Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of ...therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p<or=0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Delta7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p<or=0.0036) and maximum ulnar CMAP scores (p<or=0.0001) increased significantly.
While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects.
ClinicalTrials.gov.
This study investigated relationships between self-reported experiences of social defeat and individual dimensions of self-reported schizotypy.
1632 adults aged between 18 and 79 participated across ...two non-clinical samples (n = 920, n = 712). Multiple regression analyses tested the relationships between dimensions of schizotypy and social defeat.
The analyses demonstrated evidence of relationships between increased overall schizotypy and increased social defeat, with schizotypal suspiciousness and disorganised or constrained thought and speech consistently emerging as the two most important individual predictors.
These results suggest that increased schizotypy is associated with increased social defeat, although the specific relationships may depend on the specific aspects of social defeat and schizotypy being measured. Future research should investigate whether social defeat plays a role in the manifestation of specific schizotypy traits.
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.
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.
Double strand breaks (DSBs) represent highly deleterious DNA damage and need to be accurately repaired. Homology-directed repair and non-homologous end joining (NHEJ) are the two major DSB repair ...pathways that are highly conserved from yeast to mammals. The choice between these pathways is largely based on 5′ to 3′ DNA resection, and NHEJ proceeds only if resection has not been initiated. In yeast, yKu70/80 rapidly localizes to the break, protecting DNA ends from nuclease accessibility, and recruits additional NHEJ factors, including Nej1 and Lif1. Cells harboring the nej1-V338A mutant exhibit NHEJ-mediated repair deficiencies and hyper-resection 0.15 kb from the DSB that was dependent on the nuclease activity of Dna2–Sgs1. The integrity of Nej1 is also important for inhibiting long-range resection, 4.8 kb from the break, and for preventing the formation of large genomic deletions at sizes >700 bp around the break. Nej1V338A localized to a DSB similarly to WT Nej1, indicating that the Nej1–Lif1 interaction becomes critical for blocking hyper-resection mainly after their recruitment to the DSB. This work highlights that Nej1 inhibits 5′ DNA hyper-resection mediated by Dna2–Sgs1, a function distinct from its previously reported role in supporting Dnl4 ligase activity, and has implications for repair pathway choice and resection regulation upon DSB formation.
Subsidized dog care and population management programs (DPM) are often implemented for dog population control where for-profit veterinary care is inaccessible. However, impacts of such programs are ...rarely assessed. The goal of this project was to determine if and how previously collected intake data from ongoing high-volume spay-neuter clinics could be used to measure impacts of such DPM programs.
We used intake data collected from 2008 to 2019 from spay-neuter clinics that had been delivered repeatedly over a 10-year period in 6 First Nations communities in Alberta, to assess changes in intake dog characteristics.
Numbers of dogs brought in for spay-neuter surgery or surrendered, and their ages, sexes, breeds, weights, and body condition scores were compared. Reasons for surrender were investigated and socioeconomic factors were investigated as possible drivers for community differences in clinic participation rates and clinic sex ratios.
Socioeconomic indicators did not differ between the 6 participating communities; however, the total number of clinics requested by communities varied. In early years, female dogs were more likely to be brought to the clinics to be spayed whereas, in later years, more males were seen. The age at which animals were brought in for spay or neuter decreased over time (
< 0.05) but the surrender age did not. Breed proportions of x-large, small, and x-small breeds varied over time for both spay-neuter and surrender dogs (
< 0.05), with large-breed dogs always being the most common. However, there was an increase in small and x-small breeds in the final years of the study. Finally, weight status, a calculated estimate of body condition of spay-neuter dogs, increased over time within large and medium breeds, whereas the body condition score of surrendered dogs shifted from "thin" to "ideal" over time.
This work highlights the potential and challenges of using intake data to assess impacts of spay-neuter clinics that occur repeatedly over many years in the same communities. Overall increased weight status, high participation rates, and reduction of age at intake suggest positive effects of the assessed spay-neuter programs.
Many pediatric patients with acute liver failure (PALF) do not receive a specific diagnosis (such as herpes simplex virus or Wilson disease or fatty acid oxidation defects)-they are left with an ...indeterminate diagnosis and are more likely to undergo liver transplantation, which is contraindicated for some disorders. Strategies to facilitate complete diagnostic testing should increase identification of specific liver diseases and might reduce liver transplantation. We investigated whether performing recommended age-specific diagnostic tests (AS-DTs) at the time of hospital admission reduces the percentage PALFs with an indeterminate diagnosis.
We performed a multinational observational cohort study of 658 PALF participants in the United States and Canada, enrolled at 10 medical centers, during 3 study phases from December 1999 through December 2014. A learning collaborative approach was used to implement AS-DT using an electronic medical record admission order set at hospital admission in phase 3 of the study. Data from 10 study sites participating in all 3 phases were compared before (phases 1 and 2) and after (phase 3) diagnostic test recommendations were inserted into electronic medical record order sets.
The percentage of subjects with an indeterminate diagnosis decreased significantly between phases 1-2 (48.0%) and phase 3 (to 30.8%) (P = .0003). The 21-day cumulative incidence rates for liver transplantation were significantly different among phase 1 (34.6%), phase 2 (31.9%), and phase 3 (20.2%) (P = .030). The 21-day cumulative incidence rates for death did not differ significantly among phase 1 (17.9%), phase 2 (11.9%), and phase 3 (11.3%) (P = .20).
In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children.
Pediatric Intensive Care Unit (PICU) teams provide care for critically ill children with diverse and often complex medical and surgical conditions. Researchers often lack guidance on an approach to ...select the best outcomes when evaluating this critically ill population. Studies would be enhanced by incorporating multi-stakeholder preferences to better evaluate clinical care. This manuscript outlines the methodology currently being used to develop a PICU Core Outcome Set (COS). This PICU COS utilizes mixed methods, an inclusive stakeholder approach, and a modified Delphi consensus process that will serve as a resource for PICU research programs.
A Scoping Review of the PICU literature evaluating outcomes after pediatric critical illness, a qualitative study interviewing PICU survivors and their parents, and other relevant literature will serve to inform a modified, international Delphi consensus process. The Delphi process will derive a set of minimum domains for evaluation of outcomes of critically ill children and their families. Delphi respondents include researchers, multidisciplinary clinicians, families and former patients, research funding agencies, payors, and advocates. Consensus meetings will refine and finalize the domains of the COS, outline a battery instruments for use in future studies, and prepare for extensive dissemination for broad implementation.
The PICU COS will be a guideline resource for investigators to assure that outcomes most important to all stakeholders are considered in PICU clinical research in addition to those deemed most important to individual scientists.
Trial registration: COMET database (http://www.comet-initiative.org/, Record ID 1131, 01/01/18).
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