A practical guide for selecting continuous monitoring wearable devices for community-dwelling adults.

Importance: The burgeoning landscape of wearable devices warrants a guide for the selection of devices. Existing guidelines and recommendations provide evaluation frameworks with theoretical principles but tend to lack a pragmatic application and systematic approach for device selection. While fitness trackers exemplify the convenience of wearable technologies, their selection for specific health monitoring purposes demands a nuanced understanding of varying functionalities and user compatibilities. Objective: The objective is to develop and present a practical guide for researchers, healthcare professionals, and device users to systematically select wearable devices for continuous monitoring in community-dwelling adults. Methods & results: Based on diverse sources, such as the United States Food and Drug Administration (FDA), the Clinical Trials Transformation Initiative (CTTI), the Electronic Patient-Reported Outcome (ePRO) Consortium, and comparative analyses of wearable technology performances from feasibility and usability studies, the guide incorporates five core criteria: continuous monitoring capability, device availability and suitability, technical performance (accuracy and precision), feasibility of use, and cost evaluation. The structured criteria can be applied in device selection as well as device evaluation. Conclusions: This practical guide provides a step-by-step solution for researchers, healthcare professionals, and device users to choose suitable wearable devices for continuous monitoring. It provides a comprehensive starting point, outlining how to effectively navigate the selection process for wearable devices amidst a plethora of similar options.

Association of Race and Ethnicity With High Longevity Deceased Donor Kidney Transplantation Under the US Kidney Allocation System.

RATIONALE & OBJECTIVE: The US Kidney Allocation System (KAS) prioritizes candidates with a≤20% estimated posttransplant survival (EPTS) to receive high-longevity kidneys defined by a≤20% Kidney Donor Profile Index (KDPI). Use of EPTS in the KAS deprioritizes candidates with older age, diabetes, and longer dialysis durations. We assessed whether this use also disadvantages race and ethnicity minority candidates, who are younger but more likely to have diabetes and longer durations of kidney failure requiring dialysis. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: Adult candidates for and recipients of kidney transplantation represented in the Scientific Registry of Transplant Recipients from January 2015 through December 2020. EXPOSURE: Race and ethnicity. OUTCOME: Age-adjusted assignment to≤20% EPTS, transplantation of a≤20% KDPI kidney, and posttransplant survival in longevity-matched recipients by race and ethnicity. ANALYTIC APPROACH: Multivariable logistic regression, Fine-Gray competing risks survival analysis, and Kaplan-Meier and Cox proportional hazards methods. RESULTS: The cohort included 199,444 candidates (7% Asian, 29% Black, 19% Hispanic or Latino, and 43% White) listed for deceased donor kidney transplantation. Non-White candidates had significantly higher rates of diabetes, longer dialysis duration, and were younger than White candidates. Adjusted for age, Asian, Black, and Hispanic or Latino candidates had significantly lower odds of having a ETPS score of≤20% (odds ratio, 0.86 [95% CI, 0.81-0.91], 0.52 [95% CI, 0.50-0.54], and 0.49 [95% CI, 0.47-0.51]), and were less likely to receive a≤20% KDPI kidney (sub-hazard ratio, 0.70 [0.66-0.75], 0.89 [0.87-0.92], and 0.73 [0.71-0.76]) compared with White candidates. Among recipients with≤20% EPTS scores transplanted with a≤20% KDPI deceased donor kidney, Asian and Hispanic recipients had lower posttransplant mortality (HR, 0.45 [0.27-0.77] and 0.63 [0.47-0.86], respectively) and Black recipients had higher but not statistically significant posttransplant mortality (HR, 1.22 [0.99-1.52]) compared with White recipients. LIMITATIONS: Provider reported race and ethnicity data and 5-year post transplant follow-up period. CONCLUSIONS: The US kidney allocation system is less likely to identify race and ethnicity minority candidates as having a≤20% EPTS score, which triggers allocation of high-longevity deceased donor kidneys. These findings should inform the Organ Procurement and Transplant Network about how to remedy the race and ethnicity disparities introduced through KAS's current approach of allocating allografts with longer predicted longevity to recipients with longer estimated posttransplant survival. PLAIN-LANGUAGE SUMMARY: The US Kidney Allocation System prioritizes giving high-longevity, high-quality kidneys to patients on the waiting list who have a high estimated posttransplant survival (EPTS) score. EPTS is calculated based on the patient's age, whether the patient has diabetes, whether the patient has a history of organ transplantation, and the number of years spent on dialysis. Our analyses show that Asian, Black or African American, and Hispanic or Latino patients were less likely to receive high-longevity kidneys compared with White patients, despite having similar or better posttransplant survival outcomes.

The association between blood biological age at rehabilitation admission and physical activity during rehabilitation in geriatric inpatients: RESORT.

Geriatric rehabilitation inpatients have high levels of sedentary behaviour (SB) and low levels of physical activity (PA). Biological age predicted by blood biomarkers is indicative of adverse outcomes. The objective was to determine the association between blood biological age at rehabilitation admission and levels of SB and PA during rehabilitation in geriatric inpatients. Inpatients admitted to geriatric rehabilitation wards at the Royal Melbourne Hospital (Melbourne, Australia) from October 22, 2019, to March 29, 2020, in the REStORing health of acute unwell adulTs (RESORT) observational cohort were included. Blood biological age was predicted using SenoClock-BloodAge, a hematological ageing clock. Patients wore an inertial sensor to measure SB and PA. Logistic regression analyses were conducted. A total of 111 patients (57.7% female) with mean age 83.3 ± 7.5 years were included in the analysis. The mean blood biological age was 82.7 ± 8.4 years. Patients with 1-year higher blood biological age had higher odds of having high SB measured as non-upright time greater than 23 h/day (odds ratio (OR): 1.050, 95% confidence interval (CI): 1.000-1.102). Individuals having 1-year higher age deviation trended towards lower odds of having high levels of PA measured as stepping time greater than 7.4 min/day (OR: 0.916, CI: 0.836-1.005) and as greater than 19.5 sit-to-stand transitions/day (OR: 0.915, CI: 0.836-1.002). In conclusion, higher biological age was associated with higher levels of SB and trended towards lower PA. Incorporating blood biological age could facilitate resource allocation and the development of more tailored rehabilitation plans.

The role of G protein-coupled receptor kinases in GLP-1R ß-arrestin recruitment and internalisation.

The glucagon-like peptide 1 receptor (GLP-1R) is a validated clinical target for the treatment of type 2 diabetes and obesity. Unlike most G protein-coupled receptors (GPCRs), the GLP-1R undergoes an atypical mode of internalisation that does not require ß-arrestins. While differences in GLP-1R trafficking and ß-arrestin recruitment have been observed between clinically used GLP-1R agonists, the role of G protein-coupled receptor kinases (GRKs) in affecting these pathways has not been comprehensively assessed. In this study, we quantified the contribution of GRKs to agonist-mediated GLP-1R internalisation and ß-arrestin recruitment profiles using cells where endogenous ß-arrestins, or non-visual GRKs were knocked out using CRISPR/Cas9 genome editing. Our results confirm the previously established atypical ß-arrestin-independent mode of GLP-1R internalisation and revealed that GLP-1R internalisation is dependent on the expression of GRKs. Interestingly, agonist-mediated GLP-1R ß-arrestin 1 and ß-arrestin 2 recruitment were differentially affected by endogenous GRK knockout with ß-arrestin 1 recruitment more sensitive to GRK knockout than ß-arrestin 2 recruitment. Moreover, individual overexpression of GRK2, GRK3, GRK5 or GRK6 in a newly generated GRK2/3/4/5/6 HEK293 cells, rescued agonist-mediated ß-arrestin 1 recruitment and internalisation profiles to similar levels, suggesting that there is no specific GRK isoform that drives these pathways. This study advances mechanistic understanding of agonist-mediated GLP-1R internalisation and provides novel insights into how GRKs may fine-tune GLP-1R signalling.

Remote monitoring technologies for measuring cardiovascular functions in community-dwelling adults: a systematic review.

Remote monitoring technologies (RMTs) allow continuous, unobtrusive, and real-time monitoring of the cardiovascular system. An overview of existing RMTs measuring cardiovascular physiological variables is lacking. This systematic review aimed to describe RMTs measuring cardiovascular functions in community-dwelling adults. An electronic search was conducted via PubMed, EMBASE, and Cochrane Library from January 1, 2020, to April 7, 2022. Articles reporting on non-invasive RMTs used unsupervised in community-dwelling adults were included. Reviews and studies in institutionalized populations were excluded. Two reviewers independently assessed the studies and extracted the technologies used, cardiovascular variables measured, and wearing locations of RMTs. Validation of the RMTs was examined based on the COSMIN tool, and accuracy and precision were presented. This systematic review was registered with PROSPERO (CRD42022320082). A total of 272 articles were included representing 322,886 individuals with a mean or median age from 19.0 to 88.9 years (48.7% female). Of all 335 reported RMTs containing 216 distinct devices, photoplethysmography was used in 50.3% of RMTs. Heart rate was measured in 47.0% of measurements, and the RMT was worn on the wrist in 41.8% of devices. Nine devices were reported in more than three articles, of which all were sufficiently accurate, six were sufficiently precise, and four were commercially available in December 2022. The top four most reported technologies were AliveCor KardiaMobile®, Fitbit Charge 2, and Polar H7 and H10 Heart Rate Sensors. With over 200 distinct RMTs reported, this review provides healthcare professionals and researchers an overview of available RMTs for monitoring the cardiovascular system.

Stereoselective Metabolism of Bupropion to Active Metabolites in Cellular Fractions of Human Liver and Intestine.

Striking stereoselective disposition of the antidepressant and smoking cessation aid bupropion (BUP) and its active metabolites observed clinically influence patients' response to BUP therapy and its clinically important drug-drug interactions (DDI) with CYP2D6 substrates. However, understanding of the biochemical mechanisms responsible is incomplete. This study comprehensively examined hepatic and extrahepatic stereoselective metabolism of BUP in vitro Racemic-, R-, and S-BUP were incubated separately with pooled cellular fractions of human liver [microsomes (HLMs), S9 fractions (HLS9s), and cytosols (HLCs)] and intestinal [microsomes (HIMs), S9 fractions (HIS9s), and cytosols (HICs)] and cofactors. Formations of diastereomers of 4-hydroxyBUP (OHBUP), threohydroBUP (THBUP), and erythrohydroBUP (EHBUP) were quantified using a novel chiral ultra-high performance liquid chromatography/tandem mass spectrometry method. Racemic BUP (but not R- or S-BUP) was found suitable to determine stereoselective metabolism of BUP; both enantiomers showed complete racemization. Compared with that of RR-THBUP, the in vitro intrinsic clearance (Clint) for the formation of SS-THBUP was 42-, 19-, and 8.3-fold higher in HLMs, HLS9 fractions, and HLCs, respectively; Clint for the formation of SS-OHBUP and RS-EHBUP was also higher (2.7- to 3.9-fold) than their R-derived counterparts. In cellular fractions of human intestine, ≥ 95% of total reduction was accounted by the formation of RR-THBUP. Ours is the first to demonstrate marked stereoselective reduction of BUP in HLCs, HIMs, HIS9 fractions, and HICs, providing the first evidence for tissue- and cellular fraction-dependent stereoselective metabolism of BUP. These data may serve as the first critical step toward understanding factors dictating BUP's stereoselective disposition, effects, and DDI risks. SIGNIFICANCE STATEMENT: This work provides a deeper insight into bupropion (BUP) stereoselective oxidation and reduction to active metabolites in cellular fractions of human liver and intestine tissues. The results demonstrate tissue- and cellular fraction-dependent stereospecific metabolism of BUP. These data may improve prediction of BUP stereoselective disposition and understanding of BUP's effects and CYP2D6-dependent drug-drug interaction in vivo.

Understanding VPAC receptor family peptide binding and selectivity.

The vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) receptors are key regulators of neurological processes. Despite recent structural data, a comprehensive understanding of peptide binding and selectivity among different subfamily receptors is lacking. Here, we determine structures of active, Gs-coupled, VIP-VPAC1R, PACAP27-VPAC1R, and PACAP27-PAC1R complexes. Cryo-EM structural analyses and molecular dynamics simulations (MDSs) reveal fewer stable interactions between VPAC1R and VIP than for PACAP27, more extensive dynamics of VIP interaction with extracellular loop 3, and receptor-dependent differences in interactions of conserved N-terminal peptide residues with the receptor core. MD of VIP modelled into PAC1R predicts more transient VIP-PAC1R interactions in the receptor core, compared to VIP-VPAC1R, which may underlie the selectivity of VIP for VPAC1R over PAC1R. Collectively, our work improves molecular understanding of peptide engagement with the PAC1R and VPAC1R that may benefit the development of novel selective agonists.

Influence of CYP2B6 Pharmacogenetics on Stereoselective Inhibition and Induction of Bupropion Metabolism by Efavirenz in Healthy Volunteers.

We investigated the acute and chronic effects of efavirenz, a widely used antiretroviral drug, and CYP2B6 genotypes on the disposition of racemic and stereoisomers of bupropion (BUP) and its active metabolites, 4-hydroxyBUP, threohydroBUP and erythrohydroBUP. The primary objective of this study was to test how multiple processes unique to the efavirenz-CYP2B6 genotype interaction influence the extent of efavirenz-mediated drug-drug interaction (DDI) with the CYP2B6 probe substrate BUP. In a three-phase, sequential, open-label study, healthy volunteers (N=53) were administered a single 100 mg oral dose of BUP alone (control phase), with a single 600 mg oral efavirenz dose (inhibition phase), and after 17-days pretreatment with efavirenz (600 mg/day) (induction phase). Compared to the control phase, we show for the first time that efavirenz significantly decreases and chronically increases the exposure of hydroxyBUP and its diastereomers, respectively, and these interactions were CYP2B6 genotype dependent. Chronic efavirenz enhances the elimination of racemic BUP and its enantiomers as well as of threo- and erythro-hydroBUP and their diastereomers, suggesting additional novel mechanisms underlying efavirenz interaction with BUP. The effects of efavirenz and genotypes were nonstereospecific. In conclusion, acute and chronic administration of efavirenz inhibits and induces CYP2B6 activity. Efavirenz-BUP interaction is complex involving time- and CYP2B6 genotype-dependent inhibition and induction of primary and secondary metabolic pathways. Our findings highlight important implications to the safety and efficacy of BUP, study design considerations for future efavirenz interactions, and individualized drug therapy based on CYP2B6 genotypes. Significance Statement The effects of acute and chronic doses of efavirenz on the disposition of racemic and stereoisomers of BUP and its active metabolites were investigated in healthy volunteers. Efavirenz causes an acute inhibition, but chronic induction of CYP2B6 in a genotype dependent manner. Chronic efavirenz induces BUP reduction and the elimination of BUP active metabolites. Efavirenz's effects were non-stereospecific. These data reveal novel mechanisms underlying efavirenz DDI with BUP and provide important insights into time- and CYP2B6 genotype dependent DDIs.

Prevalence, parameters, and pathogenic mechanisms for splice-altering acceptor variants that disrupt the AG exclusion zone.

Predicting the pathogenicity of acceptor splice-site variants outside the essential AG is challenging, due to high sequence diversity of the extended splice-site region. Critical analysis of 24,445 intronic extended acceptor splice-site variants reported in ClinVar and the Leiden Open Variation Database (LOVD) demonstrates 41.9% of pathogenic variants create an AG dinucleotide between the predicted branchpoint and acceptor (AG-creating variants in the AG exclusion zone), 28.4% result in loss of a pyrimidine at the -3 position, and 15.1% result in loss of one or more pyrimidines in the polypyrimidine tract. Pathogenicity of AG-creating variants was highly influenced by their position. We define a high-risk zone for pathogenicity: > 6 nucleotides downstream of the predicted branchpoint and >5 nucleotides upstream from the acceptor, where 93.1% of pathogenic AG-creating variants arise and where naturally occurring AG dinucleotides are concordantly depleted (5.8% of natural AGs). SpliceAI effectively predicts pathogenicity of AG-creating variants, achieving 95% sensitivity and 69% specificity. We highlight clinical examples showing contrasting mechanisms for mis-splicing arising from AG variants: (1) cryptic acceptor created; (2) splicing silencer created: an introduced AG silences the acceptor, resulting in exon skipping, intron retention, and/or use of an alternative existing cryptic acceptor; and (3) splicing silencer disrupted: loss of a deep intronic AG activates inclusion of a pseudo-exon. In conclusion, we establish AG-creating variants as a common class of pathogenic extended acceptor variant and outline factors conferring critical risk for mis-splicing for AG-creating variants in the AG exclusion zone, between the branchpoint and acceptor.