The large class of adhesion G protein-coupled receptors (aGPCRs) bind extracellular matrix or neighboring cell-surface ligands to regulate organ and tissue development through an unknown activation mechanism. We examined aGPCR activation using two prototypical aGPCRs, GPR56 and GPR110. Active dissociation of the noncovalently bound GPR56 or GPR110 extracellular domains (ECDs) from the respective seven-transmembrane (7TM) domains relieved an inhibitory influence and permitted both receptors to activate defined G protein subtypes. After ECD displacement, the newly revealed short N-terminal stalk regions of the 7TM domains were found to be essential for G protein activation. Synthetic peptides comprising these stalks potently activated GPR56 or GPR110 in vitro or in cells, demonstrating that the stalks comprise a tethered agonist that was encrypted within the ECD. Establishment of an aGPCR activation mechanism provides a rational platform for the development of aGPCR synthetic modulators that could find clinical utility toward aGPCR-directed disease.

We describe a rapid method to probe for mutations in cell-surface ligand-binding proteins that affect the environment of bound ligand. The method uses fluorescence activated cell sorting to screen randomly-mutated receptors for substitutions that alter the fluorescence emission spectrum of environmentally-sensitive fluorescent ligands. When applied to the yeast α-factor receptor Ste2p, a G protein coupled receptor, the procedure identified 22 substitutions that red-shift the emission of a fluorescent agonist, including substitutions at residues previously implicated in ligand binding and at additional sites. A separate set of substitutions, identified in a screen for mutations that alter the emission of a fluorescent α-factor antagonist, occurs at sites that are unlikely to directly contact the ligand. Instead, they alter receptor conformation to increase ligand-binding affinity and provide signaling in response to antagonists of normal receptors. These results suggest that receptor-agonist interactions involve at least two sites, of which only one is specific for the receptor’s activated conformation.

Background The Pfizer-BioNTech COVID-19 vaccine uses a novel messenger RNA technology to elicit a protective immune response. Short-term physiologic responses to the vaccine have not been studied using wearable devices. Objective We aim to characterize physiologic changes in response to COVID-19 vaccination in a small cohort of participants using a wearable device (WHOOP Strap 3.0). This is a proof of concept for using consumer-grade wearable devices to monitor response to COVID-19 vaccines. Methods In this prospective observational study, physiologic data from 19 internal medicine residents at a single institution that received both doses of the Pfizer-BioNTech COVID-19 vaccine was collected using the WHOOP Strap 3.0. The primary outcomes were percent change from baseline in heart rate variability (HRV), resting heart rate (RHR), and respiratory rate (RR). Secondary outcomes were percent change from baseline in total, rapid eye movement, and deep sleep. Exploratory outcomes included local and systemic reactogenicity following each dose and prophylactic analgesic use. Results In 19 individuals (mean age 28.8, SD 2.2 years; n=10, 53% female), HRV was decreased on day 1 following administration of the first vaccine dose (mean –13.44%, SD 13.62%) and second vaccine dose (mean –9.25%, SD 22.6%). RHR and RR showed no change from baseline after either vaccine dose. Sleep duration was increased up to 4 days post vaccination, after an initial decrease on day 1. Increased sleep duration prior to vaccination was associated with a greater change in HRV. Local and systemic reactogenicity was more severe after dose two. Conclusions This is the first observational study of the physiologic response to any of the novel COVID-19 vaccines as measured using wearable devices. Using this relatively small healthy cohort, we provide evidence that HRV decreases in response to both vaccine doses, with no significant changes in RHR or RR. Sleep duration initially decreased following each dose with a subsequent increase thereafter. Future studies with a larger sample size and comparison to other inflammatory and immune biomarkers such as antibody response will be needed to determine the true utility of this type of continuous wearable monitoring in regards to vaccine responses. Our data raises the possibility that increased sleep prior to vaccination may impact physiologic responses and may be a modifiable way to increase vaccine response. These results may inform future studies using wearables for monitoring vaccine responses. Trial Registration ClinicalTrials.gov NCT04304703; https://www.clinicaltrials.gov/ct2/show/NCT04304703

In heart failure (HF) patients, remote monitoring using implantable devices may be used to predict and reduce HF exacerbations and mortality. Data from randomized controlled trials (RCTs) was assessed to determine the effectiveness of implantable remote monitoring on the improvement of outcomes in HF patients. A systematic review and meta-analysis of RCTs testing remote monitoring versus standard of care for management of HF patients was performed. Primary endpoints were all-cause mortality and a composite of cardiovascular (CV) and HF hospitalizations. Rate ratios (RRs) and 95% confidence intervals (CI) were calculated. A secondary analysis tested for heterogeneity of treatment effect (HTE) comparing right ventricular/pulmonary pressure monitoring versus impedance-based monitoring on hospitalization. A regression analysis was performed using the mean follow-up time as the moderator on each primary endpoint. Eleven RCTs (n = 6196) were identified with a mean follow-up of 21.9 months. The mean age and reported ejection fraction were 64.1 years and 27.7%, respectively. Remote monitoring did not reduce mortality (RR 0.89 [95% CI 0.77, 1.03]) or the composite of CV and HF hospitalizations (RR 0.98 [0.81, 1.19]). Subgroup analysis found significant HTE for hospitalizations between those studies that used right ventricular/pulmonary pressure monitoring versus impedance-based monitoring (I 2 = 87.1%, chi 2 = 7.75, p = 0.005). Regression analysis found no relationship between the log rate ratio of remote monitoring's effect on mortality, CV hospitalization or HF hospitalization, and mean follow-up time. Compared to standard of care, remote monitoring using implantable devices did not reduce mortality, CV, or HF hospitalizations. However, right ventricular/pulmonary pressure monitoring may reduce HF hospitalizations, which will need to be explored in future studies. Keywords Heart failure • Remote monitoring • Implantable devices • Systematic review • Meta-analysis • Randomized controlled trials Abbreviations HF Heart failure CV Cardiovascular RCT Randomized controlled trial CRT-D Cardiac resynchronization therapy defibrillator ICD Implantable cardioverter-defibrillator Highlights • Standard of care in heart failure outpatient monitoring is centered on patient-reported symptoms. • New methods of monitoring physiologic markers with implantable devices such as cardiac resynchronization therapy device and pulmonary artery pressure sensors have been developed. • Several randomized controlled trials (RCTs) have been conducted examining whether use of remote monitoring has an effect on mortality and hospitalizations. • This systematic review and meta-analysis examined 11 RCTs and showed no significant effect with implantable remote monitoring on mortality, heart failure (HF) hospitalizations, or cardiovascular hospitalizations when compared to standard of care. • A decrease in HF hospitalizations was observed in RCTs using implantable continuous cardiac/pulmonary artery pressure monitoring compared to thoracic impedance-based m...

Atrial fibrillation (AF) in patients with cardiac amyloidosis (CA) has been linked with a worse prognosis. The current study aimed to determine the outcomes of AF catheter ablation in patients with CA. The National Readmission Database (NRD) 2015-2019 was used to identify patients with AF and concomitant heart failure (HF). Among these, patients who underwent catheter ablation were classified into two groups, patients with and without CA. The adjusted odds ratio (aOR) of index-admission and 30-day readmission outcomes were calculated using a propensity score matched (PSM) analysis. A total of 148,134 patients with AF undergoing catheter ablation were identified on crude analysis. Using PSM analysis, 616 patients (293 CA-AF, 323 no-CA-AF) were selected based on a balanced distribution of baseline comorbidities. At index admission, AF ablation in patients with CA was associated with significantly higher adjusted odds of net adverse clinical events (NACE) (aOR 4.21, 95% CI 1.7-5.20), in-hospital mortality (aOR 9.03, 95% CI 1.12-72.70), and pericardial effusion (aOR 3.30, 95% CI 1.57-6.93) compared with non-CA AF. There was no significant difference in the odds of stroke, cardiac tamponade, and major bleeding between the two groups. At 30-day readmission, the incidence of NACE, and mortality remained high in patients undergoing AF ablation in CA. Compared with non-CA, AF ablation in CA patients is associated with relatively higher in-hospital all-cause mortality and net adverse events both at index admission and up to 30-day follow-up.