Response to letter to editor: 'Comment on Arch et al., Trials. 2016;17:517'

In October 2015 we published the paper ‘Measurement of HbA1c in multicentre diabetes trials – should blood samples be tested locally or sent to a central laboratory: an agreement analysis’. Chatterjee and Pradhan have submitted a letter to the editor asking critical questions regarding the methods we used. We offer this letter in response

Variation in ampicillin dosing for lower respiratory tract infections and neonatal bacterial infections in US children\u27s hospitals

OBJECTIVE: We examined ampicillin dosing in pediatric patients across 3 conditions: (1) bacterial lower respiratory tract infections (LRTIs) in infants and children \u3e3 months, (2) neonates with suspected or proven sepsis, and (3) neonates with suspected central nervous system (CNS) infections. We compared our findings to dosing guidance for these specific indications. DESIGN: Retrospective cohort study. SETTING: The study included data from 32 children\u27s hospitals in the United States. METHODS: We reviewed prescriptions from the SHARPS study of antimicrobials, a survey of antibiotic prescribing from July 2016 to December 2017. Prescriptions were analyzed for indication, total daily dose per kilogram, and presence of antimicrobial stewardship program (ASP) review. LRTI prescriptions were compared to IDSA recommendations for community-acquired pneumonia. Neonatal prescriptions were compared to recommendations from the American Academy of Pediatrics (AAP). Prescriptions were categorized as optimal (80%-120% of recommended dosing), suboptimal (\u3c80% of recommended dosing), or excessive (\u3e120% of recommended dosing). RESULTS: Among 1,038 ampicillin prescriptions, we analyzed 88 prescriptions for LRTI, 499 prescriptions for neonatal sepsis, and 27 prescriptions for neonatal CNS infection. Of the LRTI prescriptions, 77.3%were optimal. Of prescriptions for neonatal sepsis, 81.6% were excessive compared to AAP bacteremia recommendations but 78.8% were suboptimal compared to AAP meningitis guidelines. Also, 48.1% of prescriptions for neonatal CNS infection were suboptimal, and 50.6% of prescriptions were not reviewed by the ASP. CONCLUSIONS: LRTI dosing is generally within the IDSA-recommended range. However, dosing for neonatal sepsis often exceeds the recommendation for bacteremia but is below the recommendation for meningitis. This variability points to an important opportunity for future antimicrobial stewardship efforts

Selective vulnerability of inhibitory networks in multiple sclerosis.

In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination reproduces this selective neurodegeneration providing a new preclinical model for the study of neuroprotective treatments

Accelerating growth of HFC-227ea (1,1,1,2,3,3,3-heptafluoropropane) in the atmosphere

We report the first measurements of 1,1,1,2,3,3,3-heptafluoropropane (HFC-227ea), a substitute for ozone depleting compounds, in air samples originating from remote regions of the atmosphere and present evidence for its accelerating growth. Observed mixing ratios ranged from below 0.01 ppt in deep firn air to 0.59 ppt in the current northern mid-latitudinal upper troposphere. Firn air samples collected in Greenland were used to reconstruct a history of atmospheric abundance. Year-on-year increases were deduced, with acceleration in the growth rate from 0.029 ppt per year in 2000 to 0.056 ppt per year in 2007. Upper tropospheric air samples provide evidence for a continuing growth until late 2009. Furthermore we calculated a stratospheric lifetime of 370 years from measurements of air samples collected on board high altitude aircraft and balloons. Emission estimates were determined from the reconstructed atmospheric trend and suggest that current "bottom-up" estimates of global emissions for 2005 are too high by a factor of three

Sustainability in pediatric hospitals: An exploration at the intersection of quality improvement and implementation science

BACKGROUND: Although new evidence-based practices are frequently implemented in clinical settings, many are not sustained, limiting the intended impact. Within implementation science, there is a gap in understanding sustainability. Pediatric healthcare settings have a robust history of quality improvement (QI), which includes a focus on continuation of change efforts. QI capability and sustainability capacity, therefore, serve as a useful concept for connecting the broader fields of QI and implementation science to provide insights on improving care. This study addresses these gaps in understanding of sustainability in pediatric settings and its relationship to QI. METHODS: This is a cross-sectional observational study conducted within pediatric academic medical centers in the United States. Clinicians surveyed worked with one of three evidence-based clinical programs: perioperative antimicrobial stewardship prescribing, early mobility in the intensive care unit, and massive blood transfusion administration. Participants completed two assessments: (1) the Clinical Sustainability Assessment Tool (CSAT) and (2) a 19-question assessment that included demographics and validation questions, specifically a subset of questions from the RESULTS: A total of 181 individuals from three different programs and 30 sites were included in the final analyses. QI capability scores were assessed as a single construct (5-point Likert scale), with an average response of 4.16 (higher scores indicate greater QI capability). The overall CSAT score (7-point Likert scale) was the highest for massive transfusion programs (5.51, SD = 0.91), followed by early mobility (5.25, SD = 0.92) and perioperative antibiotic prescribing (4.91, SD = 1.07). Mixed-effects modeling illustrated that after controlling for person and setting level variables, higher perceptions of QI capabilities were significantly related to overall clinical sustainability. CONCLUSION: Organizations and programs with higher QI capabilities had a higher sustainability capacity, even when controlling for differences at the individual and intervention levels. Organizational factors that enable evidence-based interventions should be further studied, especially as they relate to sustainability. Issues to be considered by practitioners when planning for sustainability include bedside provider perceptions, intervention achievability, frequency of delivery, and organizational influences

The ying and yang of idebenone: Not too little, not too much - cell death in NQO1 deficient cells and the mouse retina

Idebenone has recently been investigated as a drug therapy for Leber's hereditary optic neuropathy (LHON), a rare genetic mitochondrial disease that causes rapid and progressive bilateral vision loss. Although several studies have shown that idebenone can promote vision recovery in patients with LHON, the evidence for the efficacy of idebenone is still limited. Idebenone failed to demonstrate superiority over placebo in the primary end-points of the only published randomised, double-blind, placebo-controlled trial. There appears to be a patient-specific response to idebenone with high variability in therapeutic outcomes. A recent study suggested that the cytosolic enzyme NAD(P)H: quinone acceptor oxidoreductase (NQO1) is the major enzyme involved in the activation of idebenone, and the beneficial effects of idebenone are dependent on the expression of NQO1. Here, we confirm the NQO1-dependent activity of idebenone, but we also show, for the first time, that the cytotoxicity of idebenone is linked to cellular expression of NQO1. Upon idebenone administration, cells deficient in NQO1 show a marked decrease in viability in comparison to NQO1 expressing cells, with idebenone causing ROS production and deleterious effects on ATP levels and cell viability. In addition, our data highlights that only cells expressing NQO1 can significantly activate idebenone, indicating that other proposed metabolic activation pathways, such as complex II and glycerol-3-phosphate dehydrogenase, do not play a significant role in idebenone activation. Furthermore, we provide evidence of idebenone-induced toxicity in the retina ex-vivo, which can be explained by the variation of NQO1 expression between different cell types in the mouse retina. Idebenone mediated cell rescue in the rotenone ex vivo model also indicated that this drug has a narrow therapeutic window. These findings will help to guide the development of future therapies and drug delivery strategies including intra-ocular administration. The specific dependence of idebenone activity on NQO1 may also explain the variation in patient outcomes in clinical trials

Modifications to student quarantine policies in K-12 schools implementing multiple COVID-19 prevention strategies restores in-person education without increasing SARS-CoV-2 transmission risk, January-March 2021

OBJECTIVE: To determine whether modified K-12 student quarantine policies that allow some students to continue in-person education during their quarantine period increase schoolwide SARS-CoV-2 transmission risk following the increase in cases in winter 2020-2021. METHODS: We conducted a prospective cohort study of COVID-19 cases and close contacts among students and staff (n = 65,621) in 103 Missouri public schools. Participants were offered free, saliva-based RT-PCR testing. The projected number of school-based transmission events among untested close contacts was extrapolated from the percentage of events detected among tested asymptomatic close contacts and summed with the number of detected events for a projected total. An adjusted Cox regression model compared hazard rates of school-based SARS-CoV-2 infections between schools with a modified versus standard quarantine policy. RESULTS: From January-March 2021, a projected 23 (1%) school-based transmission events occurred among 1,636 school close contacts. There was no difference in the adjusted hazard rates of school-based SARS-CoV-2 infections between schools with a modified versus standard quarantine policy (hazard ratio = 1.00; 95% confidence interval: 0.97-1.03). DISCUSSION: School-based SARS-CoV-2 transmission was rare in 103 K-12 schools implementing multiple COVID-19 prevention strategies. Modified student quarantine policies were not associated with increased school incidence of COVID-19. Modifications to student quarantine policies may be a useful strategy for K-12 schools to safely reduce disruptions to in-person education during times of increased COVID-19 community incidence