Pretreatment with beta-blockers and the frequency of hypokalemia in patients with acute chest pain

Plasma potassium concentration was measured at admission in 1234 patients who presented with acute chest pain. One hundred and ninety five patients were on P blockers before admission. The potassium concentrations of patients admitted early (within four hours of onsetof symptoms) were compared with those admitted later (4-18 hours after onset of symptoms). There was a transient fall in plasma potassium concentrations in patients not pre-treated with , B blockers. This was not seen in patients who had been on P blockers before admission. Nonselective, B blockers were more effective than cardioselective agents in maintaining concentrationsof plasma potassium. These findings suggest a mechanism for the beneficial effects of ,B blockers on morbidity and mortality in acute myocardial infarction

Measurement error in a multi-level analysis of air pollution and health: a simulation study.

BACKGROUND: Spatio-temporal models are increasingly being used to predict exposure to ambient outdoor air pollution at high spatial resolution for inclusion in epidemiological analyses of air pollution and health. Measurement error in these predictions can nevertheless have impacts on health effect estimation. Using statistical simulation we aim to investigate the effects of such error within a multi-level model analysis of long and short-term pollutant exposure and health. METHODS: Our study was based on a theoretical sample of 1000 geographical sites within Greater London. Simulations of "true" site-specific daily mean and 5-year mean NO2 and PM10 concentrations, incorporating both temporal variation and spatial covariance, were informed by an analysis of daily measurements over the period 2009-2013 from fixed location urban background monitors in the London area. In the context of a multi-level single-pollutant Poisson regression analysis of mortality, we investigated scenarios in which we specified: the Pearson correlation between modelled and "true" data and the ratio of their variances (model versus "true") and assumed these parameters were the same spatially and temporally. RESULTS: In general, health effect estimates associated with both long and short-term exposure were biased towards the null with the level of bias increasing to over 60% as the correlation coefficient decreased from 0.9 to 0.5 and the variance ratio increased from 0.5 to 2. However, for a combination of high correlation (0.9) and small variance ratio (0.5) non-trivial bias (> 25%) away from the null was observed. Standard errors of health effect estimates, though unaffected by changes in the correlation coefficient, appeared to be attenuated for variance ratios > 1 but inflated for variance ratios < 1. CONCLUSION: While our findings suggest that in most cases modelling errors result in attenuation of the effect estimate towards the null, in some situations a non-trivial bias away from the null may occur. The magnitude and direction of bias appears to depend on the relationship between modelled and "true" data in terms of their correlation and the ratio of their variances. These factors should be taken into account when assessing the validity of modelled air pollution predictions for use in complex epidemiological models

Trophy hunting certification

Adaptive certification is the best remaining option for the trophy hunting industry in Africa to demonstrate sustainable and ethical hunting practices that benefit local communities and wildlife conservation

Coevolved mutations reveal distinct architectures for two core proteins in the bacterial flagellar motor

Switching of bacterial flagellar rotation is caused by large domain movements of the FliG protein triggered by binding of the signal protein CheY to FliM. FliG and FliM form adjacent multi-subunit arrays within the basal body C-ring. The movements alter the interaction of the FliG C-terminal (FliGC) "torque" helix with the stator complexes. Atomic models based on the Salmonella entrovar C-ring electron microscopy reconstruction have implications for switching, but lack consensus on the relative locations of the FliG armadillo (ARM) domains (amino-terminal (FliGN), middle (FliGM) and FliGC) as well as changes during chemotaxis. The generality of the Salmonella model is challenged by the variation in motor morphology and response between species. We studied coevolved residue mutations to determine the unifying elements of switch architecture. Residue interactions, measured by their coevolution, were formalized as a network, guided by structural data. Our measurements reveal a common design with dedicated switch and motor modules. The FliM middle domain (FliMM) has extensive connectivity most simply explained by conserved intra and inter-subunit contacts. In contrast, FliG has patchy, complex architecture. Conserved structural motifs form interacting nodes in the coevolution network that wire FliMM to the FliGC C-terminal, four-helix motor module (C3-6). FliG C3-6 coevolution is organized around the torque helix, differently from other ARM domains. The nodes form separated, surface-proximal patches that are targeted by deleterious mutations as in other allosteric systems. The dominant node is formed by the EHPQ motif at the FliMMFliGM contact interface and adjacent helix residues at a central location within FliGM. The node interacts with nodes in the N-terminal FliGc α-helix triad (ARM-C) and FliGN. ARM-C, separated from C3-6 by the MFVF motif, has poor intra-network connectivity consistent with its variable orientation revealed by structural data. ARM-C could be the convertor element that provides mechanistic and species diversity.JK was supported by Medical Research Council grant U117581331. SK was supported by seed funds from Lahore University of Managment Sciences (LUMS) and the Molecular Biology Consortium

Prognostic role of serum cytokeratin 19 fragments in advanced non-small-cell lung cancer: association of marker changes after two chemotherapy cycles with different measures of clinical response and survival

Prognostic implication of serum cytokeratin 19 fragments (CYFRA 21-1) was explored in 60 advanced NSCLC patients, whereas in 45 patients assessable for serological response a ⩾35% CYFRA 21-1 decline after two chemotherapy cycles was strongly associated with non-progression (NP), defined as a sum of objective response (OR)+stable disease (P<0.0001) and survival (P=0.0002). Association of OR with survival was not significant. In multivariate survival analysis, ⩾35% marker decline and radiological NP status were found as major determinants of prolonged survival with RR: 0.37 (P=0.01) and 0.63 (P=0.01), respectively. In advanced NSCLC patients, NP reflects therapeutic efficacy better than traditional OR. CYFRA 21-1 ⩾35% decline seems to be a reliable surrogate marker of treatment efficacy in terms of survival

Acute lymphoblastic leukemia subsequent to temozolomide use in a 26-year-old man: a case report

<p>Abstract</p> <p>Introduction</p> <p>We report the development of acute lymphoblastic leukemia in a patient in whom temozolomide was used for the treatment of a brain tumor. Unlike that of other alkylating agents, the leukemogenic potential of temozolomide is considered to be very low, and very rarely are such cases reported.</p> <p>Case Presentation</p> <p>A 26-year-old Pakistani man who was treated for glioblastoma with temozolomide in an adjuvant setting was diagnosed to have acute lymphoblastic leukemia one year after stopping temozolomide.</p> <p>Conclusion</p> <p>Temozolomide is a highly active agent, used in the management of high-grade brain neoplasms. The agent is generally regarded to be safe, with an acceptable safety profile. Very few cases of myelodysplasia associated with temozolomide use have been reported. We report here the first case of acute lymphoblastic leukemia, which developed in a young man about one year after he finished taking temozolomide. This should provide further insight into a possible toxicity profile of this alkylating agent. This finding should be of interest to physicians in general and to medical oncologists in particular.</p

Time trends of chest pain symptoms and health related quality of life in coronary artery disease

BACKGROUND: There is at present a lack of knowledge of time trends in health related quality of life (HRQL) in common patients with coronary artery disease (CAD) treated in ordinary care. The objective of this study is to assess and compare time trends of health related quality of life (HRQL) and chest pain in patients with coronary artery disease. METHODS: 253 consecutive CAD patients in Stockholm County, Sweden – 197 males/56 females; 60 ± 8 years – were followed during two years. Perceived chest pain symptoms and three global assessments of HRQL were assessed at baseline, after one and after two years. EuroQol-5 dimension (EQ-5D) with a predefined focus on function and symptoms; the broader tapping global estimates of HRQL; EuroQol VAS (EQ-VAS) and Cardiac Health Profile (CHP) were used. Chest pain was ranked according to Canadian Cardiovascular Society (CCS). Change in HRQL was analysed by a repeated measurements ANOVA and chest pain symptoms were analysed by Friedman non-parametric ANOVA. RESULTS: Perceived chest pain decreased during the two years (p < 0.00022); CCS 0: 41–51%; CCS 1: 19–15%; CCS 2: 31–27%; CCS 3: 5–4% and CCS 4: 4–2%. By contrast, HRQL did not change: EQ-5D: 0.76 (CI 0.73–0.79) -0.78 (CI 0.75–0.81), EQ-VAS: 0.68 (CI 0.66–0.71)-0.68 (CI 0.65–0.71) and CHP: 0.66 (CI 0.64–0.69) -0.66 (CI 0.64–0.69). CONCLUSION: HRQL did not increase despite a reduction in the severity of chest pain during two years. This implies that the major part of HRQL in these consecutive ordinary patients with CAD is unresponsive to change in chest pain symptoms

Designs for clinical trials with time-to-event outcomes based on stopping guidelines for lack of benefit

<p>Abstract</p> <p>background</p> <p>The pace of novel medical treatments and approaches to therapy has accelerated in recent years. Unfortunately, many potential therapeutic advances do not fulfil their promise when subjected to randomized controlled trials. It is therefore highly desirable to speed up the process of evaluating new treatment options, particularly in phase II and phase III trials. To help realize such an aim, in 2003, Royston and colleagues proposed a class of multi-arm, two-stage trial designs intended to eliminate poorly performing contenders at a first stage (point in time). Only treatments showing a predefined degree of advantage against a control treatment were allowed through to a second stage. Arms that survived the first-stage comparison on an intermediate outcome measure entered a second stage of patient accrual, culminating in comparisons against control on the definitive outcome measure. The intermediate outcome is typically on the causal pathway to the definitive outcome (i.e. the features that cause an intermediate event also tend to cause a definitive event), an example in cancer being progression-free and overall survival. Although the 2003 paper alluded to multi-arm trials, most of the essential design features concerned only two-arm trials. Here, we extend the two-arm designs to allow an arbitrary number of stages, thereby increasing flexibility by building in several 'looks' at the accumulating data. Such trials can terminate at any of the intermediate stages or the final stage.</p> <p>Methods</p> <p>We describe the trial design and the mathematics required to obtain the timing of the 'looks' and the overall significance level and power of the design. We support our results by extensive simulation studies. As an example, we discuss the design of the STAMPEDE trial in prostate cancer.</p> <p>Results</p> <p>The mathematical results on significance level and power are confirmed by the computer simulations. Our approach compares favourably with methodology based on beta spending functions and on monitoring only a primary outcome measure for lack of benefit of the new treatment.</p> <p>Conclusions</p> <p>The new designs are practical and are supported by theory. They hold considerable promise for speeding up the evaluation of new treatments in phase II and III trials.</p