International variation in outcomes among people with cardiovascular disease or cardiovascular risk factors and impaired glucose tolerance: insights from the NAVIGATOR Trial

Background: Regional differences in risk of diabetes mellitus and cardiovascular outcomes in people with impaired glucose tolerance are poorly characterized. Our objective was to evaluate regional variation in risk of new‐onset diabetes mellitus, cardiovascular outcomes, and treatment effects in participants from the NAVIGATOR (Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial. Methods and Results: NAVIGATOR randomized people with impaired glucose tolerance and cardiovascular risk factors or with established cardiovascular disease to valsartan (or placebo) and to nateglinide (or placebo) with a median 5‐year follow‐up. Data from the 9306 participants were categorized by 5 regions: Asia (n=552); Europe (n=4909); Latin America (n=1406); North America (n=2146); and Australia, New Zealand, and South Africa (n=293). Analyzed outcomes included new‐onset diabetes mellitus; cardiovascular death; a composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke; and treatment effects of valsartan and nateglinide. Respective unadjusted 5‐year risks for new‐onset diabetes mellitus, cardiovascular death, and the composite cardiovascular outcome were 33%, 0.4%, and 4% for Asia; 34%, 2%, and 6% for Europe; 37%, 4%, and 8% for Latin America; 38%, 2%, and 6% for North America; and 32%, 4%, and 8% for Australia, New Zealand, and South Africa. After adjustment, compared with North America, European participants had a lower risk of new‐onset diabetes mellitus (hazard ratio 0.86, 95% CI 0.78–0.94; P=0.001), whereas Latin American participants had a higher risk of cardiovascular death (hazard ratio 2.68, 95% CI 1.82–3.96; P<0.0001) and the composite cardiovascular outcome (hazard ratio 1.48, 95% CI 1.15–1.92; P=0.003). No differential interactions between treatment and geographic location were identified. Conclusions: Major regional differences regarding the risk of new‐onset diabetes mellitus and cardiovascular outcomes in NAVIGATOR participants were identified. These differences should be taken into account when planning global trials

Pediatric Anesthesia and Neurodevelopmental Impairments: A Bayesian Meta-analysis

Experimental evidence of anesthesia-induced neurotoxicity has caused serious concern about the long-term effect of commonly used volatile anesthetic agents on young children. Several observational studies based on existing data have been conducted to address this concern with inconsistent results. We conducted a meta-analysis to synthesize the epidemiologic evidence on the association of anesthesia/surgery with neurodevelopmental outcomes in children. Using Bayesian meta-analytic approaches, we estimated the synthesized odds ratios (OR) and 95% credible interval (CrI) as well as the predictive distribution of a future study given the synthesized evidence. Data on 7 unadjusted and 6 adjusted measures of association were abstracted from 7 studies. The synthesized OR based on the 7 unadjusted measures for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.9 (95% CrI, 1.2-3.0). The most likely unadjusted OR from a future study was estimated to be 2.2 (95% CrI, 0.6-6.1). The synthesized OR based on the 6 adjusted measures for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.4 (95% CrI, 0.9-2.2). The most likely adjusted OR from a future study was estimated to be 1.5 (95% CrI, 0.5-4.0). We conclude that existent epidemiologic evidence suggests a modestly elevated risk of adverse behavioral or developmental outcomes in children who were exposed to anesthesia/surgery during early childhood. The evidence, however, is considerably uncertain

The bZIP Transcription Factor PERIANTHIA: A Multifunctional Hub for Meristem Control

As sessile organisms, plants are exposed to extreme variations in environmental conditions over the course of their lives. Since plants grow and initiate new organs continuously, they have to modulate the underlying developmental program accordingly to cope with this challenge. At the heart of this extraordinary developmental plasticity are pluripotent stem cells, which are maintained during the entire life-cycle of the plant and that are embedded within dynamic stem cell niches. While the complex regulatory principles of plant stem cell control under artificial constant growth conditions begin to emerge, virtually nothing is known about how this circuit adapts to variations in the environment. In addition to the local feedback system constituted by the homeodomain transcription factor WUSCHEL (WUS) and the CLAVATA signaling cascade in the center of the shoot apical meristem (SAM), the bZIP transcription factor PERIANTHIA (PAN) not only has a broader expression domain in SAM and flowers, but also carries out more diverse functions in meristem maintenance: pan mutants show alterations in environmental response, shoot meristem size, floral organ number, and exhibit severe defects in termination of floral stem cells in an environment dependent fashion. Genetic and genomic analyses indicate that PAN interacts with a plethora of developmental pathways including light, plant hormone, and meristem control systems, suggesting that PAN is as an important regulatory node in the network of plant stem cell control

Early Childhood Exposure to Anesthesia and Risk of Developmental and Behavioral Disorders in a Sibling Birth Cohort

Background: In vitro and in vivo studies of anesthetics have demonstrated serious neurotoxic effects on the developing brain. However, the clinical relevance of these findings to children undergoing anesthesia remains unclear. Using data from a sibling birth cohort, we assessed the association between exposure to anesthesia in the setting of surgery in patients younger than 3 years and the risk of developmental and behavioral disorders. Methods: We constructed a retrospective cohort of 10,450 siblings who were born between 1999 and 2005 and who were enrolled in the New York State Medicaid program. The exposed group was 304 children without a history of developmental or behavioral disorders who underwent surgery when they were younger than 3 years. The unexposed group was 10,146 children who did not receive any surgical procedures when they were younger than 3 years. Exposed children were entered into analysis at the date of surgery. Unexposed children were entered into analysis at age 10 months (the mean age at which exposed children underwent surgery). Both exposed and unexposed children were followed until diagnosis with a developmental or behavioral disorder, loss to follow-up, or the end of 2005. The association of exposure to anesthesia with subsequent developmental and behavioral disorders was assessed with both proportional hazards modeling, and pair-matched analysis. Results: The incidence of developmental and behavioral disorders was 128.2 diagnoses per 1000 person-years for the exposed cohort and 56.3 diagnoses per 1000 person-years for the unexposed cohort. With adjustment for sex and history of birth-related medical complications, and clustering by sibling status, the estimated hazard ratio of developmental or behavioral disorders associated with any exposure to anesthesia when they were younger than 3 years was 1.6 (95% confidence interval [CI]: 1.4, 1.8). The risk increased from 1.1 (95% CI: 0.8, 1.4) for 1 operation to 2.9 (94% CI: 2.5, 3.1) for 2 operations and 4.0 (95% CI: 3.5, 4.5) for ≥3 operations. The relative risk in a matched analysis of 138 sibling pairs was 0.9 (95% CI: 0.6, 1.4). Conclusion: The risk of being subsequently diagnosed with developmental and behavioral disorders in children who were enrolled in a state Medicaid program and who had surgery when they were younger than 3 years was 60% greater than that of a similar group of siblings who did not undergo surgery. More tightly matched pairwise analyses indicate that the extent to which the excess risk is causally attributable to anesthesia or mediated by unmeasured factors remains to be determined

Observation of nonequilibrium motion and equilibration in polariton rings

We present a study of the macroscopic dynamics of a polariton condensate formed by nonresonant optical excitation in a quasi-one-dimensional ring-shaped microcavity. The presence of a gradient in the cavity photon energy creates a macroscopic trap for the polaritons in which a coherent condensate is formed which evolves into a single-mode condensate at late times. With time- and energy-resolved imaging we show the role of interactions in the motion of the condensate as it undergoes equilibration in the ring. These experiments also give a direct measurement of the polariton-polariton interaction strength above the condensation threshold. Our observations are compared to the open-dissipative one-dimensional Gross-Pitaevskii equation which shows excellent qualitative agreement

Classical Evolution of Quantum Elliptic States

The hydrogen atom in weak external fields is a very accurate model for the multiphoton excitation of ultrastable high angular momentum Rydberg states, a process which classical mechanics describes with astonishing precision. In this paper we show that the simplest treatment of the intramanifold dynamics of a hydrogenic electron in external fields is based on the elliptic states of the hydrogen atom, i.e., the coherent states of SO(4), which is the dynamical symmetry group of the Kepler problem. Moreover, we also show that classical perturbation theory yields the {\it exact} evolution in time of these quantum states, and so we explain the surprising match between purely classical perturbative calculations and experiments. Finally, as a first application, we propose a fast method for the excitation of circular states; these are ultrastable hydrogenic eigenstates which have maximum total angular momentum and also maximum projection of the angular momentum along a fixed direction. %Comment: 8 Pages, 2 Figures. Accepted for publication in Phys. Rev.

A Retrospective Cohort Study of the Association of Anesthesia and Hernia Repair Surgery With Behavioral and Developmental Disorders in Young Children

Recent animal studies have shown that commonly used anesthetic agents may have serious neurotoxic effects on the developing brain. The purpose of this study was to assess the association between surgery for hernia repair and the risk of behavioral and developmental disorders in young children. We performed a retrospective cohort analysis of children who were enrollees of the New York State Medicaid program. Our analysis involved following a birth cohort of 383 children who underwent inguinal hernia repair during the first 3 years of life, and a sample of 5050 children frequency-matched on age with no history of hernia-repair before age 3. After controlling for age, sex, and complicating birth-related conditions such as low birth weight, children who underwent hernia repair under 3 years of age were more than twice as likely as children in the comparison group to be subsequently diagnosed with a developmental or behavioral disorder (adjusted hazard ratio 2.3, 95% confidence interval 1.3, 4.1). Our findings add to recent evidence of the potential association of surgery and its concurrent exposure to anesthetic agents with neurotoxicity and underscore the need for more rigorous clinical research on the long-term effects of surgery and anesthesia in children

Influence of Beta-Blocker Continuation or Withdrawal on Outcomes in Patients Hospitalized With Heart Failure Findings From the OPTIMIZE-HF Program

ObjectivesThis study ascertains the relationship between continuation or withdrawal of beta-blocker therapy and clinical outcomes in patients hospitalized with systolic heart failure (HF).BackgroundWhether beta-blocker therapy should be continued or withdrawn during hospitalization for decompensated HF has not been well studied in a broad cohort of patients.MethodsThe OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) program enrolled 5,791 patients admitted with HF in a registry with pre-specified 60- to 90-day follow-up at 91 academic and community hospitals throughout the U.S. Outcomes data were prospectively collected and analyzed according to whether beta-blocker therapy was continued, withdrawn, or not started.ResultsAmong 2,373 patients eligible for beta-blockers at discharge, there were 1,350 (56.9%) who were receiving beta-blockers before admission and continued on therapy, 632 (26.6%) newly started, 79 (3.3%) in which therapy was withdrawn, and 303 (12.8%) eligible but not treated. Continuation of beta-blockers was associated with a significantly lower risk and propensity adjusted post-discharge death (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.37 to 0.99, p = 0.044) and death/rehospitalization (odds ratio: 0.69; 95% CI: 0.52 to 0.92, p = 0.012) compared with no beta-blocker. In contrast, withdrawal of beta-blocker was associated with a substantially higher adjusted risk for mortality compared with those continued on beta-blockers (HR: 2.3; 95% CI: 1.2 to 4.6, p = 0.013), but with similar risk as HF patients eligible but not treated with beta-blockers.ConclusionsThe continuation of beta-blocker therapy in patients hospitalized with decompensated HF is associated with lower post-discharge mortality risk and improved treatment rates. In contrast, withdrawal of beta-blocker therapy is associated with worse risk and propensity-adjusted mortality. (Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure [OPTIMIZE-HF]; NCT00344513