OBJECTIVETo determine whether early and more frequent mobilization after stroke affects health-related quality of life.
METHODSA Very Early Rehabilitation Trial (AVERT) was an international, ...multicenter (56 sites), phase 3 randomized controlled trial, spanning 2006–2015. People were included if they were aged ≥18 years, presented within 24 hours of a first or recurrent stroke (ischemic or hemorrhagic), and satisfied preordained physiologic criteria. Participants were randomized to usual care alone or very early and more frequent mobilization in addition to usual care. Quality of life at 12 months was a prespecified secondary outcome, evaluated using the Assessment of Quality of Life 4D (AQoL-4D). This utility-weighted scale has scores ranging from −0.04 (worse than death) to 1 (perfect health). Participants who died were assigned an AQoL-4D score of 0.
RESULTSNo significant difference in quality of life at 12 months between intervention (median 0.47, interquartile range IQR 0.07–0.81) and usual care (median 0.49, IQR 0.08–0.81) groups was identified (p = 0.86), nor were there any group differences across the 4 AQoL-4D domains. The same lack of group difference in quality of life was observed at 3 months. When cohort data were analyzed (both groups together), quality of life was strongly associated with acute length of stay, independence in activities of daily living, cognitive function, depressive symptoms, and anxiety symptoms (all p < 0.001). Quality of life in AVERT participants was substantially lower than population norms, and the gap increased with age.
CONCLUSIONSEarlier and more frequent mobilization after stroke did not influence quality of life.
CLINICAL TRIAL REGISTRATIONanzctr.org.au; ACTRN12606000185561
CLASSIFICATION OF EVIDENCEThis study provides Class II evidence that for people with stroke, earlier and more frequent mobilization did not influence quality of life over the subsequent year.
TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT ...directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT's intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.
Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung.
To develop an integrated ...understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease.
We performed deep targeted resequencing (3.69 Mb of DNA) in cases (
= 3,624) and control subjects (
= 4,442) across genes and regions previously associated with disease. We tested for associations between disease and
) individual common variants via logistic regression and
) groups of rare variants via sequence kernel association tests.
Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the
promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (
= 9.60 × 10
). In addition to identifying for the first time that rare variation in
is associated with disease, we confirmed the role of rare variation in the
and
gene regions in the risk of IPF, and found that the
and
regions have independent common and rare variant signals.
A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.
Abstract
Species radiations, despite immense phenotypic variation, can be difficult to resolve phylogenetically when genetic change poorly matches the rapidity of diversification. Genomic potential ...furnished by palaeopolyploidy, and relative roles for adaptation, random drift and hybridisation in the apportionment of genetic variation, remain poorly understood factors. Here, we study these aspects in a model radiation,
Syzygium
, the most species-rich tree genus worldwide. Genomes of 182 distinct species and 58 unidentified taxa are compared against a chromosome-level reference genome of the sea apple,
Syzygium grande
. We show that while
Syzygium
shares an ancient genome doubling event with other Myrtales, little evidence exists for recent polyploidy events. Phylogenomics confirms that
Syzygium
originated in Australia-New Guinea and diversified in multiple migrations, eastward to the Pacific and westward to India and Africa, in bursts of speciation visible as poorly resolved branches on phylogenies. Furthermore, some sublineages demonstrate genomic clines that recapitulate cladogenetic events, suggesting that stepwise geographic speciation, a neutral process, has been important in
Syzygium
diversification.
Tendon matrix integrity is vital to ensure adequate mechanical properties for efficient function. Although historically tendon was considered to be relatively inert, recent studies have shown that ...tendon matrix turnover is active. During normal physiological activities some tendons are subjected to stress and strains much closer to their failure properties than others. Tendons with low safety margins are those which function as energy stores such as the equine superficial digital flexor tendon (SDFT) and human Achilles tendon (AT). We postulate therefore that energy storing tendons suffer a higher degree of micro-damage and thus have a higher rate of matrix turnover than positional tendons. The hypothesis was tested using tissue from the equine SDFT and common digital extensor tendon (CDET). Matrix turnover was assessed indirectly by a combination of measurements for matrix age, markers of degradation, potential for degradation and protein expression. Results show that despite higher cellularity, the SDFT has lower relative levels of mRNA for collagen types I and III. Non-collagenous proteins, although expressed at different levels per cell, do not appear to differ between tendon types. Relative levels of mRNA for MMP1, MMP13 and both pro-MMP3 and MMP13 protein activity were significantly higher in the CDET. Correspondingly levels of cross-linked carboxyterminal telopeptide of type I collagen (ICTP) were higher in the CDET and tissue fluorescence lower suggesting more rapid turnover of the collagenous component. Reduced or inhibited collagen turnover in the SDFT may account for the high level of degeneration and subsequent injury compared to the CDET.
The gender difference in cardiovascular disease has been partly attributed to higher androgenic hormone levels. Although testosterone in women may not affect lipids, it remains unknown whether it ...negates favorable estrogenic effects on endothelial function. We have investigated the effects of testosterone implant therapy on arterial reactivity encompassing endothelial-dependent and -independent vasodilation in women using hormone replacement therapy (HRT). B-mode ultrasound measurements of resting brachial artery diameter, following reactive hyperemia endothelium-dependent flow- mediated dilation (FMD) and following glyceryl trinitrate (GTN) (endothelium-independent dilation), were recorded in 33 postmenopausal women stabilized on HRT (>6 months), at baseline, and 6 weeks after a testosterone implant (50 mg), with 15 postmenopausal nonusers of HRT serving as controls. In the brachial artery, baseline resting diameter was similar (0.40 +/- 0.01 vs. 0.41 +/- 0.01 cm, P = 0.5). In the treated group, testosterone levels increased (0.99 +/- 0.08 to 4.99 +/- 0.3 nmol/L, P < 0.001), associated with a mean 42% increase in FMD (6.4% +/- 0.7 to 9.1% +/- 1.1, P = 0.03). The control group did not change (8.1% +/- 1.4 to 5.6% +/- 1.0, P = 0.4). ANOVA of repeated measures (P = 0.04) and mean change (P = 0.02) in FMD both demonstrated significantly greater improvement with testosterone compared with controls. GTN induced vasodilation increased with testosterone treatment (14.9% +/- 0.9 to 17.8% +/- 1.2, P = 0.03). Our preliminary data indicate that parenteral testosterone therapy improves both endothelial-dependent (flow-mediated) and endothelium-independent (GTN-mediated) brachial artery vasodilation in postmenopausal women using long-term estrogen therapy. The mechanisms underlying these potentially beneficial cardiovascular effects require further investigation.
Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite ...treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non‐invasive tests. Here, we propose monoamine‐derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine‐derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF‐D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L‐histidine analog, or a low L‐histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.
Synopsis
In this study, lymphangioleiomyomatosis (LAM) is characterized by active histamine metabolism and signaling, which opens new opportunities for advancing disease monitoring and/or treatment.
LAM cells have enhanced metabolism of histamine and the major metabolite product is found to be overabundant in blood plasma of patients.
Histamine plasma levels are associated with disease features and status.
LAM cells are responsive to histamine signaling through H1 histamine receptor.
Targeted inhibition of histamine metabolism or signaling hinders LAM disease in a preclinical model.
The anti‐histamine loratadine effect on LAM may be synergistic with the standard of care, rapamycin (sirolimus).
In this study, lymphangioleiomyomatosis (LAM) is characterized by active histamine metabolism and signaling, which opens new opportunities for advancing disease monitoring and/or treatment.
Remote digital health interventions to enhance physical activity provide a potential solution to improve the sedentary behaviour, physical inactivity, and poor health-related quality of life that are ...typical of chronic conditions, particularly for people with chronic kidney disease. However, there is a need for high-quality evidence to support implementation in clinical practice. The Kidney BEAM trial evaluated the clinical effect of a 12-week physical activity digital health intervention on health-related quality of life.
In a single-blind, randomised controlled trial conducted at 11 centres in the UK, adult participants (aged ≥18 years) with chronic kidney disease were recruited and randomly assigned (1:1) to the Kidney BEAM physical activity digital health intervention or a waiting list control group. Randomisation was performed with a web-based system, in randomly permuted blocks of six. Outcome assessors were masked to treatment allocation. The primary outcome was the difference in the Kidney Disease Quality of Life Short Form version 1.3 Mental Component Summary (KDQoL-SF1.3 MCS) between baseline and 12 weeks. The trial was powered to detect a clinically meaningful difference of 3 arbitrary units (AU) in KDQoL-SF1.3 MCS. Outcomes were analysed by an intention-to-treat approach using an analysis of covariance model, with baseline measures and age as covariates. The trial was registered with ClinicalTrials.gov, NCT04872933.
Between May 6, 2021, and Oct 30, 2022, 1102 individuals were assessed for eligibility, of whom 340 participants were enrolled and randomly assigned to the Kidney BEAM intervention group (n=173) or the waiting list control group (n=167). 268 participants completed the trial (112 in the Kidney BEAM group and 156 in the waiting list control group). All 340 randomly assigned participants were included in the intention-to treat population. At 12 weeks, there was a significant improvement in KDQoL-SF.13 MCS score in the Kidney BEAM group (from mean 44·6 AU SD 10·8 at baseline to 47·0 AU 10·6 at 12 weeks) compared with the waiting list control group (from 46·1 AU 10·5 to 45·0 AU 10·1; between-group difference of 3·1 AU 95% CI 1·8–4·4; p<0·0001).
The Kidney BEAM physical activity platform is an efficacious digital health intervention to improve mental health-related quality of life in patients with chronic kidney disease. These findings could facilitate the incorporation of remote digital health interventions into clinical practice and offer a potential intervention worthy of investigation in other chronic conditions.
Kidney Research UK.
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