The safety and efficacy of onabotulinumtoxinA injections for children and adolescents with chronic migraine: A systematic review and meta-analysis.

OBJECTIVE: To qualitatively and quantitatively summarize the evidence for the use of onabotulinumtoxinA injections in children and adolescents with migraine. BACKGROUND: There are limited evidence-based treatment options for youth with migraine, especially youth with chronic migraine (CM). OnabotulinumtoxinA injections are an established evidence-based treatment for adults with CM. While several studies have assessed their safety and efficacy among adolescents with CM, there are no published systematic reviews summarizing the pediatric evidence. METHODS: We carried out a systematic review, reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis, aiming to identify studies that included five or more children and adolescents aged ≤18 years with a diagnosis of migraine, who were treated with ≥50 units (U) of onabotulinumtoxinA and had outcomes assessed ≥4 weeks after one or more injection cycle. Both observational studies and randomized controlled trials (RCTs) were eligible for inclusion. Two investigators independently carried out the first (titles and abstracts) and second (full text) screening stages, as well as data extraction and quality appraisal. The American Academy of Neurology risk of bias grading scheme was used to assess study risk of bias. Studies with adequate data were pooled using random effects meta-analyses, and Hedge's g standardized mean differences with 95% confidence intervals (CIs) were generated to estimate the effect sizes of the continuous outcomes included. Studies lacking data required for meta-analysis were summarized qualitatively. RESULTS: We screened 634 studies and included 14 studies comprising 491 participants, of whom 489 had CM. Two studies were RCTs, 12 were observational uncontrolled studies, and all but one study included only youth with CM. Five Class IV observational uncontrolled studies were amenable to pooling in meta-analyses. After a mean of 2-2.6 injection cycles, headache frequency was shown to decrease significantly after treatment with onabotulinumtoxinA (Hedge's g = 0.97, 95% CI 0.58-1.35; p < 0.0001), as did severity (Hedge's g = 1.24, 95% CI 0.55-1.94; p = 0.0005), with both estimates having a large effect size magnitude. A Class I parallel-group RCT of one injection series (155 U, 74 U, or placebo), powered to detect a change in 4 headache days per month, did not find outcome differences between the active and placebo treatment arms. A Class IV crossover RCT showed superiority of active (155 U) versus placebo injections. The remaining Class IV observational studies that were excluded from the meta-analyses all showed improved outcomes with onabotulinumtoxinA injections over time. No serious adverse events related to treatment occurred. CONCLUSION: OnabotulinumtoxinA injections have established safety for use in children and adolescents with CM and are likely effective in reducing headache frequency and severity over time. However, in the absence of an adequately powered parallel-group RCT assessing the efficacy of multiple injection cycles, it remains unclear if this intervention is superior to placebo.

"This shouldn't be our job to help you do this": exploring the responses of medical schools across Canada to address anti-Black racism in 2020.

BACKGROUND: Protests against police brutality and anti-Black racism were catalyzed by the murder of George Floyd and other Black and racialized people in spring 2020. Addressing anti-Black racism had been historically minimized as an institutional priority across Canadian medical schools, but many swiftly released statements broadly condemning racism. Given that little has been documented about how institutions are responding with action, we sought to explore Black medical students' and senior faculty perspectives on Canadian medical schools' efforts to address anti-Black racism in 2020. METHODS: We conducted a qualitative, instrumental case study, grounded in critical race theory. We recruited Black medical students and deans (or delegated senior faculty administrators) and we conducted virtual, individual, semi-structured interviews with participants between Oct. 5, 2020, and Jan. 16, 2021. Interviews were transcribed and iteratively analyzed through inductive and deductive techniques. RESULTS: We interviewed 19 participants, including 8 medical students (6 in pre-clerkship; all of whom identified as Black) and 11 senior faculty administrators (4 deans, 7 delegate faculty administrators; 3 racialized). We had at least 1 student or faculty participant from 13 medical schools, and no student or faculty participants from the 4 medical schools in Quebec. Nearly all represented medical schools were described as "starting from scratch" in their responses, having previously failed to acknowledge or address anti-Black racism. In the absence of diverse faculty leaders, participants indicated that medical schools primarily relied on Black medical students to drive institutional responses, unfairly burdening students during an already difficult period. At the time of the interviews, a range of initiatives were in the planning stages or underway, and were largely related to admissions and curriculum reform. INTERPRETATION: We found that medical schools relied heavily on Black medical students to inform and drive their institutional responses related to anti-Black racism in 2020, which these students found burdensome. Medical schools lacked intrinsic capacity because of the paucity of Black faculty - a direct result of historical and ongoing structural anti-Black racism in medicine. Institutional accountability remains critical, and further research is needed to show the extent to which medical schools in Canada are successfully addressing anti-Black racism.

Perineurial Window is Critical for Experimental Reverse End-to-Side Nerve Transfer.

BACKGROUND: The depth of connective tissue window in the side of a recipient nerve in reverse end-to-side transfers (RETS) remains controversial. OBJECTIVE: To test whether the depth of connective tissue disruption influences the efficiency of donor axonal regeneration in the context of RETS. METHODS: Sprague-Dawley rats (n = 24) were assigned to 1 of the 3 groups for obturator nerve to motor femoral nerve RETS: group 1, without epineurium opening; group 2, with epineurium only opening; and group 3, with epineurium and perineurium opening. Triple retrograde labeling was used to assess the number of motor neurons that had regenerated into the recipient motor femoral branch. Thy1-GFP rats (n = 8) were also used to visualize the regeneration pathways in the nerve transfer networks at 2- and 8-week time point using light sheet fluorescence microscopy. RESULTS: The number of retrogradely labeled motor neurons that had regenerated distally toward the target muscle was significantly higher in group 3 than that in groups 1 and 2. Immunohistochemistry validated the degree of connective tissue disruption among the 3 groups, and optical tissue clearing methods demonstrated donor axons traveling outside the fascicles in groups 1 and 2 but mostly within the fascicles in group 3. CONCLUSION: Creating a perineurial window in the side of recipient nerves provides the best chances of robust donor axonal regeneration across the RETS repair site. This finding aids nerve surgeons by confirming that a deep window should be undertaken when doing a RETS procedure.

Multi-state study of Enterobacteriaceae harboring extended-spectrum beta-lactamase and carbapenemase genes in U.S. drinking water.

Community-associated acquisition of extended-spectrum beta-lactamase- (ESBL) and carbapenemase-producing Enterobacteriaceae has significantly increased in recent years, necessitating greater inquiry into potential exposure routes, including food and water sources. In high-income countries, drinking water is often neglected as a possible source of community exposure to antibiotic-resistant organisms. We screened coliform-positive tap water samples (n = 483) from public and private water systems in six states of the United States for blaCTX-M, blaSHV, blaTEM, blaKPC, blaNDM, and blaOXA-48-type genes by multiplex PCR. Positive samples were subcultured to isolate organisms harboring ESBL or carbapenemase genes. Thirty-one samples (6.4%) were positive for blaCTX-M, ESBL-type blaSHV or blaTEM, or blaOXA-48-type carbapenemase genes, including at least one positive sample from each state. ESBL and blaOXA-48-type Enterobacteriaceae isolates included E. coli, Kluyvera, Providencia, Klebsiella, and Citrobacter species. The blaOXA-48-type genes were also found in non-fermenting Gram-negative species, including Shewanella, Pseudomonas and Acinetobacter. Multiple isolates were phenotypically non-susceptible to third-generation cephalosporin or carbapenem antibiotics. These findings suggest that tap water in high income countries could serve as an important source of community exposure to ESBL and carbapenemase genes, and that these genes may be disseminated by non-Enterobacteriaceae that are not detected as part of standard microbiological water quality testing.