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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
We sought to define trends in and predictors of carbapenem consumption across community, teaching, and university-affiliated hospitals in the United States and Canada. We conducted a retrospective ...multicenter survey of carbapenem and broad-spectrum noncarbapenem beta-lactam consumption between January 2011 and December 2013. Consumption was tabulated as defined daily doses (DDD) or as days of therapy (DOT) per 1,000 patient days (PD). Multivariate mixed-effects models were explored, and final model goodness of fit was assessed by regressions of observed versus predicted values and residual distributions. A total of 20 acute-care hospitals responded. The centers treated adult patients (
= 19/20) and pediatric/neonatal patients (
= 17/20). The majority of the centers were nonprofit (
= 17/20) and not affiliated with medical/teaching institutions (
= 11/20). The median (interquartile range IQR) carbapenem consumption rates were 38.8 (17.4 to 95.7) DDD/1,000 PD and 29.7 (19.2 to 40.1) DOT/1,000 PD overall. Carbapenem consumption was well described by a multivariate linear mixed-effects model (fixed effects,
= 0.792; fixed plus random effects,
= 0.974). Carbapenem consumption increased by 1.91-fold/quarter from 48.6 DDD/1,000 PD (
= 0.004) and by 0.056-fold/quarter from 45.7 DOT/1,000 PD (
= 0.93) over the study period. Noncarbapenem consumption was independently related to increasing carbapenem consumption (beta = 0.31 for increasing noncarbapenem beta-lactam consumption;
< 0.001). Regular antibiogram publication and promotion of conversion from intravenous (i.v.) to oral (p.o.) administration independently affected carbapenem consumption rates. In the final model, 58.5% of the observed variance in consumption was attributable to between-hospital differences. Rates of carbapenem consumption across 20 North American hospitals differed greatly, and the observed differences were correlated with hospital-specific demographics. Additional studies focusing on the drivers of hospital-specific carbapenem consumption are needed to determine whether these rates are justifiable.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Objectives This article described parents' experience and identifies outcomes important to parents following their child's critical illness. Methods Semistructured interviews with 22 female ...and 4 male parents representing 26 critically ill children with predominately neurologic and respiratory diagnoses. Most children were younger than 5 years at discharge with a median (interquartile range) of 2 (2.0–3.0) years from discharge to interview. Results Many children returned home with life-altering physical and cognitive disabilities requiring months to years of rehabilitation. Parents remembered feeling unprepared and facing an intense, chaotic time when the child first returned home. They described how they suddenly had to center their daily activities around the child's needs amidst competing needs of siblings and partners, and in some cases, the medicalization of the home. They recounted negotiating adjustments almost daily with insurance agencies, medical doctors and therapists, employers, the child, and other family members to keep the family functioning. In the long term, families developed a new norm, choosing to focus on what the child could still do rather than what they could not. Even if the child returned to baseline, parents remembered the adjustments made to keep the child alive and the family functioning. Conclusion Heightened awareness of family experiences after pediatric critical illness will allow health care providers to improve family preparedness for the transition from hospital to home.
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.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
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.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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.
This study determines which of 8 doses of bevacizumab are effective in treating severe retinopathy of prematurity to carry forward to a large-scale randomized clinical trial.
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