Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response

Objective: Cyclooxygenase (COX)-2 is a key regulatory enzyme in the synthesis of prostanoids associated with trauma and inflammation. We investigated the COX-2 gene for functional variants that may influence susceptibility to disease. Methods and results: The promoter of COX-2 was screened for variants in healthy subjects by use of polymerase chain reaction-based methods. Promoter activity was investigated by using reporter expression experiments in human lung fibroblasts. Patients undergoing coronary artery bypass graft surgery, with measurements of plasma markers linked to COX-2 activity, were genotyped for association studies. A common COX-2 promoter variant, -765G>C, was found and shown to be carried by >25% of a group of healthy UK subjects. The -765C allele had significantly lower promoter activity compared with -765G, basally (28±3% lower, P<0.005) and in serum-stimulated cells (31±2% lower, P<0.005). In patients subjected to coronary artery bypass graft surgery, the magnitude of rise in levels of C-reactive protein (CRP) was strongly genotype dependent. Compared with -765G homozygotes, patients carrying the -765C allele had significantly lower plasma CRP levels at 1 to 4 days after surgery (14% lower at the peak of CRP levels on day 3, P<0.05 for all time points). Conclusions: For several acute and chronic inflammatory diseases, -765G>C may influence the variability of response observed

Improvements in Circumpolar Southern Hemisphere Extratropical Atmospheric Circulation in CMIP6 Compared to CMIP5

One of the major globally relevant systematic biases in previous generations of climate models has been an equatorward bias in the latitude of the Southern Hemisphere (SH) mid‐latitude tropospheric eddy driven westerly jet. The far reaching implications of this for Southern Ocean heat and carbon uptake and Antarctic land and sea ice are key reasons why addressing this bias is a high priority. It is therefore of primary importance to evaluate the representation of the SH westerly jet in the latest generation of global climate and earth‐system models that comprise the Coupled Model Intercomparison Project Phase 6 (CMIP6). In this paper we assess the representation of major indices of SH extratropical atmospheric circulation in CMIP6 by comparison against both observations and the previous generation of CMIP5 models. Indices assessed are the latitude and speed of the westerly jet, variability of the Southern Annular Mode (SAM) and representation of the Amundsen Sea Low (ASL). These are calculated from the historical forcing simulations of both CMIP5 and CMIP6 for time periods matching available observational and reanalysis datasets. From the 39 CMIP6 models available at the time of writing there is an overall reduction in the equatorward bias of the annual mean westerly jet from 1.9° in CMIP5 to 0.4° in CMIP6 and from a seasonal perspective the reduction is clearest in austral spring and summer. This is accompanied by a halving of the bias of SAM decorrelation timescales compared to CMIP5. However, no such overall improvements are evident for the ASL

Reproducibility of quantitative indices of lung function and microstructure from 129Xe chemical shift saturation recovery (CSSR) MR spectroscopy

Purpose To evaluate the reproducibility of indices of lung microstructure and function derived from 129Xe chemical shift saturation recovery (CSSR) spectroscopy in healthy volunteers and patients with chronic obstructive pulmonary disease (COPD), and to study the sensitivity of CSSR-derived parameters to pulse sequence design and lung inflation level. Methods Preliminary data were collected from five volunteers on three occasions, using two implementations of the CSSR sequence. Separately, three volunteers each underwent CSSR at three different lung inflation levels. After analysis of these preliminary data, five COPD patients were scanned on three separate days, and nine age-matched volunteers were scanned three times on one day, to assess reproducibility. Results CSSR-derived alveolar septal thickness (ST) and surface-area-to-volume (S/V) ratio values decreased with lung inflation level (P < 0.001; P = 0.057, respectively). Intra-subject standard deviations of ST were lower than the previously measured differences between volunteers and subjects with interstitial lung disease. The mean coefficient of variation (CV) values of ST were 3.9 ± 1.9% and 6.0 ± 4.5% in volunteers and COPD patients, respectively, similar to CV values for whole-lung carbon monoxide diffusing capacity. The mean CV of S/V in volunteers and patients was 14.1 ± 8.0% and 18.0 ± 19.3%, respectively. Conclusion 129Xe CSSR presents a reproducible method for estimation of alveolar septal thickness

Regional ventilation changes in the lung: Treatment response mapping by using hyperpolarized gas MR imaging as a quantitative biomarker

Purpose: To assess the magnitude of regional response to respiratory therapeutics in the lungs using Treatment Response Mapping (TRM) with hyperpolarized gas MRI. TRM is used to quantify regional physiological response in asthmatic adults using a bronchodilator challenge. Methods: The study was approved by the national research ethics committee and performed with informed consent. Imaging was performed in 20 adult asthmatic patients using hyperpolarized 3He ventilation MRI. Two sets of baseline images were acquired before inhalation of a bronchodilator (Inhaled Salbutamol 400 mcg) and one set was acquired after. All images were registered for voxelwise comparison. Regional treatment response, ΔR(r), is calculated as the difference in regional gas distribution (R(r) = ratio of inhaled gas to total volume of a voxel when normalized for lung inflation volume) before and after intervention. A voxelwise activation threshold from the variability of the baseline images was applied to ΔR(r) maps. The summed global TRM (ΔRnet) was then used as global lung index for comparison with metrics of bronchodilator response measured using spirometry and the global imaging metric, percentage ventilated volume (%VV). Results: ΔRnet showed significant correlation (p<0.01) with changes in FEV1 (r=0.70), FVC (r=0.84) and %VV (r=0.56). A significant (p<0.01) positive treatment effect was detected by all metrics, however ΔRnet showed a lower inter-subject coefficient of variation (CV=64%) than all of the other tests (CV≥99%). Conclusions: TRM provides regional quantitative information on changes in inhaled gas ventilation in response to therapy. This method could be used as sensitive regional outcome metric of novel respiratory interventions. Online supplemental material is available for this article

THE AMUNDSEN SEA LOW Variability, Change, and Impact on Antarctic Climate

The Amundsen Sea low (ASL) is a climatological low pressure center that exerts considerable influence on the climate of West Antarctica. Its potential to explain important recent changes in Antarctic climate, for example, in temperature and sea ice extent, means that it has become the focus of an increasing number of studies. Here, the authors summarize the current understanding of the ASL, using reanalysis datasets to analyze recent variability and trends, as well as ice-core chemistry and climate model projections, to examine past and future changes in the ASL, respectively. The ASL has deepened in recent decades, affecting the climate through its influence on the regional meridional wind field, which controls the advection of moisture and heat into the continent. Deepening of the ASL in spring is consistent with observed West Antarctic warming and greater sea ice extent in the Ross Sea. Climate model simulations for recent decades indicate that this deepening is mediated by tropical variability while climate model projections through the twenty-first century suggest that the ASL will deepen in some seasons in response to greenhouse gas concentration increases

Can current reanalyses accurately portray changes in Southern Annular Mode structure prior to 1979?

Early reanalyses are less than optimal for investigating the regional effects of ozone depletion on Southern Hemisphere (SH) high-latitude climate because the availability of satellite sounder data from 1979 significantly improved their accuracy in data sparse regions, leading to a coincident inhomogeneity. To determine whether current reanalyses are better at SH high-latitudes in the pre-satellite era, here we examine the capabilities of the European Centre for Medium-range Weather Forecasts (ECMWF) fifth generation reanalysis (ERA5), the Twentieth Century Reanalysis version 3 (20CRv3), and the Japanese Meteorological Agency (JMA) 55-year reanalysis (JRA-55) to reproduce and help explain the pronounced change in the relationship between the Southern Annular Mode (SAM) and Antarctic near-surface air temperatures (SAT) between 1950 and 1979 (EARLY period) and 1980–2020 (LATE period). We find that ERA5 best reproduces Antarctic SAT in the EARLY period and is also the most homogeneous reanalysis across the EARLY and LATE periods. ERA5 and 20CRv3 provide a good representation of SAM in both periods with JRA-55 only similarly skilful in the LATE period. Nevertheless, all three reanalyses show the marked change in Antarctic SAM-SAT relationships between the two periods. In particular, ERA5 and 20CRv3 demonstrate the observed switch in the sign of the SAM-SAT relationship in the Antarctic Peninsula: analysis of changes in SAM structure and associated meridional wind anomalies reveal that in these reanalyses positive SAM is linked to cold southerly winds during the EARLY period and warm northerly winds in the LATE period, thus providing a simple explanation for the regional SAM-SAT relationship reversal

Patterns of regional lung physiology in cystic fibrosis using ventilation magnetic resonance imaging and multiple-breath washout

Hyperpolarised helium-3 (3He) ventilation magnetic resonance imaging (MRI) and multiple-breath washout (MBW) are sensitive methods for detecting lung disease in cystic fibrosis (CF). We aimed to explore their relationship across a broad range of CF disease severity and patient age, as well as assess the effect of inhaled lung volume on ventilation distribution.32 children and adults with CF underwent MBW and 3He-MRI at a lung volume of end-inspiratory tidal volume (EIVT). In addition, 28 patients performed 3He-MRI at total lung capacity. 3He-MRI scans were quantitatively analysed for ventilation defect percentage (VDP), ventilation heterogeneity index (VHI) and the number and size of individual contiguous ventilation defects. From MBW, the lung clearance index, convection-dependent ventilation heterogeneity (Scond) and convection-diffusion-dependent ventilation heterogeneity (Sacin) were calculated.VDP and VHI at EIVT strongly correlated with lung clearance index (r=0.89 and r=0.88, respectively), Sacin (r=0.84 and r=0.82, respectively) and forced expiratory volume in 1 s (FEV1) (r=-0.79 and r=-0.78, respectively). Two distinct 3He-MRI patterns were highlighted: patients with abnormal FEV1 had significantly (p<0.001) larger, but fewer, contiguous defects than those with normal FEV1, who tended to have numerous small volume defects. These two MRI patterns were delineated by a VDP of ∼10%. At total lung capacity, when compared to EIVT, VDP and VHI reduced in all subjects (p<0.001), demonstrating improved ventilation distribution and regions of volume-reversible and nonreversible ventilation abnormalities

A within farm clinical trial to compare two treatments (parenteral antibacterials and hoof trimming) for sheep lame with footrot

From observational studies, farmers who use parenteral antibacterials to promptly treat all sheep with footrot (FR) or interdigital dermatitis (ID) have a prevalence of lameness of <2% compared with a prevalence of 9% lameness reported by farmers who treat lame sheep by trimming affected feet. We tested the hypothesis that prompt treatment of sheep lame with naturally developing FR or ID with parenteral and topical antibacterials reduces the prevalence and incidence of lameness with these conditions compared with less frequent treatment with trimming of hoof horn and applying topical antibacterials. A further hypothesis was that reduction of ID and FR would improve productivity. A lowland sheep flock with 700 ewes was used to test these hypotheses in an 18-month within farm clinical trial with four groups of ewes: two intervention and two control. The duration and severity of lameness was used to categorise sheep into three weighted scores of lameness (WLS): never lame (WLS0), mildly lame/lame for <6 days (WLS1) and severely or chronically lame (WLS2). The intervention reduced the prevalence of lameness due to FR and ID in ewes and lambs and the incidence of lameness in ewes. The WLS was also significantly lower in sheep in the intervention groups. Ewes with a higher WLS were subsequently significantly more likely to have a body condition score <2.5 and to have lame lambs. Significantly more ewes lambed and successfully reared more lambs that were ready for slaughter at a younger age in the intervention versus control groups. There was an increase in the gross margin of £630/100 ewes mated in the intervention group, including the cost of treatment of £150/100 ewes mated. We conclude that prompt parenteral and topical antibacterial treatment of sheep lame with ID and FR reduced the prevalence and incidence of these infectious conditions and led to improved health, welfare and productivity

Climate reconstruction from paired oxygen-isotope analyses of chironomid larval head capsules and endogenic carbonate (Hawes Water, UK) - Potential and problems

Temperature and the oxygen isotopic composition (δ18O) of meteoric water are both important palaeoclimatic variables, but separating their influences on proxies such as the δ18O of lake carbonates is often problematic. The large temperature variations that are known to have occurred in the northern mid-latitudes during the Late Glacial make this interval an excellent test for a novel approach that combines oxygen-isotope analyses of chironomid larval head capsules with co-occurring endogenic carbonate. We apply this approach to a Late Glacial lake sediment sequence from Hawes Water (NW England). Oxygen-isotope values in chironomid head capsules show marked variations during the Late Glacial that are similar to the oxygen isotope record from endogenic carbonate. However, summer temperature reconstructions based on the paired isotope values and fractionation between chironomids and calcite yield values between −20 and −4 °C, which are unrealistic and far lower than reconstructions based on chironomid assemblages at the same site. The composition of a limited number of samples of fossil chironomid larval head capsules determined using Pyrolysis gas-chromatography mass spectrometry indicates the presence of aliphatic geopolymers, suggesting that diagenetic alteration of the head capsules has systematically biased the isotope-derived temperature estimates. However, a similar trend in the isotope records of the two sources suggests that a palaeoclimate signal is still preserved

Validation of the DECAF score to predict hospital mortality in acute exacerbations of COPD

Background Hospitalisation due to acute exacerbations of COPD (AECOPD) is common, and subsequent mortality high. The DECAF score was derived for accurate prediction of mortality and risk strati fi cation to inform patient care. We aimed to validate the DECAF score, internally and externally, and to compare its performance to other predictive tools. Methods The study took place in the two hospitals within the derivation study (internal validation) and in four additional hospitals (external validation) between January 2012 and May 2014. Consecutive admissions were identi fi ed by screening admissions and searching coding records. Admission clinical data, including DECAF indices, and mortality were recorded. The prognostic value of DECAF and other scores were assessed by the area under the receiver operator characteristic (AUROC) curve. Results In the internal and external validation cohorts, 880 and 845 patients were recruited. Mean age was 73.1 (SD 10.3) years, 54.3% were female, and mean (SD) FEV 1 45.5 (18.3) per cent predicted. Overall mortality was 7.7%. The DECAF AUROC curve for inhospital mortality was 0.83 (95% CI 0.78 to 0.87) in the internal cohort and 0.82 (95% CI 0.77 to 0.87) in the external cohort, and was superior to other prognostic scores for inhospital or 30-day mortality. Conclusions DECAF is a robust predictor of mortality, using indices routinely available on admission. Its generalisability is supported by consistent strong performance; it can identify low-risk patients (DECAF 0 – 1) potentially suitable for Hospital at Home or early supported discharge services, and high-risk patients (DECAF 3 – 6) for escalation planning or appropriate early palliation. Trial registration number UKCRN ID 14214