Evaluation of the Quality of Guidelines for Myasthenia Gravis with the AGREE II Instrument

Background

Clinical practice guidelines (CPGs) are systematically developed statements to assist practitioners in making decisions about appropriate healthcare in specific clinical circumstances. The methodological quality of CPGs for myasthenia gravis (MG) are unclear.

Objective

To critically evaluate the methodological quality of CPGs for MG using AGREE II instrument.

Method

A systematical search strategy on PubMed, EMBASE, DynaMed, the National Guideline Clearinghouse (NGC) and the Chinese Biomedical Literature database (CBM) was performed on September 20th 2013. All guidelines related to MG were evaluated with AGREE II. The software used for analysis was SPSS 17.0.

Results

A total of 15 CPGs for MG met the inclusion criteria (12 CPGs in English, 3 CPGs in Chinese). The overall agreement among reviews was moderate or high (ICC >0.70). The mean scores (mean ± SD) for al six domains were presented as follows: scope and purpose (60.93% ±16.62%), stakeholder involvement (40.93% ±20.04%), rigor of development (37.22% ±30.46%), clarity of presentation (64.26% ±16.36%), applicability (28.19% ±20.56%) and editorial independence (27.78% ±28.28%). Compared with non-evidence-based CPGs, evidence-based CPGs had statistically significant higher quality scores for all AGREE II domains (P<0.05). All domain scores appear slightly higher for CPGs published after AGREE II instrument development and validation (P>0.05). The quality scores of CPGs developed by NGC/AAN were higher than the quality scores of CPGs developed by other organizations for all domains. The difference was statistically significant for all domains with the exception of clarity of presentation (P = 0.07).

Conclusions

The qualities of CPGs on MG were generally acceptable with several flaws. The AGREE II instrument should be adopted by guideline developers, particularly in China.     

Systematic Review of Clinical Practice Guidelines Related to Multiple Sclerosis

Background

High quality clinical practice guidelines (CPGs) can provide clinicians with explicit recommendations on how to manage health conditions and bridge the gap between research and clinical practice. Unfortunately, the quality of CPGs for multiple sclerosis (MS) has not been evaluated.

Objective

To evaluate the methodological quality of CPGs on MS using the AGREE II instrument.

Methods

According to the inclusion and exclusion criteria, we searched four databases and two websites related to CPGs, including the Cochrane library, PubMed, EMBASE, DynaMed, the National Guideline Clearinghouse (NGC), and Chinese Biomedical Literature database (CBM). The searches were performed on September 20th 2013. All CPGs on MS were evaluated by the AGREE II instrument. The software used for analysis was SPSS 17.0.

Results

A total of 27 CPGs on MS met inclusion criteria. The overall agreement among reviews was good or substantial (ICC was above 0.70). The mean scores for each of all six domains were presented as follows: scope and purpose (mean ± SD: 59.05±16.13), stakeholder involvement (mean ± SD: 29.53±17.67), rigor of development (mean ± SD: 31.52±21.50), clarity of presentation (mean ± SD: 60.39±13.73), applicability (mean ± SD: 27.08±17.66), editorial independence (mean ± SD: 28.70±22.03).

Conclusions

The methodological quality of CPGs for MS was acceptable for scope, purpose and clarity of presentation. The developers of CPGs need to pay more attention to editorial independence, applicability, rigor of development and stakeholder involvement during the development process. The AGREE II instrument should be adopted by guideline developers.     

Climate Variability,Weather and Enteric Disease Incidence in New Zealand: Time Series Analysis

Background

Evaluating the influence of climate variability on enteric disease incidence may improve our ability to predict how climate change may affect these diseases.

Objectives

To examine the associations between regional climate variability and enteric disease incidence in New Zealand.

Methods

Associations between monthly climate and enteric diseases (campylobacteriosis, salmonellosis, cryptosporidiosis, giardiasis) were investigated using Seasonal Auto Regressive Integrated Moving Average (SARIMA) models.

Results

No climatic factors were significantly associated with campylobacteriosis and giardiasis, with similar predictive power for univariate and multivariate models. Cryptosporidiosis was positively associated with average temperature of the previous month (β =  0.130, SE =  0.060, p <0.01) and inversely related to the Southern Oscillation Index (SOI) two months previously (β =  −0.008, SE =  0.004, p <0.05). By contrast, salmonellosis was positively associated with temperature (β  = 0.110, SE = 0.020, p<0.001) of the current month and SOI of the current (β  = 0.005, SE = 0.002, p<0.050) and previous month (β  = 0.005, SE = 0.002, p<0.05). Forecasting accuracy of the multivariate models for cryptosporidiosis and salmonellosis were significantly higher.

Conclusions

Although spatial heterogeneity in the observed patterns could not be assessed, these results suggest that temporally lagged relationships between climate variables and national communicable disease incidence data can contribute to disease prediction models and early warning systems.     

Determinants of Posterior Corneal Biometric Measurements in a Multi-Ethnic Asian Population

Purpose

To describe the corneal and anterior segment determinants of posterior corneal arc length (PCAL) and posterior corneal curvature (PCC).

Methods

Cross-sectional, population-based study of 1069 subjects (1069 eyes) aged 40–80 years, from three major Asian ethnic groups. All underwent anterior segment optical coherence tomography imaging and analysis with Zhongshan Angle Assessment Program. Our main outcome measures were determinants of PCAL and PCC using adjusted, multivariate linear regression analysis, adjusted for confounders to obtain the estimated marginal means (EMM) with standard error (SE).

Results

The overall mean (± SD) of PCC was: 6.51±0.39 mm; and PCAL was: 12.52±0.59 mm. Malays had a relatively longer PCAL (EMM = 12.74 mm, SE = 0.04 mm) than Chinese (EMM = 12.48 mm, SE = 0.03 mm, P<0.001), and Indians (EMM = 12.42 mm, SE = 0.03 mm, P<0.001). Anterior segment parameters had weak-moderate correlations with PCAL, which included: anterior chamber depth (ACD) (r = 0.55, P<0.001), PCC (r = 0.27, P<0.001), anterior corneal curvature (ACC) (r = 0.14, P<0.001) and central corneal thickness (CCT) (r = −0.07, P = 0.023). In multivariate analysis, anterior segment parameters explained only 37.6% of the variance of PCAL, with ACD being the most important determinant (partial R²  = 0.300; P<0.001). The determinants of PCC included ACC, PCAL and CCT (explaining 72.1% variation of PCC), with ACC being the most important determinant (partial R²  = 0.683; P<0.001).

Conclusion

There was moderate correlation of PCAL with ACD, but anterior segment parameters accounted for only a small proportion of the variation in PCAL. The significant differences in PCAL and PCC amongst different Asian ethnic groups suggests that there is a need to consider this factor when planning for anterior segment surgeries such as endothelial keratoplasty.     

Suitability of Pharmacokinetic Models for Dynamic Contrast-Enhanced MRI of Abdominal Aortic Aneurysm Vessel Wall: A Comparison

Purpose

Increased microvascularization of the abdominal aortic aneurysm (AAA) vessel wall has been related to AAA progression and rupture. The aim of this study was to compare the suitability of three pharmacokinetic models to describe AAA vessel wall enhancement using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

Materials and Methods

Patients with AAA underwent DCE-MRI at 1.5 Tesla. The volume transfer constant (K^trans), which reflects microvascular flow, permeability and surface area, was calculated by fitting the blood and aneurysm vessel wall gadolinium concentration curves. The relative fit errors, parameter uncertainties and parameter reproducibilities for the Patlak, Tofts and Extended Tofts model were compared to find the most suitable model. Scan-rescan reproducibility was assessed using the interclass correlation coefficient and coefficient of variation (CV). Further, the relationship between K^trans and AAA size was investigated.

Results

DCE-MRI examinations from thirty-nine patients (mean age±SD: 72±6 years; M/F: 35/4) with an mean AAA maximal diameter of 49±6 mm could be included for pharmacokinetic analysis. Relative fit uncertainties for K^trans based on the Patlak model (17%) were significantly lower compared to the Tofts (37%) and Extended Tofts model (42%) (p<0.001). K^trans scan-rescan reproducibility for the Patlak model (ICC = 0.61 and CV = 22%) was comparable with the Tofts (ICC = 0.61, CV = 23%) and Extended Tofts model (ICC = 0.76, CV = 22%). K^trans was positively correlated with maximal AAA diameter (Spearman’s ρ = 0.38, p = 0.02) using the Patlak model.

Conclusion

Using the presented imaging protocol, the Patlak model is most suited to describe DCE-MRI data of the AAA vessel wall with good K^trans scan-rescan reproducibility.     

Quality Assessment of Clinical Practice Guidelines on the Treatment of Hepatocellular Carcinoma or Metastatic Liver Cancer

Objectives

To assess the quality of the currently available clinical practice guidelines (CPGs) for hepatocellular carcinoma, and provide a reference for clinicians in selecting the best available clinical protocols.

Methods

The databases of PubMed, MEDLINE, Web of Science, Chinese Biomedical Literature database (CBM), China National Knowledge Infrastructure (CNKI), WanFang, and relevant CPGs websites were systematically searched through March 2014. CPGs quality was appraised using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument, and data analysis was performed using SPSS 13.0 software.

Results

A total of 20 evidence-based and 20 expert consensus-based guidelines were included. The mean percentage of the domain scores were: scope and purpose 83% (95% confidence interval (CI), 81% to 86%), clarity of presentation 79% (95% CI, 73% to 86%), stakeholder involvement 39% (95% CI, 30% to 49%), editorial independence 58% (95% CI, 52% to 64%), rigor of development 39% (95% CI, 31% to 46%), and applicability 16% (95% CI, 10% to 23%). Evidence-based guidelines were superior to those established by consensus for the domains of rigor of development (p<0.001), clarity of presentation (p = 0.01) and applicability (p = 0.021).

Conclusions

The overall methodological quality of CPGs for hepatocellular carcinoma and metastatic liver cancer is moderate, with poor applicability and potential conflict of interest issues. The evidence-based guidelines has become mainstream for high quality CPGs development; however, there is still need to further increase the transparency and quality of evidence rating, as well as the recommendation process, and to address potential conflict of interest.     

Hawthorne Effect with Transient Behavioral and Biochemical Changes in a Randomized Controlled Sleep Extension Trial of Chronically Short-Sleeping Obese Adults: Implications for the Design and Interpretation of Clinical Studies

Objective

To evaluate the effects of study participation per se at the beginning of a sleep extension trial between screening, randomization, and the run-in visit.

Design

Subjects were screened, returned for randomization (Comparison vs. Intervention) after 81 days (median), and attended run-in visit 121 days later.

Setting

Outpatient.

Patients

Obese (N = 125; M/F, 30/95; Blacks/Whites/Other, N = 73/44/8), mean weight 107.6±19.7 kg, <6.5 h sleep/night.

Intervention

Non-pharmacological sleep extension.

Measurements

Sleep duration (diaries and actigraphy watch), sleep quality (Pittsburgh Sleep Quality Index), daily sleepiness (Epworth Sleepiness Scale), fasting glucose, insulin and lipids.

Results

Prior to any intervention, marked improvements occurred between screening and randomization. Sleep duration increased (diaries: 357.4 ±51.2 vs. 388.1±48.6 min/night; mean±SD; P<0.001 screening vs. randomization; actigraphy: 344.3 ±41.9 vs. 358.6±48.2 min/night; P<0.001) sleep quality improved (9.1±3.2 vs. 8.2±3.0 PSQI score; P<0.001), sleepiness tended to improve (8.9±4.6 vs. 8.3±4.5 ESS score; P = 0.06), insulin resistance decreased (0.327±0.038 vs. 0.351±0.045; Quicki index; P<0.001), and lipids improved, except for HDL-C. Abnormal fasting glucose (25% vs. 11%; P = 0.007), and metabolic syndrome (42% vs. 29%; P = 0.007) both decreased. In absence of intervention, the earlier metabolic improvements disappeared at the run-in visit.

Limitations

Relatively small sample size.

Conclusions

Improvements in biochemical and behavioral parameters between screening and randomization changed the “true” study baseline, thereby potentially affecting outcome. While regression to the mean and placebo effect were considered, these findings are most consistent with the “Hawthorne effect”, according to which behavior measured in the setting of an experimental study changes in response to the attention received from study investigators. This is the first time that biochemical changes were documented with respect to the Hawthorne effect. The findings have implications for the design and conduct of clinical research.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00261898","term_id":"NCT00261898"}}NCT00261898.     

Contribution of Psychosocial Factors to the Association between Socioeconomic Position and Takeaway Food Consumption

Objective

To examine whether psychosocial factors mediate (explain) the association between socioeconomic position and takeaway food consumption.

Design

A cross-sectional postal survey conducted in 2009.

Setting

Participants reported their usual consumption of 22 takeaway food items, and these were grouped into a “healthy” and “less healthy” index based on each items'' nutritional properties. Principal Components Analysis was used to derive three psychosocial scales that measured beliefs about the relationship between diet and health (α = 0.73), and perceptions about the value (α = 0.79) and pleasure (α = 0.61) of takeaway food. A nutrition knowledge index was also used. Socioeconomic position was measured by highest attained education level.

Subjects

Randomly selected adults (n = 1,500) aged between 25–64 years in Brisbane, Australia (response rate  =  63.7%, N = 903).

Results

Compared with those with a bachelor degree or higher, participants with a diploma level of education were more likely to consume “healthy” takeaway food (p = 0.023) whereas the least educated (high school only) were more likely to consume “less healthy” choices (p = 0.002). The least educated were less likely to believe in a relationship between diet and health (p<0.001), and more likely to have lower nutritional knowledge compared with their highly educated counterparts (p<0.001). Education differences in beliefs about the relationship between diet and health partly and significantly mediated the association between education and “healthy” takeaway food consumption. Diet- and health-related beliefs and nutritional knowledge partly and significantly mediated the education differences in “less healthy” takeaway food consumption.

Conclusions

Interventions that target beliefs about the relationship between diet and health, and nutritional knowledge may reduce socioeconomic differences in takeaway food consumption, particularly for “less healthy” options.     

Parapapillary Atrophy: Histological Gamma Zone and Delta Zone

Background

To examine histomorphometrically the parapapillary region in human eyes.

Methodology/Principal Findings

The histomorphometric study included 65 human globes (axial length:21–37 mm). On anterior-posterior histological sections, we measured the distance Bruch''s membrane end (BME)-optic nerve margin (“Gamma zone”), BME-retinal pigment epithelium (RPE) (“Beta zone”), BME-beginning of non-occluded choriocapillaris, and BME-beginning of photoreceptor layer. “Delta zone” was defined as part of gamma zone in which blood vessels of at least 50 µm diameter were not present over a length of >300 µm. Beta zone (mean length:0.35±0.52 mm) was significantly (P = 0.01) larger in the glaucoma group than in the non-glaucomatous group. It was not significantly (P = 0.28) associated with axial length. Beta zone was significantly (P = 0.004) larger than the region with occluded choriocapillaris. Gamma zone (mean length:0.63±1.25 mm) was associated with axial length (P<0.001;r² = 0.73) with an increase starting at an axial length of 26.5 mm. It was not significantly (P = 0.24) associated with glaucomatous optic neuropathy. Delta zone (present only in eyes with axial length of ≥27 mm) was associated with axial length (P = 0.001) and scleral flange length (P<0.001) but not with glaucoma (P = 0.73).

Conclusions/Significance

Parapapillary gamma zone (peripapillary sclera without overlying choroid, Bruch''s membrane and deep retinal layers) was related with axial globe elongation and was independent of glaucoma. Delta zone (no blood vessels >50 µm diameter within gamma zone) was present only in highly axially elongated globes and was not related with glaucoma. Beta zone (Bruch''s membrane without RPE) was correlated with glaucoma but not with globe elongation. Since the region with occluded choriocapillaris was smaller than beta zone, complete loss of RPE may have occurred before complete choriocapillaris closure.     

Validity and Reliability of New Agility Test among Elite and Subelite under 14-Soccer Players

Background

Agility is a determinant component in soccer performance. This study aimed to evaluate the reliability and sensitivity of a “Modified Illinois change of direction test” (MICODT) in ninety-five U-14 soccer players.

Methods

A total of 95 U-14 soccer players (mean ± SD: age: 13.61±1.04 years; body mass: 30.52±4.54 kg; height: 1.57±0.1 m) from a professional and semi-professional soccer academy, participated to this study. Sixty of them took part in reliability analysis and thirty-two in sensitivity analysis.

Results

The intraclass correlation coefficient (ICC) that aims to assess relative reliability of the MICODT was of 0.99, and its standard error of measurement (SEM) for absolute reliability was <5% (1.24%). The MICODT’s capacity to detect change is “good”, it’s SEM (0.10 s) was ≤ SWC (0.33 s). The MICODT is significantly correlated to the Illinois change of direction speed test (ICODT) (r = 0.77; p<0.0001). The ICODT’s MDC₉₅ (0.64 s) was twice about the MICODT’s MDC₉₅ (0.28 s), indicating that MICODT presents better ability to detect true changes than ICODT. The MICODT provided good sensitivity since elite U-14 soccer players were better than non-elite one on MICODT (p = 0.005; d_z = 1.01 [large]). This was supported by an area under the ROC curve of 0.77 (CI 95%, 0.59 to 0.89, p<0.0008). The difference observed in these two groups in ICODT was not statistically significant (p = 0.14; d_z = 0.51 [small]), showing poor discriminant ability.

Conclusion

MICODT can be considered as more suitable protocol for assessing agility performance level than ICODT in U-14 soccer players.     

Reliability and Validity of the Transport and Physical Activity Questionnaire (TPAQ) for Assessing Physical Activity Behaviour

Background

No current validated survey instrument allows a comprehensive assessment of both physical activity and travel behaviours for use in interdisciplinary research on walking and cycling. This study reports on the test-retest reliability and validity of physical activity measures in the transport and physical activity questionnaire (TPAQ).

Methods

The TPAQ assesses time spent in different domains of physical activity and using different modes of transport for five journey purposes. Test-retest reliability of eight physical activity summary variables was assessed using intra-class correlation coefficients (ICC) and Kappa scores for continuous and categorical variables respectively. In a separate study, the validity of three survey-reported physical activity summary variables was assessed by computing Spearman correlation coefficients using accelerometer-derived reference measures. The Bland-Altman technique was used to determine the absolute validity of survey-reported time spent in moderate-to-vigorous physical activity (MVPA).

Results

In the reliability study, ICC for time spent in different domains of physical activity ranged from fair to substantial for walking for transport (ICC = 0.59), cycling for transport (ICC = 0.61), walking for recreation (ICC = 0.48), cycling for recreation (ICC = 0.35), moderate leisure-time physical activity (ICC = 0.47), vigorous leisure-time physical activity (ICC = 0.63), and total physical activity (ICC = 0.56). The proportion of participants estimated to meet physical activity guidelines showed acceptable reliability (k = 0.60). In the validity study, comparison of survey-reported and accelerometer-derived time spent in physical activity showed strong agreement for vigorous physical activity (r = 0.72, p<0.001), fair but non-significant agreement for moderate physical activity (r = 0.24, p = 0.09) and fair agreement for MVPA (r = 0.27, p = 0.05). Bland-Altman analysis showed a mean overestimation of MVPA of 87.6 min/week (p = 0.02) (95% limits of agreement −447.1 to +622.3 min/week).

Conclusion

The TPAQ provides a more comprehensive assessment of physical activity and travel behaviours and may be suitable for wider use. Its physical activity summary measures have comparable reliability and validity to those of similar existing questionnaires.     

Estimating Causal Effects from Family Planning Health Communication Campaigns Using Panel Data: The “Your Health,Your Wealth” Campaign in Egypt

Background

Health communication campaigns – involving mass media and interpersonal communication - have long been utilized by national family planning programs to create awareness about contraceptive methods, to shift social norms related to fertility control, and to promote specific behaviors, such as the use of condoms, injectable methods or permanent sterilization. However, demonstrating the effectiveness of these campaigns is often complicated because the infeasibility of experimental designs generally yields statistically non-equivalent samples of campaign-exposed and unexposed individuals.

Methods

Using data from a panel survey of reproductive age women in Egypt, we estimate the effects of the multimedia health communication campaign “Your Health, Your Wealth” (“Sahatek Sarwetek”) on precursors to contraceptive use (e.g., spousal communication, birth spacing attitudes) and on modern contraceptive use. Difference-in-differences and fixed effects estimators that exploit the panel nature of the data are employed to control for both observed and unobserved heterogeneity in the sample of women who self-report recall of the messages, thereby potentially improving upon methods that make no such controls or that rely solely on cross-sectional data.

Findings

All of the estimators find positive effects of the “Your Health, Your Wealth” campaign on reproductive health outcomes, though the magnitudes of those effects diverge, often considerably. Difference-in-differences estimators find that exposure to the campaign increases the likelihood of spousal discussions by 14.4 percentage points (pp.) (SE = .039, p<0.001) but has no effect on contraceptive use. In contrast, the fixed effects, instrumental variables estimator, controlling for unobserved heterogeneity, finds a large, statistically significant effect on modern contraceptive use (27.4 pp., SE = 0.135, p = 0.043).

Conclusions

The difficulties of evaluating family planning communication programs may be surmountable using panel data and analytic methods that address both observed and unobserved heterogeneity in exposure. Not controlling for such effects may lead to substantial underestimates of the effectiveness of such campaigns.     

Oncostatin M Mediates STAT3-Dependent Intestinal Epithelial Restitution via Increased Cell Proliferation,Decreased Apoptosis and Upregulation of SERPIN Family Members

Objective

Oncostatin M (OSM) is produced by activated T cells, monocytes, and dendritic cells and signals through two distinct receptor complexes consisting of gp130 and LIFR (I) or OSMR-β and gp130 (II), respectively. Aim of this study was to analyze the role of OSM in intestinal epithelial cells (IEC) and intestinal inflammation.

Methods

OSM expression and OSM receptor distribution was analyzed by PCR and immunohistochemistry experiments, signal transduction by immunoblotting. Gene expression studies were performed by microarray analysis and RT-PCR. Apoptosis was measured by caspases-3/7 activity. IEC migration and proliferation was studied in wounding and water soluble tetrazolium assays.

Results

The IEC lines Caco-2, DLD-1, SW480, HCT116 and HT-29 express mRNA for the OSM receptor subunits gp130 and OSMR-β, while only HCT116, HT-29 and DLD-1 cells express LIFR mRNA. OSM binding to its receptor complex activates STAT1, STAT3, ERK-1/2, SAPK/JNK-1/2, and Akt. Microarray analysis revealed 79 genes that were significantly up-regulated (adj.-p≤0.05) by OSM in IEC. Most up-regulated genes belong to the functional categories “immunity and defense” (p = 2.1×10⁻⁷), “apoptosis” (p = 3.7×10⁻⁴) and “JAK/STAT cascade” (p = 3.4×10⁻⁶). Members of the SERPIN gene family were among the most strongly up-regulated genes. OSM significantly increased STAT3- and MEK1-dependent IEC cell proliferation (p<0.05) and wound healing (p = 3.9×10⁻⁵). OSM protein expression was increased in colonic biopsies of patients with active inflammatory bowel disease (IBD).

Conclusions

OSM promotes STAT3-dependent intestinal epithelial cell proliferation and wound healing in vitro. Considering the increased OSM expression in colonic biopsy specimens of patients with active IBD, OSM upregulation may modulate a barrier-protective host response in intestinal inflammation. Further in vivo studies are warranted to elucidate the exact role of OSM in intestinal inflammation and the potential of OSM as a drug target in IBD.     

Evaluation of 41 Candidate Gene Variants for Obesity in the EPIC-Potsdam Cohort by Multi-Locus Stepwise Regression

Objective

Obesity has become a leading preventable cause of morbidity and mortality in many parts of the world. It is thought to originate from multiple genetic and environmental determinants. The aim of the current study was to introduce haplotype-based multi-locus stepwise regression (MSR) as a method to investigate combinations of unlinked single nucleotide polymorphisms (SNPs) for obesity phenotypes.

Methods

In 2,122 healthy randomly selected men and women of the EPIC-Potsdam cohort, the association between 41 SNPs from 18 obesity-candidate genes and either body mass index (BMI, mean = 25.9 kg/m², SD = 4.1) or waist circumference (WC, mean = 85.2 cm, SD = 12.6) was assessed. Single SNP analyses were done by using linear regression adjusted for age, sex, and other covariates. Subsequently, MSR was applied to search for the ‘best’ SNP combinations. Combinations were selected according to specific AIC_c and p-value criteria. Model uncertainty was accounted for by a permutation test.

Results

The strongest single SNP effects on BMI were found for TBC1D1 rs637797 (β = −0.33, SE = 0.13), FTO rs9939609 (β = 0.28, SE = 0.13), MC4R rs17700144 (β = 0.41, SE = 0.15), and MC4R rs10871777 (β = 0.34, SE = 0.14). All these SNPs showed similar effects on waist circumference. The two ‘best’ six-SNP combinations for BMI (global p-value = 3.45⋅10^–6 and 6.82⋅10^–6) showed effects ranging from −1.70 (SE = 0.34) to 0.74 kg/m² (SE = 0.21) per allele combination. We selected two six-SNP combinations on waist circumference (global p-value = 7.80⋅10^–6 and 9.76⋅10^–6) with an allele combination effect of −2.96 cm (SE = 0.76) at maximum. Additional adjustment for BMI revealed 15 three-SNP combinations (global p-values ranged from 3.09⋅10^–4 to 1.02⋅10^–2). However, after carrying out the permutation test all SNP combinations lost significance indicating that the statistical associations might have occurred by chance.

Conclusion

MSR provides a tool to search for risk-related SNP combinations of common traits or diseases. However, the search process does not always find meaningful SNP combinations in a dataset.     

Long-Term Prognostic Value of Restitution Slope in Patients with Ischemic and Dilated Cardiomyopathies

Background

An action potential duration (APD) restitution curve with a steep slope ≥1 has been associated with increased susceptibility for malignant ventricular arrhythmias. We aimed to evaluate the “restitution hypothesis” and tested ventricular APD restitution slope as well as effective refractory period (ERP)/APD ratio for long-term prognostic value in patients with ischemic (ICM) or dilated cardiomyopathy (DCM).

Methodology/Principal Findings

Monophasic action potentials were recorded in patients with ICM (n = 32) and DCM (n = 42) undergoing routine programmed ventricular stimulation (PVS). Left ventricular ejection fraction was 32±7% and 28±9%, respectively. APD and ERP were measured at baseline stimulation (S₁) and upon introduction of one to three extrastimuli (S₂–S₄). ERP/APD ratios and the APD restitution curve were calculated and the maximum restitution slope was determined. After a mean follow-up of 6.1±3.0 years, the combined end-point of mortality and and/or implantable cardioverter-defibrillator shock was not predicted by restitution slope or ERP/APD ratios. Comparing S₂ vs. S₃ vs. S₄ extrastimuli for restitution slope (1.5±0.6 vs. 1.4±0.4 vs. 1.3±0.5; p = NS), additional extrastimuli did not lead to a steepening restitution slope. ERP/APD ratio decreased with additional extrastimuli (0.98±0.09 [S₁] vs. 0.97±0.10 [S₂] vs. 0.93±0.11 [S₃]; p = 0.03 S₁ vs. S₃). Positive PVS was strongly predictive of outcome (p = 0.006).

Conclusions/Significance

Neither ventricular APD restitution slope nor ERP/APD ratios predict outcome in patients with ICM or DCM.     

Understanding of Statistical Terms Routinely Used in Meta-Analyses: An International Survey among Researchers

Objective

Biomedical literature is increasingly enriched with literature reviews and meta-analyses. We sought to assess the understanding of statistical terms routinely used in such studies, among researchers.

Methods

An online survey posing 4 clinically-oriented multiple-choice questions was conducted in an international sample of randomly selected corresponding authors of articles indexed by PubMed.

Results

A total of 315 unique complete forms were analyzed (participation rate 39.4%), mostly from Europe (48%), North America (31%), and Asia/Pacific (17%). Only 10.5% of the participants answered correctly all 4 “interpretation” questions while 9.2% answered all questions incorrectly. Regarding each question, 51.1%, 71.4%, and 40.6% of the participants correctly interpreted statistical significance of a given odds ratio, risk ratio, and weighted mean difference with 95% confidence intervals respectively, while 43.5% correctly replied that no statistical model can adjust for clinical heterogeneity. Clinicians had more correct answers than non-clinicians (mean score ± standard deviation: 2.27±1.06 versus 1.83±1.14, p<0.001); among clinicians, there was a trend towards a higher score in medical specialists (2.37±1.07 versus 2.04±1.04, p = 0.06) and a lower score in clinical laboratory specialists (1.7±0.95 versus 2.3±1.06, p = 0.08). No association was observed between the respondents'' region or questionnaire completion time and participants'' score.

Conclusion

A considerable proportion of researchers, randomly selected from a diverse international sample of biomedical scientists, misinterpreted statistical terms commonly reported in meta-analyses. Authors could be prompted to explicitly interpret their findings to prevent misunderstandings and readers are encouraged to keep up with basic biostatistics.     

The Vitamin D Status in Inflammatory Bowel Disease

Context

There is no consensus on the vitamin D status of children and adolescents with inflammatory bowel disease (IBD).

Aim

To determine the vitamin D status of patients with IBD by comparing their serum 25(OH)D concentration to that of healthy controls.

Hypothesis

Serum 25(OH)D concentration will be lower in patients with IBD compared to controls.

Subjects and Methods

A case-controlled retrospective study of subjects with IBD (n = 58) of 2–20 years (male n = 31, age 16.38±2.21 years; female n = 27, age16.56±2.08 years) and healthy controls (n = 116; male n = 49, age 13.90±4.59 years; female n = 67, age 15.04±4.12years). Study subject inclusion criteria: diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC). Vitamin D deficiency was defined as 25(OH)D of (<20 ng/mL) (<50 nmol/L), overweight as BMI of ≥85^th but <95^th percentile, and obesity as BMI ≥95^th percentile. Data were expressed as mean ± SD.

Results

Patients with CD, UC, and their controls had mean serum 25(OH)D concentrations of 61.69±24.43 nmol/L, 53.26±25.51, and 65.32±27.97 respectively (ANOVA, p = 0.196). The overweight/obese controls had significantly lower 25(OH)D concentration compared to the normal-weight controls (p = 0.031); whereas 25(OH)D concentration was similar between the normal-weight and overweight/obese IBD patients (p = 0.883). There was no difference in 25(OH)D between patients with UC and CD, or between subjects with active IBD and controls. However, IBD subjects with elevated ESR had significantly lower 25(OH)D than IBD subjects with normal ESR (p = 0.025), as well as controls (65.3±28.0 nmol/L vs. 49.5±25.23, p = 0.045).

Conclusion

There is no difference in mean serum 25(OH)D concentration between children and adolescents with IBD and controls. However, IBD subjects with elevated ESR have significantly lower 25(OH)D than controls. Therefore, IBD subjects with elevated ESR should be monitored for vitamin D deficiency.     

Beneficial Effect of Isoniazid Preventive Therapy and Antiretroviral Therapy on the Incidence of Tuberculosis in People Living with HIV in Ethiopia

Background

IPT with or without concomitant administration of ART is a proven intervention to prevent tuberculosis among PLHIV. However, there are few data on the routine implementation of this intervention and its effectiveness in settings with limited resources.

Objectives

To measure the level of uptake and effectiveness of IPT in reducing tuberculosis incidence in a cohort of PLHIV enrolled into HIV care between 2007 and 2010 in five hospitals in southern Ethiopia.

Methods

A retrospective cohort analysis of electronic patient database was done. The independent effects of no intervention, “IPT-only,” “IPT-before-ART,” “IPT-and-ART started simultaneously,” “ART-only,” and “IPT-after-ART” on TB incidence were measured. Cox-proportional hazards regression was used to assess association of treatment categories with TB incidence.

Results

Of 7,097 patients, 867 were excluded because they were transferred-in; a further 823 (12%) were excluded from the study because they were either identified to have TB through screening (292 patients) or were on TB treatment (531). Among the remaining 5,407 patients observed, IPT had been initiated for 39% of eligible patients. Children, male sex, advanced disease, and those in Pre-ART were less likely to be initiated on IPT. The overall TB incidence was 2.6 per 100 person-years. As compared to those with no intervention, use of “IPT-only” (aHR = 0.36, 95% CI = 0.19–0.66) and “ART-only” (aHR = 0.32, 95% CI = 0.24–0.43) were associated with significant reduction in TB incidence rate. Combining ART and IPT had a more profound effect. Starting IPT-before-ART (aHR = 0.18, 95% CI = 0.08–0.42) or simultaneously with ART (aHR = 0.20, 95% CI = 0.10–0.42) provided further reduction of TB at ∼80%.

Conclusions

IPT was found to be effective in reducing TB incidence, independently and with concomitant ART, under programme conditions in resource-limited settings. The level of IPT provision and effectiveness in reducing TB was encouraging in the study setting. Scaling up and strengthening IPT service in addition to ART can have beneficial effect in reducing TB burden among PLHIV in settings with high TB/HIV burden.     

Quantification of Tumor Vessels in Glioblastoma Patients Using Time-of-Flight Angiography at 7 Tesla: A Feasibility Study

Purpose

To analyze if tumor vessels can be visualized, segmented and quantified in glioblastoma patients with time of flight (ToF) angiography at 7 Tesla and multiscale vessel enhancement filtering.

Materials and Methods

Twelve patients with newly diagnosed glioblastoma were examined with ToF angiography (TR = 15 ms, TE = 4.8 ms, flip angle = 15°, FOV = 160×210 mm², voxel size: 0.31×0.31×0.40 mm³) on a whole-body 7 T MR system. A volume of interest (VOI) was placed within the border of the contrast enhancing part on T1-weighted images of the glioblastoma and a reference VOI was placed in the non-affected contralateral white matter. Automated segmentation and quantification of vessels within the two VOIs was achieved using multiscale vessel enhancement filtering in ImageJ.

Results

Tumor vessels were clearly visible in all patients. When comparing tumor and the reference VOI, total vessel surface (45.3±13.9 mm² vs. 29.0±21.0 mm² (p<0.035)) and number of branches (3.5±1.8 vs. 1.0±0.6 (p<0.001) per cubic centimeter were significantly higher, while mean vessel branch length was significantly lower (3.8±1.5 mm vs 7.2±2.8 mm (p<0.001)) in the tumor.

Discussion

ToF angiography at 7-Tesla MRI enables characterization and quantification of the internal vascular morphology of glioblastoma and may be used for the evaluation of therapy response within future studies.