Comparison of commonly used methods in random effects meta-analysis:Application to preclinical data in drug discovery research

Background Meta-analysis of preclinical data is used to evaluate the consistency of findings and to inform the design and conduct of future studies. Unlike clinical meta-analysis, preclinical data often involve many heterogeneous studies reporting outcomes from a small number of animals. Here, we review the methodological challenges in preclinical meta-analysis in estimating and explaining heterogeneity in treatment effects.Methods Assuming aggregate-level data, we focus on two topics: (1) estimation of heterogeneity using commonly used methods in preclinical meta-analysis: method of moments (DerSimonian and Laird; DL), maximum likelihood (restricted maximum likelihood; REML) and Bayesian approach; (2) comparison of univariate versus multivariable meta-regression for adjusting estimated treatment effects for heterogeneity. Using data from a systematic review on the efficacy of interleukin-1 receptor antagonist in animals with stroke, we compare these methods, and explore the impact of multiple covariates on the treatment effects.Results We observed that the three methods for estimating heterogeneity yielded similar estimates for the overall effect, but different estimates for between-study variability. The proportion of heterogeneity explained by a covariate is estimated larger using REML and the Bayesian method as compared with DL. Multivariable meta-regression explains more heterogeneity than univariate meta-regression.Conclusions Our findings highlight the importance of careful selection of the estimation method and the use of multivariable meta-regression to explain heterogeneity. There was no difference between REML and the Bayesian method and both methods are recommended over DL. Multiple meta-regression is worthwhile to explain heterogeneity by more than one variable, reducing more variability than any univariate models and increasing the explained proportion of heterogeneity

Study protocol for a randomized controlled trial comparing the efficacy of a specialist and a generic parenting programme for the treatment of preschool ADHD

BACKGROUND: The New Forest Parenting Programme (NFPP) is a home-delivered, evidence-based parenting programme to target symptoms of attention-deficit/hyperactivity disorder (ADHD) in preschool children. It has been adapted for use with 'hard-to-reach' or 'difficult-to-treat' children. This trial will compare the adapted-NFPP with a generic parenting group-based programme, Incredible Years (IY), which has been recommended for children with preschool-type ADHD symptoms.METHODS/DESIGN: This multicentre randomized controlled trial comprises three arms: adapted-NFPP, IY and treatment as usual (TAU). A sample of 329 parents of preschool-aged children with a research diagnosis of ADHD enriched for hard-to-reach and potentially treatment-resistant children will be allocated to the arms in the ratio 3:3:1. Participants in the adapted-NFPP and IY arms receive an induction visit followed by 12 weekly parenting sessions of 1½ hours (adapted-NFPP) or 2½ hours (IY) over 2.5 years. Adapted-NFPP will be delivered as a one-to-one home-based intervention; IY, as a group-based intervention. TAU participants are offered a parenting programme at the end of the study. The primary objective is to test whether the adapted-NFPP produces beneficial effects in terms of core ADHD symptoms. Secondary objectives include examination of the treatment impact on secondary outcomes, a study of cost-effectiveness and examination of the mediating role of treatment-induced changes in parenting behaviour and neuropsychological function. The primary outcome is change in ADHD symptoms, as measured by the parent-completed version of the SNAP-IV questionnaire, adjusted for pretreatment SNAP-IV score. Secondary outcome measures are: a validated index of behaviour during child's solo play; teacher-reported SNAP-IV (ADHD scale); teacher and parent SNAP-IV (ODD) Scale; Eyberg Child Behaviour Inventory - Oppositional Defiant Disorder scale; Revised Client Service Receipt Inventory - Health Economics Costs measure and EuroQol (EQ5D) health-related quality-of-life measure. Follow-up measures will be collected 6 months after treatment for participants allocated to adapted-NFPP and IY.DISCUSSION: This trial will provide evidence as to whether the adapted-NFPP is more effective and cost-effective than the recommended treatment and TAU. It will also provide information about mediating factors (improved parenting and neuropsychological function) and moderating factors (parent and child genetic factors) in any increased benefit.TRIAL REGISTRATION: Current Controlled Trials, ISRCTN39288126.</p

MAGIQ at the W. M. Keck Observatory: initial deployment of a new acquisition, guiding, and image quality monitoring system

The W. M. Keck Observatory has completed the development and initial deployment of MAGIQ, the Multi-function Acquisition, Guiding and Image Quality monitoring system. MAGIQ is an integrated system for acquisition, guiding and image quality measurement for the Keck telescopes. This system replaces the acquisition and guiding hardware and software for existing instruments at the Observatory and is now the standard for visible wavelength band acquisition cameras for future instrumentation. In this paper we report on the final design and implementation of this new system, which includes three major components: a visible wavelength band acquisition camera, image quality measurement capability, and software for acquisition, guiding and image quality monitoring. The overall performance is described, as well as the details of our approach to integrating low order wavefront sensing capability in order to provide closed loop control of telescope focus

Admission Blood Glucose Level and Its Association With Cardiovascular and Renal Complications in Patients Hospitalized With COVID-19

OBJECTIVE: To investigate the association between admission blood glucose levels and risk of in-hospital cardiovascular and renal complications. RESEARCH DESIGN AND METHODS: In this multicenter prospective study of 36,269 adults hospitalized with COVID-19 between 6 February 2020 and 16 March 2021 (N = 143,266), logistic regression models were used to explore associations between admission glucose level (mmol/L and mg/dL) and odds of in-hospital complications, including heart failure, arrhythmia, cardiac ischemia, cardiac arrest, coagulation complications, stroke, and renal injury. Nonlinearity was investigated using restricted cubic splines. Interaction models explored whether associations between glucose levels and complications were modified by clinically relevant factors. RESULTS: Cardiovascular and renal complications occurred in 10,421 (28.7%) patients; median admission glucose level was 6.7 mmol/L (interquartile range 5.8-8.7) (120.6 mg/dL [104.4-156.6]). While accounting for confounders, for all complications except cardiac ischemia and stroke, there was a nonlinear association between glucose and cardiovascular and renal complications. For example, odds of heart failure, arrhythmia, coagulation complications, and renal injury decreased to a nadir at 6.4 mmol/L (115 mg/dL), 4.9 mmol/L (88.2 mg/dL), 4.7 mmol/L (84.6 mg/dL), and 5.8 mmol/L (104.4 mg/dL), respectively, and increased thereafter until 26.0 mmol/L (468 mg/dL), 50.0 mmol/L (900 mg/dL), 8.5 mmol/L (153 mg/dL), and 32.4 mmol/L (583.2 mg/dL). Compared with 5 mmol/L (90 mg/dL), odds ratios at these glucose levels were 1.28 (95% CI 0.96, 1.69) for heart failure, 2.23 (1.03, 4.81) for arrhythmia, 1.59 (1.36, 1.86) for coagulation complications, and 2.42 (2.01, 2.92) for renal injury. For most complications, a modifying effect of age was observed, with higher odds of complications at higher glucose levels for patients age <69 years. Preexisting diabetes status had a similar modifying effect on odds of complications, but evidence was strongest for renal injury, cardiac ischemia, and any cardiovascular/renal complication. CONCLUSIONS: Increased odds of cardiovascular or renal complications were observed for admission glucose levels indicative of both hypo- and hyperglycemia. Admission glucose could be used as a marker for risk stratification of high-risk patients. Further research should evaluate interventions to optimize admission glucose on improving COVID-19 outcomes

Admission Blood Glucose Level and Its Association With Cardiovascular and Renal Complications in Patients Hospitalized With COVID-19

ObjectiveTo investigate the association between admission blood glucose levels and risk of in-hospital cardiovascular and renal complications.Research design and methodsIn this multicenter prospective study of 36,269 adults hospitalized with COVID-19 between 6 February 2020 and 16 March 2021 (N = 143,266), logistic regression models were used to explore associations between admission glucose level (mmol/L and mg/dL) and odds of in-hospital complications, including heart failure, arrhythmia, cardiac ischemia, cardiac arrest, coagulation complications, stroke, and renal injury. Nonlinearity was investigated using restricted cubic splines. Interaction models explored whether associations between glucose levels and complications were modified by clinically relevant factors.ResultsCardiovascular and renal complications occurred in 10,421 (28.7%) patients; median admission glucose level was 6.7 mmol/L (interquartile range 5.8-8.7) (120.6 mg/dL [104.4-156.6]). While accounting for confounders, for all complications except cardiac ischemia and stroke, there was a nonlinear association between glucose and cardiovascular and renal complications. For example, odds of heart failure, arrhythmia, coagulation complications, and renal injury decreased to a nadir at 6.4 mmol/L (115 mg/dL), 4.9 mmol/L (88.2 mg/dL), 4.7 mmol/L (84.6 mg/dL), and 5.8 mmol/L (104.4 mg/dL), respectively, and increased thereafter until 26.0 mmol/L (468 mg/dL), 50.0 mmol/L (900 mg/dL), 8.5 mmol/L (153 mg/dL), and 32.4 mmol/L (583.2 mg/dL). Compared with 5 mmol/L (90 mg/dL), odds ratios at these glucose levels were 1.28 (95% CI 0.96, 1.69) for heart failure, 2.23 (1.03, 4.81) for arrhythmia, 1.59 (1.36, 1.86) for coagulation complications, and 2.42 (2.01, 2.92) for renal injury. For most complications, a modifying effect of age was observed, with higher odds of complications at higher glucose levels for patients age ConclusionsIncreased odds of cardiovascular or renal complications were observed for admission glucose levels indicative of both hypo- and hyperglycemia. Admission glucose could be used as a marker for risk stratification of high-risk patients. Further research should evaluate interventions to optimize admission glucose on improving COVID-19 outcomes

Big data and data repurposing – using existing data to answer new questions in vascular dementia research

Introduction: Traditional approaches to clinical research have, as yet, failed to provide effective treatments for vascular dementia (VaD). Novel approaches to collation and synthesis of data may allow for time and cost efficient hypothesis generating and testing. These approaches may have particular utility in helping us understand and treat a complex condition such as VaD. Methods: We present an overview of new uses for existing data to progress VaD research. The overview is the result of consultation with various stakeholders, focused literature review and learning from the group’s experience of successful approaches to data repurposing. In particular, we benefitted from the expert discussion and input of delegates at the 9th International Congress on Vascular Dementia (Ljubljana, 16-18th October 2015). Results: We agreed on key areas that could be of relevance to VaD research: systematic review of existing studies; individual patient level analyses of existing trials and cohorts and linking electronic health record data to other datasets. We illustrated each theme with a case-study of an existing project that has utilised this approach. Conclusions: There are many opportunities for the VaD research community to make better use of existing data. The volume of potentially available data is increasing and the opportunities for using these resources to progress the VaD research agenda are exciting. Of course, these approaches come with inherent limitations and biases, as bigger datasets are not necessarily better datasets and maintaining rigour and critical analysis will be key to optimising data use

Does pre-enrichment of anodes with acetate to select for Geobacter spp. enhance performance of microbial fuel cells when switched to more complex substrates?

Many factors affect the performance of microbial fuel cells (MFCs). Considerable attention has been given to the impact of cell configuration and materials on MFC performance. Much less work has been done on the impact of the anode microbiota, particularly in the context of using complex substrates as fuel. One strategy to improve MFC performance on complex substrates such as wastewater, is to pre-enrich the anode with known, efficient electrogens, such as Geobacter spp. The implication of this strategy is that the electrogens are the limiting factor in MFCs fed complex substrates and the organisms feeding the electrogens through hydrolysis and fermentation are not limiting. We conducted a systematic test of this strategy and the assumptions associated with it. Microbial fuel cells were enriched using three different substrates (acetate, synthetic wastewater and real domestic wastewater) and three different inocula (Activated Sludge, Tyne River sediment, effluent from an MFC). Reactors were either enriched on complex substrates from the start or were initially fed acetate to enrich for Geobacter spp. before switching to synthetic or real wastewater. Pre-enrichment on acetate increased the relative abundance of Geobacter spp. in MFCs that were switched to complex substrates compared to MFCs that had been fed the complex substrates from the beginning of the experiment (wastewater-fed MFCs - 21.9 ± 1.7% Geobacter spp.; acetate-enriched MFCs, fed wastewater - 34.9 ± 6.7% Geobacter spp.; Synthetic wastewater fed MFCs – 42.5 ± 3.7% Geobacter spp.; acetate-enriched synthetic wastewater-fed MFCs - 47.3 ± 3.9% Geobacter spp.). However, acetate pre-enrichment did not translate into significant improvements in cell voltage, maximum current density, maximum power density or substrate removal efficiency. Nevertheless, coulombic efficiency (CE) was higher in MFCs pre-enriched on acetate when complex substrates were fed following acetate enrichment (wastewater-fed MFCs – CE = 22.0 ± 6.2%; acetate-enriched MFCs, fed wastewater – CE =58.5 ± 3.5%; Synthetic wastewater fed MFCs – CE = 22.0 ± 3.2%; acetate-enriched synthetic wastewater-fed MFCs – 28.7 ± 4.2%.) The relative abundance of Geobacter ssp. and CE represents the average of the nine replicate reactors inoculated with three different inocula for each substrate. Efforts to improve the performance of anodic microbial communities in MFCs utilizing complex organic substrates should therefore focus on enhancing the activity of organisms driving hydrolysis and fermentation rather the terminal-oxidizing electrogens

The feasibility of testing whether Fasciola hepatica is associated with increased risk of verocytotoxin producing Escherichia coli O157 from an existing study protocol

The parasite Fasciola hepatica is a major cause of economic loss to the agricultural community worldwide as a result of morbidity and mortality in livestock, including cattle. Cattle are the principle reservoir of verocytotoxigenic Escherichia coli O157 (VTEC O157), an important cause of disease in humans. To date there has been little empirical research on the interaction between F. hepatica and VTEC O157. It is hypothesised that F. hepatica, which is known to suppress type 1 immune responses and induce an anti-inflammatory or regulatory immune environment in the host, may promote colonisation of the bovine intestine with VTEC O157. Here we assess whether it is statistically feasible to augment a prospective study to quantify the prevalence of VTEC O157 in cattle in Great Britain with a pilot study to test this hypothesis. We simulate data under the framework of a mixed-effects logistic regression model in order to calculate the power to detect an association effect size (odds ratio) of 2. In order to reduce the resources required for such a study, we exploit the fact that the test results for VTEC O157 will be known in advance of testing for F. hepatica by restricting analysis to farms with a VTEC O157 sample prevalence of >0% and <100%. From a total of 270 farms (mean 27 cows per farm) that will be tested for VTEC O157, power of 87% can be achieved, whereby testing of F. hepatica would only be necessary for an expected 50 farms, thus considerably reducing costs. Pre-study sample size calculations are an important part of any study design. The framework developed here is applicable to the study of other co-infections

The MyD88+ phenotype is an adverse prognostic factor in epithelial ovarian cancer

The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p<0.05. MiR-21 and miR-146a expression was significantly increased in MyD88 negative cancers (p<0.05), indicating their participation in regulation. Significant alterations in MyD88 mRNA expression were observed between chemosensitive and chemoresistant cells and tissue. Knockdown of TLR4 in SKOV-3 ovarian cells recovered chemosensitivity. Knockdown of MyD88 alone did not. MyD88 expression was down-regulated in differentiated embryonal carcinoma (NTera2) cells, supporting the MyD88+ cancer stem cell hypothesis. Our findings demonstrate that expression of MyD88 is associated with significantly reduced patient survival and altered microRNA levels and suggest an intact/functioning TLR4/MyD88 pathway is required for acquisition of the chemoresistant phenotype. Ex vivo manipulation of ovarian cancer stem cell (CSC) differentiation can decrease MyD88 expression, providing a potentially valuable CSC model for ovarian cancer

Beverage specific alcohol intake in a population-based study: Evidence for a positive association between pulmonary function and wine intake

BACKGROUND: Lung function is a strong predictor of cardiovascular and all-cause mortality. Previous studies suggest that alcohol exposure may be linked to impaired pulmonary function through oxidant-antioxidant mechanisms. Alcohol may be an important source of oxidants; however, wine contains several antioxidants. In this study we analyzed the relation of beverage specific alcohol intake with forced expiratory volume in one second (FEV(1)) and forced vital capacity (FVC) in a random sample of 1555 residents of Western New York, USA. METHODS: We expressed pulmonary function as percent of predicted normal FEV(1) (FEV(1)%) and FVC (FVC%) after adjustment for height, age, gender and race. To obtain information on alcohol intake we used a questionnaire that reliably queries total alcohol and beverage specific recent (past 30 days) and lifetime alcohol consumption. Results: Using multiple linear regression analysis after adjustment for covariates (pack-years of smoking, weight, smoking status, education, nutritional factors and for FEV(1)%, in addition, eosinophil count), we observed no significant correlation between total alcohol intake and lung function. However, we found positive associations of recent and lifetime wine intake with FEV(1)% and FVC%. When we analyzed white and red wine intake separately, the association of lung function with red wine was weaker than for white wine. CONCLUSION: While total alcohol intake was not related to lung function, wine intake showed a positive association with lung function. Although we cannot exclude residual confounding by healthier lifestyle in wine drinkers, differential effects of alcoholic beverages on lung health may exist