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Study designSecondary data analysis.ObjectiveTo characterize heart rate (HR) changes during autonomic dysreflexia (AD) in daily life for individuals with chronic spinal cord injury (SCI).SettingUniversity-based laboratory/community-based outpatient.MethodsCardiovascular data, previously collected during a 24-h ambulatory surveillance period in individuals with chronic SCI, were assessed. Any systolic blood pressure (SBP) increase ≥20 mmHg from baseline was identified and categorized into confirmed AD (i.e., diarized trigger), unknown (i.e., no diary entry), or unlikely AD (i.e., potential exertion driven SBP increase) groups. SBP-associated HR changes were categorized as unchanged, increased or decreased compared to baseline.ResultsForty-five individuals [8 females, median age and time since injury of 43 years (lower and upper quartiles 36–50) and 17 years (6–23), respectively], were included for analysis. Overall, 797 episodes of SBP increase above AD threshold were identified and classified as confirmed (n = 250, 31.4%), unknown (n = 472, 59.2%) or unlikely (n = 75, 9.4%). The median number of episodes per individual within the 24-h period was 13 (8–28). HR-decrease/increase ratio was 3:1 for confirmed and unknown, and 1.5:1 for unlikely episodes. HR changes resulting in brady-/tachycardia were 34.4%/2.8% for confirmed, 39.6%/3.4% unknown, and 26.7%/9.3% for unlikely episodes, respectively.ConclusionsOur findings suggest that the majority of confirmed AD episodes are associated with a HR decrease. Using wearable-sensors-derived measures of physical activity in future studies could provide a more detailed characterization of HR changes during AD and improve AD identification.

Study designSecondary data analysis.ObjectivesTo characterize autonomic dysreflexia (AD) associated heart rate (HR) changes during penile vibrostimulation (PVS) and urodynamic studies (UDS).SettingUniversity-based laboratory.MethodsWe analyzed blood pressure (BP) and HR data, recorded continuously, from 21 individuals (4 females; median age 41 years [lower and upper quartile, 37; 47]; median time post-injury 18 years [7; 27]; all motor-complete spinal cord injury (SCI) except one; cervical SCI = 15, thoracic [T1–T6] SCI = 6), who underwent PVS (11/21) or UDS (10/21).ResultsOverall, 47 AD episodes were recorded (i.e. PVS = 37, UDS = 10), with at least one AD episode in each participant. At AD threshold, bradycardia was observed during PVS and UDS in 43% and 30%, respectively. At AD peak (i.e., maximum increase in systolic BP from baseline), bradycardia was observed during PVS and UDS in 65% and 50%, respectively. Tachycardia was detected at AD peak only once during UDS. Our study was limited by a small cohort of participants and the distribution of sex and injury characteristics.ConclusionsOur findings reveal that AD-associated HR changes during PVS and UDS appear to be related to the magnitude of systolic BP increases. Highly elevated systolic BP associated with bradycardia suggests the presence of severe AD. Therefore, we recommend cardiovascular monitoring (preferably with continuous beat-to-beat recordings) during PVS and UDS to detect AD early. Stopping assessments before systolic BP reaches dangerously elevated levels, could reduce the risk of life-threatening complications in this cohort.

Pilot data of our phase IV clinical trial (pre/post study design) highlighted a beneficial effect of intradetrusor onabotulinumtoxinA (200 IU) injections to reduce autonomic dysreflexia (AD) in individuals with chronic spinal cord injury (SCI) at T6 or above. After trial completion, we assessed whether our primary expectation (i.e., decrease of AD severity in 50% of participants during urodynamics [UDS]) was met. Secondary outcome measures were reduction of spontaneous AD in daily life as well as amelioration of AD-related and urinary incontinence-related quality of life (QoL). In addition, we conducted injury-level–dependent analysis—i.e., cervical and upper thoracic—to explore group-specific treatment efficacy. Post-treatment, AD severity decreased in 82% (28/34) of all participants during UDS and in 74% (25/34) in daily life assessed with 24-h ambulatory blood pressure monitoring. In addition, urinary incontinence-related QoL was improved, cystometric capacity was increased, and maximum detrusor pressure during storage was reduced (all p < 0.001). Further, the treatment was well tolerated, with only minor complications (grade I [n = 7] and II [n = 7]) in accordance with the Clavien-Dindo classification recorded in 11 individuals (cervical n = 9, upper thoracic n = 2). Injury-level–dependent analysis revealed lower incidence (cervical n = 15/23, upper thoracic n = 6/11) and lesser severity (cervical p = 0.009; upper thoracic p = 0.06 [Pearson r = −0.6, i.e., large effect size]) of AD during UDS. Further, reduced AD severity in daily life, improved urinary incontinence-related QoL, greater cystometric capacity, and lower maximum detrusor pressure during storage (all p < 0.05) were found in both groups post-treatment. Intradetrusor onabotulinumtoxinA injections are an effective and safe second-line treatment option that ameliorates AD while improving lower urinary tract function and urinary incontinence-related QoL in individuals with cervical and upper thoracic SCI.

IntroductionManaging and preventing risk factors associated with cardiovascular and cerebrovascular impairment is well studied in able-bodied individuals. However, individuals with spinal cord injury (SCI) at or above the spinal segment T6 are prone to experience autonomic dysreflexia (AD) but also to suffer from neurogenic detrusor overactivity (NDO). Treatment of NDO would not only improve lower urinary tract function but could also reduce the severity and frequency of life-threatening episodes of AD. Fesoterodine, an antimuscarinic drug, has been successfully employed as a first-line treatment for detrusor overactivity in individuals without an underlying neurological disorder. Thus, our aim is to investigate the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with SCI.Methods and analysisThis phase II, open-label exploratory, non-blinded, non-randomised, single-centre study will investigate the efficacy of fesoterodine to improve NDO and ameliorate AD in individuals with chronic SCI at or above T6. During screening, we will interview potential candidates (with a previous history of NDO and AD) and assess their injury severity. At baseline, we will perform cardiovascular and cerebrovascular monitoring (blood pressure (BP), heart rate and cerebral blood flow velocity) during urodynamics (UDS) and 24-hour ambulatory BP monitoring (ABPM) during daily life to assess severity and frequency of AD episodes (ie, maximum increase in systolic BP). The primary outcome is a reduction of artificially induced (during UDS) and spontaneous (during daily life) episodes of AD as a display of treatment efficacy. To answer this, we will repeat UDS and 24-hour ABPM during the last cycle of the treatment phase (12 weeks overall, ie, three cycles of 4 weeks each). At the end of each treatment cycle, participants will be asked to answer standardised questionnaires (AD symptoms and quality of life) and present bladder and bowel diaries, which will provide additional subjective information.Ethics and disseminationThe University of British Columbia Research Ethics Boards (H15-02364), Vancouver Coastal Health Research Institute (V15-02364) and Health Canada (205857) approved this study. The findings of the study will be published in peer-reviewed journals and presented at national and international scientific meetings. This protocol adheres to the Standard Protocol Items: Recommendations for Interventional Trials and CONsolidated Standards Of Reporting Trials statements.Trial registration number NCT02676154; Pre-results.

When applied in large scale to electronic medical record data, the PheWAS approach replicates GWAS associations and reveals potentially new pleiotropic associations. Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10 −6 (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort ( n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.

There are currently no specific biomarkers to identify patients with abdominal aortic aneurysms (AAAs). Circulating exosomes contain microRNAs (miRNA) that are potential biomarkers for the presence of disease. This study aimed to characterize the exosomal miRNA expression profile of patients with AAAs in order to identify novel biomarkers of disease. Patients undergoing duplex ultrasound (US) or computed tomography (CT) for screening or surveillance of an AAA were screened to participate in the study. Cases with AAA were defined as having a max aortic diameter >3 cm. Circulating plasma exosomes were isolated using Cushioned-Density Gradient Ultracentrifugation and total RNA was extracted. Next Generation Sequencing was performed on the Illumina HiSeq4000 SE50. Differential miRNA expression analysis was performed using DESeq2 software with a Benjamini-Hochberg correction. MicroRNA expression profiles were validated by Quantitative Real-Time PCR. A total of 109 patients were screened to participate in the study. Eleven patients with AAA and 15 non-aneurysmal controls met study criteria and were enrolled. Ultrasound measured aortic diameter was significantly larger in the AAA group (mean maximum diameter 4.3 vs 2.0 cm, P = 6.45x10-6). More AAA patients had coronary artery disease (5/11 vs 1/15, P = 0.05) as compared to controls, but the groups did not differ significantly in the rates of peripheral arterial disease and chronic obstructive pulmonary disease. A total of 40 miRNAs were differentially expressed (P<0.05). Of these, 18 miRNAs were downregulated and 22 were upregulated in the AAA group compared to controls. After false discovery rate (FDR) adjustment, only miR-122-5p was expressed at significantly different levels in the AAA group compared to controls (fold change = 5.03 controls vs AAA; raw P = 1.8x10-5; FDR P = 0.02). Plasma exosomes from AAA patients have significantly reduced levels of miRNA-122-5p compared to controls. This is a novel exosome-associated miRNA that warrants further investigation to determine its use as a diagnostic biomarker and potential implications in AAA pathogenesis.

Comprehensively mapping the genetic basis of human disease across diverse individuals is a long-standing goal for the field of human genetics 1 – 4 . The All of Us Research Program is a longitudinal cohort study aiming to enrol a diverse group of at least one million individuals across the USA to accelerate biomedical research and improve human health 5 , 6 . Here we describe the programme’s genomics data release of 245,388 clinical-grade genome sequences. This resource is unique in its diversity as 77% of participants are from communities that are historically under-represented in biomedical research and 46% are individuals from under-represented racial and ethnic minorities. All of Us identified more than 1 billion genetic variants, including more than 275 million previously unreported genetic variants, more than 3.9 million of which had coding consequences. Leveraging linkage between genomic data and the longitudinal electronic health record, we evaluated 3,724 genetic variants associated with 117 diseases and found high replication rates across both participants of European ancestry and participants of African ancestry. Summary-level data are publicly available, and individual-level data can be accessed by researchers through the All of Us Researcher Workbench using a unique data passport model with a median time from initial researcher registration to data access of 29 hours. We anticipate that this diverse dataset will advance the promise of genomic medicine for all. A study describes the release of clinical-grade whole-genome sequence data for 245,388 diverse participants by the All of Us Research Program and characterizes the properties of the dataset.

The objective of this systematic review and meta-analysis was to assess the prevalence of hypertension in populations living at altitude in Latin America and the Caribbean. We conducted a systematic search from January 1, 2000 to January 10, 2023 in Web of Science (WoS)/Core Collection, WoS/Medline, WoS/Scielo, Scopus, PubMed and Embase databases. We included studies that assessed the prevalence of hypertension in altitude populations (>1500 m.a.s.l.) and these were meta-analyzed using a random-effects model. To assess the sources of heterogeneity, we performed subgroup and meta-regression analyses. Thirty cross-sectional studies (117 406 participants) met the inclusion criteria. Studies used different cut-off points. The prevalence of hypertension in the studies that considered the cut-off point of [greater than or equal to] 140/90 mmHg in the general population was 19.1%, [greater than or equal to] 130/85 mmHg was 13.1%, and [greater than or equal to] 130/80 mmHg was 43.4%. There was a tendency for the prevalence of hypertension to be higher in men. In meta-regression analyses, no association was found between altitude, mean age, year of publication, risk of bias and prevalence of hypertension. The prevalence of hypertension in the altitude population of Latin America and the Caribbean is lower than that reported in populations living at sea level and lower than other altitude populations such as Tibetans.

Decarbonization of electricity generation can support climate-change mitigation and presents an opportunity to address pollution resulting from fossil-fuel combustion. Generally, renewable technologies require higher initial investments in infrastructure than fossil-based power systems. To assess the tradeoffs of increased up-front emissions and reduced operational emissions, we present, to our knowledge, the first global, integrated life-cycle assessment (LCA) of long-term, wide-scale implementation of electricity generation from renewable sources (i.e., photovoltaic and solar thermal, wind, and hydropower) and of carbon dioxide capture and storage for fossil power generation. We compare emissions causing particulate matter exposure, freshwater ecotoxicity, freshwater eutrophication, and climate change for the climate-change-mitigation (BLUE Map) and business-as-usual (Baseline) scenarios of the International Energy Agency up to 2050. We use a vintage stock model to conduct an LCA of newly installed capacity year-by-year for each region, thus accounting for changes in the energy mix used to manufacture future power plants. Under the Baseline scenario, emissions of air and water pollutants more than double whereas the low-carbon technologies introduced in the BLUE Map scenario allow a doubling of electricity supply while stabilizing or even reducing pollution. Material requirements per unit generation for low-carbon technologies can be higher than for conventional fossil generation: 11–40 times more copper for photovoltaic systems and 6–14 times more iron for wind power plants. However, only two years of current global copper and one year of iron production will suffice to build a low-carbon energy system capable of supplying the world's electricity needs in 2050. Significance Life-cycle assessments commonly used to analyze the environmental costs and benefits of climate-mitigation options are usually static in nature and address individual power plants. Our paper presents, to our knowledge, the first life-cycle assessment of the large-scale implementation of climate-mitigation technologies, addressing the feedback of the electricity system onto itself and using scenario-consistent assumptions of technical improvements in key energy and material production technologies.

Mangroves are widely recognised as key ecosystems for climate change mitigation as they capture and store significant amounts of sediment organic carbon (SOC). Yet, there is incomplete knowledge on how sources of SOC and their differential preservation vary between mangrove sites in relation to environmental gradients. To address this, sediment depth profiles were sampled from mangrove sites ranging from river-dominated to marine-dominated sites and including old and young mangrove sites in the Guayas delta (Ecuador). The stable carbon isotope ratios (δ13C) and the elemental composition (OC %, C : N) of sediment profiles, local vegetation (i.e. autochthonous carbon) and externally supplied suspended particulate matter (i.e. allochthonous carbon) were obtained to assess variations in the amount and sources of SOC at different locations throughout the delta. In general, across all sites, we found that increasing SOC contents and stocks are associated with decreasing δ13C and increasing C : N ratios, indicating that SOC stocks and sources are intrinsically related. The SOC stocks (down to 0.64 m depth profiles) are significantly lower in young mangrove sites (46–55 Mg C ha−1) than in old sites (78–92 Mg C ha−1). The SOC in the young mangrove sites is mainly of allochthonous origin (estimated on average at 79 %), whereas in the old sites there is a slight dominance of autochthonous OC (on average 59 %). Moreover, from river- to marine-dominated sites, a pattern was found of increasing SOC stocks and increasing autochthonous SOC contribution. These observed differences along the two studied gradients are hypothesised to be mainly driven by (1) expected higher sedimentation rates in the river-dominated and lower-elevation younger sites, thereby `diluting' the SOC content and decreasing the relative autochthonous contribution, and (2) potential differences in preservation of the different SOC sources. Our finding of high contributions of allochthonous SOC, especially in young mangroves, implies that this carbon is not originating from CO2 sequestration by the mangrove ecosystem itself but is externally supplied from other terrestrial, marine or estuarine ecosystems. We argue that accounting for lower SOC stocks and higher contribution of allochthonous SOC in young and river-dominated mangrove sites, as compared to old and marine-dominated sites, is particularly relevant for designing and valuing nature-based climate mitigation programmes based on mangrove reforestation.