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IMPORTANCE: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders. OBSERVATIONS: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings. CONCLUSIONS AND RELEVANCE: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

The NeuroNEXT SMA Infant Biomarker Study, a two year, longitudinal, multi-center study of infants with SMA type 1 and healthy infants, presented a unique opportunity to assess multi-site rater reliability on three infant motor function tests (MFTs) commonly used to assess infants with SMA type 1. To determine the effect of prospective MFT rater training and the effect of rater experience on inter-rater and intra-rater reliability for the Test of Infant Motor Performance Screening Items (TIMPSI), the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Alberta Infant Motor Scale (AIMS). Training was conducted utilizing a novel set of motor function test (MFT) videos to optimize accurate MFT administration and reliability for the study duration. Inter- and intra-rater reliability of scoring for the TIMPSI and inter-rater reliability of scoring for the CHOP INTEND and the AIMS was assessed using intraclass correlation coefficients (ICC). Effect of rater experience on reliability was examined using ICC. Agreement with ‘expert’ consensus scores was examined using Pearson’s correlation coefficients. Inter-rater reliability on all MFTs was good to excellent. Intra-rater reliability for the primary MFT, the TIMPSI, was excellent for the study duration. Agreement with ‘expert’ consensus was within predetermined limits (≥85%) after training. Evaluator experience with SMA and MFTs did not affect reliability. Reliability of scores across evaluators was demonstrated for all three study MFTs and scores were reproducible on repeated administration. Evaluator experience had no effect on reliability.

Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible.

IMPORTANCE We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and α-synuclein, but not β-amyloid 1-42 (Aβ1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. OBJECTIVE To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (Aβ1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau181], and α-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson’s Progression Markers Initiative (PPMI) study. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. MAIN OUTCOMES AND MEASURES The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (Aβ1-42, T-tau, and P-tau181; Innogenetics Inc) or by enzyme-linked immunosorbent assay (α-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. RESULTS Slightly, but significantly, lower levels of Aβ1-42, T-tau, P-tau181, α-synuclein, and T-tau/Aβ1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower Aβ1-42 and P-tau181 levels were associated with PD diagnosis and that decreased CSF T-tau and α-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF Aβ1-42 and P-tau181 concentrations were associated with the postural instability–gait disturbance–dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of α-synuclein with the levels of T-tau and P-tau181. CONCLUSIONS AND RELEVANCE In this first report of CSF biomarkers in PPMI study subjects, we found that measures of CSF Aβ1-42, T-tau, P-tau181, and α-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression.

Positive relationships between hospital volume and outcomes have been demonstrated for several surgeries and medical conditions. However, little is known about the volume-outcome relationship in patients admitted to medical ICUs.

AbstractBackground:Antimicrobial resistance is a growing clinical and public health crisis. Experts have recommended measures to monitor antimicrobial resistance; however, little is known regarding their use.Objective:We describe the use of procedures to detect and report antimicrobial resistance in U.S. hospitals and the organizational and epidemiologic factors associated with their use.Methods:In 2001, we surveyed laboratory directors (n = 108) from a random national sample of hospitals. We studied five procedures to monitor antimicrobial resistance: (1) disseminating antibiograms to physicians at least annually, (2) notifying physicians of antimicrobial-resistant infections, (3) reporting susceptibility results within 24 hours, (4) using automated testing procedures, and (5) offering molecular typing. Explanatory variables included organizational characteristics and patterns of antimicrobial resistance for oxacillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, quinolone-resistant Escherichia coli, and extended-spectrum beta-lactamase-producing Klebsiellaspecies. Generalized estimating equations accounting for the correlation among outcomes at the facility level were used to identify predictors of the five outcomes.Results:Use of the procedures ranged from 85% (automated testing) to 33% (offering molecular typing) and was related to teaching hospital status (OR, 3.1; CI95, 1.5–6.5), participation of laboratory directors on the infection control committee (OR, 1.7; CI95, 1.1–2.8), and having at least one antimicrobial-resistant pathogen with a prevalence greater than 10% (OR, 2.2; CI95, 1.4–3.3).Conclusion:U.S. hospitals underutilize procedures to monitor the spread of antimicrobial resistance. Use of these procedures varies and is related to organizational and epidemiologic factors. Further efforts are needed to increase their use by hospitals.

AbstractObjective:To examine the extent to which the strategies recommended by the National Foundation for Infectious Diseases (NFID)-Centers for Disease Control and Prevention (CDC) co-sponsored workshop, Antimicrobial Resistance in Hospitals: Strategies to Improve Antimicrobial Use and Prevent Nosocomial Transmission of Antimicrobial-Resistant Microorganisms, have been implemented and the relationship between the degree of implementation and hospital culture, leadership, and organizational factors.Design:Survey.Setting:A representative sample of U.S. hospitals stratified by teaching status, bed size, and geographic region.Participants:Infection control professionals.Results:Surveyed hospitals had implemented strategies to optimize the use of antimicrobials and to detect, report, and prevent transmission of antimicrobial-resistant microorganisms. Multivariate analyses found that hospitals with a greater degree of implementation of the NFID–CDC strategic goals were more likely to have management support, education of staff, and interdisciplinary groups specifically to address these issues; they were also more likely to engage in benchmarking on broader quality of care indicators.Conclusions:Most surveyed hospitals had implemented some measures to address the NFID–CDC recommendations; however, hospitals need to do much more to improve antimicrobial use and to increase their efforts to detect, report, and control the spread of antimicrobial resistance. A supportive hospital administration must foster a culture of ongoing support, education, and interdisciplinary work groups focused on this important issue to successfully accomplish these goals.

Hospitals use numerous guideline implementation approaches with varying success. Approaches have been classified as consistently, variably, or minimally effective, with multiple approaches being most effective. This project assesses the Department of Veterans Affairs (VA) use of effective guideline implementation approaches. A survey of 123 VA quality managers assessed the approaches used to implement the chronic obstructive pulmonary disease, diabetes mellitus, congestive heart failure, and major depressive disorder guidelines. Approaches were categorized based on their effectiveness, and the total number of approaches used was calculated. Commonly used approaches were clinical meetings, summaries, and revised forms. Consistently and minimally effective approaches were used most frequently. Most hospitals used 4P7 approaches. Odds ratios demonstrated that consistently effective approaches were paired with minimally and variably effective approaches. The frequent use of consistently effective approaches and multiple approaches benefits VA adherence. However, VA hospitals should consider selective combinations of approaches to ensure the use of the most effective implementation methods.

Optimal diabetes management relies on providers adhering to evidence-based practice guidelines in the processes of care delivery and patients adhering to self-management recommendations to maximize patient outcomes.