Objectively measured physical activity and cardiac biomarkers: A cross sectional population based study in older men.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity Troponin T (hsTnT) are markers of cardiac injury used in diagnosis of heart failure and myocardial infarction respectively, and associated with increased risk of cardiovascular disease. Since physical activity is protective against cardiovascular disease and heart failure, we investigated whether higher levels of physical activity, and less sedentary behaviour were associated with lower NT-proBNP and hsTnT. METHODS AND RESULTS: Cross sectional study of 1130 men, age 70-91years, from the British Regional Heart Study, measured in 2010-2012. Fasting blood samples were analysed for NT-proBNP and hsTnT. Physical activity and sedentary behaviour were measured using ActiGraph GT3X accelerometers. Relationships between activity and NT-proBNP or hsTnT were non-linear; biomarker levels were lower with higher total activity, steps, moderate/vigorous activity and light activity only at low to moderate levels of activity. For example, for each additional 10min of moderate/vigorous activity, NT-proBNP was lower by 35.7% (95% CI -47.9, -23.6) and hsTnT by 8.4% (95% CI -11.1, -5.6), in men who undertook <25 or 50min of moderate/vigorous activity per day respectively. Biomarker levels increased linearly with increasing sedentary behaviour, but not independently of moderate/vigorous activity. CONCLUSION: Associations between biomarkers and moderate/vigorous activity (and between hsTnT and light activity) were independent of sedentary behaviour, suggesting activity is driving the relationships. In these older men with concomitantly low levels of physical activity, activity may be more important in protecting against cardiac health deterioration in less active individuals, although reverse causality might be operating

Programmable Ligand Detection System in Plants through a Synthetic Signal Transduction Pathway

There is an unmet need to monitor human and natural environments for substances that are intentionally or unintentionally introduced. A long-sought goal is to adapt plants to sense and respond to specific substances for use as environmental monitors. Computationally re-designed periplasmic binding proteins (PBPs) provide a means to design highly sensitive and specific ligand sensing capabilities in receptors. Input from these proteins can be linked to gene expression through histidine kinase (HK) mediated signaling. Components of HK signaling systems are evolutionarily conserved between bacteria and plants. We previously reported that in response to cytokinin-mediated HK activation in plants, the bacterial response regulator PhoB translocates to the nucleus and activates transcription. Also, we previously described a plant visual response system, the de-greening circuit, a threshold sensitive reporter system that produces a visual response which is remotely detectable and quantifiable.We describe assembly and function of a complete synthetic signal transduction pathway in plants that links input from computationally re-designed PBPs to a visual response. To sense extracellular ligands, we targeted the computational re-designed PBPs to the apoplast. PBPs bind the ligand and develop affinity for the extracellular domain of a chemotactic protein, Trg. We experimentally developed Trg fusions proteins, which bind the ligand-PBP complex, and activate intracellular PhoR, the HK cognate of PhoB. We then adapted Trg-PhoR fusions for function in plants showing that in the presence of an external ligand PhoB translocates to the nucleus and activates transcription. We linked this input to the de-greening circuit creating a detector plant.Our system is modular and PBPs can theoretically be designed to bind most small molecules. Hence our system, with improvements, may allow plants to serve as a simple and inexpensive means to monitor human surroundings for substances such as pollutants, explosives, or chemical agents

Ataxia, Dementia, and Hypogonadotropism Caused by Disordered Ubiquitination

In recent years, we have seen great advances in the elucidation of genetic causes of cerebellar ataxia, with newly identified genes regulating a wide spectrum of cellular functions, including intracellular signaling, tau regulation, and mitochondrial function.1 However, a genetic defect cannot be found in approximately 40% of patients with ataxia,1 including those in whom ataxia is associated with reproductive endocrine failure, a syndrome first reported by Gordon Holmes in 1908.2 Most patients with this syndrome have a hypogonadotropic condition, with defective secretion of gonadotropins by the pituitary gland.3-12 Strikingly, genes associated with ataxia have little functional overlap with genes associated with hypogonadotropic hypogonadism, which encode proteins involved in the biologic function of the neurons that secrete gonadotropin-releasing hormone (GnRH).13 A decade ago, we described a consanguineous family with a syndrome of cerebellar ataxia, dementia, and hypogonadotropic hypogonadism.12 Here we report the results of whole-exome and targeted sequencing performed to identify mutations that underlie the syndrome in this kindred and in unrelated patients

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Introduction: the blackest and whitest of swans

[Extract] We would like to begin this introduction to Seeing into Screens: Eye Tracking the Moving Image with a brief reading of the preliminary research we have conducted on the opening six minutes to Black Swan (Darren Aronofsky 2010). The research affords us the opportunity to demonstrate what eye-tracking data reveals and conceals, and enables us to introduce the ‘two sides’ to the collection’s structure: in this sequence, we see the eye engaging with the duplicitous nature of the text, and we see the eye seeing, motivated by the fractured fictions it is presented with

Seeing into screens : eye tracking and the moving image

ix, 275 p. : ill. ; 24 cm

Media Comforts and International Student Mobility: Managing Hopes, Host and Home

10.1080/07256868.2021.1939277Journal of Intercultural Studies424406-42

Verbal learning and memory in cannabis and alcohol users: An event-related potential investigation

Aims: Long-term heavy use of cannabis and alcohol are known to be associated with memory impairments. In this study, we used event-related potentials to examine verbal learning and memory processing in a commonly used behavioral task. Method: We conducted two studies: first, a small pilot study of adolescent males, comprising 13 Drug-Naive Controls (DNC), 12 heavy drinkers (HD) and 8 cannabis users (CU). Second, a larger study of young adults, comprising 45 DNC (20 female), 39 HD (16 female), and 20 CU (9 female). In both studies, participants completed a modified verbal learning task (the Rey Auditory Verbal Learning Test, RAVLT) while brain electrical activity was recorded. ERPs were calculated for words which were subsequently remembered vs. those which were not remembered, and for presentations of learnt words, previously seen words, and new words in a subsequent recognition test. Pre-planned principal components analyses (PCA) were used to quantify the ERP components in these recall and recognition phases separately for each study. Results: Memory performance overall was slightly lower than published norms using the standardized RAVLT delivery, but was generally similar and showed the expected changes over trials. Few differences in performance were observed between groups; a notable exception was markedly poorer delayed recall in HD relative to DNC (Study 2). PCA identified components expected from prior research using other memory tasks. At encoding, there were no between-group differences in the usual P2 recall effect (larger for recalled than not-recalled words). However, alcohol-related differences were observed in a larger P540 (indexing recollection) in HD than DNC, and cannabis-related differences were observed in a smaller N340 (indexing familiarity) and a lack of previously seen \u3e new words effect for P540 in Study 2. Conclusions: This study is the first examination of ERPs in the RAVLT in healthy control participants, as well as substance-using individuals, and represents an important advance in methodology. The results indicate alterations in recognition memory processing, which even if not manifesting in overt behavioral impairment, underline the potential for brain dysfunction with early exposure to alcohol and cannabis