Integrated multiple mediation analysis: A robustness–specificity trade-off in causal structure

Recent methodological developments in causal mediation analysis have addressed several issues regarding multiple mediators. However, these developed methods differ in their definitions of causal parameters, assumptions for identification, and interpretations of causal effects, making it unclear which method ought to be selected when investigating a given causal effect. Thus, in this study, we construct an integrated framework, which unifies all existing methodologies, as a standard for mediation analysis with multiple mediators. To clarify the relationship between existing methods, we propose four strategies for effect decomposition: two-way, partially forward, partially backward, and complete decompositions. This study reveals how the direct and indirect effects of each strategy are explicitly and correctly interpreted as path-specific effects under different causal mediation structures. In the integrated framework, we further verify the utility of the interventional analogues of direct and indirect effects, especially when natural direct and indirect effects cannot be identified or when cross-world exchangeability is invalid. Consequently, this study yields a robustness–specificity trade-off in the choice of strategies. Inverse probability weighting is considered for estimation. The four strategies are further applied to a simulation study for performance evaluation and for analyzing the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer data set from Taiwan to investigate the causal effect of hepatitis C virus infection on mortality

Is BMI alone a sufficient outcome to evaluate interventions for child obesity?

BACKGROUND: BMI is often used to evaluate the effectiveness of childhood obesity interventions, but such interventions may have additional benefits independent of effects on adiposity. We investigated whether benefits to health outcomes following the Mind, Exercise, Nutrition…Do It! (MEND) childhood obesity intervention were independent of or associated with changes in zBMI. METHODS: A total of 79 obese children were measured at baseline; 71 and 42 participants were followed-up at 6 and 12 months respectively, and split into four groups depending on magnitude of change in zBMI. Differences between groups for waist circumference, cardiovascular fitness, physical and sedentary activities, and self-esteem were investigated. RESULTS: Apart from waist circumference and its z-score, there were no differences or trends across zBMI subgroups for any outcome. Independent of the degree of zBMI change, benefits in several parameters were observed in children participating in this obesity intervention. CONCLUSION: We concluded that isolating a single parameter like zBMI change and neglecting other important outcomes is restrictive and may undermine the evaluation of childhood obesity intervention effectiveness

Estimating metabolic rate for butadiene at steady state using a Bayesian physiologically-based pharmacokinetic model

In a study of 133 volunteer subjects, demographic, physiologic and pharmacokinetic data through exposure to 1,3-Butadiene (BD) were collected in order to estimate the percentage of BD concentration metabolized at steady state, and to determine whether this percentage varies across gender, racial, and age groups. During the 20 min of continuous exposure to 2 parts per million (ppm) of BD, five measurements of exhaled concentration were made on each subject. In the following 40 min washout period, another five measurements were collected. A Bayesian hierarchical compartmental physiologically-based pharmacokinetic model (PKPB) was used. Using prior information on the model parameters, Markov Chain Monte Carlo (MCMC) simulation was conducted to obtain posterior distributions. The overall estimate of the mean percent of BD metabolized at steady state was 12.7% (95% credible interval: 7.7–17.8%). There was no significant difference in gender with males having a mean of 13.5%, and females 12.3%. Among the racial groups, Hispanic (13.9%), White (13.0%), Asian (12.1%), and Black (10.9%), the significant difference came from the difference between Black and Hispanic with a 95% credible interval from −5.63 to −0.30%. Those older than 30 years had a mean of 12.2% versus 12.9% for the younger group; although this was not a statistically significant difference. Given a constant inhalation input of 2 ppm, at steady state, the overall mean exhaled concentrationwas estimated to be 1.75ppm (95% credible interval: 1.64–1.84).An equivalent parameter, first-order metabolic rate constant, was also estimated and found to be consistent with the percent of BD metabolized at steady state across gender, race, and age strata

The efficacy and safety of a shortened duration of antimicrobial therapy for group A Streptococcus bacteremia

Objectives: To determine if shorter courses of antibiotic therapy for group A Streptococcus (GAS) bacteremia are associated with excess mortality. Methods: In this retrospective study of consecutive cases of GAS bacteremia in tropical Australia, the duration of antibiotic therapy was correlated with 90-day all-cause mortality. Results: There were 286 episodes of GAS bacteremia; the patients’ median (interquartile range) age was 60 (48-71) years and 169/286 (59.1%) patients identified as an Indigenous Australian. There were 227/286 (79.4%) patients with a significant comorbidity. The all-cause 90-day mortality was 16/286 (5.6%); however, 12/16 (81.3%) patients died while still receiving their initial course of antibiotics and only 7/16 (43.8%) deaths were directly attributable to the GAS infection. After excluding patients who died while taking their initial course of antibiotics and those in whom the duration of therapy was uncertain, there was no difference in 90-day mortality between patients receiving ≤5 days of intravenous antibiotics and those receiving longer courses (1/137 [0.7%] vs 3/107 [2.8%], P-value = 0.32) nor in patients receiving ≤10 days of total therapy and those receiving longer courses (1/67 [1.5%] vs 3/178 [1.7%], P-value = 1.0). Conclusion: Even among patients with significant comorbidity, shorter antibiotic courses for GAS bacteremia are not associated with excess mortality

Infantile thiamine deficiency in South and Southeast Asia: An age-old problem needing new solutions

Infantile beriberi, a potentially fatal disorder caused by thiamine deficiency, is often viewed as a disease confined to history in regions of the world with predominant white rice consumption. Recent case reports have, however, highlighted the persistence of thiamine deficiency as a cause of infant mortality in South and Southeast Asia. Low infant thiamine status and incidence of beriberi is attributable to maternal thiamine deficiency and insufficient breast milk thiamine. Poor dietary diversity, food preparation and cooking practices and traditional post-partum food restrictions likely play a role in these high-risk regions. Given the contribution of thiamine deficiency to infant mortality and emerging evidence of long-lasting neurodevelopmental deficits of severe and even subclinical deficiency in early life, public health strategies to prevent thiamine deficiency are urgently needed. However, efforts are hampered by uncertainties surrounding the identification and assessment of thiamine deficiency, due to the broad non-specific clinical manifestations, commonly referred to as thiamine deficiency disorders (TDD), that overlap with other conditions resulting in frequent misdiagnosis and missed treatment opportunities, and secondly the lack of readily available and agreed upon biomarker analysis and cut-off thresholds. This review will discuss the key challenges and limitations in the current understanding of TDD and explore how ongoing initiatives plan to fill persistent knowledge gaps, namely in the development of a standardised case definition to help more accurately diagnose and treat TDD in low-resource settings. Given more attention and ensuring greater recognition of TDD will support the design and implementation of treatment and prevention programmes, and ensure beriberi can truly be considered 'the forgotten disease of Asia'

Widespread association between the ericoid mycorrhizal fungus Rhizoscyphus ericae and a leafy liverwort in the maritime and sub-Antarctic

A recent study identified a fungal isolate from the Antarctic leafy liverwort Cephaloziella varians as the ericoid mycorrhizal associate Rhizoscyphus ericae. However, nothing is known about the wider Antarctic distribution of R. ericae in C. varians, and inoculation experiments confirming the ability of the fungus to form coils in the liverwort are lacking. Using direct isolation and baiting with Vaccinium macrocarpon seedlings, fungi were isolated from C. varians sampled from eight sites across a 1875-km transect through sub- and maritime Antarctica. The ability of an isolate to form coils in aseptically grown C. varians was also tested. Fungi with 98–99% sequence identity to R. ericae internal transcribed spacer (ITS) region and partial large subunit ribosomal (r)DNA sequences were frequently isolated from C. varians at all sites sampled. The EF4/Fung5 primer set did not amplify small subunit rDNA from three of five R. ericae isolates, probably accounting for the reported absence of the fungus from C. varians in a previous study. Rhizoscyphus ericae was found to colonize aseptically-grown C. varians intracellularly, forming hyphal coils. This study shows that the association between R. ericae and C. varians is apparently widespread in Antarctica, and confirms that R. ericae is at least in part responsible for the formation of the coils observed in rhizoids of field-collected C. varians

Portfolio-based appraisal: superficial or useful?

This paper outlines the growing role played by performance appraisal within medical regulation, supported by learning portfolios. It investigates if these are superficial or useful tools. In doing so it argues that caution must be exercised in promoting such tools to help modernise medical regulatory frameworks