Identification of SOD1 as the mutated protein in a significant subset of familial amyotrophic lateral sclerosis (FALS) cases has led to the generation of transgenic rodent models of autosomal dominant SOD1 FALS. Mice carrying 23 copies of the human SOD1(G93A) transgene are considered the standard model for FALS and ALS therapeutic studies. To date, there have been at least 50 publications describing therapeutic agents that extend the lifespan of this mouse. However, no therapeutic agent besides riluzole has shown corresponding clinical efficacy. We used computer modeling and statistical analysis of 5429 SOD1(G93A) mice from our efficacy studies to quantify the impact of several critical confounding biological variables that must be appreciated and should be controlled for when designing and interpreting efficacy studies. Having identified the most critical of these biological variables, we subsequently instituted parameters for optimal study design in the SOD1(G93A) mouse model. We retested several compounds reported in major animal studies (minocycline, creatine, celecoxib, sodium phenylbutyrate, ceftriaxone, WHI-P131, thalidomide, and riluzole) using this optimal study design and found no survival benefit in the SOD1(G93A) mouse for any compounds (including riluzole) administered by their previously reported routes and doses. The presence of these uncontrolled confounding variables in the screening system, and the failure of these several drugs to demonstrate efficacy in adequately designed and powered repeat studies, leads us to conclude that the majority of published effects are most likely measurements of noise in the distribution of survival means as opposed to actual drug effect. We recommend a minimum study design for this mouse model to best address and manage this inherent noise and to facilitate more significant and reproducible results among all laboratories employing the SOD1(G93A) mouse.

A systematic program of contact with persons who are at risk of suicide and who refuse to remain in the health care system appears to exert a significant preventive influence for at least two years. Diminution of the frequency of contact and discontinuation of contact appear to reduce and eventually eliminate this preventive influence.

The majority of prospective studies on alcohol use and mortality risk indicates that abstainers are at increased risk of mortality from both all causes and coronary heart disease (CHD). This meta-analysis of 54 published studies tested the extent to which a systematic misclassification error was committed by including as 'abstainers' many people who had reduced or stopped drinking, a phenomenon associated with ageing and ill health. The studies judged to be error free found no significant all-cause or cardiac protection, suggesting that the cardiac protection afforded by alcohol may have been over-estimated. Estimates of mortality from heavier drinking may also be higher than previously estimated.

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Post-transplantation recurrence is increasing in patients with HCV. Early antiviral therapy may be of benefit in this setting. Thus, accurate and early prediction of progression may help select candidates for treatment. We developed a model based on pre-and/or early post-transplantation variables, which may predict progression to severe disease. Clinical and histologic outcomes were assessed in 554 liver recipients. A total of 1,353 biopsy specimens obtained after 1 year (median of 2 biopsies per patient; range, 1-8) were scored. Two outcome measures were used: cumulative probability of developing severe disease (fibrosis 3 and 4) within 5 years and actual progression to severe disease in 2 years. We used Cox proportional hazard survival analysis for the whole cohort. Predictors analyzed included HCV genotype and recipient, donor, and transplant-related variables. The cumulative risk of progressing to fibrosis 3 and 4 was significantly greater in patients transplanted recently (P < .001) and was present in all centers. Factors increasing this risk were genotype, induction with mycophenolate, donor age, short course of azathioprine, and prednisone (<12 months). To create a model of prediction, 285 patients with 2-year follow-up were used to create a logistic regression analysis. The estimated probability of being at high risk for severe disease was calculated from a formula that included donor age and recipient therapy as critical variables.