Primary versus secondary anastomosis in intestinal atresia

Purpose

Neonates with intestinal atresia (IA) undergo either primary anastomosis (PA) or ostomy creation with secondary anastomosis (SA). Our purpose was to compare outcomes for PA and SA and to assess factors influencing procedure selection.

Baseline sensitivity of HSV-1 and HSV-2 clinical isolates and defined acyclovir-resistant strains to the helicase–primase inhibitor pritelivir

Fifty-nine US isolates of HSV-1 and HSV-2 obtained between 1998 and 2004 were tested for sensitivity to the helicase–primase inhibitor, pritelivir (AIC316, BAY 57-1293) by plaque-reduction assay. All isolates, which were collected prior to any clinical use of primase–helicase inhibitors, were sensitive and showed mean EC₅₀ values of 0.026 and 0.029 μM for HSV-1 and HSV-2, respectively. Furthermore, several laboratory-selected acyclovir-resistant HSV mutants were also sensitive to pritelivir. These data provide a baseline for HSV sensitivity to pritelivir in general population before it is introduced and broadly used to treat HSV infection. The data also validate pritelivir as an appropriate therapy for nucleoside-resistant HSV infections.     

Modeling the long-term antibody response of a hepatitis E vaccine

BackgroundThe first commercialized hepatitis E vaccine, HEV 239, has been shown to be safe and highly immunogenic, the protection as well as the vaccine-induced anti-HEV maintained for at least 4.5 years. However, the longer term persistence of the vaccine-induced anti-HEV responses is unknown.MethodsTwo statistical models, the power-law model and the modified power-law model, were applied to predict the long-term antibody response of the HEV 239 vaccine. The models were fit using the anti-HEV IgG data from a modeling subpopulation of 1278 baseline seronegative vaccinees who seroconverted within one month after finishing the whole vaccination course in the phase 3 trial of HEV 239. In addition, antibody data from a validation subpopulation were used to validate the robustness of the derived models.ResultsIn the vaccinees without pre-vaccination immunity, the power-law model and the modified power-law model estimated that the median duration of the detectable antibody (≥0.077 WU/ml) was 8 years and 13 years, respectively. The power-law model and the modified power-law model estimated that 50% of these vaccinees will maintain detectable levels of anti-HEV IgG for 8 years and >30 years, respectively.ConclusionsThe recombinant hepatitis E vaccine HEV 239 is predicted to provide from 8 years to nearly life-long persistence of anti-HEV IgG above detectable levels. Model predictions are based on conservative mathematical assumptions.(NCT01014845).     

Hepatic disposal of advanced glycation end products during maturation and aging

Aging is characterized by progressive loss of metabolic and biochemical functions and accumulation of metabolic by-products, including advanced glycation end products (AGEs), which are observed in several pathological conditions. A number of waste macromolecules, including AGEs are taken up from the circulation by endocytosis mainly into liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs). However, AGEs still accumulate in different tissues with aging, despite the presence of this clearance mechanism. The aim of the present study was to determine whether the efficiency of LSECs and KCs for disposal of AGEs changes through aging.     

Estimation of safe dietary intake levels of acrylamide for humans

Acrylamide (AA), a human neurotoxicant and rat tumorigen, is produced in starchy foods when cooked. AA is also an industrial chemical used in polyacrylamide production. A safety evaluation of ingested AA by humans was conducted using a newly developed, state-of-the-art physiologically-based toxicokinetic (PBPK or PBTK) model to compare internal doses of AA and its metabolite glycidamide (GA) in humans and rats. Based on modes of action (MoA), a nonlinear dose–response approach was applied for neurotoxicity (non-genotoxicity) and carcinogenicity (mixed: genotoxicity and epigenetic MoA). Tolerable daily intake (TDI) for neurotoxicity from AA was estimated to be 40 μg/kg-day; TDIs for cancer were estimated to be 2.6 and 16 μg/kg-day based on AA or GA, respectively. Margins of exposure (MoE) were calculated for average AA consumers to be 300 and 500 based on AA and GA, respectively; for cancer, the MoE for average AA consumers was estimated to be 200 and 1200 based on AA and GA, respectively. For high consumers of AA, MoEs were somewhat less.     

3'-Azido-3'-deoxythymidine (AZT) is a competitive inhibitor of thymidine phosphorylation in isolated rat heart and liver mitochondria

Long-term use of 3'-azido-3'-deoxythymidine (AZT) is associated with various tissue toxicities, including hepatotoxicity and cardiomyopathy, and with mitochondrial DNA depletion. AZT-5'-triphosphate (AZTTP) is a known inhibitor of the mitochondrial DNA polymerase gamma and has been targeted as the source of the mitochondrial DNA depletion. However, in previous work from this laboratory with isolated rat heart and liver mitochondria, AZT itself was shown to be a more potent inhibitor of thymidine phosphorylation (IC50 of 7.0+/-1.0 microM AZT in heart mitochondria and of 14.4+/-2.6 microM AZT in liver mitochondria) than AZTTP is of polymerase gamma (IC50 of >100 microM AZTTP), suggesting that depletion of mitochondrial stores of TTP may limit replication and could be the cause of the mitochondrial DNA depletion observed in tissues affected by AZT toxicity. The purpose of this work is to characterize the nature of AZT inhibition of thymidine phosphorylation in isolated rat heart and rat liver mitochondria. In both of these tissues, AZT was found to be a competitive inhibitor of the phosphorylation of thymidine to TMP, catalyzed by thymidine kinase 2. The inhibition constant (Ki) for heart mitochondria is 10.6+/-4.5 microM AZT, and for liver mitochondria Ki is 14.0+/-2.5 microM AZT. Since AZT is functioning as a competitive inhibitor, increasing thymidine concentrations may be one mechanism to overcome the inhibition and decrease AZT-related toxicity in these tissues.     

Gene expression profiling for prognosis using Cox regression

Given the promise of rich biological information in microarray data we will expect an increasing demand for a robust, practical and well-tested methodology to provide patient prognosis based on gene expression data. In standard settings, with few clinical predictors, such a methodology has been provided by the Cox proportional hazard model, but no corresponding methodology is available to deal with the full set of genes in microarray data. Furthermore, we want the procedure to be able to deal with the general survival data that include censored information. Conceptually such a procedure can be constructed quite easily, but its implementation will never be straightforward due to computational problems. We have developed an approach that relies on an extension of the Cox proportional likelihood that allows random effects parameters. In this approach, we use the full set of genes in the analysis and deal with survival data in the most general way. We describe the development of the model and the steps in the implementation, including a fast computational formula based on a subsampling of the risk set and the singular value decomposition. Finally, we illustrate the methodology using a data set obtained from a cohort of breast cancer patients.     

Using generalized additive models to reduce residual confounding

Traditionally, confounding by continuous variables is controlled by including a linear or categorical term in a regression model. Residual confounding occurs when the effect of the confounder on the outcome is mis-modelled. A continuous representation of a covariate was previously shown to result in a less biased estimate of the adjusted exposure effect than categorization provided the functional form of the covariate-outcome relationship is correctly specified. However, this is rarely known. In contrast to parametric regression, generalized additive models (GAM) fit a smooth dose-response curve to the data, without requiring a priori knowledge of the functional form. We used simulations to compare parametric multiple logistic regression vs its non-parametric GAM extension in their ability to control for a continuous confounder. We also investigated several issues related to the implementation of GAM in this context, including: (i) selecting the degrees of freedom; and (ii) alternative criteria for inclusion/exclusion of the potential confounder and for choosing between parametric and non-parametric representation of its effect. The impact of the shape and strength of the confounder-disease association, sample size, and the correlation between the confounder and exposure were investigated. Simulations showed that when the confounder has a non-linear association with the outcome, compared to a parametric representation, GAM modelling (i) reduced the mean squared error for the adjusted exposure effect; (ii) avoided inflation of the type I error for testing the exposure effect. When the true confounder-outcome relationship was linear, GAM performed as well as the parametric logistic regression. When modelling a continuous exposure non-parametrically, in the presence of a continuous confounder, our results suggest that assuming a linear effect of the confounder and focussing on the non-linearity of the exposure-outcome relationship leads to spurious findings of non-linearity: joint non-linear modelling is necessary. Overall, our results suggest that the use of GAM to reduce residual confounding offers several improvements over conventional parametric modelling.     

对医疗机构分类管理政策的回顾与反思

通过回顾与分析医疗机构分类管理政策出台的背景，指出该政策出台的必然性。同时，指出卫生行政部门自身的权限决定了它主持制定的分类管理政策无法解决公立医疗机构改革的诸多关键性问题。分析了该政策实施效果不佳的原因是由于与该政策配套的营利性医疗机构税收政策和工商登记要求不尽合理。而导致目前该政策进退两难的原因则是由于该政策赋予工商和税务这两个部门在营利性医疗机构经济监管中较大的权限，使部门利益已经形成，卫生部门在与上述部门协调修改有关规定时难度极大，包括医疗机构管理体制改革在内的所有事业单位改革，仅仅依靠各行业主管部门无法取得突破性进展，国务院必须加强有关部门的协调，必须对事业单位改革做出全盘性的规划。     

A randomized clinical trial of a brief motivational intervention for alcohol-positive adolescents treated in an emergency department

We tested whether a brief motivational interview (MI) would reduce alcohol-related consequences and use among adolescents treated in an emergency department (ED) after an alcohol-related event. Patients aged 13 to 17 years (N = 152) with a positive blood alcohol concentration (BAC) by lab test or self-report were recruited in the ED and randomly assigned to receive either MI or standard care (SC). Both conditions resulted in reduced quantity of drinking during the 12-month follow-up, whereas alcohol-related negative consequences were relatively low and stayed low at follow-up. Adolescents who screened positive for problematic alcohol use at baseline reported significantly more improvement on 2 of 3 alcohol use outcomes (average number of drinking days per month and frequency of high-volume drinking) if they received MI compared with SC. We conclude that brief interventions are recommended for adolescents who present to an ED with an alcohol-related event and report preexisting problematic alcohol use.