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Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo. Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of \"sitters\" (cohort 1) and an ambulatory group of \"walkers\" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures. At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007). This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials. Clinicaltrials.gov NCT00227266.

The health impacts of intimate partner violence against women and childhood sexual abuse are not fully understood. Here we conducted a systematic review by comprehensively searching seven electronic databases for literature on intimate partner violence-associated and childhood sexual abuse-associated health effects. Following the burden of proof methodology, we evaluated the evidence strength linking intimate partner violence and/or childhood sexual abuse to health outcomes supported by at least three studies. Results indicated a moderate association of intimate partner violence with major depressive disorder and with maternal abortion and miscarriage (63% and 35% increased risk, respectively). HIV/AIDS, anxiety disorders and self-harm exhibited weak associations with intimate partner violence. Fifteen outcomes were evaluated for their relationship to childhood sexual abuse, which was shown to be moderately associated with alcohol use disorders and with self-harm (45% and 35% increased risk, respectively). Associations between childhood sexual abuse and 11 additional health outcomes, such as asthma and type 2 diabetes mellitus, were found to be weak. Although our understanding remains limited by data scarcity, these health impacts are larger in magnitude and more extensive than previously reported. Renewed efforts on violence prevention and evidence-based approaches that promote healing and ensure access to care are necessary. A meta-analysis using the burden of proof risk function identified consistent evidence supporting harmful associations between the exposure to intimate partner violence against women and childhood sexual abuse on health outcomes.

Despite a gradual decline in smoking rates over time, exposure to secondhand smoke (SHS) continues to cause harm to nonsmokers, who are disproportionately children and women living in low- and middle-income countries. We comprehensively reviewed the literature published by July 2022 concerning the adverse impacts of SHS exposure on nine health outcomes. Following, we quantified each exposure–response association accounting for various sources of uncertainty and evaluated the strength of the evidence supporting our analyses using the Burden of Proof Risk Function methodology. We found all nine health outcomes to be associated with SHS exposure. We conservatively estimated that SHS increases the risk of ischemic heart disease, stroke, type 2 diabetes and lung cancer by at least around 8%, 5%, 1% and 1%, respectively, with the evidence supporting these harmful associations rated as weak (two stars). The evidence supporting the harmful associations between SHS and otitis media, asthma, lower respiratory infections, breast cancer and chronic obstructive pulmonary disease was weaker (one star). Despite the weak underlying evidence for these associations, our results reinforce the harmful effects of SHS on health and the need to prioritize advancing efforts to reduce active and passive smoking through a combination of public health policies and education initiatives. A meta-analysis using the Burden of Proof method reported consistent evidence supporting harmful associations between exposures to secondhand smoke and nine health outcomes.

How managers acquire, leverage, and protect technological competencies in order to innovate successfully and enhance firm performance is central to the field of strategic management. When tensions across acquisition, leverage, and protection activities are resolved and synergies are captured, the value derived from technological competencies can be used to fuel a virtuous cycle in which fewer resources are needed to perpetuate a firm's advantage. The papers in this issue examine the mechanisms underlying acquisition, leverage, and protection, and are particularly useful in resolving these tensions and highlighting potential synergies. We develop a typology to describe the research domain and relate these papers to one another. Based on gaps in this typology and issues raised by these papers, we offer observations for future research on the acquisition, leverage, and protection of technological competencies. Copyright © 2004 John Wiley & Sons, Ltd.

Multiple lines of evidence have suggested that valproic acid (VPA) might benefit patients with spinal muscular atrophy (SMA). The SMA CARNIVAL TRIAL was a two part prospective trial to evaluate oral VPA and L-carnitine in SMA children. Part 1 targeted non-ambulatory children ages 2-8 in a 12 month cross over design. We report here Part 2, a twelve month prospective, open-label trial of VPA and L-carnitine in ambulatory SMA children. This study involved 33 genetically proven type 3 SMA subjects ages 3-17 years. Subjects underwent two baseline assessments over 4-6 weeks and then were placed on VPA and L-carnitine for 12 months. Assessments were performed at baseline, 3, 6 and 12 months. Primary outcomes included safety, adverse events and the change at 6 and 12 months in motor function assessed using the Modified Hammersmith Functional Motor Scale Extend (MHFMS-Extend), timed motor tests and fine motor modules. Secondary outcomes included changes in ulnar compound muscle action potential amplitudes (CMAP), handheld dynamometry, pulmonary function, and Pediatric Quality of Life Inventory scores. Twenty-eight subjects completed the study. VPA and carnitine were generally well tolerated. Although adverse events occurred in 85% of subjects, they were usually mild and transient. Weight gain of 20% above body weight occurred in 17% of subjects. There was no significant change in any primary outcome at six or 12 months. Some pulmonary function measures showed improvement at one year as expected with normal growth. CMAP significantly improved suggesting a modest biologic effect not clinically meaningful. This study, coupled with the CARNIVAL Part 1 study, indicate that VPA is not effective in improving strength or function in SMA children. The outcomes used in this study are feasible and reliable, and can be employed in future trials in SMA. TRIAL REGSITRATION: Clinicaltrials.gov NCT00227266.

The debate over firearm policies in the United States has developed a well-established rhetoric in the past few decades; some might even argue that it has reached a stalemate. Issues of debate include the Second Amendment to the U.S. Constitution and whether it confers an individual right to bear arms 1 – 3 ; the risks and benefits of handgun possession 4 – 6 ; the frequency of the defensive use of guns 7 – 9 ; and the relative effectiveness of gun policies. 10 , 11 Recently, however, several policies that circumvent the most troublesome and contentious issues of the debate have been proposed. These policies would . . .

Knox and Caine, authors of the recent artide \"Establishing Priorities for Reducing Suicide and Its Antecedents in the United States,\" admonish the public health community for neglecting the toll of suicide among men in their middle years.1 We find no fault with the article as a piece of descriptive epidemiology. However, in an artide claiming to establish priorities for reducing suicide in the United States, the authors' disregard of the central role of firearms in American suicides is a stunning oversight Nowhere is it noted, for example, that firearms are the mechanism involved in more than half of all US suicides, including those among middle-aged men.2 Knox and Caine are right to claim mat population-based approaches to preventing suicide have been neglected. While there is some indication that restriction of firearms in the homes of adolescents with previous histories of self-harm may be effective in reducing the risk of suicide,2 the focus of our article was to move priority-setting discussions beyond consideration of death rates (which are highest among older White men) and beyond common areas of public attention (most often involving school-aged children) to a broader view of the burdens of death and loss associated with suicide.

In addition to the need to identify homicide trends among well-documented risk groups, this investigation was conducted to expand the limited existing knowledge about the risk of homicide according to educational attainment and among 2 growing ethnic groups, Hispanics and Asians. We examined the death certificates of the 69,621 persons who died of homicide in California from 1970 through 1993. Age, sex, race and ethnicity, and education level of the victim, along with the homicide method, were abstracted from each record. Frequencies, rates, and relative risk were calculated. Substantial increases in the homicide rates occurred for 15- to 19-year-olds (4.0-fold), men (1.9-fold), Hispanics (2.5-fold), and Asians or others (1.7-fold) from 1970 to 1993. The use of firearms consistently accounted for a growing proportion of all homicides, reaching a high in 1993 of 75% for all persons and 90% for 15- to 19-year-olds. High school dropouts have the highest homicide risk of all education groups. Homicide risk differentials by ethnicity, sex, and age all increased during the study period. Persons of color and youth have been disproportionately affected by homicide for many years, and these data indicate that things are getting worse. Redoubled collaborative prevention and intervention efforts are needed to reverse this trend.