Citations

Objective The prevalence, disability, progression, and treatment needs associated with chronic migraine ( CM ) mandate epidemiological, clinical, and basic research to better understand the clinical course of this disorder and to facilitate development of more effective therapies. Such efforts have been significantly impeded by lack of agreement within the headache specialist community of the most appropriate diagnostic criteria for CM . Methods This paper reviews the pertinent nosological literature and extensive field testing already performed. Results We recommend that the I nternational C lassification of H eadache D isorders‐3β criteria for CM be modified. We would remove the need for 5 prior migraine attacks and would replace “Headache considered by patient to be onset migraine and relieved by a triptan or an ergotamine derivative” with “criteria A and B for 1.5 probable migraine .” Conclusions The proposed criteria are guided by the aims of accurately characterizing patients with migraine who develop primary chronic daily headache, reflecting the large numbers of patients with CM in clinical practice, and facilitating research into a disorder that is an academic and clinical priority.

Abstract INTRODUCTION High-sensitivity cardiac troponin assays have potent prognostic value in stable cardiovascular disease cohorts. Our objective was to assess the prognostic utility of a novel cardiac troponin I (cTnI) high-sensitivity assay, independently and in combination with amino-terminal pro–B-type natriuretic peptide (NT-proBNP), for the future development of heart failure and mortality in the general community. METHODS A well-characterized community-based cohort of 2042 participants underwent clinical assessment and echocardiographic evaluation. Baseline measurements of cTnI with a high-sensitivity assay and NT-proBNP were obtained in 1843 individuals. Participants were followed for new-onset heart failure and mortality with median (25th, 75th percentile) follow-up of 10.7 (7.9, 11.6) and 12.1 (10.4, 13.0) years, respectively. RESULTS When measured with a high-sensitivity assay, cTnI greater than the sex-specific 80th percentile was independently predictive of heart failure [hazard ratio 2.56 (95% confidence interval 1.88–3.50), P < 0.001] and mortality [1.91(1.49–2.46), P < 0.001] beyond conventional risk factors in this community-based cohort, with significant increases in the net reclassification improvement for heart failure. The prognostic utility of cTnI measured with a high-sensitivity assay goes beyond NT-proBNP, yet our data suggest that these 2 assays are complementary and most beneficial when evaluated together in identifying at-risk individuals in the community. CONCLUSIONS Our findings lay the foundation for prospective studies aimed at identification of individuals at high risk by use of a multimarker approach, followed by aggressive prevention strategies to prevent subsequent heart failure.

AbstractBackgroundRegulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development.MethodsThe Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data.ResultsThe literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011.ConclusionsWe summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

Wheezing is a major long-term respiratory morbidity in preterm infants with and without bronchopulmonary dysplasia. We hypothesized that mild vs. severe hyperoxic exposure in neonatal mice differentially affects airway smooth muscle hypertrophy and resultant airway reactivity. Newborn mice were exposed to 7 days of mild (40% oxygen) or severe (70% oxygen) hyperoxia vs. room air controls. Respiratory system resistance (Rrs), compliance (Crs), and airway reactivity were measured 14 days after oxygen exposure ended under ketamine/xylazine anesthesia. Baseline Rrs increased and Crs decreased in both treatment groups. Methacholine challenge dose dependently increased Rrs and decreased Crs in 40% oxygen-exposed mice, whereas Rrs and Crs responses were similar between 70% oxygen-exposed and normoxic controls. Airway smooth muscle thickness was increased in 40%- but not 70%-exposed mice, whereas collagen increased and both alveolar number and radial alveolar counts decreased after 40% and 70% oxygen. These data indicate that severity of hyperoxia may differentially affect structural and functional changes in the developing mouse airway that contribute to longer-term hyperreactivity. These findings may be important to our understanding of the complex role of neonatal supplemental oxygen therapy in postnatal development of airway responsiveness.

ABSTRACTObjectives:The lactulose:mannitol (L:M) diagnostic test is frequently used in field studies of environmental enteropathy (EE); however, heterogeneity in test administration and disaccharide measurement has limited the comparison of results between studies and populations. We aim to assess the agreement between L:M measurement between high‐performance liquid chromatography with pulsed amperometric detection (HPLC‐PAD) and liquid chromatography‐tandem mass spectrometry (LC‐MSMS) platforms.Methods:The L:M test was administered in a cohort of Peruvian infants considered at risk for EE. A total of 100 samples were tested for lactulose and mannitol at 3 independent laboratories: 1 running an HPLC‐PAD platform and 2 running LC‐MSMS platforms. Agreement between the platforms was estimated.Results:The Spearman correlation between the 2 LC‐MSMS platforms was high (ρ ≥ 0.89) for mannitol, lactulose, and the L:M ratio. The correlation between the HPLC‐PAD platform and LC‐MSMS platform was ρ = 0.95 for mannitol, ρ = 0.70 for lactulose, and ρ = 0.43 for the L:M ratio. In addition, the HPLC‐PAD platform overestimated the lowest disaccharide concentrations to the greatest degree.Conclusions:Given the large analyte concentration range, the improved accuracy of LC‐MSMS has important consequences for the assessment of lactulose and mannitol following oral administration in populations at risk for EE. We recommend that researchers wishing to implement a dual‐sugar test as part of a study of EE use an LC‐MSMS platform to optimize the accuracy of results and increase comparability between studies.

OBJECTIVES: ImproveCareNow (ICN) is the largest pediatric learning health system in the nation and started as a quality improvement collaborative. To test the feasibility and validity of using ICN data for clinical research, we evaluated the effectiveness of anti-tumor necrosis factor-α (anti-TNFα) agents in the management of pediatric Crohn disease (CD). METHODS: Data were collected in 35 pediatric gastroenterology practices (April 2007 to March 2012) and analyzed as a sequence of nonrandomized trials. Patients who had moderate to severe CD were classified as initiators or non-initiators of anti-TNFα therapy. Among 4130 patients who had pediatric CD, 603 were new users and 1211 were receiving anti-TNFα therapy on entry into ICN. RESULTS: During a 26-week follow-up period, rate ratios obtained from Cox proportional hazards models, adjusting for patient and disease characteristics and concurrent medications, were 1.53 (95% confidence interval [CI], 1.20–1.96) for clinical remission and 1.74 (95% CI, 1.33–2.29) for corticosteroid-free remission. The rate ratio for corticosteroid-free remission was comparable to the estimate produced by the adult SONIC study, which was a randomized controlled trial on the efficacy of anti-TNFα therapy. The number needed to treat was 5.2 (95% CI, 3.4–11.1) for clinical remission and 5.0 (95% CI, 3.4–10.0) for corticosteroid-free remission. CONCLUSIONS: In routine pediatric gastroenterology practice settings, anti-TNFα therapy was effective at achieving clinical and corticosteroid-free remission for patients who had Crohn disease. Using data from the ICN learning health system for the purpose of observational research is feasible and produces valuable new knowledge.