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.

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.

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.

Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy.

X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy characterised by generalised weakness and respiratory insufficiency. XLMTM is associated with pathogenic variants in MTM1; a gene encoding the lipid phosphatase myotubularin. Whole genome sequencing (WGS) of an exome-negative male proband with severe hypotonia, respiratory insufficiency and centralised nuclei on muscle biopsy identified a deep intronic MTM1 variant NG_008199.1(NM_000252.2):c.1468-577A>G, which strengthened a cryptic 5' splice site (A>G substitution at the +5 position). Muscle RNA sequencing was non-diagnostic due to low read depth. Reverse transcription PCR (RT-PCR) of muscle RNA confirmed the c.1468-577A>G variant activates inclusion of a pseudo-exon encoding a premature stop codon into all detected MTM1 transcripts. Western blot analysis establishes deficiency of myotubularin protein, consistent with the severe XLMTM phenotype. We expand the genotypic spectrum of XLMTM and highlight benefits of screening non-coding regions of MTM1 in male probands with phenotypically concordant XLMTM who remain undiagnosed following exome sequencing.