We present a transparent and validated
climate-conditioned catastrophe flood model for the UK, that simulates
pluvial, fluvial and coastal flood risks at 1 arcsec spatial resolution
(∼ 20–25 m). ...Hazard layers for 10 different return periods
are produced over the whole UK for historic, 2020, 2030, 2050 and 2070
conditions using the UK Climate Projections 2018 (UKCP18) climate simulations. From these, monetary losses
are computed for five specific global warming levels above pre-industrial
values (0.6, 1.1, 1.8, 2.5 and 3.3 ∘C). The analysis contains a
greater level of detail and nuance compared to previous work, and represents
our current best understanding of the UK's changing flood risk landscape.
Validation against historical national return period flood maps yielded
critical success index values of 0.65 and 0.76 for England and Wales,
respectively, and maximum water levels for the Carlisle 2005 flood were
replicated to a root mean square error (RMSE) of 0.41 m without calibration. This level of skill is similar to local modelling with site-specific data. Expected annual damage in 2020 was GBP 730 million, which compares favourably to the observed
value of GBP 714 million reported by the Association of British Insurers. Previous UK flood loss estimates based on government data are
∼ 3× higher, and lie well outside our modelled loss
distribution, which is plausibly centred on the observations. We estimate
that UK 1 % annual probability flood losses were ∼ 6 %
greater for the average climate conditions of 2020 (∼ 1.1 ∘C of warming) compared to those of 1990 (∼ 0.6 ∘C of warming), and this increase can be kept to around
∼ 8 % if all countries' COP26 2030 carbon emission reduction
pledges and “net zero” commitments are implemented in full. Implementing
only the COP26 pledges increases UK 1 % annual probability flood losses by 23 % above average 1990 values, and potentially 37 % in a “worst case” scenario where carbon reduction targets are missed and climate sensitivity
is high.
Study objective We determine the association between emergency medical services (EMS) out-of-hospital times and mortality in trauma patients presenting to an urban Level I trauma center. Methods We ...conducted a secondary analysis of a prospective cohort registry of trauma patients presenting to a Level I trauma center during a 14-year period (1996 to 2009). Inclusion criteria were patients sustaining traumatic injury who presented to an urban Level I trauma center. Exclusion criteria were extrication, missing or erroneous out-of-hospital times, and intervals exceeding 5 hours. The primary outcome was inhospital mortality. EMS out-of-hospital intervals (scene time and transport time) were evaluated with multivariate logistic regression. Results There were 19,167 trauma patients available for analysis, with 865 (4.5%) deaths; 16,170 (84%) injuries were blunt, with 596 (3.7%) deaths, and 2,997 (16%) were penetrating, with 269 (9%) deaths. Mean age and sex for blunt and penetrating trauma were 34.5 years (68% men) and 28.1 years (90% men), respectively. Of those with Injury Severity Score less than or equal to 15, 0.4% died, and 26.1% of those with a score greater than 15 died. We analyzed the relationship of scene time and transport time with mortality among patients with Injury Severity Score greater than 15, controlling for age, sex, Injury Severity Score, and Revised Trauma Score. On multivariate regression of patients with penetrating trauma, we observed that a scene time greater than 20 minutes was associated with higher odds of mortality than scene time less than 10 minutes (odds ratio OR 2.90; 95% confidence interval CI 1.09 to 7.74). Scene time of 10 to 19 minutes was not significantly associated with mortality (OR 1.19; 95% CI 0.66 to 2.16). Longer transport times were likewise not associated with increased odds of mortality in penetrating trauma cases; OR for transport time greater than or equal to 20 minutes was 0.40 (95% CI 0.14 to 1.19), and OR for transport time 10 to 19 minutes was 0.64 (95% CI 0.35 to 1.15). For patients with blunt trauma, we did not observe any association between scene or transport times and increased odds of mortality. Conclusion In this analysis of patients presenting to an urban Level I trauma center during a 14-year period, we observed increased odds of mortality among patients with penetrating trauma if scene time was greater than 20 minutes. We did not observe associations between increased odds of mortality and out-of-hospital times in blunt trauma victims. These findings should be validated in an external data set.
To determine whether microwave ablation with high-power triaxial antennas creates significantly larger ablation zones than radiofrequency (RF) ablation with similarly sized internally cooled ...electrodes.
Twenty-eight 12-minute ablations were performed in an in vivo porcine kidney model. RF ablations were performed with a 200-W pulsed generator and either a single 17-gauge cooled electrode (n = 9) or three switched electrodes spaced 1.5 cm apart (n = 7). Microwave ablations were performed with one (n = 7), two (n = 3), or three (n = 2) 17-gauge triaxial antennas to deliver 90 W continuous power per antenna. Multiple antennas were powered simultaneously. Temperatures 1 cm from the applicator were measured during two RF and microwave ablations each. Animals were euthanized after ablation and ablation zone diameter, cross-sectional area, and circularity were measured. Comparisons between groups were performed with use of a mixed-effects model with P values less than .05 indicating statistical significance.
No adverse events occurred during the procedures. Three-electrode RF (mean area, 14.7 cm(2)) and single-antenna microwave (mean area, 10.9 cm(2)) ablation zones were significantly larger than single-electrode RF zones (mean area, 5.6 cm(2); P = .001 and P = .0355, respectively). No significant differences were detected between single-antenna microwave and multiple-electrode RF. Ablation zone circularity was similar across groups (P > .05). Tissue temperatures were higher during microwave ablation (maximum temperature of 123 degrees C vs 100 degrees C for RF).
Microwave ablation with high-power triaxial antennas created larger ablation zones in normal porcine kidneys than RF ablation with similarly sized applicators.
N-of-1 trials are a useful tool for clinicians who want to determine the effectiveness of a treatment in a particular individual. The reporting of N-of-1 trials has been variable and incomplete, ...hindering their usefulness in clinical decision making and by future researchers. This document presents the CONSORT (Consolidated Standards of Reporting Trials) extension for N-of-1 trials (CENT 2015). CENT 2015 extends the CONSORT 2010 guidance to facilitate the preparation and appraisal of reports of an individual N-of-1 trial or a series of prospectively planned, multiple, crossover N-of-1 trials. CENT 2015 elaborates on 14 items of the CONSORT 2010 checklist, totalling 25 checklist items (44 sub-items), and recommends diagrams to help authors document the progress of one participant through a trial or more than one participant through a trial or series of trials, as applicable. Examples of good reporting and evidence based rationale for CENT 2015 checklist items are provided.
E2 enzymes catalyze attachment of ubiquitin and ubiquitin-like proteins to lysine residues directly or through E3-mediated reactions. The small ubiquitin-like modifier SUMO regulates nuclear ...transport, stress response, and signal transduction in eukaryotes and is essential for cell-cycle progression in yeast. In contrast to most ubiquitin conjugation, the SUMO E2 enzyme Ubc9 is sufficient for substrate recognition and lysine modification of known SUMO targets. Crystallographic analysis of a complex between mammalian Ubc9 and a C-terminal domain of RanGAP1 at 2.5 Å reveals structural determinants for recognition of consensus SUMO modification sequences found within SUMO-conjugated proteins. Structure-based mutagenesis and biochemical analysis of Ubc9 and RanGAP1 reveal distinct motifs required for substrate binding and SUMO modification of p53, IκBα, and RanGAP1.
Physiological closed-loop controlled (PCLC) medical devices, such as those designed for blood pressure regulation, can be tested for safety and efficacy in real-world clinical settings. However, ...relying solely on limited animal and clinical studies may not capture the diverse range of physiological conditions. Credible mathematical models can complement these studies by allowing the testing of the device against simulated patient scenarios. This research involves the development and validation of a low-order lumped-parameter mathematical model of the cardiovascular system's response to fluid perturbation. The model takes rates of hemorrhage and fluid infusion as inputs and provides hematocrit and blood volume, heart rate, stroke volume, cardiac output and mean arterial blood pressure as outputs. The model was calibrated using data from 27 sheep subjects, and its predictive capability was evaluated through a leave-one-out cross-validation procedure, followed by independent validation using 12 swine subjects. Our findings showed small model calibration error against the training dataset, with the normalized root-mean-square error (NRMSE) less than 10% across all variables. The mathematical model and virtual patient cohort generation tool demonstrated a high level of predictive capability and successfully generated a sufficient number of subjects that closely resembled the test dataset. The average NRMSE for the best virtual subject, across two distinct samples of virtual subjects, was below 12.7% and 11.9% for the leave-one-out cross-validation and independent validation dataset. These findings suggest that the model and virtual cohort generator are suitable for simulating patient populations under fluid perturbation, indicating their potential value in PCLC medical device evaluation.
A significant portion of the increased risk of cancer and respiratory disease from exposure to cigarette smoke is attributed to volatile organic compounds (VOCs). In this study, 21 VOCs were ...quantified in mainstream cigarette smoke from 50U.S. domestic brand varieties that included high market share brands and 2 Kentucky research cigarettes (3R4F and 1R5F).
Mainstream smoke was generated under ISO 3308 and Canadian Intense (CI) smoking protocols with linear smoking machines with a gas sampling bag collection followed by solid phase microextraction/gas chromatography/mass spectrometry (SPME/GC/MS) analysis.
For both protocols, mainstream smoke VOC amounts among the different brand varieties were strongly correlated between the majority of the analytes. Overall, Pearson correlation (r) ranged from 0.68 to 0.99 for ISO and 0.36 to 0.95 for CI. However, monoaromatic compounds were found to increase disproportionately compared to unsaturated, nitro, and carbonyl compounds under the CI smoking protocol where filter ventilation is blocked.
Overall, machine generated "vapor phase" amounts (µg/cigarette) are primarily attributed to smoking protocol (e.g., blocking of vent holes, puff volume, and puff duration) and filter ventilation. A possible cause for the disproportionate increase in monoaromatic compounds could be increased pyrolysis under low oxygen conditions associated with the CI protocol.
This is the most comprehensive assessment of volatile organic compounds (VOCs) in cigarette smoke to date, encompassing 21 toxic VOCs, 50 different cigarette brand varieties, and 2 different machine smoking protocols (ISO and CI). For most analytes relative proportions remain consistent among U.S. cigarette brand varieties regardless of smoking protocol, however the CI smoking protocol did cause up to a factor of 6 increase in the proportion of monoaromatic compounds. This study serves as a basis to assess VOC exposure as cigarette smoke is a principle source of overall population-level VOC exposure in the United States.
Aims
Systematic annual screening to detect sight‐threatening diabetic retinopathy (STDR) is established in the United Kingdom. We designed an observational cohort study to provide up‐to‐date data for ...policy makers and clinical researchers on incidence of key screening endpoints in people with diabetes attending one screening programme running for over 30 years.
Methods
All people with diabetes aged ≥12 years registered with general practices in the Liverpool health district were offered inclusion. Data sources comprised: primary care (demographics, systemic risk factors), Liverpool Diabetes Eye Screening Programme (retinopathy grading), Hospital Eye Services (slit lamp biomicroscopy assessment of screen positives).
Results
133,366 screening episodes occurred in 28,384 people over 11 years. Overall incidences were: screen positive 6.7% (95% CI 6.5–6.8), screen positive for retinopathy 3.1% (3.0–3.1), unassessable images 2.6% (2.5–2.7), other significant eye diseases 1.0% (1.0–1.1). 1.6% (1.6–1.7) had sight‐threatening retinopathy confirmed by slit lamp biomicroscopy. The annual incidence of screen positive and screen positive for retinopathy showed consistent declines from 8.8%–10.6% and 4.4%–4.6% in 2007/09 to 4.4%–6.8% and 2.3%–2.9% in 2013/17, respectively. Rates of STDR (true positive) were consistently below 2% after 2008/09. Screen positive rates were higher in first time attenders (9.9% 9.4–10.2 vs. 6.1% 6.0–6.2) in part due to ungradeable images (4.1% vs. 2.3%) and other eye disease (2.4% vs. 0.8%). 4.5% (3.9–5.2) of previous non‐attenders had sight‐threatening retinopathy. Compared with people with type 2 diabetes, those with type 1 disease demonstrated higher rates of screen positive (11.9% vs. 6.0%) and STDR (6.4% vs. 1.2%). Overall prevalence of any retinopathy was 27.2% (27.0–27.4).
Conclusions
In an established screening programme with a stable population screen, positive rates show a consistent fall over time to a low level. Of those who are screen positive, fewer than 50% are screen positive for diabetic retinopathy. Most are due to sight threatening maculopathy. The annual incidence of STDR is under 2% suggesting future work on redefining screen positive and supporting extended intervals for people at low risk. Higher rates of screen positive and STDR are seen in first time attenders. Those who have never attended for screening should be specifically targeted.
Increasing evidence indicates that neurodegenerative diseases, including Alzheimer's disease (AD), are a product of gene-by-environment interplay. The immune system is a major contributor mediating ...these interactions. Signaling between peripheral immune cells and those within the microvasculature and meninges of the central nervous system (CNS), at the blood-brain barrier, and in the gut likely plays an important role in AD. The cytokine tumor necrosis factor (TNF) is elevated in AD patients, regulates brain and gut barrier permeability, and is produced by central and peripheral immune cells. Our group previously reported that soluble TNF (sTNF) modulates cytokine and chemokine cascades that regulate peripheral immune cell traffic to the brain in young 5xFAD female mice, and in separate studies that a diet high in fat and sugar (HFHS) dysregulates signaling pathways that trigger sTNF-dependent immune and metabolic responses that can result in metabolic syndrome, which is a risk factor for AD. We hypothesized that sTNF is a key mediator of peripheral immune cell contributions to gene-by-environment interactions to AD-like pathology, metabolic dysfunction, and diet-induced gut dysbiosis.
Female 5xFAD mice were subjected to HFHS diet for 2 months and then given XPro1595 to inhibit sTNF for the last month or saline vehicle. We quantified immune cell profiles by multi-color flow cytometry on cells isolated from brain and blood; metabolic, immune, and inflammatory mRNA and protein marker biochemical and immunhistological analyses, gut microbiome, and electrophysiology in brain slices were also performed.
Here, we show that selective inhibition of sTNF signaling via the biologic XPro1595 modulates the effects of an HFHS diet in 5xFAD mice on peripheral and central immune profiles including CNS-associated CD8+ T cells, the composition of gut microbiota, and long-term potentiation deficits.
Obesogenic diet induces immune and neuronal dysfunction in 5xFAD mice and sTNF inhibition mitigates its effects. A clinical trial in subjects at risk for AD due to genetic predisposition and underlying inflammation associated with peripheral inflammatory co-morbidities will be needed to investigate the extent to which these findings translate to the clinic.
Mutations in copper, zinc superoxide dismutase (SOD) have been implicated in the selective death of motor neurons in 2 percent of amyotrophic lateral sclerosis (ALS) patients. The loss of zinc from ...either wild-type or ALS-mutant SODs was sufficient to induce apoptosis in cultured motor neurons. Toxicity required that copper be bound to SOD and depended on endogenous production of nitric oxide. When replete with zinc, neither ALS-mutant nor wild-type copper, zinc SODs were toxic, and both protected motor neurons from trophic factor withdrawal. Thus, zinc-deficient SOD may participate in both sporadic and familial ALS by an oxidative mechanism involving nitric oxide.
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