Evidence for changes in historic and future groundwater levels in the UK

We examine the evidence for climate-change impacts on groundwater levels provided by studies of the historical observational record, and future climate-change impact modelling. To date no evidence has been found for systematic changes in groundwater drought frequency or intensity in the UK, but some evidence of multi-annual to decadal coherence of groundwater levels and large-scale climate indices has been found, which should be considered when trying to identify any trends. We analyse trends in long groundwater level time-series monitored in seven observation boreholes in the Chalk aquifer, and identify statistically significant declines at four of these sites, but do not attempt to attribute these to a change in a stimulus. The evidence for the impacts of future climate change on UK groundwater recharge and levels is limited. The number of studies that have been undertaken is small and different approaches have been adopted to quantify impacts. Furthermore, these studies have generally focused on relatively small regions and reported local findings. Consequently, it has been difficult to compare them between locations. We undertake some additional analysis of the probabilistic outputs of the one recent impact study that has produced coherent multi-site projections of changes in groundwater levels. These results suggest reductions in annual and average summer levels, and increases in average winter levels, by the 2050s under a high greenhouse gas emissions scenario, at most of the sites modelled, when expressed by the median of the ensemble of simulations. It is concluded, however, that local hydrogeological conditions can be an important control on the simulated response to a future climate projection

Rolofylline, an adenosine A1−receptor antagonist, in acute heart failure

Background: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1−receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure. Methods: We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient’s clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes. Results: Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists. Conclusions: Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.

Characterising the vertical separation of shale-gas source rocks and aquifers across England and Wales (UK)

Shale gas is considered by many to have the potential to provide the UK with greater energy security, economic growth and jobs. However, development of a shale gas industry is highly contentious due to environmental concerns including the risk of groundwater pollution. Evidence suggests that the vertical separation between exploited shale units and aquifers is an important factor in the risk to groundwater from shale gas exploitation. A methodology is presented to assess the vertical separation between different pairs of aquifers and shales that are present across England and Wales. The application of the method is then demonstrated for two of these pairs—the Cretaceous Chalk Group aquifer and the Upper Jurassic Kimmeridge Clay Formation, and the Triassic sandstone aquifer and the Carboniferous Bowland Shale Formation. Challenges in defining what might be considered criteria for ‘safe separation’ between a shale gas formation and an overlying aquifer are discussed, in particular with respect to uncertainties in geological properties, aquifer extents and determination of socially acceptable risk levels. Modelled vertical separations suggest that the risk of aquifer contamination from shale exploration will vary greatly between shale–aquifer pairs and between regions and this will need to be considered carefully as part of the risk assessment and management for any shale gas development

A combined clinical and biomarker approach to predict diuretic response in acute heart failure

Background: Poor diuretic response in acute heart failure is related to poor clinical outcome. The underlying mechanisms and pathophysiology behind diuretic resistance are incompletely understood. We evaluated a combined approach using clinical characteristics and biomarkers to predict diuretic response in acute heart failure (AHF). Methods and results: We investigated explanatory and predictive models for diuretic response—weight loss at day 4 per 40 mg of furosemide—in 974 patients with AHF included in the PROTECT trial. Biomarkers, addressing multiple pathophysiological pathways, were determined at baseline and after 24 h. An explanatory baseline biomarker model of a poor diuretic response included low potassium, chloride, hemoglobin, myeloperoxidase, and high blood urea nitrogen, albumin, triglycerides, ST2 and neutrophil gelatinase-associated lipocalin (r2 = 0.086). Diuretic response after 24 h (early diuretic response) was a strong predictor of diuretic response (β = 0.467, P < 0.001; r2 = 0.523). Addition of diuretic response after 24 h to biomarkers and clinical characteristics significantly improved the predictive model (r2 = 0.586, P < 0.001). Conclusions: Biomarkers indicate that diuretic unresponsiveness is associated with an atherosclerotic profile with abnormal renal function and electrolytes. However, predicting diuretic response is difficult and biomarkers have limited additive value. Patients at risk of poor diuretic response can be identified by measuring early diuretic response after 24 h

A network analysis to compare biomarker profiles in patients with and without diabetes mellitus in acute heart failure

Aims: It is unclear whether distinct pathophysiological processes are present among patients with acute heart failure (AHF), with and without diabetes. Network analysis of biomarkers may identify correlative associations that reflect different pathophysiological pathways. Methods and results: We analysed a panel of 48 circulating biomarkers measured within 24 h of admission for AHF in a subset of patients enrolled in the PROTECT trial. In patients with and without diabetes, we performed a network analysis to identify correlations between measured biomarkers. Compared with patients without diabetes (n = 1111), those with diabetes (n = 922) had a higher prevalence of ischaemic heart disease and traditional coronary risk factors. After multivariable adjustment, patients with and without diabetes had significantly different levels of biomarkers across a spectrum of pathophysiological domains, including inflammation (TNFR-1a, periostin), cardiomyocyte stretch (BNP), angiogenesis (VEGFR, angiogenin), and renal function (NGAL, KIM-1) (adjusted P-value <0.05). Among patients with diabetes, network analysis revealed that periostin strongly clustered with C-reactive protein and interleukin-6. Furthermore, renal markers (creatinine and NGAL) closely associated with potassium and glucose. These findings were not seen among patients without diabetes. Conclusion: Patients with AHF and diabetes, compared with those without diabetes, have distinct biomarker profiles. Network analysis suggests that cardiac remodelling, inflammation, and fibrosis are closely associated with each other in patients with diabetes. Furthermore, potassium levels may be sensitive to changes in renal function as reflected by the strong renal–potassium–glucose correlation. These findings were not seen among patients without diabetes and may suggest distinct pathophysiological processes among AHF patients with diabetes

Biomarker profiles of acute heart failure patients with a mid-range ejection fraction

OBJECTIVES: In this study, the authors used biomarker profiles to characterize differences between patients with acute heart failure with a midrange ejection fraction (HFmrEF) and compare them with patients with a reduced (heart failure with a reduced ejection fraction [HFrEF]) and preserved (heart failure with a preserved ejection fraction [HFpEF]) ejection fraction. BACKGROUND: Limited data are available on biomarker profiles in acute HFmrEF. METHODS: A panel of 37 biomarkers from different pathophysiological domains (e.g., myocardial stretch, inflammation, angiogenesis, oxidative stress, hematopoiesis) were measured at admission and after 24 h in 843 acute heart failure patients from the PROTECT trial. HFpEF was defined as left ventricular ejection fraction (LVEF) of ≥50% (n = 108), HFrEF as LVEF of <40% (n = 607), and HFmrEF as LVEF of 40% to 49% (n = 128). RESULTS: Hemoglobin and brain natriuretic peptide levels (300 pg/ml [HFpEF]; 397 pg/ml [HFmrEF]; 521 pg/ml [HFrEF]; ptrend <0.001) showed an upward trend with decreasing LVEF. Network analysis showed that in HFrEF interactions between biomarkers were mostly related to cardiac stretch, whereas in HFpEF, biomarker interactions were mostly related to inflammation. In HFmrEF, biomarker interactions were both related to inflammation and cardiac stretch. In HFpEF and HFmrEF (but not in HFrEF), remodeling markers at admission and changes in levels of inflammatory markers across the first 24 h were predictive for all-cause mortality and rehospitalization at 60 days (pinteraction <0.05). CONCLUSIONS: Biomarker profiles in patients with acute HFrEF were mainly related to cardiac stretch and in HFpEF related to inflammation. Patients with HFmrEF showed an intermediate biomarker profile with biomarker interactions between both cardiac stretch and inflammation markers. (PROTECT-1: A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function; NCT00328692)

Serum potassium levels and outcome in acute heart failure (data from the PROTECT and COACH trials)

Serum potassium is routinely measured at admission for acute heart failure (AHF), but information on association with clinical variables and prognosis is limited. Potassium measurements at admission were available in 1,867 patients with AHF in the original cohort of 2,033 patients included in the Patients Hospitalized with acute heart failure and Volume Overload to Assess Treatment Effect on Congestion and Renal FuncTion trial. Patients were grouped according to low potassium (<3.5 mEq/l), normal potassium (3.5 to 5.0 mEq/l), and high potassium (>5.0 mEq/l) levels. Results were verified in a validation cohort of 1,023 patients. Mean age of patients was 71 – 11 years, and 66% were men. Low potassium was present in 115 patients (6%), normal potassium in 1,576 (84%), and high potassium in 176 (9%). Potassium levels increased during hospitalization (0.18 – 0.69 mEq/l). Patients with high potassium more often used angiotensin-converting enzyme inhibitors and mineralocorticoid receptor antagonists before admission, had impaired baseline renal function and a better diuretic response (p [ 0.005), independent of mineralocorticoid receptor antagonist usage. During 180-day follow-up, a total of 330 patients (18%) died. Potassium levels at admission showed a univariate linear association with mortality (hazard ratio [log] 2.36, 95% confidence interval 1.07 to 5.23; p [ 0.034) but not after multivariate adjustment. Changes of potassium levels during hospitalization or potassium levels at discharge were not associated with outcome after multivariate analysis. Results in the validation cohort were similar to the index cohort. In conclusion, high potassium levels at admission are associated with an impaired renal function but a better diuretic response. Changes in potassium levels are common, and overall levels increase during hospitalization. In conclusion, potassium levels at admission or its change during hospitalization are not associated with mortality after multivariate adjustment

Can Acute Galactic Cosmic Radiation-Induced Bone Loss Be Mitigated By Dietary Modulation Of Inflammatory Cytokines?

The space environment includes weightlessness and galactic cosmic radiation (GCR), both of which can have a negative impact on bone parameters. In particular, acute exposures to space-relevant doses (2 Gy or less) of simulated GCR lead to a rapid acceleration of bone resorption activity and suppression of bone forming osteoblasts, resulting in diminished bone mineral density (BMD), strength and altered microarchitecture. A key mechanism driving these changes may be a radiation-induced increase in pro-inflammatory cytokines, such as TNF-α. Consuming a diet rich in omega-3 fatty acids has been associated with attenuated reductions in bone parameters in astronauts, mice and elderly humans with corresponding reductions in circulating inflammatory cytokines. PURPOSE: To test the hypothesis thata diet high in omega-3 fatty acids will mitigate radiation-induced bone loss and reduce inflammatory cytokines in bone osteocytes and serum. METHODS: Adult (30- to 50-week-old) female Lgr5-EGFP C57BL/6 mice (n=4-6 per group) were acclimated to a corn oil/cellulose (COC) or fish oil/pectin (FOP) diet for 3 weeks. Animals were subsequently randomized to total body low dose high-energy radiation (0.1, 0.25, 0.5 Gy of 1000 MeV/n 56Fe at 25 cGy/min at Brookhaven National Lab) or non-irradiated control (sham) and euthanized 8 weeks later. MicroCT (ScanCo, Switzerland) analyses were performed to assess bone geometry and microarchitecture at the mid-shaft and distal end of the femur. Significance was assessed using an αof 0.10. RESULTS:There was a significant main effect of diet on mid-shaft femur periosteal diameter (Peri.Dm) (p=0.001) and endocortical diameter (Endo. Dm.) (p\u3c0.001). The FOP diet led to larger Peri.Dm. (p\u3c0.051 for all) and Endo.Dm. (p\u3c0.41 for all) than did the COC diet at all doses. We could not detect an impact of 56Fe on cortical area or cancellous bone volume at the distal femur. Irradiation with 0.25 and 0.5 Gy in the FOP mice showed significant increases in distal femur volumetric BMD (p=0.014, p=0.063) and trabecular thickness (p=0.058, p=0.028), as compared with sham FOP mice. CONCLUSION: Though we did not detect a significant impact of radiation on bone parameters, these early data analyses suggest some modest benefits from a diet high in omega-3 fatty acids on cortical and cancellous bone parameters