on HR due to increased availability of RDV metabolites.

Cardiovascular autonomic modulation during passive heating protocols: a systematic review.

Objective.To conduct a systematic review of the possible effects of passive heating protocols on cardiovascular autonomic control in healthy individuals.Approach.The studies were obtained from MEDLINE (PubMed), LILACS (BVS), EUROPE PMC (PMC), and SCOPUS databases, simultaneously. Studies were considered eligible if they employed passive heating protocols and investigated cardiovascular autonomic control by spontaneous methods, such as heart rate variability (HRV), systolic blood pressure variability (SBPV), and baroreflex sensitivity (BRS), in healthy adults. The revised Cochrane risk-of-bias tool (RoB-2) was used to assess the risk of bias in each study.Main results.Twenty-seven studies were included in the qualitative synthesis. Whole-body heating protocols caused a reduction in cardiac vagal modulation in 14 studies, and two studies reported both increased sympathetic modulation and vagal withdrawal. Contrariwise, local-heating protocols and sauna bathing seem to increase cardiac vagal modulation. A reduction of BRS was reported in most of the studies that used whole-body heating protocols. However, heating effects on BRS remain controversial due to methodological differences among baroreflex analysis and heating protocols.Significance.Whole-body heat stress may increase sympathetic and reduce vagal modulation to the heart in healthy adults. On the other hand, local-heating therapy and sauna bathing seem to increase cardiac vagal modulation, opposing sympathetic modulation. Nonetheless, further studies should investigate acute and chronic effects of thermal therapy on cardiovascular autonomic control.