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Several studies have illustrated that transcutaneous vagus nerve stimulation (tVNS) can elicit therapeutic effects that are similar to those produced by its invasive counterpart, vagus nerve stimulation (VNS). VNS is an FDA-approved therapy for the treatment of both depression and epilepsy, but it is limited to the management of more severe, intervention-resistant cases as a second or third-line treatment option due to perioperative risks involved with device implantation. In contrast, tVNS is a non-invasive technique that involves the application of electrical currents through surface electrodes at select locations, most commonly targeting the auricular branch of the vagus nerve (ABVN) and the cervical branch of the vagus nerve in the neck. Although it has been shown that tVNS elicits hypo- and hyperactivation in various regions of the brain associated with anxiety and mood regulation, the mechanism of action and influence of stimulation parameters on clinical outcomes remains predominantly hypothetical. Suppositions are largely based on correlations between the neurobiology of the vagus nerve and its effects on neural activity. However, tVNS has also been investigated for several other disorders, including tinnitus, migraine and pain, by targeting the vagus nerve at sites in both the ear and the neck. As most of the described methods differ in the parameters and protocols applied, there is currently no firm evidence on the optimal location for tVNS or the stimulation parameters that provide the greatest therapeutic effects for a specific condition. This review presents the current status of tVNS with a focus on stimulation parameters, stimulation sites, and available devices. For tVNS to reach its full potential as a non-invasive and clinically relevant therapy, it is imperative that systematic studies be undertaken to reveal the mechanism of action and optimal stimulation modalities.

Asians are predisposed to a lean heart failure (HF) phenotype. Data on the 'obesity paradox', reported in Western populations, are scarce in Asia and have only utilised the traditional classification of body mass index (BMI). We aimed to investigate the association between obesity (defined by BMI and abdominal measures) and HF outcomes in Asia. Utilising the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry (11 Asian regions including Taiwan, Hong Kong, China, India, Malaysia, Thailand, Singapore, Indonesia, Philippines, Japan, and Korea; 46 centres with enrolment between 1 October 2012 and 6 October 2016), we prospectively examined 5,964 patients with symptomatic HF (mean age 61.3 ± 13.3 years, 26% women, mean BMI 25.3 ± 5.3 kg/m2, 16% with HF with preserved ejection fraction [HFpEF; ejection fraction ≥ 50%]), among whom 2,051 also had waist-to-height ratio (WHtR) measurements (mean age 60.8 ± 12.9 years, 24% women, mean BMI 25.0 ± 5.2 kg/m2, 7% HFpEF). Patients were categorised by BMI quartiles or WHtR quartiles or 4 combined groups of BMI (low, <24.5 kg/m2 [lean], or high, ≥24.5 kg/m2 [obese]) and WHtR (low, <0.55 [thin], or high, ≥0.55 [fat]). Cox proportional hazards models were used to examine a 1-year composite outcome (HF hospitalisation or mortality). Across BMI quartiles, higher BMI was associated with lower risk of the composite outcome (ptrend < 0.001). Contrastingly, higher WHtR was associated with higher risk of the composite outcome. Individuals in the lean-fat group, with low BMI and high WHtR (13.9%), were more likely to be women (35.4%) and to be from low-income countries (47.7%) (predominantly in South/Southeast Asia), and had higher prevalence of diabetes (46%), worse quality of life scores (63.3 ± 24.2), and a higher rate of the composite outcome (51/232; 22%), compared to the other groups (p < 0.05 for all). Following multivariable adjustment, the lean-fat group had higher adjusted risk of the composite outcome (hazard ratio 1.93, 95% CI 1.17-3.18, p = 0.01), compared to the obese-thin group, with high BMI and low WHtR. Results were consistent across both HF subtypes (HFpEF and HF with reduced ejection fraction [HFrEF]; pinteraction = 0.355). Selection bias and residual confounding are potential limitations of such multinational observational registries. In this cohort of Asian patients with HF, the 'obesity paradox' is observed only when defined using BMI, with WHtR showing the opposite association with the composite outcome. Lean-fat patients, with high WHtR and low BMI, have the worst outcomes. A direct correlation between high WHtR and the composite outcome is apparent in both HFpEF and HFrEF. Asian Sudden Cardiac Death in HF (ASIAN-HF) Registry ClinicalTrials.gov Identifier: NCT01633398.

The landscape of aortic valve replacement (AVR) has evolved dramatically over the years, but time-varying outcomes have yet to be comprehensively explored. This study aimed to compare the all-cause mortality among 3 AVR techniques: transcatheter (TAVI), minimally invasive (MIAVR), and conventional AVR (CAVR). An electronic literature search was performed for randomized controlled trials (RCTs) comparing TAVI with CAVR and RCTs or propensity score-matched (PSM) studies comparing MIAVR with CAVR or MIAVR to TAVI. Individual patient data for all-cause mortality were derived from graphical reconstruction of Kaplan-Meier curves. Pairwise comparisons and network meta-analysis were conducted. Sensitivity analyses were performed in the TAVI arm for high risk and low/intermediate risk, as well as patients who underwent transfemoral (TF) TAVI. A total of 27 studies with 16,554 patients were included. In the pairwise comparisons, TAVI showed superior mortality to CAVR until 37.5 months, beyond which there was no significant difference. When restricted to TF TAVI versus CAVR, a consistent mortality benefit favoring TF TAVI was seen (shared frailty hazard ratio [HR] = 0.86, 95% confidence interval [CI] = 0.76 to 0.98, p = 0.024). In the network meta-analysis involving majority PSM data, MIAVR demonstrated significantly lower mortality than TAVI (HR = 0.70, 95% CI = 0.59 to 0.82) and CAVR (HR = 0.69, 95% CI = 0.59 to 0.80); this association remained compared with TF TAVI but with a lower extent of benefit (HR = 0.80, 95% CI = 0.65 to 0.99). In conclusion, the initial short- to medium-term mortality benefit for TAVI over CAVR was attenuated over the longer term. In the subset of patients who underwent TF TAVI, a consistent benefit was found. Among majority PSM data, MIAVR showed improved mortality compared with TAVI and CAVR but less than the TF TAVI subset, which requires validation by robust RCTs. [Display omitted]

The use of consumer-grade wearables for purposes beyond fitness tracking has not been comprehensively explored. We generated and analyzed multidimensional data from 233 normal volunteers, integrating wearable data, lifestyle questionnaires, cardiac imaging, sphingolipid profiling, and multiple clinical-grade cardiovascular and metabolic disease markers. We show that subjects can be stratified into distinct clusters based on daily activity patterns and that these clusters are marked by distinct demographic and behavioral patterns. While resting heart rates (RHRs) performed better than step counts in being associated with cardiovascular and metabolic disease markers, step counts identified relationships between physical activity and cardiac remodeling, suggesting that wearable data may play a role in reducing overdiagnosis of cardiac hypertrophy or dilatation in active individuals. Wearable-derived activity levels can be used to identify known and novel activity-modulated sphingolipids that are in turn associated with insulin sensitivity. Our findings demonstrate the potential for wearables in biomedical research and personalized health.

Comorbidities are common in patients with heart failure (HF) and complicate treatment and outcomes. We identified patterns of multimorbidity in Asian patients with HF and their association with patients' quality of life (QoL) and health outcomes. We used data on 6,480 patients with chronic HF (1,204 with preserved ejection fraction) enrolled between 1 October 2012 and 6 October 2016 in the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry. The ASIAN-HF registry is a prospective cohort study, with patients prospectively enrolled from in- and outpatient clinics from 11 Asian regions (Hong Kong, Taiwan, China, Japan, Korea, India, Malaysia, Thailand, Singapore, Indonesia, and Philippines). Latent class analysis was used to identify patterns of multimorbidity. The primary outcome was defined as a composite of all-cause mortality or HF hospitalization within 1 year. To assess differences in QoL, we used the Kansas City Cardiomyopathy Questionnaire. We identified 5 distinct multimorbidity groups: elderly/atrial fibrillation (AF) (N = 1,048; oldest, more AF), metabolic (N = 1,129; obesity, diabetes, hypertension), young (N = 1,759; youngest, low comorbidity rates, non-ischemic etiology), ischemic (N = 1,261; ischemic etiology), and lean diabetic (N = 1,283; diabetic, hypertensive, low prevalence of obesity, high prevalence of chronic kidney disease). Patients in the lean diabetic group had the worst QoL, more severe signs and symptoms of HF, and the highest rate of the primary combined outcome within 1 year (29% versus 11% in the young group) (p for all <0.001). Adjusting for confounders (demographics, New York Heart Association class, and medication) the lean diabetic (hazard ratio [HR] 1.79, 95% CI 1.46-2.22), elderly/AF (HR 1.57, 95% CI 1.26-1.96), ischemic (HR 1.51, 95% CI 1.22-1.88), and metabolic (HR 1.28, 95% CI 1.02-1.60) groups had higher rates of the primary combined outcome compared to the young group. Potential limitations include site selection and participation bias. Among Asian patients with HF, comorbidities naturally clustered in 5 distinct patterns, each differentially impacting patients' QoL and health outcomes. These data underscore the importance of studying multimorbidity in HF and the need for more comprehensive approaches in phenotyping patients with HF and multimorbidity. ClinicalTrials.gov NCT01633398.

Background Air pollution has a significant health impact. Most data originate from temperate regions. We aim to study the health impact of air pollution, particularly among the elderly, in a tropical region. Methods A daily time-series analysis was performed to estimate excess risk (ER) of various air pollutants on daily death counts amongst the general population in Singapore from 2001 to 2013. Air pollutants included particulate matters smaller than 10 μm, and 2.5 μm (PM 10 , PM 2.5 ), carbon monoxide (CO), nitrogen dioxide (NO 2 ), ozone (O 3 ) and sulphur dioxide (SO 2 ). The studied outcomes were non-accidental and cardiovascular mortality. Single-day lag and distributed lag models were studied and adjusted for confounders. Results In single-day lag models, a 10 μg/m 3 increase in particulate matter was associated with significant increases in non-accidental (PM 10 ER: 0.627%; 95% confidence interval (CI): 0.260–0.995% and PM 2.5 ER: 0.660%; 95% CI: 0.204–1.118%) and cardiovascular mortality (PM 10 ER: 0.897; 95% CI: 0.283–1.516 and PM 2.5 ER: 0.883%; 95% CI: 0.121–1.621%). This was significant in the elderly ≥ 65 years but not in those < 65 years and were seen in the acute phase of lag 0-5 days. Effects by other pollutants were minimal. For cardiovascular mortality, the effects turned protective at a cumulative lag of 30 days in the elderly and could due to “harvesting”. Conclusions These first contemporary population-based data from an equatorial country with tropical climate show that exposure to particulate air pollution was significantly associated with non-accidental mortality and cardiovascular mortality, especially in the elderly.

Recent hypertension guidelines recommend ambulatory blood pressure monitoring (ABPM) for accurate diagnosis and monitoring. However, patients' experiences with cuff and wearable ABPM devices in primary care remain unclear. This study compared the acceptance of three devices (oscillometry cuff, tonometry wrist, and photoplethysmography chest devices) among patients with hypertension in primary care. A multi-method study was conducted. Thirty-five participants with hypertension were recruited from two public primary care clinics in Singapore. All participants used cuff-based and either wrist or chest wearable devices for 24 hours. Structured surveys and in-depth audio-recorded interviews were used to gather feedback on their views, experiences, and challenges using the devices. The interviews were thematically analysed, and the surveys were analysed using descriptive statistics. All participants used the cuff (n = 35) device, while the wrist and chest devices were used by two-thirds (n = 22) and a third (n = 11) of the participants, respectively. The device usability questionnaire found that most participants were satisfied with the chest device, which did not disrupt their daily activities. Conversely, cuff arm devices interfered with daily activities (48%) and sleep (26%), were cumbersome (32%), and caused embarrassment (26%). The wrist device was uncomfortable (33%) and painful (22%) for some participants. The qualitative data were categorised into five themes: comfort, convenience, perceived accuracy, and impact on routine and sleep. Participants found the chest device more comfortable and convenient than the cuff and wrist devices. The cuff device was perceived as the most accurate due to its inflation-based BP measurement. All devices minimally affected routines and sleep, though participants expressed safety concerns about the cuff device, particularly while driving. While wearable ABPM devices offer increased comfort, convenience and reduced impact on patient's daily activities, concerns regarding their accuracy must be addressed before the widespread adoption of these devices in routine clinical practice.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a well-established risk factor for cardiovascular disease, with ethnic and regional differences noted. With the recent surge of research within this field, we re-examine the evidence associating NAFLD with subclinical atherosclerosis, and investigate potential regional differences.MethodsThis is a systematic review and meta-analysis. PubMed and EMBASE were systematically searched for publications from January 1967 to July 2020 using standardised criteria. Original, observational studies investigating the association between NAFLD and either carotid intima-media thickness (CIMT) and/or coronary artery calcification (CAC) were included. Key outcomes included differences in mean CIMT, the presence of increased CIMT, the presence of CAC and the development/progression of CAC. Pooled ORs and pooled standard differences in means were calculated using random-effects models. Between-study heterogeneity was quantified using the Q statistic and I². Subgroup analyses stratified by region of study (Asian vs Western) were also conducted.Results64 studies involving a total of 172 385 participants (67 404 with NAFLD) were included. 44 studies assessed the effect of NAFLD on CIMT, with the presence of NAFLD associated with increased CIMT (OR 2.00, 95% CI 1.56 to 2.56). 22 studies assessed the effects of NAFLD on CAC score, with the presence of NAFLD associated with the presence of any coronary calcification (OR 1.21, 95% CI 1.12 to 1.32), and the development/progression of CAC (OR 1.26, 95% CI 1.04 to 1.52). When stratified by region, these associations remained consistent across both Asian and Western populations (p>0.05). The majority (n=39) of studies were classified as ‘high quality’, with the remaining 25 of ‘moderate quality’.ConclusionsThere is a significant positive association between various measures of subclinical atherosclerosis and NAFLD, seen across both Western and Asian populations. These results re-emphasise the importance of early risk evaluation and prophylactic intervention measures to preclude progression to clinical cardiovascular disease in patients with NAFLD.

The hallmark of severe COVID-19 involves systemic cytokine storm and multi-organ injury including testicular inflammation, reduced testosterone, and germ cell depletion. The ACE2 receptor is also expressed in the resident testicular cells, however, SARS-CoV-2 infection and mechanisms of testicular injury are not fully understood. The testicular injury could be initiated by direct virus infection or exposure to systemic inflammatory mediators or viral antigens. We characterized SARS-CoV-2 infection in different human testicular 2D and 3D culture systems including primary Sertoli cells, Leydig cells, mixed seminiferous tubule cells (STC), and 3D human testicular organoids (HTO). Data shows that SARS-CoV-2 does not productively infect any testicular cell type. However, exposure of STC and HTO to inflammatory supernatant from infected airway epithelial cells and COVID-19 plasma decreased cell viability and resulted in the death of undifferentiated spermatogonia. Further, exposure to only SARS-CoV-2 Envelope protein caused inflammatory response and cytopathic effects dependent on TLR2, while Spike 1 or Nucleocapsid proteins did not. A similar trend was observed in the K18-hACE2 transgenic mice which demonstrated a disrupted tissue architecture with no evidence of virus replication in the testis that correlated with peak lung inflammation. Virus antigens including Spike 1 and Envelope proteins were also detected in the serum during the acute stage of the disease. Collectively, these data strongly suggest that testicular injury associated with SARS-CoV-2 infection is likely an indirect effect of exposure to systemic inflammation and/or SARS-CoV-2 antigens. Data also provide novel insights into the mechanism of testicular injury and could explain the clinical manifestation of testicular symptoms associated with severe COVID-19.

Consumer-grade wearable devices enable detailed recordings of heart rate and step counts in free-living conditions. Recent studies have shown that summary statistics from these wearable recordings have potential uses for longitudinal monitoring of health and disease states. However, the relationship between higher resolution physiological dynamics from wearables and known markers of health and disease remains largely uncharacterized. We aimed to derive high-resolution digital phenotypes from observational wearable recordings and to examine their associations with modifiable and inherent markers of cardiometabolic disease risk. We introduced a principled framework to extract interpretable high-resolution phenotypes from wearable data recorded in free-living conditions. The proposed framework standardizes the handling of data irregularities; encodes contextual information regarding the underlying physiological state at any given time; and generates a set of 66 minimally redundant features across active, sedentary, and sleep states. We applied our approach to a multimodal data set, from the SingHEART study (NCT02791152), which comprises heart rate and step count time series from wearables, clinical screening profiles, and whole genome sequences from 692 healthy volunteers. We used machine learning to model nonlinear relationships between the high-resolution phenotypes on the one hand and clinical or genomic risk markers for blood pressure, lipid, weight and sugar abnormalities on the other. For each risk type, we performed model comparisons based on Brier scores to assess the predictive value of high-resolution features over and beyond typical baselines. We also qualitatively characterized the wearable phenotypes for participants who had actualized clinical events. We found that the high-resolution features have higher predictive value than typical baselines for clinical markers of cardiometabolic disease risk: the best models based on high-resolution features had 17.9% and 7.36% improvement in Brier score over baselines based on age and gender and resting heart rate, respectively (P<.001 in each case). Furthermore, heart rate dynamics from different activity states contain distinct information (maximum absolute correlation coefficient of 0.15). Heart rate dynamics in sedentary states are most predictive of lipid abnormalities and obesity, whereas patterns in active states are most predictive of blood pressure abnormalities (P<.001). Moreover, in comparison with standard measures, higher resolution patterns in wearable heart rate recordings are better able to represent subtle physiological dynamics related to genomic risk for cardiometabolic disease (improvement of 11.9%-22.0% in Brier scores; P<.001). Finally, illustrative case studies reveal connections between these high-resolution phenotypes and actualized clinical events, even for borderline profiles lacking apparent cardiometabolic risk markers. High-resolution digital phenotypes recorded by consumer wearables in free-living states have the potential to enhance the prediction of cardiometabolic disease risk and could enable more proactive and personalized health management.