Mortality study of 18 000 patients treated with omeprazole.

Background: The long term safety of potent gastric acid suppressive therapy has yet to be established. Method: General practice record review at a median interval of 26 months followed by retrieval of details of all deaths within four years using the UK National Health Service Central Registers in 17 936 patients prescribed omeprazole in 1993–1995. Death rates were compared with general population rates. Results: Records of 17 489 patients (97.5%) were examined. A total of 12 703 patients received further scripts for antisecretory drugs, 8097 for omeprazole only (65.6%): 3097 patients have died. All cause mortality was higher in the first year (observed/expected (O/E) 1.44 (95% confidence intervals (CI) 1.34–1.55); p<0.0001) but had fallen to population expectation by the fourth year. There were significant mortality increases in the first year, falling to or below population expectation by the fourth year, for deaths ascribed to neoplasms (1.82 (95% CI 1.58–2.08); p<0.0001), circulatory diseases (1.27 (95% CI 1.13–1.43); p<0.0001), and respiratory diseases (1.37 (95% CI 1.12–1.64); p<0.001). Increased mortality ascribed to digestive diseases (2.56 (95% CI 1.87–3.43); p<0.0001) persisted, although reduced. Increased mortality rates for cancers of the stomach (4.06 (95% CI 2.60–6.04); p<0.0001), colon and rectum (1.40 (95% CI 0.84–2.18); p=0.075), and trachea, bronchus, and lung (1.64 (95% CI 1.19–2.19); p<0.01) seen in the first year had disappeared by the fourth year but that for cancer of the oesophagus had not (O/E 7.35 (95% CI 5.20–10.09) (p<0.0001) in year 1; 2.88 (95% CI 1.62–4.79) (p<0.001) in year 4). Forty of 78 patients dying of oesophageal cancer had the disease present at registration. Twenty seven of those remaining cases had clinical evidence of Barrett’s disease, stricture, ulcer, or oesophagitis at registration (O/E 3.30 (95% CI 2.17–4.80)). Six deaths occurred in patients with hiatal hernia or reflux only (O/E 1.02 (95% CI 0.37–2.22)) and five in patients without oesophageal disease (O/E 0.77 (95% CI 0.25–1.80)). No relationships were detected with numbers of omeprazole scripts received. Conclusions: Increases in mortality associated with treatment are due to pre- existing illness, including pre-existing severe oesophageal disease. There was no evidence of an increased risk of oesophageal adenocarcinoma in those without oesophageal mucosal damage recorded at registration

Elevated anticardiolipin antibodies in acute liver failure

AbstractAntibodies to cardiolipin (aCLA), a phospholipid primarily localized in inner mitochondrial membranes, were transiently elevated (P<0.01) when mice were exposed to an industrial surfactant and then infected with influenza B virus, a model of acute liver failure (ALF). Children with ALF also had elevated levels of aCLA

The JAK inhibitor ruxolitinib reduces inflammation in an ILC3-independent model of innate immune colitis

Innate immunity contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the mechanisms of IBD mediated by innate immunity are incompletely understood and there are limited models of spontaneous innate immune colitis to address this question. Here we describe a new robust model of colitis occurring in the absence of adaptive immunity. RAG1-deficient mice expressing TNFAIP3 in intestinal epithelial cells (TRAG mice) spontaneously developed 100% penetrant, early-onset colitis that was limited to the colon and dependent on intestinal microbes but was not transmissible to co-housed littermates. TRAG colitis was associated with increased mucosal numbers of innate lymphoid cells (ILCs) and depletion of ILC prevented colitis in TRAG mice. ILC depletion also therapeutically reversed established colitis in TRAG mice. The colitis in TRAG mice was not prevented by interbreeding to mice lacking group 3 ILC nor by depletion of TNF. Treatment with the JAK inhibitor ruxolitinib ameliorated colitis in TRAG mice. This new model of colitis, with its predictable onset and colon-specific inflammation, will have direct utility in developing a more complete understanding of innate immune mechanisms that can contribute to colitis and in pre-clinical studies for effects of therapeutic agents on innate immune-mediated IBD

Multi-century trends to wetter winters and drier summers in the England and Wales precipitation series explained by observational and sampling bias in early records

Globally, few precipitation records extend to the 18th century. The England Wales Precipitation (EWP) series is a notable exception with continuous monthly records from 1766. EWP has found widespread use across diverse fields of research including trend detection, evaluation of climate model simulations, as a proxy for mid-latitude atmospheric circulation, a predictor in long-term European gridded precipitation data sets, the assessment of drought and extremes, tree-ring reconstructions and as a benchmark for other regional series. A key finding from EWP has been the multi-centennial trends towards wetter winters and drier summers. We statistically reconstruct seasonal EWP using independent, quality-assured temperature, pressure and circulation indices. Using a sleet and snow series for the UK derived by Profs. Gordon Manley and Elizabeth Shaw to examine winter reconstructions, we show that precipitation totals for pre-1870 winters are likely biased low due to gauge under-catch of snowfall and a higher incidence of snowfall during this period. When these factors are accounted for in our reconstructions, the observed trend to wetter winters in EWP is no longer evident. For summer, we find that pre-1820 precipitation totals are too high, likely due to decreasing network density and less certain data at key stations. A significant trend to drier summers is not robustly present in our reconstructions of the EWP series. While our findings are more certain for winter than summer, we highlight (a) that extreme caution should be exercised when using EWP to make inferences about multi-centennial trends, and; (b) that assessments of 18th and 19th Century winter precipitation should be aware of potential snow biases in early records. Our findings underline the importance of continual re-appraisal of established long-term climate data sets as new evidence becomes available. It is also likely that the identified biases in winter EWP have distorted many other long-term European precipitation series

Statistical comparison of electron loss and enhancement in the outer radiation belt during storms

The near-relativistic electron population in the outer Van Allen radiation belt is highly dynamic and strongly coupled to geomagnetic activity such as storms and substorms, which are driven by the interaction of the magnetosphere with the solar wind. The energy, content and spatial extent of electrons in the outer radiation belt can vary on timescales of hours to days, dictated by the continuously evolving influence of acceleration and loss processes. While net changes in the electron population are directly observable, the relative influence of different processes is far from fully understood. Using a continuous 12-year dataset from the Proton Electron Telescope (PET) on board the Solar Anomalous Magnetospheric Particle Explorer (SAMPEX), we statistically compare the relative variations of trapped electrons to those in the bounce loss cone. Our results show that there is a proportional increase in flux entering the bounce loss cone outside the plasmapause during storm main phase and early recovery phase. Loss enhancement is sustained on the dawnside throughout the recovery phase while loss on the duskside is enhanced around minimum Sym-H and quickly diminishes. Spatial variations are also examined in relation to geomagnetic activity, making comparisons to possible causal wave modes such as whistler-mode chorus and plasmaspheric hiss

The 'dirty dozen' of freshwater science: detecting then reconciling hydrological data biases and errors

Sound water policy and management rests on sound hydrometeorological and ecological data. Conversely, unrepresentative, poorly collected, or erroneously archived data introduce uncertainty regarding the magnitude, rate, and direction of environmental change, in addition to undermining confidence in decision-making processes. Unfortunately, data biases and errors can enter the information flow at various stages, starting with site selection, instrumentation, sampling/measurement procedures, postprocessing and ending with archiving systems. Techniques such as visual inspection of raw data, graphical representation, and comparison between sites, outlier, and trend detection, and referral to metadata can all help uncover spurious data. Tell-tale signs of ambiguous and/or anomalous data are highlighted using 12 carefully chosen cases drawn mainly from hydrology (‘the dirty dozen’). These include evidence of changes in site or local conditions (due to land management, river regulation, or urbanization); modifications to instrumentation or inconsistent observer behavior; mismatched or misrepresentative sampling in space and time; treatment of missing values, postprocessing and data storage errors. Also for raising awareness of pitfalls, recommendations are provided for uncovering lapses in data quality after the information has been gathered. It is noted that error detection and attribution are more problematic for very large data sets, where observation networks are automated, or when various information sources have been combined. In these cases, more holistic indicators of data integrity are needed that reflect the overall information life-cycle and application(s) of the hydrological data

Extreme Birkeland Currents Are More Likely During Geomagnetic Storms on the Dayside of the Earth

We examine the statistical distribution of large-scale Birkeland currents measured by the Active Magnetosphere and Planetary Electrodynamics Response Experiment in four unique categories of geomagnetic activity for the first time: quiet times, storm times, quiet-time substorms, and storm-time substorms. A novel method is employed to sort data into one of these four categories, and the categorizations are provided for future research. The mean current density is largest during substorms and its standard deviation is largest during geomagnetic storms. Current densities which are above a low threshold are more likely during substorms, but extreme currents are far more likely during geomagnetic storms, consistent with a paradigm in which geomagnetic storms represent periods of enhanced variability over quiet times. We demonstrate that extreme currents are most likely to flow within the Region 2 current during geomagnetic storms. This is unexpected in a paradigm of the current systems in which Region 1 current is generally larger

Rapid assessment of antibiotic susceptibility using a fully 3D-printed impedance- based biosensor

The sustained misuse and overuse of antibacterial agents is accelerating the emergence of antimicrobial resistance (AMR), which is becoming one of the major threats to public health. Abuse of antibiotics drives spontaneous evolution, bacterial mutation, and exchange of resistant genes through lateral gene transfer. Mitigating the worldwide impact of AMR requires enhanced antibiotic stewardship through faster diagnostic testing. In this work, we aim to tackle this issue via development of a fully 3D-printed electrochemical, gel-modified biosensor for rapid bacterial growth monitoring. By using electrochemical impedance spectroscopy, we have successfully identified growth profiles and confirmed antibiotic susceptibility of two ESKAPE pathogens, Escherichia coli and Pseudomonas aeruginosa, following overnight culture it was possible to determine antibiotic sensitivity in 90 min, altogether faster than the 24–48 h current gold standard of culture-based antimicrobial susceptibility testing with significant scope for optimisation. Results show a clear distinction between growth profiles in the presence and absence of amoxicillin, gentamicin, and fosfomycin, therefore demonstrating a rapid, cost-efficient platform for phenotypic antibiotic susceptibility testing within clinically relevant concentration ranges for conditions such as urinary tract infections and pneumonia