Robust analysis of stepped wedge trials using cluster-level summaries within periods.

In stepped-wedge trials (SWTs), the intervention is rolled out in a random order over more than 1 time-period. SWTs are often analysed using mixed-effects models that require strong assumptions and may be inappropriate when the number of clusters is small. We propose a non-parametric within-period method to analyse SWTs. This method estimates the intervention effect by comparing intervention and control conditions in a given period using cluster-level data corresponding to exposure. The within-period intervention effects are combined with an inverse-variance-weighted average, and permutation tests are used. We present an example and, using simulated data, compared the method to (1) a parametric cluster-level within-period method, (2) the most commonly used mixed-effects model, and (3) a more flexible mixed-effects model. We simulated scenarios where period effects were common to all clusters, and when they varied according to a distribution informed by routinely collected health data. The non-parametric within-period method provided unbiased intervention effect estimates with correct confidence-interval coverage for all scenarios. The parametric within-period method produced confidence intervals with low coverage for most scenarios. The mixed-effects models' confidence intervals had low coverage when period effects varied between clusters but had greater power than the non-parametric within-period method when period effects were common to all clusters. The non-parametric within-period method is a robust method for analysing SWT. The method could be used by trial statisticians who want to emphasise that the SWT is a randomised trial, in the common position of being uncertain about whether data will meet the assumptions necessary for mixed-effect models

Height and risk of death among men and women: aetiological implications of associations with cardiorespiratory disease and cancer mortality

OBJECTIVES: Height is inversely associated with cardiovascular disease mortality risk and has shown variable associations with cancer incidence and mortality. The interpretation of findings from previous studies has been constrained by data limitations. Associations between height and specific causes of death were investigated in a large general population cohort of men and women from the West of Scotland. DESIGN: Prospective observational study. SETTING: Renfrew and Paisley, in the West of Scotland. SUBJECTS: 7052 men and 8354 women aged 45-64 were recruited into a study in Renfrew and Paisley, in the West of Scotland, between 1972 and 1976. Detailed assessments of cardiovascular disease risk factors, morbidity and socioeconomic circumstances were made at baseline. MAIN OUTCOME MEASURES: Deaths during 20 years of follow up classified into specific causes. RESULTS: Over the follow up period 3347 men and 2638 women died. Height is inversely associated with all cause, coronary heart disease, stroke, and respiratory disease mortality among men and women. Adjustment for socioeconomic position and cardiovascular risk factors had little influence on these associations. Height is strongly associated with forced expiratory volume in one second (FEV1) and adjustment for FEV1 considerably attenuated the association between height and cardiorespiratory mortality. Smoking related cancer mortality is not associated with height. The risk of deaths from cancer unrelated to smoking tended to increase with height, particularly for haematopoietic, colorectal and prostate cancers. Stomach cancer mortality was inversely associated with height. Adjustment for socioeconomic position had little influence on these associations. CONCLUSION: Height serves partly as an indicator of socioeconomic circumstances and nutritional status in childhood and this may underlie the inverse associations between height and adulthood cardiorespiratory mortality. Much of the association between height and cardiorespiratory mortality was accounted for by lung function, which is also partly determined by exposures acting in childhood. The inverse association between height and stomach cancer mortality probably reflects Helicobacter pylori infection in childhood resulting inor being associated withshorter height. The positive associations between height and several cancers unrelated to smoking could reflect the influence of calorie intake during childhood on the risk of these cancers

Five questions to consider before conducting a stepped wedge trial.

Researchers should consider five questions before starting a stepped wedge trial. Why are you planning one? Researchers sometimes think that stepped wedge trials are useful when there is little doubt about the benefit of the intervention being tested. However, if the primary reason for an intervention is to measure its effect, without equipoise there is no ethical justification for delaying implementation in some clusters. By contrast, if you are undertaking pragmatic research, where the primary reason for rolling out the intervention is for it to exert its benefits, and if phased implementation is inevitable, a stepped wedge trial is a valid option and provides better evidence than most non-randomized evaluations. What design will you use? Two common stepped wedge designs are based on the recruitment of a closed or open cohort. In both, individuals may experience both control and intervention conditions and you should be concerned about carry-over effects. In a third, continuous-recruitment, short-exposure design, individuals are recruited as they become eligible and experience either control or intervention condition, but not both. How will you conduct the primary analysis? In stepped wedge trials, control of confounding factors through secular variation is essential. 'Vertical' approaches preserve randomization and compare outcomes between randomized groups within periods. 'Horizontal' approaches compare outcomes before and after crossover to the intervention condition. Most analysis models used in practice combine both types of comparison. The appropriate analytic strategy should be considered on a case-by-case basis. How large will your trial be? Standard sample size calculations for cluster randomized trials do not accommodate the specific features of stepped wedge trials. Methods exist for many stepped wedge designs, but simulation-based calculations provide the greatest flexibility. In some scenarios, such as when the intracluster correlation coefficient is moderate or high, or the cluster size is large, a stepped wedge trial may require fewer clusters than a parallel cluster trial. How will you report your trial? Stepped wedge trials are currently challenging to report using CONSORT principles. Researchers should consider how to demonstrate balance achieved by randomization and how to describe trends for outcomes in both intervention and control clusters

A rapid method for the determination of lithium transference numbers

Lithium ion-conducting polymer electrolytes are of increasing interest for use in lithium-polymer batteries. Lithium transference numbers, the net fraction of current carried by lithium in a cell, are key figures of merit for potential lithium battery electrolytes. The authors describe the Electrophoretic NMR (ENMR) method for the determination of lithium ion transference numbers (T{sub Li}). The work presented is a proof-of-concept of the application of the ENMR method to lithium ion transference measurements for several different lithium salts in gelled electrolytes. The NMR method allows accurate determination of T{sub Li} values, as indicated by the similarity of T{sub Li} in the gelled electrolytes to those in aqueous electrolyte solutions at low salt concentration. Based on calculated tradeoffs of various experimental parameters, they also discuss some conclusions concerning the range of applicability of the method to other electrolytes with lower lithium mobility

Cohort analysis of programme data to estimate HIV incidence and uptake of HIV-related services among female sex workers in Zimbabwe, 2009-14.

BACKGROUND: HIV epidemiology and intervention uptake among female sex workers (FSW) in sub-Saharan Africa remain poorly understood. Data from outreach programmes are a neglected resource. METHODS: Analysis of data from FSW consultations with Zimbabwe's National Sex Work programme, 2009-14. At each visit, data were collected on socio-demographic characteristics, HIV testing history, HIV tests conducted by the programme and antiretroviral (ARV) history. Characteristics at first visit and longitudinal data on programme engagement, repeat HIV testing and HIV sero-conversion were analysed using a cohort approach. RESULTS: Data were available for 13360 women, 31389 visits, 14579 reported HIV tests, 2750 tests undertaken by the programme and 2387 reported ARV treatment initiations. At first visit, 72% of FSW had tested for HIV; 50% of these reported being HIV-positive. Among HIV-positive women, 41% reported being on ARV. 56% of FSW attended the programme only once. FSW who had not previously had an HIV positive test had been tested within the last 6 months 27% of the time during follow up. After testing HIV-positive, women started on ARV at a rate of 23 / 100 person years of follow-up. Among those with two or more HIV tests, the HIV sero-conversion rate was 9.8 / 100 person years of follow-up (95% confidence interval 7.1-15.9). CONCLUSIONS: Individual-level outreach programme data can be used to estimate HIV incidence and intervention uptake among FSW in Zimbabwe. Current data suggest very high HIV prevalence and incidence among this group and help identify areas for programme improvement. Further methodological validation is required.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially.<br/

Electrophoretic NMR measurements of lithium transference numbers in polymer gel electrolytes

Polymer gel electrolytes are of increasing interest for plastic lithium batteries largely because of their high room temperature conductivity. Several studies have probed their conductivity and electrochemical stability but very little work has been done related to lithium transference numbers. Lithium ion transference numbers, the net number of Faradays carried by lithium upon the passage of 1 Faraday of charge across a cell, are key figures of merit for any potential lithium battery electrolytes. The authors describe here their application of electrophoretic NMR (ENMR) to the determination of transference numbers of lithium ions in polymer gel electrolytes. Two types of polymer gel electrolytes were selected for this study: PAN/PC/EC/LiX and Kynar/PC/LiX. Results obtained for the two types of gels are compared and the effects of anion, polymer-ion interactions and ion-ion interactions on lithium transference numbers are discussed. Significant differences in the behavior of transference numbers with salt concentration are observed for the two types of gels. This may be due to the extent of interaction between the polymer and the ions. Implications for solid polymer electrolytes are discussed

Trial Protocol: Randomised controlled trial of the effects of very low calorie diet, modest dietary restriction, and sequential behavioural programme on hunger, urges to smoke, abstinence and weight gain in overweight smokers stopping smoking

Background\ud Weight gain accompanies smoking cessation, but dieting during quitting is controversial as hunger may increase urges to smoke. This is a feasibility trial for the investigation of a very low calorie diet (VLCD), individual modest energy restriction, and usual advice on hunger, ketosis, urges to smoke, abstinence and weight gain in overweight smokers trying to quit. \ud \ud Methods\ud This is a 3 armed, unblinded, randomized controlled trial in overweight (BMI > 25 kg/$m^2$), daily smokers (CO > 10 ppm); with at least 30 participants in each group. Each group receives identical behavioural support and NRT patches (25 mg(8 weeks),15 mg(2 weeks),10 mg(2 weeks)). The VLCD group receive a 429-559 kcal/day liquid formula beginning 1 week before quitting and continuing for 4 weeks afterwards. The modest energy restricted group (termed individual dietary and activity planning(IDAP)) engage in goal-setting and receive an energy prescription based on individual basal metabolic rate(BMR) aiming for daily reduction of 600 kcal. The control group receive usual dietary advice that accompanies smoking cessation i.e. avoiding feeling hungry but eating healthy snacks. After this, the VLCD participants receive IDAP to provide support for changing eating habits in the longer term; the IDAP group continues receiving this support. The control group receive IDAP 8 weeks after quitting. This allows us to compare IDAP following a successful quit attempt with dieting concurrently during quitting. It also aims to prevent attrition in the unblinded, control group by meeting their need for weight management. Follow-up occurs at 6 and 12 months. \ud \ud Outcome measures include participant acceptability, measured qualitatively by semi-structured interviewing and quantitatively by recruitment and attrition rates. Feasibility of running the trial within primary care is measured by interview and questionnaire of the treatment providers. Adherence to the VLCD is verified by the presence of urinary ketones measured weekly. Daily urges to smoke, hunger and withdrawal are measured using the Mood and Physical Symptoms Scale-Combined (MPSS-C) and a Hunger Craving Score (HCS). 24 hour, 7 day point prevalence and 4-week prolonged abstinence (Russell Standard) is confirmed by CO < 10 ppm. Weight, waist and hip circumference and percentage body fat are measured at each visit. \ud \ud Trial Registration\ud Current controlled trials ISRCTN83865809\ud \u

Electromigration-Induced Propagation of Nonlinear Surface Waves

Due to the effects of surface electromigration, waves can propagate over the free surface of a current-carrying metallic or semiconducting film of thickness h_0. In this paper, waves of finite amplitude, and slow modulations of these waves, are studied. Periodic wave trains of finite amplitude are found, as well as their dispersion relation. If the film material is isotropic, a wave train with wavelength lambda is unstable if lambda/h_0 < 3.9027..., and is otherwise marginally stable. The equation of motion for slow modulations of a finite amplitude, periodic wave train is shown to be the nonlinear Schrodinger equation. As a result, envelope solitons can travel over the film's surface.Comment: 13 pages, 2 figures. To appear in Phys. Rev.

On nonsupersymmetric \BC^4/\BZ_N, tachyons, terminal singularities and flips

We investigate nonsupersymmetric \BC^4/\BZ_N orbifold singularities using their description in terms of the string worldsheet conformal field theory and its close relation with the toric geometry description of these singularities and their possible resolutions. Analytic and numerical study strongly suggest the absence of nonsupersymmetric Type II terminal singularities (i.e. with no marginal or relevant blowup modes) so that there are always moduli or closed string tachyons that give rise to resolutions of these singularities, although supersymmetric and Type 0 terminal singularities do exist. Using gauged linear sigma models, we analyze the phase structure of these singularities, which often involves 4-dimensional flip transitions, occurring between resolution endpoints of distinct topology. We then discuss 4-dim analogs of unstable conifold-like singularities that exhibit flips, in particular their Type II GSO projection and the phase structure. We also briefly discuss aspects of M2-branes stacked at such singularities and nonsupersymmetric AdS_4\times S^7/\BZ_N backgrounds.Comment: Latex, 43pgs incl. appendices, 2 eps figs, v2. minor clarifications added, to appear in JHE