An in vivo evaluation of Brilliant Blue G in animals and humans.
To evaluate the retinal toxicity of Brilliant Blue G (BBG) following intravitreal injection in rat eyes and examine the biocompatibility and the staining properties in humans. BBG was injected into the 11 rat eyes to evaluate toxic effects with balanced salt solution (BSS) serving as control. Retinal toxicity was assessed by retinal ganglion cell (RGC) counts and by light microscopy 7 days later. In addition, BBG was applied during vitrectomy for macular hole (MH) (n = 15) or epiretinal membranes (ERM) (n = 3) in a prospective, non-comparative consecutive series of patients. Before and after surgery, all patients underwent a complete clinical examination including measurement of best corrected visual acuity (VA) and intraocular pressure, perimetry, fundus photography and optical coherence tomography. Patients were seen 1 day before surgery and then in approximately four weeks intervals. No significant reduction in RGC numbers and no morphological alterations were noted. A sufficient staining of the internal limiting membrane (ILM) was seen in patients with MH, while the staining pattern in ERM cases was patchy, indicating that parts of the ILM were peeled off along with the ERM in a variable extent. All MHs could be closed successfully. VA improved in 10 eyes (56%; 8/15 MH patients, 2/3 ERM patients), was unchanged in four eyes (22%; all MH patients) and was reduced in four eyes (22%; 3/15 MH, 1/3 ERM). No toxic effects attributable to the dye were noted during patient follow-up. The ultrastructure of tissue harvested during surgery was unremarkable. Brilliant Blue provides a sufficient and selective staining of the ILM. No retinal toxicity or adverse effects related to the dye were observed in animal and human studies. The long-term safety of this novel dye will have to be evaluated in larger patient series and a longer follow-up.


Environmental Impact of Buildings--What Matters?
The goal of this study was to identify drivers of environmental impact and quantify their influence on the environmental performance of wooden and massive residential and office buildings. We performed a life cycle assessment and used thermal simulation to quantify operational energy demand and to account for differences in thermal inertia of building mass. Twenty-eight input parameters, affecting operation, design, material, and exogenic building properties were sampled in a Monte Carlo analysis. To determine sensitivity, we calculated the correlation between each parameter and the resulting life cycle inventory and impact assessment scores. Parameters affecting operational energy demand and energy conversion are the most influential for the building's total environmental performance. For climate change, electricity mix, ventilation rate, heating system, and construction material rank the highest. Thermal inertia results in an average 2-6% difference in heat demand. Nonrenewable cumulative energy demand of wooden buildings is 18% lower, compared to a massive variant. Total cumulative energy demand is comparable. The median climate change impact is 25% lower, including end-of-life material credits and 22% lower, when credits are excluded. The findings are valid for small offices and residential buildings in Switzerland and regions with similar building culture, construction material production, and climate.


Growing Up, Hooking Up, and Drinking: A Review of Uncommitted Sexual Behavior and Its Association With Alcohol Use and Related Consequences Among Adolescents and Young Adults in the United States.
Hookups are uncommitted sexual encounters that range from kissing to intercourse and occur between individuals in whom there is no current dating relationship and no expressed or acknowledged expectations of a relationship following the hookup. Research over the last decade has begun to focus on hooking up among adolescents and young adults with significant research demonstrating how alcohol is often involved in hooking up. Given alcohol's involvement with hooking up behavior, the array of health consequences associated with this relationship, as well as its increasing prevalence from adolescence to young adulthood, it is important to determine the predictors and consequences associated with alcohol-related hooking up. The current review extends prior reviews by adding more recent research, including both qualitative and experimental studies (i.e., expanding to review more diverse methods), research that focuses on the use of technology in alcohol-related hookups (i.e., emerging issues), further develops prevention and intervention potentials and directions, and also offers a broader discussion of hooking up outside of college student populations (i.e., expanding generalization). This article will review the operationalization and ambiguity of the phrase hooking up, the relationship between hooking up and alcohol use at both the global and event levels, predictors of alcohol-related hooking up, and both positive and negative consequences, including sexual victimization, associated with alcohol-related hookups. Throughout, commentary is provided on the methodological issues present in the field, as well as limitations of the existing research. Future directions for research that could significantly advance our understanding of hookups and alcohol use are provided.


Comparison of Strategies in Development and Manufacturing of Low Viscosity, Ultra-High Concentration Formulation for IgG1 Antibody.
Monoclonal antibodies requiring higher doses for exerting therapeutic effect but having lower stability, are administered as dilute infusions, or as two (low concentration) injections both resulting in reduced patient compliance. Present research summarizes impact of manufacturing conditions on ultra-high concentration (≥150 mg/mL) IgG1 formulation, which can be administered as one subcutaneous injection. IgG1 was concentrated to ~200 mg/mL using tangential flow filtration (TFF). Alternatively, spray dried (SPD) and spray freeze dried (SFD) IgG1, was reconstituted in 30%v/v propylene glycol to form ultra-high concentration (~200 mg/mL) injectable formulation. Reconstituted, SPD and SFD IgG1 formulations, increased viscosity beyond an acceptable range for subcutaneous injections (<20 cP). Formulations developed by reconstitution of SPD IgG1, demonstrated increase in high and low molecular weight impurities, at accelerated and stressed conditions. Whereas, the stability data suggested reconstituted SFD IgG1 was comparable to control IgG1 formulation concentrated by TFF. Also, formulation of IgG1 diafiltered with proline using TFF, reduce viscosity from ~21.9 cP to ~11 cP at 25 °C and had better stability. Thus, conventional TFF technique stands to be one of the preferred methods for manufacturing of ultra-high concentration IgG1 formulations. Additionally, SFD could be an alternative method for long term storage of IgG1 in a dry powder state.


Efficacy and safety of a booster dose of influenza vaccination in solid organ transplant recipients, TRANSGRIPE 1-2: study protocol for a multicenter, randomized, controlled clinical trial.
Despite administration of annual influenza vaccination, influenza-associated complications in transplant recipients continue to be an important cause of hospitalization and death. Although influenza vaccination has been proven to be the most effective measure to reduce influenza infection after transplantation, transplant recipients are still vulnerable to influenza infections, with lower serological responses to vaccination compared to the general population. In order to assess the efficacy and safety of an alternative immunization scheme for solid organ transplant recipients, the TRANSGRIPE1-2 Study Group aimed to test a booster dose administration 5 weeks after the standard vaccination. The primary objective of this trial was to compare short-term and long-term neutralizing antibody immunogenicity of a booster dose of influenza vaccination to the standard single-dose immunization scheme. Secondary objectives included the evaluation of the efficacy and/or safety, cellular immune response, incidence of influenza infection, graft rejection, retransplant and mortality rates. This phase III, randomized, controlled, open-label clinical trial was conducted between October 2012 and December 2013 in 12 Spanish public referral hospitals. Solid organ transplant recipients (liver, kidney, heart or lung), older than 16 years of age more than 30 days after transplantation were eligible to participate. Patients (N = 514) were stratified 1:1 by center, type of organ and time after transplantation and who either received the standard single dose (n = 257) or were treated according to a novel influenza vaccination schedule comprising the administration of a booster dose 5 weeks after standard vaccination (n = 254). Seroconversion rates were measured as a determinant of protection against influenza (main outcome). Efficacy and safety outcomes were followed until 1 year after influenza vaccination with assessment of short-term (0, 5, 10 and 15 weeks) and long-term (12 months) results. Intention-to-treat, per-protocol and safety analyses will be performed. This trial will increase knowledge about the safety and efficacy of a booster dose of influenza vaccine in solid organ transplant recipients. At the time the manuscript was submitted for publication, trial recruitment was closed with a total of 499 participants included during a 2-month period (within the seasonal influenza vaccination campaign). ClinicalTrials.gov Identifier: NCT01761435 (registered 13 December 2012). EudraCT Identifier: 2011-003243-21 (registered 4 July 2011).


Women with Turner syndrome are at high risk of lifestyle-related disease -From questionnaire surveys by the Foundation for Growth Science in Japan.
In this study, the prevalence of obesity and complications of lifestyle-related diseases, such as diabetes mellitus, hypertension, dyslipidemia and liver dysfunction, as well as the relationship with karyotypes, were investigated in 492 patients with Turner syndrome (TS) aged 17 years or older. Data were obtained through questionnaire surveys administered by attending physicians throughout Japan. Collected data were compared with data from the National Health and Nutrition Survey. Patient ages ranged from 17.1 to 42.5 years (mean ± standard error, 26.6±0.2). The prevalence of lifestyle-related diseases at age 20 or over was 6.3% for diabetes, 8.7% for hypertension, 20.2% for dyslipidemia and 12.4% for liver dysfunction. These four diseases were clearly associated with severity of obesity. Obesity (BMI ≥25 kg/m(2)) was observed in 106 out of 426 patients with TS aged 15 to 39 years (24.7%) and the prevalence was significantly higher than that of the general female population (9.4%). The mean BMI in age subgroups without any complications ranged from 21.2 to 22.7, which although was within normal ranges was significantly higher than that in the general female population (20.3-21.3). In this study population, patients with TS had more complications related to lifestyle-related diseases that were highly related to obesity. Few associations between complications and karyotypes were found. In the follow-up of patients with TS, the presence of lifestyle-related disease should be considered in the evaluation and treatment of the disease.


Ecological consequences of shifting the timing of burning tallgrass prairie.
In the Kansas Flint Hills, grassland burning is conducted during a relatively narrow window because management recommendations for the past 40 years have been to burn only in late spring. Widespread prescribed burning within this restricted time frame frequently creates smoke management issues downwind. A potential remedy for the concentrated smoke production in late spring is to expand burning to times earlier in the year. Yet, previous research suggested that burning in winter or early spring reduces plant productivity and cattle weight gain while increasing the proportion of undesirable plant species. In order to better understand the ecological consequences of burning at different times of the year, plant production and species abundance were measured for 20 years on ungrazed watersheds burned annually in autumn, winter, or spring. We found that there were no significant differences in total grass production among the burns on either upland or lowland topographic positions, although spring burned watersheds had higher grass culm production and lower forb biomass than autumn and winter burned watersheds. Burning in autumn or winter broadened the window of grass productivity response to precipitation, which reduces susceptibility to mid-season drought. Burning in autumn or winter also increased the phenological range of species by promoting cool-season graminoids without a concomitant decrease in warm-season grasses, potentially widening the seasonal window of high-quality forage. Incorporating autumn and winter burns into the overall portfolio of tallgrass prairie management should increase the flexibility in managing grasslands, promote biodiversity, and minimize air quality issues caused by en masse late-spring burning with little negative consequences for cattle production.


Hypoxic activation of arterial chemoreceptors inhibits sympathetic outflow to brown adipose tissue in rats.
In urethane-chloralose anaesthetized, neuromuscularly blocked, artificially ventilated rats, we demonstrated that activation of carotid chemoreceptors inhibits the elevated levels of brown adipose tissue (BAT) sympathetic nerve activity (SNA) evoked by hypothermia, by microinjection of prostaglandin E2 into the medial preoptic area or by disinhibition of neurones in the raphe pallidus area (RPa). Peripheral chemoreceptor stimulation with systemic administration of NaCN (50 microg in 0.1 ml) or with hypoxic ventilation (8% O2-92% N2, 30 s) completely inhibited BAT SNA. Arterial chemoreceptor-evoked inhibition of BAT SNA was eliminated by prior bilateral transections of the carotid sinus nerves or by prior inhibition of neurones within the commissural nucleus tractus solitarii (commNTS) with glycine (40 nmol/80 nl) or with the GABAA receptor agonist muscimol (160 pmol/80 nl; 77 +/- 10% attenuation), or by prior blockade of ionotropic excitatory amino acid receptors in the commNTS with kynurenate (8 nmol/80 nl; 82 +/- 10% attenuation). Furthermore, activation of commNTS neurones following local microinjection of bicuculline (30 pmol/60 nl) completely inhibited the elevated level of BAT SNA resulting from disinhibition of neurones in the RPa. These results demonstrate that hypoxic stimulation of arterial chemoreceptor afferents leads to an inhibition of BAT SNA and BAT thermogenesis through an EAA-mediated activation of second-order, arterial chemoreceptor neurones in the commNTS. Peripheral chemoreceptor-evoked inhibition of BAT SNA could directly contribute to (or be permissive for) the hypoxia-evoked reductions in body temperature and oxygen consumption that serve as an adaptive response to decreased oxygen availability.


A global-scale screening of non-native aquatic organisms to identify potentially invasive species under current and future climate conditions.
The threat posed by invasive non-native species worldwide requires a global approach to identify which introduced species are likely to pose an elevated risk of impact to native species and ecosystems. To inform policy, stakeholders and management decisions on global threats to aquatic ecosystems, 195 assessors representing 120 risk assessment areas across all six inhabited continents screened 819 non-native species from 15 groups of aquatic organisms (freshwater, brackish, marine plants and animals) using the Aquatic Species Invasiveness Screening Kit. This multi-lingual decision-support tool for the risk screening of aquatic organisms provides assessors with risk scores for a species under current and future climate change conditions that, following a statistically based calibration, permits the accurate classification of species into high-, medium- and low-risk categories under current and predicted climate conditions. The 1730 screenings undertaken encompassed wide geographical areas (regions, political entities, parts thereof, water bodies, river basins, lake drainage basins, and marine regions), which permitted thresholds to be identified for almost all aquatic organismal groups screened as well as for tropical, temperate and continental climate classes, and for tropical and temperate marine ecoregions. In total, 33 species were identified as posing a 'very high risk' of being or becoming invasive, and the scores of several of these species under current climate increased under future climate conditions, primarily due to their wide thermal tolerances. The risk thresholds determined for taxonomic groups and climate zones provide a basis against which area-specific or climate-based calibrated thresholds may be interpreted. In turn, the risk rankings help decision-makers identify which species require an immediate 'rapid' management action (e.g. eradication, control) to avoid or mitigate adverse impacts, which require a full risk assessment, and which are to be restricted or banned with regard to importation and/or sale as ornamental or aquarium/fishery enhancement.


A Randomized Trial of Prenatal n-3 Fatty Acid Supplementation and Preterm Delivery.
Previous studies have suggested that maternal supplementation with n-3 long-chain polyunsaturated fatty acids may reduce the incidence of preterm delivery but may also prolong gestation beyond term; however, more data are needed regarding the role of n-3 long-chain polyunsaturated fatty acids in pregnancy. We performed a multicenter, double-blind, randomized trial in which women who were pregnant with single or multiple fetuses were assigned to receive either fish-oil capsules that contained 900 mg of n-3 long-chain polyunsaturated fatty acids (n-3 group) or vegetable-oil capsules that contained trace n-3 long-chain polyunsaturated fatty acids (control group) daily, beginning before 20 weeks of gestation and continuing to 34 weeks of gestation or delivery, whichever occurred first. The primary outcome was early preterm delivery, defined as delivery before 34 completed weeks of gestation. Other pregnancy and neonatal outcomes were also assessed. A total of 5544 pregnancies in 5517 women were randomly assigned at six centers in Australia; 5486 pregnancies were included in the primary analysis. Early preterm delivery occurred in the case of 61 of 2734 pregnancies (2.2%) in the n-3 group and 55 of 2752 pregnancies (2.0%) in the control group; the between-group difference was not significant (adjusted relative risk, 1.13; 95% confidence interval [CI], 0.79 to 1.63; P = 0.50). There were no significant differences between the groups in the incidence of interventions in post-term (>41 weeks of gestation) deliveries, in adverse events, or in other pregnancy or neonatal outcomes, except that a higher percentage of infants born to women in the n-3 group than in the control group were very large for gestational age at birth (adjusted relative risk, 1.30; 95% CI, 1.02 to 1.65). Percentages of serious adverse events did not differ between the groups. Minor gastrointestinal disturbances were more commonly reported in the n-3 group than in the control group. Supplementation with n-3 long-chain polyunsaturated fatty acids from early pregnancy (<20 weeks of gestation) until 34 weeks of gestation did not result in a lower incidence of early preterm delivery or a higher incidence of interventions in post-term deliveries than control. (Funded by the Australian National Health and Medical Research Council and the Thyne Reid Foundation; ORIP Australian New Zealand Clinical Trials Registry number, ACTRN12613001142729.).


Photobiomodulation therapy for repeated closed head injury in rats.
Repeated traumatic brain injury, leads to cumulative neuronal injury and neurological impairments. There are currently no effective treatments to prevent these consequences. Growing interest is building in the use of transcranial photobiomodulation (PBM) therapy to treat traumatic brain injury. Here, we examined PBM in a repeated closed head injury (rCHI) rat model. Rats were administered a total of three closed head injuries, with each injury separated by 5 days. PBM treatment was initiated 2 hours after the first injury and administered daily for a total of 15 days. We found that PBM-treated rCHI rats had a significant reduction in motor ability, anxiety and cognitive deficits compared to CHI group. PBM group showed an increase of synaptic proteins and surviving neurons, along with a reduction in reactive gliosis and neuronal injury. These findings highlight the complexity of gliosis and neuronal injury following rCHI and suggest that PBM may be a viable treatment option to mitigate these effects and their detrimental consequences.


Baseline and stress-induced corticosterone levels across birds and reptiles do not reflect urbanization levels.
Rates of human-induced environmental change continue increasing with human population size, potentially altering animal physiology and negatively affecting wildlife. Researchers often use glucocorticoid concentrations (hormones that can be associated with stressors) to gauge the impact of anthropogenic factors (e.g. urbanization, noise and light pollution). Yet, no general relationships between human-induced environmental change and glucocorticoids have emerged. Given the number of recent studies reporting baseline and stress-induced corticosterone (the primary glucocorticoid in birds and reptiles) concentrations worldwide, it is now possible to conduct large-scale comparative analyses to test for general associations between disturbance and baseline and stress-induced corticosterone across species. Additionally, we can control for factors that may influence context, such as life history stage, environmental conditions and urban adaptability of a species. Here, we take a phylogenetically informed approach and use data from HormoneBase to test if baseline and stress-induced corticosterone are valid indicators of exposure to human footprint index, human population density, anthropogenic noise and artificial light at night in birds and reptiles. Our results show a negative relationship between anthropogenic noise and baseline corticosterone for birds characterized as urban avoiders. While our results potentially indicate that urban avoiders are more sensitive to noise than other species, overall our study suggests that the relationship between human-induced environmental change and corticosterone varies across species and contexts; we found no general relationship between human impacts and baseline and stress-induced corticosterone in birds, nor baseline corticosterone in reptiles. Therefore, it should not be assumed that high or low levels of exposure to human-induced environmental change are associated with high or low corticosterone levels, respectively, or that closely related species, or even individuals, will respond similarly. Moving forward, measuring alternative physiological traits alongside reproductive success, health and survival may provide context to better understand the potential negative effects of human-induced environmental change.


Alkanethiolate-capped palladium nanoparticles for selective catalytic hydrogenation of dienes and trienes.
Selective hydrogenation of dienes and trienes is an important process in the pharmaceutical and chemical industries. Our group previously reported that the thiosulfate protocol using a sodium S-alkylthiosulfate ligand could generate catalytically active Pd nanoparticles (PdNP) capped with a lower density of alkanethio-late ligands. This homogeneously soluble PdNP catalyst offers several advantages such as little contamination via Pd leaching and easy separation and recycling. In addition, the high activity of PdNP allows the reactions to be completed under mild conditions, at room temperature and atmospheric pressure. Herein, a PdNP catalyst capped with octanethiolate ligands (C8 PdNP) is investigated for the selective hydrogenation of conjugated dienes into monoenes. The strong influence of the thiolate ligands on the chemical and electronic properties of the Pd surface is confirmed by mechanistic studies and highly selective catalysis results. The studies also suggest two major routes for the conjugated diene hydrogenation: the 1,2-addition and 1,4-addition of hydrogen. The selectivity between two mono-hydrogenation products is controlled by the steric interaction of substrates and the thermodynamic stability of products. The catalytic hydrogenation of trienes also results in the almost quantitative formation of mono-hydrogenation products, the isolated dienes, from both ocimene and myrcene.


A randomized controlled trial of a 3-year home exercise program in cystic fibrosis.
To evaluate the effects of a 3-year home exercise program on pulmonary function and exercise tolerance in mildly to moderately impaired patients with cystic fibrosis (CF) and to assess whether regular aerobic exercise is a realistic treatment option. Seventy-two patients with CF (7-19 years) were randomly assigned to an exercise group (a minimum of 20 minutes of aerobic exercise, at a heart rate of approximately 150 beats/min, 3 times weekly) or a control group (usual physical activity participation). Pulmonary function, exercise tolerance, clinical status, hospitalizations, and compliance with therapy were monitored during scheduled visits to the hospital's CF clinic. Sixty-five patients were included in the analyses. The control group demonstrated a greater annual decline in percent of predicted forced vital capacity compared with the exercise group (mean slope +/- SD, -2.42 +/- 4.15 vs -0.25 +/- 2.81; P =.02), with a similar trend for forced expiratory volume in 1 second (-3.47 +/- 4.93 vs -1.46 +/- 3. 55; P =.07). Patients remained compliant with the exercise program over the study period. An improved sense of well-being was reported with exercise. Pulmonary function declined more slowly in the exercise group than in the control group, suggesting a benefit for patients with CF participating in regular aerobic exercise. Consistent compliance with the home exercise program and a self-reported positive attitude toward exercise provide further evidence of the feasibility and value of including an aerobic exercise program in the conventional treatment regimen of patients with CF.


Characterization of an Arabidopsis enzyme family that conjugates amino acids to indole-3-acetic acid.
Substantial evidence indicates that amino acid conjugates of indole-3-acetic acid (IAA) function in auxin homeostasis, yet the plant enzymes involved in their biosynthesis have not been identified. We tested whether several Arabidopsis thaliana enzymes that are related to the auxin-induced soybean (Glycine max) GH3 gene product synthesize IAA-amino acid conjugates. In vitro reactions with six recombinant GH3 enzymes produced IAA conjugates with several amino acids, based on thin layer chromatography. The identity of the Ala, Asp, Phe, and Trp conjugates was verified by gas chromatography-mass spectrometry. Insertional mutations in GH3.1, GH3.2, GH3.5, and GH3.17 resulted in modestly increased sensitivity to IAA in seedling root. Overexpression of GH3.6 in the activation-tagged mutant dfl1-D did not significantly alter IAA level but resulted in 3.2- and 4.5-fold more IAA-Asp than in wild-type seedlings and mature leaves, respectively. In addition to IAA, dfl1-D was less sensitive to indole-3-butyric acid and naphthaleneacetic acid, consistent with the fact that GH3.6 was active on each of these auxins. By contrast, GH3.6 and the other five enzymes tested were inactive on halogenated auxins, and dfl1-D was not resistant to these. This evidence establishes that several GH3 genes encode IAA-amido synthetases, which help to maintain auxin homeostasis by conjugating excess IAA to amino acids.


Characteristics and Correlates of Increasing Use of Surgery in Taiwanese Cancer Patients' Last Month of Life, 2001-2010.
Surgery offers the potential to relieve symptoms for patients with cancer at the end of life (EOL) but at significant physiological and economic costs. However, the characteristics and correlates of surgery in last month of life (EOL surgery) of patients with cancer have not been comprehensively explored. This population-based study characterized EOL surgery use and identified its correlates. This retrospective cohort study examined administrative data among 339,546 Taiwanese cancer decedents, 2001 to 2010. We classified procedures according to their likely intent. Approximately 1 in 10 (11.44%, range: 11.08%-11.86%) patients underwent EOL surgery with an increasing utilization over time. The intention for EOL surgery was primarily palliative, followed by cancer-directed, nonmalignancy-directed, and diagnostic. EOL surgery for palliative intent increased whereas other intents decreased significantly over time. EOL surgery was more likely among those who were male, younger, and married; not diagnosed with hepatic-pancreatic or lung cancers; had no comorbidity or documented metastatic codes; and survived less than 1 year from diagnosis. The likelihood of EOL surgery use was higher for patients who received care in a teaching hospital with more acute care hospital beds and higher EOL care intensity. Rates of EOL surgery are lower in Taiwan than those reported in the United States. The increasing use of EOL surgery in Taiwan is primarily for palliative intent. Appropriateness of EOL surgery should be carefully evaluated to avoid underutilizing potentially beneficial, palliative-intent surgery and overutilizing cancer-directed and other surgical procedures, especially for physicians working in hospitals with abundant health care resources and a tendency to treat at-risk patients with cancer aggressively.


Promoting regular mammography screening I. A systematic assessment of validity in a randomized trial.
Most health promotion trials in cancer screening offer limited evidence of external validity. We assessed internal and external validity in a nationwide, population-based trial of an intervention to promote regular mammography screening. Beginning in September 2000, study candidates age 52 years and older (n = 23,000) were randomly selected from the National Registry of Women Veterans and sent an eligibility survey. Consistent with intention-to-treat principles for effectiveness trials, we randomly assigned eligible respondents and nonrespondents to one of five groups. We mailed baseline surveys to groups 1-3 followed by intervention materials of varying personalization to groups 1 and 2. We delayed mailing baseline surveys to two additional control groups to coincide with the mailing of postintervention follow-up surveys to groups 1-3 at year 1 (group 4) and year 2 (group 5). Mammography rates were determined from self-report and Veterans Health Administration records. To assess internal validity, we compared groups on participation and factors associated with mammography screening at each stage. To assess external validity, we compared groups 3, 4, and 5 on mammography rates at the most recent follow-up to detect any cueing effects of prior surveys and at the respective baselines to uncover any secular trends. We also compared nonparticipants with participants on factors associated with mammography screening at the trial's end. We established study eligibility for 21,340 (92.8%) of the study candidates. Groups 1-3 were similar throughout the trial in participation and correlates of mammography screening. No statistically significant survey cueing effects or differences between nonparticipants and participants across groups were observed. Mammography screening rates over the 30 months preceding the respective baselines were lower in group 5 (82.3% by self-report) than in groups 1-4 (85.1%, P = .024, group 5 vs groups 1-4 combined), suggesting a decline over time similar to that reported for US women in general. This systematic assessment provides evidence of the trial's internal and external validity and illustrates an approach to evaluating validity that is readily adaptable to future trials of behavioral interventions.


Cyclic guanosine monophosphate: effects on short-circuit current and water permeability.
In the isolated toad bladder, cyclic guanosine monophosphate induces an increase in short-circuit current similar to that produced by cyclic adenosine monophosphate. In contrast, cyclic guanosine monophosphate has no effect on water permeability in this organ. This finding raises the possibility that different and independent intra-cellular secondary messengers may exist.


CD22 as a target for cancer therapy.
Targeted therapies with monoclonal antibodies have been increasingly incorporated into the treatment for both lymphoid and myeloid hematological malignancies. Rituximab, the first approved monoclonal antibody for the treatment of cancer, has revolutionized our approach to the management of chronic lymphocytic leukemia and non-Hodgkin's lymphoma. However, there is still an unmet medical need for novel therapeutic approaches, especially for patients in the relapsed/refractory setting. Therapeutic agents with specificity against different surface antigens on malignant B cells hold promise for improving clinical outcome in these patients. Throughout the last decade, CD22, a B-cell-restricted phosphoglycoprotein of the immunoglobulin superfamily, has gained considerable interest as a therapeutic target for B-cell-directed therapies. Several novel therapeutic agents that selectively target CD22 are being developed as an alternative approach for cancer treatment. This review summarizes the current knowledge of CD22 and discusses the rationale for targeting CD22 in B-cell malignancies with immunotherapeutic agents. This review also describes some of the most promising investigational anti-CD22 agents for the treatment of B-cell malignancies.


Conformational coupling in DNA polymerase fidelity.
The fidelity of DNA polymerases is largely attributable to a two-step nucleotide binding mechanism. In the first step, binding contacts are initially made between the template and the incoming dNTP. The selectivity of this ground-state binding is similar in magnitude to the selectivity seen in forming base pairs in solution. In the second step, a change in protein conformation occurs, which leads to rapid incorporation of the dNTP into the growing polymer. This conformational change appears to occur globally in that it is inhibited by mismatches in the dNTP or in any of the three terminal base pairs of the primer/template. The open conformation allows rapid binding of the dNTP from solution, while the closed conformation provides steric checks for the proper Watson-Crick base pair geometry. This conformational change accounts for the extraordinary fidelity of polymerization and also provides selectivity to the exonuclease by inhibiting polymerization over a mismatch in the primer/template. The overall fidelity approaches one error in 10(10) by a combination of selectivity in polymerization (10(5)-10(6)) and in proofreading (10(3)-10(4)). This paradigm provides the theoretical basis for further investigation of the structural basis for fidelity by pointing to the essential elements of the polymerization reaction that need to be examined in order to evaluate active-site-directed mutants of polymerases to test appropriate structure/function relationships.


Functional Alignment of Metabolic Networks.
Network alignment has become a standard tool in comparative biology, allowing the inference of protein function, interaction, and orthology. However, current alignment techniques are based on topological properties of networks and do not take into account their functional implications. Here we propose, for the first time, an algorithm to align two metabolic networks by taking advantage of their coupled metabolic models. These models allow us to assess the functional implications of genes or reactions, captured by the metabolic fluxes that are altered following their deletion from the network. Such implications may spread far beyond the region of the network where the gene or reaction lies. We apply our algorithm to align metabolic networks from various organisms, ranging from bacteria to humans, showing that our alignment can reveal functional orthology relations that are missed by conventional topological alignments.


Effects of flunixin meglumine on postponement of ovulation in mares.
OBJECTIVE To evaluate use of flunixin meglumine as a treatment to postpone ovulation in mares, mare fertility after flunixin meglumine treatment during estrous cycles, and effects of flunixin meglumine on function of the corpus luteum after ovulation. ANIMALS 13 healthy mares. PROCEDURES A single-blinded, placebo-controlled, crossover study was conducted. Flunixin meglumine (1.1 mg/kg, IV, q 24 h) or lactated Ringer solution (placebo treatment) was administered for 2 days to mares with a dominant follicle (≥ 35 mm in diameter) and behavioral signs of estrus. Mares then were bred by artificial insemination. Number of days to ovulation from initial detection of a follicle ≥ 30 mm in diameter, uterine edema score, and pregnancy were determined by ultrasonography; the examiner was unaware of the treatment of each mare. Serum progesterone concentrations were evaluated 5 and 12 days after ovulation by use of radioimmunoassay. RESULTS Data were available for 45 estrus cycles of the 13 mares. Number of days to ovulation from initial detection of a follicle ≥ 30 mm was not significantly affected by administration of flunixin meglumine versus the placebo. Per-cycle pregnancy rate was not significantly different between flunixin meglumine (20/24 [83%] breedings) and the placebo (13/19 [68%] breedings). Flunixin meglumine did not significantly affect behavioral signs of estrus, uterine edema, or serum progesterone concentrations. CONCLUSIONS AND CLINICAL RELEVANCE Findings did not support the use of flunixin meglumine to postpone ovulation in mares.


Correlations between histologic endometrial lesions in mares and clinical response to intrauterine exposure with Streptococcus zooepidemicus.
The relationship between histologic lesions in endometrial biopsy specimens and susceptibility to chronic uterine infection (CUI) in mares was investigated. Mares were allotted to 4 groups on the basis of degree of endometrial lesions. Mares in group 1 (n = 6) had no pathologic changes, mares in group 2 (n = 5) had only mild pathologic changes, group-3 mares (n = 7) had moderate changes, and group-4 mares (n = 7) had severe inflammatory and fibrotic endometrial changes. Susceptibility to CUI was determined by the inflammatory response to intrauterine inoculation of 5 x 10(6) Streptococcus zooepidemicus. The inoculum was given on the third day of behavioral estrus and in the presence of a follicle > 30 mm. Mares with > 1 neutrophil/5 high-magnification (400 x) microscopic fields and > 20 colonies of S zooepidemicus at 96 hours after inoculation were considered to be susceptible to CUI. There was a significant association between biopsy grade and susceptibility to CUI among the groups. Histologically normal endometrium was associated with resistance to CUI, and severe histopathologic changes in the endometrium were associated with susceptibility to CUI. Mild to moderate endometrial lesions did not correlate consistently with susceptibility or resistance to CUI.


Oncogenic function and early detection potential of miRNA-10b in oral cancer as identified by microRNA profiling.
The miRNA participates in a variety of biologic processes, and dysregulation of miRNA is associated with malignant transformation. In this study, we determined specific profile of miRNA associated with oral cancer by using miRNA array screening method. There were 23 miRNAs found with considerably differential expressions between six oral cancer cell lines and five lines of normal oral keratinocytes, in which, 10 miRNAs showed the highest significant difference after independent examination by reverse transcription quantitative PCR. Eight molecules were upregulated, miR-10b, miR-196a, miR-196b, miR-582-5p, miR-15b, miR-301, miR-148b, and miR-128a, and two molecules, miR-503 and miR-31, were downregulated. The most upregulated miR-10b was further examined, and its functions were characterized in two oral cancer cell lines. The miR-10b actively promotes cell migration (2.6- to 3.6-fold) and invasion (1.7- to 1.9-fold) but has minimal effect on cell growth or chemo-/radiosensitivity. Furthermore, miR-10b was considerably elevated in the plasma of xenografted tumor mice (20-fold). This upregulation of miR-10b in plasma was further shown in the patients with oral cancer [P < 0.0001, area under curve (AUC) = 0.932] and precancer lesions (P < 0.0001, AUC = 0.967), suggesting that miR-10b possesses a high potential to discriminate the normal subjects. In conclusion, we have identified at least 10 miRNAs significantly associated with oral cancer, including the most elevated miR-10b. The miR-10b actively participates in cancer formation by promoting cell migration and invasion. Our study using clinical samples suggests that plasma miR-10b has high potential as an early detection marker for oral cancer.


Repeated evolution of exaggerated dewlaps and other throat morphology in lizards.
The existence of elaborate ornamental structures in males is often assumed to reflect the outcome of female mate choice for showy males. However, female mate choice appears weak in many iguanian lizards, but males still exhibit an array of ornament-like structures around the throat. We performed a phylogenetic comparative study to assess whether these structures have originated in response to male-male competition or the need for improved signal efficiency in visually difficult environments. We found little evidence for the influence of male-male competition. Instead, forest species were more likely to exhibit colourful throat appendages than species living in open habitats, suggesting selection for signal efficiency. On at least three independent occasions, throat ornamentation has become further elaborated into a large, conspicuously coloured moving dewlap. Although the function of the dewlap is convergent, the underlying hyoid apparatus has evolved very differently, revealing the same adaptive outcome has been achieved through multiple evolutionary trajectories. More generally, our findings highlight that extravagant, ornament-like morphology can evolve in males without the direct influence of female mate choice and that failure to consider alternative hypotheses for the evolution of these structures can obscure the true origins of signal diversity among closely related taxa.


2019 HRS/EHRA/APHRS/LAHRS expert consensus statement on catheter ablation of ventricular arrhythmias.
Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the 2009 EHRA/HRS Expert Consensus on Catheter Ablation of Ventricular Arrhythmias. An expert writing group, after reviewing and discussing the literature, including a systematic review and meta-analysis published in conjunction with this document, and drawing on their own experience, drafted and voted on recommendations and summarized current knowledge and practice in the field. Each recommendation is presented in knowledge byte format and is accompanied by supportive text and references. Further sections provide a practical synopsis of the various techniques and of the specific ventricular arrhythmia sites and substrates encountered in the electrophysiology lab. The purpose of this document is to help electrophysiologists around the world to appropriately select patients for catheter ablation, to perform procedures in a safe and efficacious manner, and to provide follow-up and adjunctive care in order to obtain the best possible outcomes for patients with ventricular arrhythmias.


A novel common single nucleotide polymorphism in the promoter region of the C-reactive protein gene associated with the plasma concentration of C-reactive protein.
The plasma CRP concentration has consistently been shown to be associated with the risk of future coronary heart disease (CHD) and recent studies have suggested that CRP has a pathogenic role in CHD. Family studies and genotype-phenotype association studies of known polymorphisms in the intron, second exon and 3'-untranslated region (UTR) have suggested that plasma CRP concentrations are under genetic control. However, no functional polymorphisms have so far been reported in the promoter region of the CRP gene. Screening of 1600 base pair (bp) of the promoter region of the CRP gene, using denaturing high performance liquid chromatography, revealed two novel common single nucleotide polymorphisms (SNPs). One of them, a three allelic SNP located at position -286 from the transcription start, was strongly associated with the plasma CRP concentration, predominantly in patients with CHD. No difference in allele frequency was seen between middle-aged post-infarction patients and population-based controls. The prognostic role and therapeutic implications in CHD and the functionality of this polymorphism remain to be determined.


The association of vascular risk factors with visual loss in giant cell arteritis.
Blindness is a recognized complication of GCA; however, the frequency of and risk factors for this complication have not been firmly established. The aim of this study was to examine the incidence and determinants of blindness in patients with GCA, using a large international cohort. The analysis was conducted among subjects recruited into the Diagnosis and Classification Criteria in Vasculitis Study. The study captures consecutive patients presenting to clinic-based physicians. New-onset blindness was assessed 6 months after diagnosis by completion of the Vasculitis Damage Index. Logistic regression analysis was used to assess the association between blindness and clinical variables. Of 433 patients with GCA from 26 countries, 7.9% presented with blindness in at least one eye at 6 months. Risk factors identified at baseline for blindness at 6 months were identified and included prevalent stroke [odds ratio (OR) = 4.47, 95% CI: 1.30, 15.41] and peripheral vascular disease (OR = 10.44, 95% CI: 2.94, 37.03). This is the largest study to date of subjects with incident GCA and confirms that blindness remains a common complication of disease and is associated with established vascular disease. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov , NCT01066208.


Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study.
Type 2 diabetes (diabetes) is characterized by accelerated cognitive decline and higher dementia risk. Controversy exists regarding the impact of metformin, which is associated with both increased and decreased dementia rates. The objective of this study was to determine the association of metformin use with incident dementia and cognitive decline over 6 years in participants with diabetes compared with those not receiving metformin and those without diabetes. A prospective observational study was conducted of N = 1,037 community-dwelling older participants without dementia aged 70-90 years at baseline (the Sydney Memory and Ageing Study). Exclusion criteria were dementia, major neurological or psychiatric disease, or progressive malignancy. Neuropsychological testing measured cognitive function every 2 years; a battery of tests measured executive function, memory, attention/speed, language, and visuospatial function individually. These were used to determine the measure of global cognition. Incident dementia was ascertained by a multidisciplinary panel. Total brain, hippocampal, and parahippocampal volumes were measured by MRI at baseline and 2 years (n = 526). Data were analyzed by linear mixed modeling, including the covariates of age, sex, education, BMI, heart disease, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. Of n = 1,037, 123 had diabetes; 67 received metformin (DM+MF) and were demographically similar to those who did not (DM-noMF) and participants without diabetes (no-DM). DM+MF had significantly slower global cognition and executive function decline compared with DM-noMF. Incident dementia was significantly higher in DM-noMF compared with DM+MF (odds ratio 5.29 [95% CI 1.17-23.88]; P = 0.05). Older people with diabetes receiving metformin have slower cognitive decline and lower dementia risk. Large randomized studies in people with and without diabetes will determine whether these associations can be attributed to metformin.


In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2.
Hepcidin is the principal iron-regulatory hormone and a pathogenic factor in anemia of inflammation. Patients with multiple myeloma (MM) frequently present with anemia. We showed that MM patients had increased serum hepcidin, which inversely correlated with hemoglobin, suggesting that hepcidin contributes to MM-related anemia. Searching for hepcidin-inducing cytokines in MM, we quantified the stimulation of hepcidin promoter-luciferase activity in HuH7 cells by MM sera. MM sera activated the hepcidin promoter significantly more than did normal sera. We then examined the role of bone morphogenetic proteins (BMPs) and interleukin-6 (IL-6), the major transcriptional regulators of hepcidin. Mutations in both BMP-responsive elements abrogated the activation dramatically, while mutations in the IL-6-responsive signal transducer and activator of transcription 3-binding site (STAT3-BS) had only a minor effect. Cotreatment with anti-BMP-2/4 or noggin-Fc blocked the promoter induction with all MM sera, anti-IL-6 blocked it with a minority of sera, whereas anti-BMP-4, -6, or -9 antibodies had no effect. BMP-2-immunodepleted MM sera had decreased promoter stimulatory capacity, and BMP-2 concentrations in MM sera were significantly higher than in normal sera. Our results demonstrate that BMP-2 is a major mediator of the hepcidin stimulatory activity of MM sera.


The illusion of end-of-life resource savings with advance directives. SUPPORT Investigators. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatment.
Would increasing the documentation of advance directives (ADs) lead to a reduction in resource utilization? We examined this question by conducting three secondary analyses: (1) we tested for a change in resource use among those who died in the hospital at a time before and after an intervention that increased the documentation of ADs in the medical record; (2) we replicated analyses of published studies that reported an association of chart documentation of ADs and hospital resource use; and (3) we examined whether a potential explanation of the observed association is biased documentation of ADs among patients who have completed an AD. Replication of analysis of previous published studies using data from a prospective cohort study and block-randomized controlled trial. Five teaching hospitals in the United States. A total of 9105 seriously ill patients were enrolled in the Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments (SUPPORT), including 4301 patients in the 2 years (1989-91) before the Patient Self-Determination Act (PSDA) and 4804 in the 2 years (1992-94) after the PSDA implementation, with 2652 patients receiving the intervention and 2152 serving as controls. The SUPPORT intervention provided a nurse to facilitate communication among patients, surrogates, and physicians about preferences for and outcomes of treatments. Documenting existing advance directives was also one of this nurse's tasks. The Patient Self-Determination Act required that health care institutions inquire about and document existing advance directives at the time of hospital admission. Hospital resource use was derived from the Therapeutic Intensity Scoring System and hospital length of stay, converted into 1994 dollars. Chart documentation of existing advance directives at the time of study admission increased with both the PSDA and the SUPPORT intervention. We found that intervention patients were more likely to have pre-existing ADs documented. Despite this increase, there was no corresponding change in hospital resource use for those who died during the enrollment hospitalization. Replication of analyses from published studies using data from the block randomized controlled trial found that ADs documented by the third day of serious illness were associated with a 23% reduction in hospital resource use among control patients ($21,284 with ADs documented compared with $26,127 without, 95% CI 1-48% reduction). However, this association was not observed among intervention patients, who had more pre-existing ADs documented in the medical record. Intervention patients with early documentation of ADs showed a trend toward greater cost ($28,017 compared with $24,178 among those without AD documentation, 95% CI 0-25% increase). The rate of documentation and characteristics of those with documentation differed between control and intervention patients. Intervention patients were more likely (as reported by patient or surrogate interview) to have ADs documented in the medical record by the third day (55% vs 32%, P < .001). In contrast to intervention patients, control patients who were older, less wealthy, less educated, more likely to prefer to forgo CPR, and more likely to want life-sustaining treatment limited had their ADs documented. These associations were not found among intervention patients when comparison was made between those with and those without an AD documented in the medical record. Increasing the documentation of pre-existing ADs was not associated with a reduction in hospital resource use. ADs documented without further intervention by the third day of a serious illness were associated with decreased hospital resource use. However, we did not find this association with an intervention that increased AD documentation. One potential explanation of these findings is that classification of those with an AD was based on cha


Percutaneous uptake rate of 2-butoxyethanol in the guinea pig.
The percutaneous absorption rate and elimination kinetics of 2-butoxyethanol (ethylene glycol monobutyl ether) were estimated in the guinea pig. An intravenous bolus dose of 42 or 92 mumol/kg of body weight was administered into the jugular vein of 10 pentobarbital-anesthetized animals. Epicutaneous administration of 2-butoxyethanol followed 2.5 h later in one or two sealed glass rings on the clipped back of the animal. Arterial blood samples were obtained and then analyzed for 2-butoxyethanol by gas chromatography. Following the intravenous dose, the apparent total clearance and mean residence time of 2-butoxyethanol were calculated to be 128 ml X min-1 X kg-1 (SD 30%) and 4.7 min (SD 30%), respectively. During the latter part of the 2-h skin exposure, the concentration of 2-butoxyethanol in the blood appeared to level off at an average concentration of 21 mumol/l (SD 45%). The absorption rate through the skin was estimated to be 0.25 (range 0.05-0.46) mumol X min-1 X cm-2 (SD 49%). The skin uptake rate in the guinea pig was extrapolated to man for a comparison of the percutaneous absorption of liquid solvent with respiratory uptake of solvent vapor. The extrapolation indicated a risk of acute adverse effects when large areas of the skin are exposed to 2-butoxyethanol.


Lztfl1/BBS17 controls energy homeostasis by regulating the leptin signaling in the hypothalamic neurons.
Leptin receptor (LepRb) signaling pathway in the hypothalamus of the forebrain controls food intake and energy expenditure in response to an altered energy state. Defects in the LepRb signaling pathway can result in leptin-resistance and obesity. Leucine zipper transcription factor like 1 (Lztfl1)/BBS17 is a member of the Bardet-Biedl syndrome (BBS) gene family. Human BBS patients have a wide range of pathologies including obesity. The cellular and molecular mechanisms underlying Lztfl1-regulated obesity are unknown. Here, we generated Lztfl1f/f mouse model in which Lztfl1 can be deleted globally and in tissue-specific manner. Global Lztfl1 deficiency resulted in pleiotropic phenotypes including obesity. Lztfl1-/- mice are hyperphagic and showed similar energy expenditure as WT littermates. The obese phenotype of Lztfl1-/- mice is caused by the loss of Lztfl1 in the brain but not in the adipocytes. Lztfl1-/- mice are leptin-resistant. Inactivation of Lztfl1 abolished phosphorylation of Stat3 in the LepRb signaling pathway in the hypothalamus upon leptin stimulation. Deletion of Lztfl1 had no effect on LepRb membrane localization. Furthermore, we observed that Lztfl1-/- mouse embryonic fibroblasts (MEFs) have significantly longer cilia than WT MEFs. We identified several proteins that potentially interact with Lztfl1. As these proteins are known to be involved in regulation of actin/cytoskeleton dynamics, we suggest that Lztfl1 may regulate leptin signaling and ciliary structure via these proteins. Our study identified Lztfl1 as a novel player in the LepRb signaling pathway in the hypothalamus that controls energy homeostasis.


Warming can boost denitrification disproportionately due to altered oxygen dynamics.
Global warming and the alteration of the global nitrogen cycle are major anthropogenic threats to the environment. Denitrification, the biological conversion of nitrate to gaseous nitrogen, removes a substantial fraction of the nitrogen from aquatic ecosystems, and can therefore help to reduce eutrophication effects. However, potential responses of denitrification to warming are poorly understood. Although several studies have reported increased denitrification rates with rising temperature, the impact of temperature on denitrification seems to vary widely between systems. We explored the effects of warming on denitrification rates using microcosm experiments, field measurements and a simple model approach. Our results suggest that a three degree temperature rise will double denitrification rates. By performing experiments at fixed oxygen concentrations as well as with oxygen concentrations varying freely with temperature, we demonstrate that this strong temperature dependence of denitrification can be explained by a systematic decrease of oxygen concentrations with rising temperature. Warming decreases oxygen concentrations due to reduced solubility, and more importantly, because respiration rates rise more steeply with temperature than photosynthesis. Our results show that denitrification rates in aquatic ecosystems are strongly temperature dependent, and that this is amplified by the temperature dependencies of photosynthesis and respiration. Our results illustrate the broader phenomenon that coupling of temperature dependent reactions may in some situations strongly alter overall effects of temperature on ecological processes.


Interaction of J-protein co-chaperone Jac1 with Fe-S scaffold Isu is indispensable in vivo and conserved in evolution.
The ubiquitous mitochondrial J-protein Jac1, called HscB in Escherichia coli, and its partner Hsp70 play a critical role in the transfer of Fe-S clusters from the scaffold protein Isu to recipient proteins. Biochemical results from eukaryotic and prokaryotic systems indicate that formation of the Jac1-Isu complex is important for both targeting of the Isu for Hsp70 binding and stimulation of Hsp70's ATPase activity. However, in apparent contradiction, we previously reported that an 8-fold decrease in Jac1's affinity for Isu1 is well tolerated in vivo, raising the question as to whether the Jac1:Isu interaction actually plays an important biological role. Here, we report the determination of the structure of Jac1 from Saccharomyces cerevisiae. Taking advantage of this information and recently published data from the homologous bacterial system, we determined that a total of eight surface-exposed residues play a role in Isu binding, as assessed by a set of biochemical assays. A variant having alanines substituted for these eight residues was unable to support growth of a jac1-Δ strain. However, replacement of three residues caused partial loss of function, resulting in a significant decrease in the Jac1:Isu1 interaction, a slow growth phenotype, and a reduction in the activity of Fe-S cluster-containing enzymes. Thus, we conclude that the Jac1:Isu1 interaction plays an indispensable role in the essential process of mitochondrial Fe-S cluster biogenesis.


Are buffers around home representative of physical activity spaces among adults?
Residential buffers are frequently used to assess built environment characteristics relevant to physical activity (PA), yet little is known about how well they represent the spatial areas in which individuals undertake PA. We used System for Observing Play and Recreation in Communities data for 217 adults from five US states who wore an accelerometer and a GPS for three weeks to create newly defined PA-specific activity spaces. These PA spaces were based on PA occurring in bouts of ≥10min and were defined as 1) the single minimum convex polygon (MCP) containing all of a participant's PA bout minutes and 2) the combination of many MCPs constructed using each PA bout independently. Participants spent a large proportion of their PA bout time outside of 0.5, 1, and 5 mile residential buffers, and these residential buffers were a poor approximation of the spatial areas in which PA bouts occurred. The newly proposed GPS-based PA spaces can be used in future studies in place of the more general concept of activity space to better approximate built environments experienced during PA.


Role of RANKL (TNFSF11)-dependent osteopetrosis in the dental phenotype of Msx2 null mutant mice.
The MSX2 homeoprotein is implicated in all aspects of craniofacial skeletal development. During postnatal growth, MSX2 is expressed in all cells involved in mineralized tissue formation and plays a role in their differentiation and function. Msx2 null (Msx2 (-/-)) mice display complex craniofacial skeleton abnormalities with bone and tooth defects. A moderate form osteopetrotic phenotype is observed, along with decreased expression of RANKL (TNFSF11), the main osteoclast-differentiating factor. In order to elucidate the role of such an osteopetrosis in the Msx2 (-/-) mouse dental phenotype, a bone resorption rescue was performed by mating Msx2 (-/-) mice with a transgenic mouse line overexpressing Rank (Tnfrsf11a). Msx2 (-/-) Rank(Tg) mice had significant improvement in the molar phenotype, while incisor epithelium defects were exacerbated in the enamel area, with formation of massive osteolytic tumors. Although compensation for RANKL loss of function could have potential as a therapy for osteopetrosis, but in Msx2 (-/-) mice, this approach via RANK overexpression in monocyte-derived lineages, amplified latent epithelial tumor development in the peculiar continuously growing incisor.


BloodSpot: a database of gene expression profiles and transcriptional programs for healthy and malignant haematopoiesis.
Research on human and murine haematopoiesis has resulted in a vast number of gene-expression data sets that can potentially answer questions regarding normal and aberrant blood formation. To researchers and clinicians with limited bioinformatics experience, these data have remained available, yet largely inaccessible. Current databases provide information about gene-expression but fail to answer key questions regarding co-regulation, genetic programs or effect on patient survival. To address these shortcomings, we present BloodSpot (www.bloodspot.eu), which includes and greatly extends our previously released database HemaExplorer, a database of gene expression profiles from FACS sorted healthy and malignant haematopoietic cells. A revised interactive interface simultaneously provides a plot of gene expression along with a Kaplan-Meier analysis and a hierarchical tree depicting the relationship between different cell types in the database. The database now includes 23 high-quality curated data sets relevant to normal and malignant blood formation and, in addition, we have assembled and built a unique integrated data set, BloodPool. Bloodpool contains more than 2000 samples assembled from six independent studies on acute myeloid leukemia. Furthermore, we have devised a robust sample integration procedure that allows for sensitive comparison of user-supplied patient samples in a well-defined haematopoietic cellular space.


Influence of subfertility and assisted reproductive technology treatment on mortality of women after delivery.
To compare incidence, risk factors, and etiology of women's deaths in fertile, subfertile, and undergoing assisted reproductive technology (ART) in the years after delivery. Retrospective cohort. University hospital. Women who had delivered in Massachusetts. This study used data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System linked to vital records, hospital stays, and the Massachusetts death file. Mortality of patients delivered from 2004-2013 was evaluated through 2015. The exposure groups, determined on the basis of the last delivery, were ART-treated (linked to Society for Assisted Reproductive Technology Clinic Outcome Reporting System), subfertile (no ART but with indicators of subfertility including birth certificate checkbox for fertility treatment, prior hospitalization for infertility [International Classification of Disease codes 9 628 or V23], and/or prior delivery with checkbox or ART), or fertile (neither ART nor subfertile). Numbers (per 100,000 women-years) and causes of death were obtained from the Massachusetts death file. Mortality of women after delivery in each of the three fertility groups and the most common etiology of death in each. We included 483,547 women: 16,429 ART, 11,696 subfertile, and 455,422 fertile among whom there were 1,280 deaths with 21.1, 25.5, and 44.7 deaths, respectively, per 100,000 women-years. External causes (violence, accidents, and poisonings) were the most common reasons for death in the fertile group. Deaths occurred on average 46 months after delivery. When external causes of death were removed, there were 19.1, 17.0, and 25.6 deaths per 100,000 women-years and leading causes of death in all groups were cancer and circulatory problems. The study presents reassuring data that death rates within 5 years of delivery in ART-treated and subfertile women do not differ from those in fertile women.


Barriers and facilitators to humanizing birth care in Tanzania: findings from semi-structured interviews with midwives and obstetricians.
In Tanzania, the provision of humanized care is increasingly being emphasized in midwifery practice, yet studies regarding perceptions and practices of skilled health personnel towards the humanization of birth care are scare. Previous reviews have identified that abuse and disrespect is not limited to individuals but reflects systematic failures and deeply embedded provider attitudes and beliefs. Therefore, the current study aims to explore the perceptions and practices of skilled health personnel on humanizing birth care in Tanzania by identifying current barriers and facilitators. Semi-structured interviews were held with skilled health personnel including midwives (n = 6) and obstetricians (n = 2) working in the two district hospitals of Tanzania. Data were analyzed using thematic coding. Skilled health personnel identified systematic barriers to providing humanizing birth care. Systematic barriers included lack of space and limited facilities. Institutional norms and practices prohibited family involvement during the birth process,including beliefs that limited choice of birth position as well as disrespected beliefs, traditions, and culture. Participants also acknowledged four facilitators that improve the likelihood of humanized care during childbirth in Tanzania: ongoing education of skilled health personnel on respectful maternal care, institutional norms designed for continuous clinic support during childbirth, belief in the benefit of having family become active participants, and respecting maternal wishes when appropriate. To move forward with humanizing the birth process in Tanzania, it will be essential that systematic barriers are addressed as well as changing the mindset of personnel towards respectful maternal care. It will be essential for the government and private hospitals to revalue their labour wards to increase the space and staff allocated to each mother to enhance family-integrated care. Additionally, in-service training as well as incorporation of respectful maternal care during pre-service training is key to changing the culture in the labour ward.


Effects of extra-intracranial arterial bypass on cerebral blood flow and oxygen metabolism in humans.
Twelve patients, eleven with a carotid obstruction and one with an occlusion of the middle cerebral artery, were studied before and after a successful unilateral extra-intracranial arterial by-pass, (EIAB) using PET and the 15-0 steady-state technique to measure regional cerebral blood flow (CBF), oxygen extraction fraction and oxygen metabolic rate (CMRO2). In the whole group of patients, both CBF and CMRO2 increased significantly on both cerebral hemispheres after EIAB, returning toward control levels defined in age-matched subjects. Mean oxygen extraction fraction, on the other hand, was not affected. Individually, three different effects of EIAB emerged: 1) Alleviation of a state of long standing unilateral "misery-perfusion", as reported earlier; 2) parallel increase of CBF and CMRO2 bilaterally, which appeared due to improvement of a hemodynamic depression of metabolism, the precise mechanism of which remains obscure; 3) Complex, unexpected changes in the CBF-CMRO2 couple again resulting in increases in CMRO2. This metabolic improvement afforded by EIAB in our patients has not been reported before; it suggests that long-standing hemodynamic failure may induce a metabolic depression that is still potentially reversible by surgical revascularization.


[Broadening the scope of triatomine research in the attendance of notifications of Triatoma sordida (Stål, 1859) in the State of São Paulo].
The objective of this study was to broaden the inspection of home units to a radius of 200 meters from the residence of each notified case. The notifications received by the regional Services of SUCEN of São José do Rio Preto, Araçatuba and Presidente Prudente were evaluated in August, September and October of 2002. There was a total of 263 notifications of triatomines, of which 79 were positive. Broadening the scope meant another 610 domestic units were included in the investigation and in 14.5% of these triatomines were found. It was observed that 24.7% of the domestic units neighboring the house of the notified case presented positive results in the triatomines investigation. When a notified domestic unit presented a positive result, broadening the scope showed positivity in 42.5% of neighboring domestic units (Odds ratio 2.252 (1.25<OR<4.06, with a 95% confidence limit). This study demonstrated that it is necessary to broaden the scope of investigation when attending notifications by the local population.


Cross-reactivity of Olea europaea with other Oleaceae species in allergic rhinitis and bronchial asthma.
Cross-reactivity between pollen extracts of four species of Oleaceae was studied: olive (Olea europaea), ash (Fraxinus excelsior), privet (Ligustrum vulgare), and lilac (Syringa vulgaris). Thus, 51 patients and 13 atopic controls were studied, by means of intracutaneous skin tests, histamine-release tests against the four extracts, and specific IgE to O. europaea. The proteic content of the four extracts was assessed by SDS-PAGE and immunoblotting, and similarity of all the extracts studied was observed after electrophoresis and immunodetection. Six common bands were found to be responsible for the cross-reactivity, with apparent molecular weights of 49.6, 40, 36.7, 19.7, 16.7, and 14 kDa, respectively. The cross-reactivity was also corroborated by immunoblotting inhibition and FEIA inhibition. The patients had a similar response to the four allergenic extracts used, although the response to Olea was greatest. When the patients were compared by their geographic origin (northern or southern Spain, according to the distribution of areas of olive pollen influence), there were no significant differences between the two groups in skin reactivity, but a higher histamine release was observed for the four extracts in the southern group, although it was significant only for Fraxinus and Ligustrum. This work corroborated the practicality of the diagnostic methods used and the cross-reactivity between the four species studied, as demonstrated by the different methods used. Therefore, we suggest that only O. europaea extract be used in diagnosis and immunotherapy in Oleaceae pollen allergy.


Bayesian hierarchical mixture modeling to assign copy number from a targeted CNV array.
Accurate assignment of copy number at known copy number variant (CNV) loci is important for both increasing understanding of the structural evolution of genomes as well as for carrying out association studies of copy number with disease. As with calling SNP genotypes, the task can be framed as a clustering problem but for a number of reasons assigning copy number is much more challenging. CNV assays have lower signal-to-noise ratios than SNP assays, often display heavy tailed and asymmetric intensity distributions, contain outlying observations and may exhibit systematic technical differences among different cohorts. In addition, the number of copy-number classes at a CNV in the population may be unknown a priori. Due to these complications, automatic and robust assignment of copy number from array data remains a challenging problem. We have developed a copy number assignment algorithm, CNVCALL, for a targeted CNV array, such as that used by the Wellcome Trust Case Control Consortium's recent CNV association study. We use a Bayesian hierarchical mixture model that robustly identifies both the number of different copy number classes at a specific locus as well as relative copy number for each individual in the sample. This approach is fully automated which is a critical requirement when analyzing large numbers of CNVs. We illustrate the methods performance using real data from the Wellcome Trust Case Control Consortium's CNV association study and using simulated data.


Discovery of an expanded set of avian leukosis subgroup E proviruses in chickens using Vermillion, a novel sequence capture and analysis pipeline [corrected].
Transposable elements (TEs), such as endogenous retroviruses (ERVs), are common in the genomes of vertebrates. ERVs result from retroviral infections of germ-line cells, and once integrated into host DNA they become part of the host's heritable genetic material. ERVs have been ascribed positive effects on host physiology such as the generation of novel, adaptive genetic variation and resistance to infection, as well as negative effects as agents of tumorigenesis and disease. The avian leukosis virus subgroup E family (ALVE) of endogenous viruses of chickens has been used as a model system for studying the effects of ERVs on host physiology, and approximately 30 distinct ALVE proviruses have been described in the Gallus gallus genome. In this report we describe the development of a software tool, which we call Vermillion, and the use of this tool in combination with targeted next-generation sequencing (NGS) to increase the number of known proviruses belonging to the ALVE family of ERVs in the chicken genome by 4-fold, including expanding the number of known ALVE elements on chromosome 1 (Gga1) from the current 9 to a total of 40. Although we focused on the discovery of ALVE elements in chickens, with appropriate selection of target sequences Vermillion can be used to develop profiles of other families of ERVs and TEs in chickens as well as in species other than the chicken.


Focal aggregation of voltage-gated, Kv2.1 subunit-containing, potassium channels at synaptic sites in rat spinal motoneurones.
Delayed rectifier K+ currents are involved in the control of alpha-motoneurone excitability, but the precise spatial distribution and organization of the membrane ion channels that contribute to these currents have not been defined. Voltage-activated Kv2.1 channels have properties commensurate with a contribution to delayed rectifier currents and are expressed in neurones throughout the mammalian central nervous system. A specific antibody against Kv2.1 channel subunits was used to determine the surface distribution and clustering of Kv2.1 subunit-containing channels in the cell membrane of alpha-motoneurones and other spinal cord neurones. In alpha-motoneurones, Kv2.1 immunoreactivity (-IR) was abundant in the surface membrane of the soma and large proximal dendrites, and was present also in smaller diameter distal dendrites. Plasma membrane-associated Kv2.1-IR in alpha-motoneurones was distributed in a mosaic of small irregularly shaped, and large disc-like, clusters. However, only small to medium clusters of Kv2.1-IR were observed in spinal interneurones and projection neurones, and some interneurones, including Renshaw cells, lacked demonstrable Kv2.1-IR. In alpha-motoneurones, dual immunostaining procedures revealed that the prominent disc-like domains of Kv2.1-IR are invariably apposed to presynaptic cholinergic C-terminals. Further, Kv2.1-IR colocalizes with immunoreactivity against postsynaptic muscarinic (m2) receptors at these locations. Ultrastructural examination confirmed the postsynaptic localization of Kv2.1-IR at C-terminal synapses, and revealed clusters of Kv2.1-IR at a majority of S-type, presumed excitatory, synapses. Kv2.1-IR in alpha-motoneurones is not directly associated with presumed inhibitory (F-type) synapses, nor is it present in presynaptic structures apposed to the motoneurone. Occasionally, small patches of extrasynaptic Kv2.1-IR labelling were observed in surface membrane apposed by glial processes. Voltage-gated potassium channels responsible for the delayed rectifier current, including Kv2.1, are usually assigned roles in the repolarization of the action potential. However, the strategic localization of Kv2.1 subunit-containing channels at specific postsynaptic sites suggests that this family of voltage-activated K+ channels may have additional roles and/or regulatory components.


On the interaction between perceptual and response selection: neuropsychological evidence.
We examined the relations between selection for perception and selection for action in a patient FK, with bilateral damage to his temporal and medial frontal cortices. The task required a simple grasp response to a common object (a cup) in the presence of a distractor (another cup). The target was cued by colour or location, and FK made manual responses. We examined the effects on performance of cued and uncued dimensions of both the target and the distractor. FK was impaired at perceptually selecting the target when cued by colour, when the target colour but not its location changed on successive trials. The effect was sensitive to the relative orientations of targets and distractors, indicating an effect of action selection on perceptual selection, when perceptual selection was weakly instantiated. The dimension-specific carry-over effect on reaching was enhanced when there was a temporal delay between a cue and the response, and it disappeared when there was a between-trial delay. The results indicate that perceptual and action selection systems interact to determine the efficiency with which actions are selected to particular objects.


Control of periplasmic nitrate reductase gene expression (napEDABC) from Paracoccus pantotrophus in response to oxygen and carbon substrates.
The napEDABC operon of Paracoccus pantotrophus encodes a periplasmic nitrate reductase (NAP), together with electron-transfer components and proteins required for the synthesis of a fully functional enzyme. Previously, it had been shown that high NAP activity was observed when P. pantotrophus was grown aerobically on highly reduced carbon sources such as butyrate or caproate, but not when cultured on more oxidized substrates such as succinate or malate. The enzyme is not present to any extent when the organism is grown anaerobically under denitrifying conditions, regardless of the carbon source. Transcriptional analyses of the nap operon have now identified two initiation sites which were differentially regulated in response to the carbon source, with expression being maximal when cells were grown aerobically with butyrate. Analysis of a P. pantotrophus mutant (M6) deregulated for NAP activity identified a single C-->A transversion in a heptameric inverted-repeat sequence that partially overlapped the proximal promoter. Transcription analysis of this mutant revealed that expression of nap was completely derepressed under all growth conditions examined. Taken together, these findings indicate that nap transcription is negatively regulated during anaerobiosis, such that expression is restricted to aerobic growth, but only when the carbon source is highly reduced.


Ag2Cu3Cr2O8(OH)4: a new bidimensional silver-copper mixed-oxyhydroxide with in-plane ferromagnetic coupling.
Ag2Cu3Cr2O8(OH)4, a new Ag-Cu-Cr-O layered mixed oxide, prepared by soft hydrothermal heterogeneous reactions, is reported. The new phase is an oxyhydroxide and presents a structure with alternating brucite-like Cu-O and Ag-O layers connected by individual chromate groups. The crystallographic structure has been solved and refined from high resolution powder X-ray diffraction data and is supported by density functional theory calculations, yielding a triclinic, space group P1[combining macron], a = 5.3329(1) Å, b = 5.3871(1) Å, c = 10.0735(1) Å, α = 80.476(1)°, β = 87.020(1)°, γ = 62.383(1)°. Bond valence sums suggest the formulation of Ag+2Cu2+3Cr6+2O8(OH)4, an electronic state fully supported by X-ray photoelectron spectroscopy (XPS) and Cr K-edge X-ray absorption near edge structure (XANES) measurements. Ag2Cu3Cr2O8(OH)4 exhibits bidimensional Cu-O-Cu ferromagnetic correlations that are apparent at much higher temperatures than in other similar Cu-O layered structures, without coupling between Cu-O layers, which represents a unique case in the recent family of silver copper oxides. The role of Ag inducing bidimensionality in copper oxides is therefore expanded further with the presence of chromate anions. Ab initio calculations using density functional theory show that the electronic states involved originate mainly from Cu and OH orbitals, with minor contributions from Cr and the O atoms linking the Cr tetrahedra to the brucitic Cu-O layer, and almost no contribution from Ag. Further modeling of the in-plane magnetic interactions between Cu atoms suggests that the coupled magnetized stripes are responsible for the observed behavior. The results are discussed in relation with previous Ag-Cu mixed oxide phases where metallic behavior or ferro-antiferro transitions had been observed. The structure of this new Ag-Cu-O phase as compared with previous silver copper oxides supports the conclusion that the Ag-Cu layered ordering is favored under oxidizing conditions.


Four-beam laser trap of neutral atoms.
An efficient spontaneous-force laser trap of neutral atoms without standing waves is demonstrated by using the Ne 1s(5) metastable state. The metastable Ne beam is decelerated by a laser by using Zeeman tuning and is trapped in a trap consisting of a quadrupole magnetic field and four laserbeams in a tetrahedral configuration. The dynamics of atomic motion from the deceleration stage to the trap is discussed.


Price promotions on healthier compared with less healthy foods: a hierarchical regression analysis of the impact on sales and social patterning of responses to promotions in Great Britain.
There is a growing concern, but limited evidence, that price promotions contribute to a poor diet and the social patterning of diet-related disease. We examined the following questions: 1) Are less-healthy foods more likely to be promoted than healthier foods? 2) Are consumers more responsive to promotions on less-healthy products? 3) Are there socioeconomic differences in food purchases in response to price promotions? With the use of hierarchical regression, we analyzed data on purchases of 11,323 products within 135 food and beverage categories from 26,986 households in Great Britain during 2010. Major supermarkets operated the same price promotions in all branches. The number of stores that offered price promotions on each product for each week was used to measure the frequency of price promotions. We assessed the healthiness of each product by using a nutrient profiling (NP) model. A total of 6788 products (60%) were in healthier categories and 4535 products (40%) were in less-healthy categories. There was no significant gap in the frequency of promotion by the healthiness of products neither within nor between categories. However, after we controlled for the reference price, price discount rate, and brand-specific effects, the sales uplift arising from price promotions was larger in less-healthy than in healthier categories; a 1-SD point increase in the category mean NP score, implying the category becomes less healthy, was associated with an additional 7.7-percentage point increase in sales (from 27.3% to 35.0%; P < 0.01). The magnitude of the sales uplift from promotions was larger for higher-socioeconomic status (SES) groups than for lower ones (34.6% for the high-SES group, 28.1% for the middle-SES group, and 23.1% for the low-SES group). Finally, there was no significant SES gap in the absolute volume of purchases of less-healthy foods made on promotion. Attempts to limit promotions on less-healthy foods could improve the population diet but would be unlikely to reduce health inequalities arising from poorer diets in low-socioeconomic groups.


Density-dependent migratory waves in the marine pelagic ecosystem.
The migration of large aggregations of animals that sweep through the landscape is a phenomenon with large consequences in many ecosystems. It has been suggested that such migrations are mediated by resource depletion. Under this hypothesis it has been shown that simple foraging rules may generate density-dependent migratory waves (DDMW) in which the speed and amplitude increase with animal abundance. We tested these predictions on a 32-year data set of the spatial distribution of the two youngest age groups of a small pelagic schooling fish, the capelin (Mallotus villosus), by the end of their annual feeding migration in the Barents Sea. Our data suggest that the two age groups divided the Barents Sea by forming migratory waves that moved in opposite directions. The aggregation and spatial displacement of these waves increased with increasing age-specific abundance. However, possibly through social interactions, migratory pattern was modified by the abundance of the other age group.


Structural Transition States Explored With Minimalist Coarse Grained Models: Applications to Calmodulin.
Transitions between different conformational states are ubiquitous in proteins, being involved in signaling, catalysis, and other fundamental activities in cells. However, modeling those processes is extremely difficult, due to the need of efficiently exploring a vast conformational space in order to seek for the actual transition path for systems whose complexity is already high in the stable states. Here we report a strategy that simplifies this task attacking the complexity on several sides. We first apply a minimalist coarse-grained model to Calmodulin, based on an empirical force field with a partial structural bias, to explore the transition paths between the apo-closed state and the Ca-bound open state of the protein. We then select representative structures along the trajectory based on a structural clustering algorithm and build a cleaned-up trajectory with them. We finally compare this trajectory with that produced by the online tool MinActionPath, by minimizing the action integral using a harmonic network model, and with that obtained by the PROMPT morphing method, based on an optimal mass transportation-type approach including physical constraints. The comparison is performed both on the structural and energetic level, using the coarse-grained and the atomistic force fields upon reconstruction. Our analysis indicates that this method returns trajectories capable of exploring intermediate states with physical meaning, retaining a very low computational cost, which can allow systematic and extensive exploration of the multi-stable proteins transition pathways.


Color enhancement of nimbus high resolution infrared radiometer data.
Two examples of Nimbus high resolution infrared radiometer (HRIR) data processed by a color display enhancement system demonstrate possible meteorological, oceanographic, and geomorphological applications of this technique for geophysical research. A commonly used means of displaying radiation temperatures mapped by the HRIR has been a black and white photofacsimile film strip. However, the human eye can distinguish many more colors than shades of gray, and this characteristic permits an analyst to evaluate quantitatively radiation values mapped in color more readily than in black and white.


High prevalence of obstructive sleep apnea in pregnant women with class III obesity: a prospective cohort study.
To determine the prevalence of obstructive sleep apnea (OSA) in a cohort of women with class III obesity, and a comparator lean group, in the second and third trimesters of pregnancy. Secondary objectives were to compare characteristics of women with obesity with and without OSA and to assess factors that were predictive of OSA. We performed a prospective cohort study involving 33 women with class III obesity (mean body mass index 43.5 ± 3.9 kg/m2) and 39 lean women (body mass index 22.0 ± 1.7 kg/m2) with singleton pregnancies. Participants completed 2 level 3 sleep studies between 12-22 weeks and 32-38 weeks gestation. OSA was defined as a respiratory event index ≥ 5 events/h (≥ 3% desaturation criteria). Levels of interleukin-6, glucose, and C-peptide were quantified in maternal blood. Logistic regression analysis was performed to determine predictors of OSA. OSA was identified in 12 (37.5%) and 14 (50.0%) women with obesity and in 1 (2.6%) and 3 (9.1%) lean women in the second and third trimesters, respectively. Women with obesity with OSA were older than those with no OSA but otherwise had similar characteristics. In unadjusted analysis of women with obesity, increased age, body mass index, homeostatic model assessment of insulin resistance, and history of nonsmoking were associated with increased odds of OSA. In multivariable analysis, only increased age remained significantly associated with OSA. OSA is highly prevalent in pregnant women with class III obesity. Further research is required to establish effective management strategies for the growing number of women in this high-risk group. Johns EC, Hill EA, Williams S, et al. High prevalence of obstructive sleep apnea in pregnant women with class III obesity: a prospective cohort study. J Clin Sleep Med. 2022;18(2):423-432.


Integrating health promotion and occupational safety and health in manufacturing worksites: Perspectives of leaders in small-to-medium sized businesses.
Accumulating evidence suggests that worksite interventions integrating worksite health promotion (WHP) and occupational safety and health (OSH) may be more efficacious and have higher participation rates than health promotion programs offered alone. However, dissemination of integrated programs is complicated by lack of tools for implementation - particularly for small and medium-sized businesses (SMBs). The goal of this study is to describe perceptions of acceptability and feasibility of implementing an integrated approach to worker health that coordinates WHP and OSH in SMBs. In September to November 2012, decision-makers for employee health programming within SMBs (< 750 employees) in greater Minneapolis were identified. Fourteen semi-structured interviews were conducted and analyzed to develop an understanding of perceived benefits and barriers, awareness, and capacity for implementing an integrated approach. Worker health was widely valued by participants. They reported strong management support for improving employee health and safety. Most participants indicated that their company was open to making changes in their approach to worker health; however, cost and staffing considerations were frequently perceived as barriers. There are opportunities for implementing integrated worksite health programs in SMBs with existing resources and values. However, challenges to implementation exist, as these worksites may lack the appropriate resources.


A polymorphism in the regulatory region of PRNP is associated with increased risk of sporadic Creutzfeldt-Jakob disease.
Creutzfeldt-Jakob disease (CJD) is a rare transmissible neurodegenerative disorder. An important determinant for CJD risk and phenotype is the M129V polymorphism of the human prion protein gene (PRNP), but there are also other coding and non-coding polymorphisms inside this gene. We tested whether three non-coding polymorphism located inside the PRNP regulatory region (C-101G, G310C and T385C) were associated with risk of CJD and with age at onset in a United Kingdom population-based sample of 131 sporadic CJD (sCJD) patients and 194 controls. We found no disease association for either PRNP C-101G or PRNP T385C. Although the crude analysis did not show a significant association between PRNP G310C and sCJD (OR: 1.5; 95%CI = 0.7 to 2.9), after adjusting by PRNP M129V genotype, it resulted that being a C allele carrier at PRNP G310C was significantly (p = 0.03) associated with a 2.4 fold increased risk of developing sCJD (95%CI = 1.1 to 5.4). Additionally, haplotypes carrying PRNP 310C coupled with PRNP 129M were significantly overrepresented in patients (p = 0.02) compared to controls. Cases of sCJD carrying a PRNP 310C allele presented at a younger age (on average 8.9 years younger than those without this allele), which was of statistical significance (p = 0.05). As expected, methionine and valine homozygosity at PRNP M129V increased significantly the risk of sCJD, alone and adjusted by PRNP G310C (OR MM/MV = 7.3; 95%CI 3.9 to 13.5 and OR VV/MV = 4.0; 95%CI 1.7 to 9.3). Our findings support the hypothesis that genetic variations in the PRNP promoter may have a role in the pathogenesis of sCJD.


Australian experience of neuro-oncology care coordination: a conversation.
The role of care coordinator was introduced to support patients, caregivers, and healthcare professionals who work within a specialty, as well as to optimize and standardize care. Specifically, the role of neuro-oncology care coordinator is a developing one-and one that has encountered various barriers and difficulties. Patients diagnosed with neurologic cancer must endure a disease trajectory and multimodal treatment approach that present unique challenges to themselves and to the healthcare system. Consequently, the care coordinator role is needed. This article focuses on the role of the neuro-oncology care coordinator, including its challenges, the needs of patients with neurologic cancer, and the benefits this role can bring. Three neuro-oncology care coordinators from New South Wales, Australia, discussed their role in the healthcare system via structured meetings, conversations, and email correspondence. Making others aware of the issues faced by neuro-oncology care coordinators, as well as their patients, may help to solidify necessary supportive roles within the healthcare system.


Inter-polarization mixers for coherent detection of optical signals.
Electro-magnetic (EM) mixers are fundamental building blocks in communication systems. They are used in frequency/wavelength filters, interferometric modulators, amplitude-phase receivers, to name a few. Traditional EM mixers have two or more input ports and work only for co-polarized signal and local-oscillator (LO) incident on its inputs. Here we report on novel designs, in silicon, of inter-polarization EM mixers operating at 1550 nm wavelength. The 180-degree optical mixer comprising a single input port is demonstrated to coherently mix orthogonally polarized signal and LO. Using the proposed 180-degree mixer, we report on a novel design for a 90-degree optical mixer on silicon with small footprint, broadband response, low loss and good fabrication tolerance. It exploits birefringence of a waveguide to achieve broadband and fabrication-tolerant 90° phase difference between the signal/LO relative phase in the in-phase and quadrature components. A monolithic silicon photonics coherent receiver is demonstrated using the reported 90-degree mixer, and its operation at 22 Gbaud and 44 Gbaud is shown. These mixers pave the way for novel coherent receiver architectures in long-haul, metro, passive optical networks and data-center interconnect applications.