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

Effect of P2X4 and P2X7 receptor antagonism on the pressure diuresis relationship in rats.

Reduced glomerular filtration, hypertension and renal microvascular injury are hallmarks of chronic kidney disease, which has a global prevalence of ~10%. We have shown previously that the Fischer (F344) rat has lower GFR than the Lewis rat, and is more susceptible to renal injury induced by hypertension. In the early stages this injury is limited to the pre-glomerular vasculature. We hypothesized that poor renal hemodynamic function and vulnerability to vascular injury are causally linked and genetically determined. In the present study, normotensive F344 rats had a blunted pressure diuresis relationship, compared with Lewis rats. A kidney microarray was then interrogated using the Endeavour enrichment tool to rank candidate genes for impaired blood pressure control. Two novel candidate genes, P2rx7 and P2rx4, were identified, having a 7- and 3- fold increased expression in F344 rats. Immunohistochemistry localized P2X4 and P2X7 receptor expression to the endothelium of the pre-glomerular vasculature. Expression of both receptors was also found in the renal tubule; however there was no difference in expression profile between strains. Brilliant Blue G (BBG), a relatively selective P2X7 antagonist suitable for use in vivo, was administered to both rat strains. In Lewis rats, BBG had no effect on blood pressure, but increased renal vascular resistance, consistent with inhibition of some basal vasodilatory tone. In F344 rats BBG caused a significant reduction in blood pressure and a decrease in renal vascular resistance, suggesting that P2X7 receptor activation may enhance vasoconstrictor tone in this rat strain. BBG also reduced the pressure diuresis threshold in F344 rats, but did not alter its slope. These preliminary findings suggest a physiological and potential pathophysiological role for P2X7 in controlling renal and/or systemic vascular function, which could in turn affect susceptibility to hypertension-related kidney damage

Combination schemes for turning point prediction

We propose new forecast combination schemes for predicting turning points of business cycles. The combination schemes deal with the forecasting performance of a given set of models and possibly providing better turning point predictions. We consider turning point predictions generated by autoregressive (AR) and Markov-Switching AR models, which are commonly used for business cycle analysis. In order to account for parameter uncertainty we consider a Bayesian approach to both estimation and prediction and compare, in terms of statistical accuracy, the individual models and the combined turning point predictions for the United States and Euro area business cycles

Functional near infrared spectroscopy (fNIRS) to assess cognitive function in infants in rural Africa

Cortical mapping of cognitive function during infancy is poorly understood in low-income countries due to the lack of transportable neuroimaging methods. We have successfully piloted functional near infrared spectroscopy (fNIRS) as a neuroimaging tool in rural Gambia. Four-to-eight month old infants watched videos of Gambian adults perform social movements, while haemodynamic responses were recorded using fNIRS. We found distinct regions of the posterior superior temporal and inferior frontal cortex that evidenced either visual-social activation or vocally selective activation (vocal > non-vocal). The patterns of selective cortical activation in Gambian infants replicated those observed within similar aged infants in the UK. These are the first reported data on the measurement of localized functional brain activity in young infants in Africa and demonstrate the potential that fNIRS offers for field-based neuroimaging research of cognitive function in resource-poor rural communities

Functional near infrared spectroscopy (fNIRS) to assess cognitive function in infants in rural Africa

Cortical mapping of cognitive function during infancy is poorly understood in low-income countries due to the lack of transportable neuroimaging methods. We have successfully piloted functional near infrared spectroscopy (fNIRS) as a neuroimaging tool in rural Gambia. Four-to-eight month old infants watched videos of Gambian adults perform social movements, while haemodynamic responses were recorded using fNIRS. We found distinct regions of the posterior superior temporal and inferior frontal cortex that evidenced either visual-social activation or vocally selective activation (vocal > non-vocal). The patterns of selective cortical activation in Gambian infants replicated those observed within similar aged infants in the UK. These are the first reported data on the measurement of localized functional brain activity in young infants in Africa and demonstrate the potential that fNIRS offers for field-based neuroimaging research of cognitive function in resource-poor rural communities

Nitrogen and sulphur management: challenges for organic sources in temperate agricultural systems

A current global trend towards intensification or specialization of agricultural enterprises has been accompanied by increasing public awareness of associated environmental consequences. Air and water pollution from losses of nutrients, such as nitrogen (N) and sulphur (S), are a major concern. Governments have initiated extensive regulatory frameworks, including various land use policies, in an attempt to control or reduce the losses. This paper presents an overview of critical input and loss processes affecting N and S for temperate climates, and provides some background to the discussion in subsequent papers evaluating specific farming systems. Management effects on potential gaseous and leaching losses, the lack of synchrony between supply of nutrients and plant demand, and options for optimizing the efficiency of N and S use are reviewed. Integration of inorganic and organic fertilizer inputs and the equitable re-distribution of nutrients from manure are discussed. The paper concludes by highlighting a need for innovative research that is also targeted to practical approaches for reducing N and S losses, and improving the overall synchrony between supply and demand

Optimal functional outcome measures for assessing treatment for Dupuytren's disease: A systematic review and recommendations for future practice

This article is available through the Brunel Open Access Publishing Fund. Copyright © 2013 Ball et al.; licensee BioMed Central Ltd.Background: Dupuytren's disease of the hand is a common condition affecting the palmar fascia, resulting in progressive flexion deformities of the digits and hence limitation of hand function. The optimal treatment remains unclear as outcomes studies have used a variety of measures for assessment. Methods: A literature search was performed for all publications describing surgical treatment, percutaneous needle aponeurotomy or collagenase injection for primary or recurrent Dupuytren’s disease where outcomes had been monitored using functional measures. Results: Ninety-one studies met the inclusion criteria. Twenty-two studies reported outcomes using patient reported outcome measures (PROMs) ranging from validated questionnaires to self-reported measures for return to work and self-rated disability. The Disability of Arm, Shoulder and Hand (DASH) score was the most utilised patient-reported function measure (n=11). Patient satisfaction was reported by eighteen studies but no single method was used consistently. Range of movement was the most frequent physical measure and was reported in all 91 studies. However, the methods of measurement and reporting varied, with seventeen different techniques being used. Other physical measures included grip and pinch strength and sensibility, again with variations in measurement protocols. The mean follow-up time ranged from 2 weeks to 17 years. Conclusions: There is little consistency in the reporting of outcomes for interventions in patients with Dupuytren’s disease, making it impossible to compare the efficacy of different treatment modalities. Although there are limitations to the existing generic patient reported outcomes measures, a combination of these together with a disease-specific questionnaire, and physical measures of active and passive individual joint Range of movement (ROM), grip and sensibility using standardised protocols should be used for future outcomes studies. As Dupuytren’s disease tends to recur following treatment as well as extend to involve other areas of the hand, follow-up times should be standardised and designed to capture both short and long term outcomes

Examining intra-rater and inter-rater response agreement: A medical chart abstraction study of a community-based asthma care program

<p>Abstract</p> <p>Background</p> <p>To assess the intra- and inter-rater agreement of chart abstractors from multiple sites involved in the evaluation of an Asthma Care Program (ACP).</p> <p>Methods</p> <p>For intra-rater agreement, 110 charts randomly selected from 1,433 patients enrolled in the ACP across eight Ontario communities were re-abstracted by 10 abstractors. For inter-rater agreement, data abstractors reviewed a set of eight fictitious charts. Data abstraction involved information pertaining to six categories: physical assessment, asthma control, spirometry, asthma education, referral visits, and medication side effects. Percentage agreement and the kappa statistic (κ) were used to measure agreement. Sensitivity and specificity estimates were calculated comparing results from all raters against the gold standard.</p> <p>Results</p> <p>Intra-rater re-abstraction yielded an overall kappa of 0.81. Kappa values for the chart abstraction categories were: physical assessment (κ 0.84), asthma control (κ 0.83), spirometry (κ 0.84), asthma education (κ 0.72), referral visits (κ 0.59) and medication side effects (κ 0.51). Inter-rater abstraction of the fictitious charts produced an overall kappa of 0.75, sensitivity of 0.91 and specificity of 0.89. Abstractors demonstrated agreement for physical assessment (κ 0.88, sensitivity and specificity 0.95), asthma control (κ 0.68, sensitivity 0.89, specificity 0.85), referral visits (κ 0.77, sensitivity 0.88, specificity 0.95), and asthma education (κ 0.49, sensitivity 0.87, specificity 0.77).</p> <p>Conclusion</p> <p>Though collected by multiple abstractors, the results show high sensitivity and specificity and substantial to excellent inter- and intra-rater agreement, assuring confidence in the use of chart abstraction for evaluating the ACP.</p

Proprioception deficiency in articular cartilage lesions of the knee

Purpose: The purpose of this study is to investigate the proprioceptive function of patients with isolated articular cartilage lesions of the knee as compared to normal controls. Methods: The Cartilage group consisted of eight subjects with radiologically and arthroscopically confirmed, isolated, unilateral, articular cartilage lesions of the knee (Outerbridge grade III or IV). They were compared to 50 normal controls. Knee proprioception was assessed by dynamic postural stabilometry using the Biodex Balance SD System. Patient-reported outcome measures (PROMs) were used to evaluate all subjects. Results: Proprioception of the injured knee of the Cartilage group was significantly poorer compared to that of the control group (p < 0.001). A significant proprioceptive deficit also was observed when the uninjured knees of the Cartilage group were compared to those in the Control group (p = 0.003). There was no significant proprioceptive difference between the injured and the contra-lateral uninjured knee of the Cartilage group (p = 0.116). A significant correlation was found between the proprioception measurements of the injured and uninjured knee of the Cartilage group (r = 0.76, p = 0.030). A significant difference was observed in all PROMs (p < 0.001) between the Cartilage and Control groups. Conclusions: Patients with isolated articular cartilage lesions of the knee had a significant proprioceptive deficit as compared to normal controls. The deficiency was profound and even affected the proprioceptive function of the contra-lateral uninjured knee. This study has shown that articular cartilage lesions have a major influence on knee proprioception. However, it remains uncertain as to whether a proprioceptive deficit leads to osteoarthritis or is a consequence of it