Downward Neighborhood Poverty Mobility during Childhood Is Associated with Child Asthma: Evidence from the Geographic Research on Wellbeing (GROW) Survey.

Causal evidence regarding neighborhood effects on health remains tenuous. Given that children have little agency in deciding where they live and spend proportionally more of their lives in neighborhoods than adults, their exposure to neighborhood conditions could make their health particularly sensitive to neighborhood effects. In this paper, we examine the relationship between exposure to poor neighborhoods from birth to ages 4-10 and childhood asthma. We used data from the 2003-2007 California Maternal Infant and Health Assessment (MIHA) and the 2012-2013 Geographic Research on Wellbeing (GROW) survey (N = 2619 mother/child dyads) to fit relative risks of asthma for children who experience different types of neighborhood poverty mobility using Poisson regression controlling for individual-level demographic and socioeconomic characteristics, and neighborhood satisfaction. Our results demonstrate that [1] living in a poor neighborhood at baseline and follow-up and [2] moving into a poor neighborhood were each associated with higher risk of asthma, compared with children not living in a poor neighborhood at either time. Exposure to impoverished neighborhoods and downward neighborhood poverty mobility matters for children's health, particularly for asthma. Public health practitioners and policymakers need to address downward neighborhood economic mobility, in addition to downward family economic mobility, in order to improve children's health.

How are we currently training and maintaining clinical readiness of US and UK military surgeons responsible for managing head, face and neck wounds on deployment?

INTRODUCTION: The conflicts in Iraq and Afghanistan provided military surgeons from the USA and the UK with extensive experience into the management of injuries to the head, face and neck (HFN) from high energy bullets and explosive weaponry. The challenge is now to maintain the expertise in managing such injuries for future military deployments. METHODS: The manner in which each country approaches four parameters required for a surgeon to competently treat HFN wounds in deployed military environments was compared. These comprised initial surgical training (residency/registrar training), surgical fellowships, hospital type and appointment as an attending (USA) or consultant (UK) and predeployment training. RESULTS: Neither country has residents/registrars undertaking surgical training that is military specific. The Major Trauma and Reconstructive Fellowship based in Birmingham UK and the Craniomaxillofacial Trauma fellowship at Duke University USA provide additional training directly applicable to managing HFN trauma on deployment. Placement in level 1 trauma/major trauma centres is encouraged by both countries but is not mandatory. US surgeons attend one of three single-service predeployment courses, of which HFN skills are taught on both cadavers and in a 1-week clinical placement in a level 1 trauma centre. UK surgeons attend the Military Operational Surgical Training programme, a 1-week course that includes 1 day dedicated to teaching HFN injury management on cadavers. CONCLUSIONS: Multiple specialties of surgeon seen in the civilian environment are unlikely to be present, necessitating development of extended competencies. Military-tailored fellowships are capable of generating most of these skills early in a career. Regular training courses including simulation are required to maintain such skills and should not be given only immediately prior to deployment. Strong evidence exists that military consultants and attendings should only work at level 1/major trauma centres.

Integrated safety analysis of rolapitant with coadministered drugs from phase II/III trials: an assessment of CYP2D6 or BCRP inhibition by rolapitant.

BACKGROUND: Rolapitant, a long-acting neurokinin (NK)1 receptor antagonist (RA), has demonstrated efficacy in prevention of chemotherapy-induced nausea and vomiting in patients administered moderately or highly emetogenic chemotherapy. Unlike other NK1 RAs, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancer resistance protein (BCRP). To analyze potential drug-drug interactions between rolapitant and concomitant medications, this integrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined adverse events (AEs) by use versus non-use of drug substrates of CYP2D6 or BCRP. PATIENTS AND METHODS: Patients were randomized to receive either 180 mg oral rolapitant or placebo ∼1-2 h before chemotherapy in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Data for treatment-emergent AEs (TEAEs) and treatment-emergent serious AEs (TESAEs) during cycle 1 were pooled across the four studies and summarized in the overall population and by concomitant use/non-use of CYP2D6 or BCRP substrate drugs. RESULTS: In the integrated safety population, 828 of 1294 patients (64%) in the rolapitant group and 840 of 1301 patients (65%) in the control group experienced at least one TEAE. Frequencies of common TEAEs were similar in the rolapitant and control populations. Overall, 53% of patients received CYP2D6 substrate drugs, none of which had a narrow therapeutic index (like thioridazine or pimozide), and 63% received BCRP substrate drugs. When grouped by concomitant use versus non-use of CYP2D6 or BCRP substrate drugs, TEAEs and TESAEs occurred with similar frequency in the rolapitant and control populations. CONCLUSIONS: The results of this study support the safety of rolapitant as part of an antiemetic triple-drug regimen in patients receiving emetogenic chemotherapy, including those administered concomitant medications that are substrates of CYP2D6 or BCRP, such as ondansetron, docetaxel, or irinotecan.

Impact of trauma centre capacity and volume on the mortality risk of incoming new admissions.

INTRODUCTION: Trauma centre capacity and surge volume may affect decisions on where to transport a critically injured patient and whether to bypass the closest facility. Our hypothesis was that overcrowding and high patient acuity would contribute to increase the mortality risk for incoming admissions. METHODS: For a 6-year period, we merged and cross-correlated our institutional trauma registry with a database on Trauma Resuscitation Unit (TRU) patient admissions, movement and discharges, with average capacity of 12 trauma bays. The outcomes of overall hospital and 24 hours mortality for new trauma admissions (NEW) were assessed by multivariate logistic regression. RESULTS: There were 42 003 (mean=7000/year) admissions having complete data sets, with 36 354 (87%) patients who were primary trauma admissions, age ≥18 and survival ≥15 min. In the logistic regression model for the entire cohort, NEW admission hospital mortality was only associated with NEW admission age and prehospital Glasgow Coma Scale (GCS) and Shock Index (SI) (all p<0.05). When TRU occupancy reached ≥16 patients, the factors associated with increased NEW admission hospital mortality were existing patients (TRU >1 hour) with SI ≥0.9, recent admissions (TRU ≤1 hour) with age ≥65, NEW admission age and prehospital GCS and SI (all p<0.05). CONCLUSION: The mortality of incoming patients is not impacted by routine trauma centre overcapacity. In conditions of severe overcrowding, the number of admitted patients with shock physiology and a recent surge of elderly/debilitated patients may influence the mortality risk of a new trauma admission.

Fish as model systems.

Fish represent the largest and most diverse group of vertebrates. Their evolutionary position relative to other vertebrates and their ability to adapt to a wide variety of environments make them ideal for studying both organismic and molecular evolution. A number of other characteristics make them excellent experimental models for studies in embryology, neurobiology, endocrinology, environmental biology, and other areas. In fact, they have played a critical role in the development of several of these disciplines. Research techniques that enable scientists to make isogenic lines in a single generation, create and maintain mutants, culture cells, and transfer cloned genes into embryos signal an increasing role for fish as experimental models.

Hemoglobin adaptation for fast and slow water habitats in sympatric catostomid fishes.

The oxygen equilibria of Catostomus insignis hemoglobins are pH dependent. Catostomus clarkii hemoglobins have some components (20 percent) whose oxygen equilibria are independent of pH because the alpha chains have NH(2)-termini that are blocked and the beta chains lack the "usual" COOH-terminal histidine. Since the Bohr effect is normally a beneficial phenomenon, the maintenance of some hemoglobins without a Bohr effect must provide a physiological advantage that is habitat specific. The intrastream ecological preferences of these sympatric catostomids suggest that the hemoglobins without the Bohr effect confer an ecological advantage in a swift water habitat.

A molecular genetic classification of zooxanthellae and the evolution of animal-algal symbioses.

Zooxanthellae are unicellular algae that occur as endosymbionts in many hundreds of marine invertebrate species. Because zooxanthellae have traditionally been difficult to classify, little is known about the natural history of these symbioses. Zooxanthellae were isolated from 131 individuals in 22 host taxa and characterized by the use of restriction fragment length polymorphisms (RFLPs) in nuclear genes that encode small ribosomal subunit RNA (ssRNA). Six algal RFLPs, distributed host species specifically, were detected. Individual hosts contained one algal RFLP. Zooxanthella phylogenetic relationships were estimated from 22 algal ssRNA sequences-one from each host species. Closely related algae were found in dissimilar hosts, suggesting that animal and algal lineages have maintained a flexible evolutionary relation with each other.

Physiological basis for swimming endurance differences between LDH-B genotypes of Fundulus heteroclitus.

Adenosine triphosphate levels in erythrocytes are correlated with LDH-B genotype in Fundulus heteroclitus. Adenosine triphosphate is the fish's allosteric modifier of hemoglobin oxygen affinity. Since oxygen delivery to muscle affects swimming performance, fish of each homozygous LDH-B phenotype were swum to exhaustion at 10 degrees or 25 degrees C to determine whether in vitro differences attributed to the LDH-B allelic isozymes were manifest in vivo. At 10 degrees C, the critical swimming speed of the LDH-BaBa phenotype was 3.6 body lengths per second, whereas that of the LDH-BbBb phenotype was 4.3 body lengths per second. At 25 degrees C there were no differences between LDH-B phenotypes in erythrocyte adenosine triphosphate levels, blood oxygen affinity, or swimming performance.

Evidence of lactate dehydrogenase-B allozyme effects in the teleost, Fundulus heteroclitus.

The evolutionary significance of protein polymorphisms has long been debated. Exponents of the balanced theory advocate that selection operates to maintain polymorphisms, whereas the neoclassical school argues that most genetic variation is neutral. Some studies have suggested that protein polymorphisms are not neutral, but their significance has been questioned because one cannot eliminate the possibility that linked loci were responsible for the observed differences. Evidence is presented that an enzymatic phenotype can affect carbon flow through a metabolic pathway. Glucose flux differences between lactate dehydrogenase-B phenotypes of Fundulus heteroclitus were reversed by substituting the Ldh-B gene product of one homozygous genotype with that of another.

Probing steric and hydrophobic effects on enzyme-substrate interactions by protein engineering.

Steric and hydrophobic effects on substrate specificity were probed by protein engineering of subtilisin. Subtilisin has broad peptidase specificity and contains a large hydrophobic substrate binding cleft. A conserved glycine (Gly(166)), located at the bottom of the substrate binding left, was replaced by 12 nonionic amino acids by the cassette mutagenesis method. Mutant enzymes showed large changes in specificity toward substrates of increasing size and hydrophobicity. In general, the catalytic efficiency (k(cat)/K(m)) toward small hydrophobic substrates was increased (up to 16 times) by hydrophobic substitutions at position 166 in the binding cleft. Exceeding the optimal binding volume of the cleft ( approximately 160 A(3)), by enlarging either the substrate side chain or the side chain at position 166, evoked precipitous drops in catalytic efficiency (k(cat)/K(m)) (up to 5000 times) as a result of steric hindrance.

Silicon optical fiber.

Described herein are initial experimental details and properties of a silicon core, silica glass-clad optical fiber fabricated using conventional optical fiber draw methods. Such semiconductor core fibers have potential to greatly influence the fields of nonlinear fiber optics, infrared and THz power delivery. More specifically, x-ray diffraction and Raman spectroscopy showed the core to be highly crystalline silicon. The measured propagation losses were 4.3 dB/m at 2.936 microm, which likely are caused by either microcracks in the core arising from the large thermal expansion mismatch with the cladding or to SiO(2) precipitates formed from oxygen dissolved in the silicon melt. Suggestions for enhancing the performance of these semiconductor core fibers are provided. Here we show that lengths of an optical fiber containing a highly crystalline semiconducting core can be produced using scalable fiber fabrication techniques.

Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice.

Current theories propose that systemic lupus erythematosus develops when genetically predisposed individuals are exposed to certain environmental agents, although how these agents trigger lupus is uncertain. Some of these agents, such as procainamide, hydralazine, and UV-light inhibit T cell DNA methylation, increase lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) expression, and induce autoreactivity in vitro, and adoptive transfer of T cells that are made autoreactive by this mechanism causes a lupuslike disease. The mechanism by which these cells cause autoimmunity is unknown. In this report, we present evidence that LFA-1 overexpression is sufficient to induce autoimmunity. LFA-1 overexpression was induced on cloned murine Th2 cells by transfection, resulting in autoreactivity. Adoptive transfer of the transfected, autoreactive cells into syngeneic recipients caused a lupuslike disease with anti-DNA antibodies, an immune complex glomerulonephritis and pulmonary alveolitis, similar to that caused by cells treated with procainamide. These results indicate that agents or events which modify T cell DNA methylation may induce autoimmunity by causing T cell LFA-1 overexpression. Since T cells from patients with active lupus have hypomethylated DNA and overexpressed LFA-1, this mechanism could be important in the development of human autoimmunity.

Removal of EEG noise and artifact using blind source separation.

A study was performed to investigate and compare the relative performance of blind signal separation (BSS) algorithms at separating common types of contamination from EEG. The study develops a novel framework for investigating and comparing the relative performance of BSS algorithms that incorporates a realistic EEG simulation with a known mixture of known signals and an objective performance metric. The key finding is that although BSS is an effective and powerful tool for separating and removing contamination from EEG, the quality of the separation is highly dependant on the type of contamination, the degree of contamination, and the choice of BSS algorithm. BSS appears to be most effective at separating muscle and blink contamination and less effective at saccadic and tracking contamination. For all types of contamination, principal components analysis is a strong performer when the contamination is greater in amplitude than the brain signal whereas other algorithms such as second-order blind inference and Infomax are generally better for specific types of contamination of lower amplitude.

Rolapitant Absolute Bioavailability and PET Imaging Studies in Healthy Adult Volunteers.

Rolapitant, a selective, long-acting neurokinin-1 (NK-1) receptor antagonist, demonstrated efficacy in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly or moderately emetogenic chemotherapy. Two studies in healthy volunteers evaluated 1) absolute bioavailability and 2) NK-1 receptor occupancy of oral rolapitant. Absolute bioavailability, determined by the ratio of dose-normalized exposure following a 180-mg oral dose vs. an intravenous microdose, was ∼100%. Brain imaging by positron emission tomography 120 h after a single dose showed that NK-1 receptor occupancy increased with escalating doses (4.5-180 mg) but was not dose-proportional; a 180-mg dose resulted in near-saturable binding to NK-1 receptors (mean ± standard deviation: 94% ± 9%). A pharmacokinetic-pharmacodynamic model predicted that rolapitant plasma concentrations >348 ng/mL would result in >90% NK-1 receptor occupancy in the cortex up to 120 h postdose. These results support administration of a single 180-mg oral dose of rolapitant for CINV prevention.

Optimising ballistic facial coverage from military fragmenting munitions: a consensus statement.

VIRTUS is the first United Kingdom (UK) military personal armour system to provide components that are capable of protecting the whole face from low velocity ballistic projectiles. Protection is modular, using a helmet worn with ballistic eyewear, a visor, and a mandibular guard. When all four components are worn together the face is completely covered, but the heat, discomfort, and weight may not be optimal in all types of combat. We organized a Delphi consensus group analysis with 29 military consultant surgeons from the UK, United States, Canada, Australia, and New Zealand to identify a potential hierarchy of functional facial units in order of importance that require protection. We identified the causes of those facial injuries that are hardest to reconstruct, and the most effective combinations of facial protection. Protection is required from both penetrating projectiles and burns. There was strong consensus that blunt injury to the facial skeleton was currently not a military priority. Functional units that should be prioritised are eyes and eyelids, followed consecutively by the nose, lips, and ears. Twenty-nine respondents felt that the visor was more important than the mandibular guard if only one piece was to be worn. Essential cover of the brain and eyes is achieved from all directions using a combination of helmet and visor. Nasal cover currently requires the mandibular guard unless the visor can be modified to cover it as well. Any such prototype would need extensive ergonomics and assessment of integration, as any changes would have to be acceptable to the people who wear them in the long term.

A collaborative hit-to-lead investigation leveraging medicinal chemistry expertise with high throughput library design, synthesis and purification capabilities.

High throughput screening (HTS) campaigns, where laboratory automation is used to expose biological targets to large numbers of materials from corporate compound collections, have become commonplace within the lead generation phase of pharmaceutical discovery. Advances in genomics and related fields have afforded a wealth of targets such that screening facilities at larger organizations routinely execute over 100 hit-finding campaigns per year. Often, 10(5) or 10(6) molecules will be tested within a campaign/cycle to locate a large number of actives requiring follow-up investigation. Due to resource constraints at every organization, traditional chemistry methods for validating hits and developing structure activity relationships (SAR) become untenable when challenged with hundreds of hits in multiple chemical families per target. To compound the issue, comparison and prioritization of hits versus multiple screens, or physical chemical property criteria, is made more complex by the informatics issues associated with handling large data sets. This article describes a collaborative research project designed to simultaneously leverage the medicinal chemistry and drug development expertise of the Novartis Institutes for Biomedical Research Inc. (NIBRI) and ArQule Inc.'s high throughput library design, synthesis and purification capabilities. The work processes developed by the team to efficiently design, prepare, purify, assess and prioritize multiple chemical classes that were identified during high throughput screening, cheminformatics and molecular modeling activities will be detailed.

Tumorigenicity of the cyc- variant of the S49 murine lymphoma deficient in the Gs-alpha subunit of adenylate cyclase.

S49 cyc- lymphoma cells contain a mutation resulting in loss of a functional guanine nucleotide regulatory protein rendering their adenylate cyclase refractory to most stimuli. S49 wild-type and cyc- clones were used in the present study to investigate the possible association of altered cAMP metabolism with tumorigenicity and metastatic potential. The S49 clones were implanted i.v., i.p., and intracerebrally in both athymic nude mice and syngeneic, immunocompetent BALB/c mice. Both S49 clones gave rise to tumors when inoculated into athymic mice, and no differences were observed in the tumorigenicity or metastatic potential of S49 wild-type and cyc- cells. Implantation of S49 clones in syngeneic BALB/c mice gave rise to few tumors except when administered intracerebrally, where wild-type cells were more tumorigenic than cyc- cells. This raises the possibility of differences in immunogenicity between the S49 clones. Analysis of cell lines derived from tumors grown in athymic mice showed that they retained the phenotype of the S49 clones used for inoculations. The results indicate that, despite differences in adenylate cyclase responsiveness, S49 wild-type and cyc- cells are both highly tumorigenic and metastatic.

Automatic determination of EMG-contaminated components and validation of independent component analysis using EEG during pharmacologic paralysis.

OBJECTIVE: Validate independent component analysis (ICA) for removal of EMG contamination from EEG, and demonstrate a heuristic, based on the gradient of EEG spectra (slope of graph of log EEG power vs log frequency, 7-70 Hz) from paralysed awake humans, to automatically identify and remove components that are predominantly EMG. METHODS: We studied the gradient of EMG-free EEG spectra to quantitatively inform the choice of threshold. Then, pre-existing EEG from 3 disparate experimental groups was examined before and after applying the heuristic to validate that the heuristic preserved neurogenic activity (Berger effect, auditory odd ball, visual and auditory steady state responses). RESULTS: (1) ICA-based EMG removal diminished EMG contamination up to approximately 50 Hz, (2) residual EMG contamination using automatic selection was similar to manual selection, and (3) task-induced cortical activity remained, was enhanced, or was revealed using the ICA-based methodology. CONCLUSION: This study further validates ICA as a powerful technique for separating and removing myogenic signals from EEG. Automatic processing based on spectral gradients to exclude EMG-containing components is a conceptually simple and valid technique. SIGNIFICANCE: This study strengthens ICA as a technique to remove EMG contamination from EEG whilst preserving neurogenic activity to 50 Hz.

Structural and functional differences in the promoter and 5' flanking region of Ldh-B within and between populations of the teleost Fundulus heteroclitus.

We have investigated the mechanisms underlying differences in the transcriptional regulation of lactate dehydrogenase-B (Ldh-B) between northern and southern populations of a teleost fish, Fundulus heteroclitus. A 1-kb region immediately 5' of the gene was sequenced from populations throughout the species range. There were two major allele classes in the sample, one containing alleles from Maine and another containing those from Florida. Populations from intermediate localities contained both allele classes. Some individuals from Georgia had sequences intermediate between the two classes, representing either ancestral alleles or recombinants. Tests of neutrality were applied to determine whether observed variation was consistent with neutral expectations. Significant deviations from neutral expectations were detected for the 5' flanking region, but not for other loci. The functional consequences of flanking sequence variation were assessed by transfection of reporter gene constructs into cultured cells and injection into living fish. Consistent with observed variation in Ldh-B transcription rate between populations, significant differences in reporter gene activity were driven by flanking regions from northern and southern populations both in cell culture and in vivo. This functional differentiation, coupled with departures from neutral expectations, suggests that selection may have acted on the regulation of Ldh-B in F. heteroclitus.

End-stage renal disease in specific ethnic and racial groups: risk factors and benefits of antihypertensive therapy.

During the past few years, it has become apparent that there are factors that place a person at greater risk for the development and progression of renal failure. This has been documented since the early 1980s by the United States Renal Data System that has collected data confirming that end-stage renal disease occurs at a greater rate in certain subpopulations of Americans. It is evident from an examination of the data that African Americans and American Indians have an incidence of end-stage renal disease that is not proportional to their percentage of the total population. In fact, African Americans and American Indians are reported to have at least a 4-fold greater incidence of end-stage renal disease than white Americans. There have been 5 factors identified: hypertension, glucose intolerance, insulin resistance, salt sensitivity, and hyperlipidemia, which may play a greater role in these subpopulations. In addition, as with other populations, lifestyle issues may serve to alter these primary risk factors or may act as direct modulators of renal disease progression. There is also a possibility that interactions between risk factors frequently occur that may modify the development or progression of the disease. This article reviews these risk factors and emphasizes the interaction between hypertension and the other factors. In addition, the effects of antihypertensive agents on risk factors and on renal outcome are emphasized. Where possible, issues specific to African Americans and American Indians are underscored; however, one must accept that the database on these populations is only now developing. This review should help the clinician make appropriate choices when prescribing antihypertensive therapy for patients who may be at risk of developing progressive renal failure.