Developmental origins of type 2 diabetes: a perspective from China.
There has been a marked increase in the prevalence of diabetes in Asia, including China, over the last few decades. While the increased prevalence of diabetes has often been attributed to the nutritional transition associated with recent economic development, emerging data suggest that early-life exposures also play a major role in shaping developmental trajectories, and contributes to alter an individual's susceptibility to diabetes and other non-communicable diseases (NCDs). Early-life exposures such as in utero exposure to undernutrition has been consistently linked with later risk of diabetes and obesity. Furthermore, in utero exposure to maternal hyperglycemia, maternal obesity and excess gestational weight gain are all linked with increased childhood obesity and later risk of diabetes. Emerging data have also highlighted the potential link between early-feeding practices, the role of one-carbon metabolism in metabolic programming and endocrine disrupting chemicals (EDCs) with later risk of diabetes. These different developmental exposures may all be highly relevant to the current epidemic of diabetes in China. For example, the prevalence of gestational diabetes has increased markedly over the last two decades, and may contribute to the diabetes epidemic by driving macrosomia, childhood obesity and later risk of diabetes. In order to address the current burden of diabetes, a lifecourse perspective, incorporating multisectoral efforts from public health policy down to the individuals, will be needed. Several major initiatives have been launched in China as part of its national plans for NCD prevention and treatment, and the experience from these efforts would be invaluable.


Administration of a synthetic antiprotease reduces smoke-induced lung injury.
Our previous studies suggest that a neutrophil-mediated inflammatory injury causes a major fraction of the pulmonary edema that occurs after smoke inhalation. Because activated neutrophils extrude cytotoxic proteases, the current study was conducted to evaluate the role of proteases in the pulmonary microvascular injury. Twelve sheep, instrumented for collection of lung lymph, were insufflated with cotton smoke. The sheep were treated 30 min after smoke inhalation with either gabexate mesilate (an inhibitor of serine proteases) or vehicle. Smoke inhalation resulted in an increased protease activity in the lung interstitium, as evidenced by decreases in both antiprotease activity and immunoreactive alpha 2-macroglobulin. Intravenous infusion of gabexate mesilate prevented the decrease in antiprotease activity. The protease inhibitor significantly attenuated the smoke-induced increase in transvascular fluid and protein flux, with untreated animals exhibiting 460% increases in flux compared with 180% in the inhibitor treated sheep. The protease inhibitor also eliminated the functional degradation in gas exchange that was observed in the untreated sheep. These studies strongly suggest that an increase in pulmonary proteolytic enzyme activity is responsible for a significant fraction of the degradation in microvascular integrity and gas exchange that is associated with smoke inhalation injury.


Iso-oriented monolayer α-MoO3(010) films epitaxially grown on SrTiO3(001).
The ability to synthesize well-ordered two-dimensional materials under ultra-high vacuum and directly characterize them by other techniques in situ can greatly advance our current understanding on their physical and chemical properties. In this paper, we demonstrate that iso-oriented α-MoO3 films with as low as single monolayer thickness can be reproducibly grown on SrTiO3(001) substrates by molecular beam epitaxy ((010)(MoO3)‖(001)(STO), [100](MoO3)‖[100](STO) or [010](STO)) through a self-limiting process. While one in-plane lattice parameter of the MoO3 is very close to that of the SrTiO3 (a(MoO3) = 3.96 Å, a(STO) = 3.905 Å), the lattice mismatch along other direction is large (∼5%, c(MoO3) = 3.70 Å), which leads to relaxation as clearly observed from the splitting of streaks in reflection high-energy electron diffraction (RHEED) patterns. A narrow range in the growth temperature is found to be optimal for the growth of monolayer α-MoO3 films. Increasing deposition time will not lead to further increase in thickness, which is explained by a balance between deposition and thermal desorption due to the weak van der Waals force between α-MoO3 layers. Lowering growth temperature after the initial iso-oriented α-MoO3 monolayer leads to thicker α-MoO3(010) films with excellent crystallinity.


Skipping Breakfast and a Meal at School: Its Correlates in Adiposity Context. Report from the ABC of Healthy Eating Study of Polish Teenagers.
Little is known on skipping breakfast and a meal at school, especially considered together. The study identified nutrition knowledge-related, lifestyle (including diet quality, physical activity, and screen time) and socioeconomic correlates of skipping breakfast and a meal at school, considered together or alone and assessed the association of skipping these meals with adiposity markers in Polish teenagers. The sample consisted of 1566 fourth and fifth grade elementary school students (11-13 years). The study was designed as a cross-sectional study. Data related to the consumption of selected food items and meals, physical activity, screen time, sociodemographic factors, and nutrition knowledge (all self-reported) were collected (in 2015-2016) with a short form of a food frequency questionnaire. Respondents reported the usual consumption of breakfast (number of days/week) and a meal or any food eaten at school (number of school days/week) labelled as 'a meal at school'. The measurements of body weight, height, and waist circumference were taken. BMI-for-age ≥25 kg/m2 was considered as a marker of overweight/obesity (general adiposity), while waist-to-height ratio ≥0.5 as a marker of central obesity (central adiposity). A multivariate logistic regression was applied to verify the association between variables. A total of 17.4% of teenagers frequently skipped breakfast (4-7 days/week), 12.9% frequently skipped a meal at school (3-5 school days/week), while 43.6% skipped both of these meals a few times a week. Predictors of skipping breakfast and/or a meal at school were female gender, age over 12 years, urban residence, lower family affluence, lower nutrition knowledge, higher screen time, and lower physical activity. In comparison to "never-skippers," "frequent breakfast skippers" were more likely to be overweight/obese (odds ratio, OR 1.89; 95% confidence interval, 95%CI 1.38, 2.58) and centrally obese (OR 1.63; 95%CI 1.09, 2.44), while skippers a few times a week of both of these meals were more likely to be overweight/obese (OR 1.37; 95%CI 1.06, 1.78). Concluding, we estimated that a large percentage of Polish teenagers (approx. 44%) usually skipped both breakfast and a meal at school a few times a week. Similar predictors of skipping breakfast and predictors of skipping a meal at school were identified. Special attention should be paid to promoting shortening screen time and increasing physical activity and teenagers' nutrition knowledge which are relatively easily modifiable correlates. The study shows that skipping both of these meals a few times a week was associated with general adiposity and also strengthens previous evidence showing the association of frequent skipping breakfast with general and central adiposity.


Learning Trajectory Distributions for Assisted Teleoperation and Path Planning.
Several approaches have been proposed to assist humans in co-manipulation and teleoperation tasks given demonstrated trajectories. However, these approaches are not applicable when the demonstrations are suboptimal or when the generalization capabilities of the learned models cannot cope with the changes in the environment. Nevertheless, in real co-manipulation and teleoperation tasks, the original demonstrations will often be suboptimal and a learning system must be able to cope with new situations. This paper presents a reinforcement learning algorithm that can be applied to such problems. The proposed algorithm is initialized with a probability distribution of demonstrated trajectories and is based on the concept of relevance functions. We show in this paper how the relevance of trajectory parameters to optimization objectives is connected with the concept of Pearson correlation. First, we demonstrate the efficacy of our algorithm by addressing the assisted teleoperation of an object in a static virtual environment. Afterward, we extend this algorithm to deal with dynamic environments by utilizing Gaussian Process regression. The full framework is applied to make a point particle and a 7-DoF robot arm autonomously adapt their movements to changes in the environment as well as to assist the teleoperation of a 7-DoF robot arm in a dynamic environment.


Improvement of two-dimensional image quality in coherent optical systems.
When coherent light is used for imaging transparent objects, the images may be inferior because of Fresnel diffraction patterns from scattered light or may be degraded by granularity from diffuse illumination. This paper proposes a technique for improving image quality by using a spatially phase-modulated wavefront to illuminate the object. Analysis shows that the resulting image should be free from Fresnel diffraction patterns and should have a negligible amount of residual granularity. Experimental results verify these conclusions. Requirements of the imaging system and the wavefront are discussed. The technique is applicable to any nondiffuse, two-dimensional object and can be used in holography or with any other coherent imaging system.


The interleukin-1 cluster, dyslipidaemia and risk of myocardial infarction.
Coronary heart disease (CHD) is among the most serious worldwide health problems. Recent genetic studies have robustly identified a number of polymorphic loci throughout the genome that are associated with disease risk but it is certain that more remain to be discovered. It is well established that inflammation plays a key role in the pathophysiology of CHD. Determining whether or not polymorphisms in genes involved in the inflammatory cascade affect the risk of CHD is of considerable interest with respect to understanding the direction of the causal arrow between increased expression of inflammatory genes and CHD. Establishing an association between the variation in inflammatory genes and CHD would provide conceptual support for the use of appropriately specific anti-inflammatory agents in CHD prevention and, potentially, suggest new therapeutic targets. This month in BMC Medicine, Benjamin Brown and colleagues adopt a family-based case-control association study design to address this question. In a large number of CHD cases and healthy sibling controls genotyped for 51 mainly coding single nucleotide polymorphisms (SNPs), they find evidence for the association of a common haplotype at the Interleukin-1 (IL-1) cluster with CHD which appears to be stronger in younger cases without hypercholesterolaemia. They also find suggestive evidence for an association between this same haplotype and hypercholesterolaemia. If replicated in other cohorts, these results could be of substantial importance in advancing the understanding of the way in which inflammatory genes affect coronary heart disease risk.See the associated research paper by Brown et al: http://www.biomedcentral.com/1741-7015/8/5.


Epidemic gasoline exposures following Hurricane Sandy.
Major adverse climatic events (MACEs) in heavily-populated areas can inflict severe damage to infrastructure, disrupting essential municipal and commercial services. Compromised health care delivery systems and limited utilities such as electricity, heating, potable water, sanitation, and housing, place populations in disaster areas at risk of toxic exposures. Hurricane Sandy made landfall on October 29, 2012 and caused severe infrastructure damage in heavily-populated areas. The prolonged electrical outage and damage to oil refineries caused a gasoline shortage and rationing unseen in the USA since the 1970s. This study explored gasoline exposures and clinical outcomes in the aftermath of Hurricane Sandy. Prospectively collected, regional poison control center (PCC) data regarding gasoline exposure cases from October 29, 2012 (hurricane landfall) through November 28, 2012 were reviewed and compared to the previous four years. The trends of gasoline exposures, exposure type, severity of clinical outcome, and hospital referral rates were assessed. Two-hundred and eighty-three gasoline exposures were identified, representing an 18 to 283-fold increase over the previous four years. The leading exposure route was siphoning (53.4%). Men comprised 83.0% of exposures; 91.9% were older than 20 years of age. Of 273 home-based calls, 88.7% were managed on site. Asymptomatic exposures occurred in 61.5% of the cases. However, minor and moderate toxic effects occurred in 12.4% and 3.5% of cases, respectively. Gastrointestinal (24.4%) and pulmonary (8.4%) symptoms predominated. No major outcomes or deaths were reported. Hurricane Sandy significantly increased gasoline exposures. While the majority of exposures were managed at home with minimum clinical toxicity, some patients experienced more severe symptoms. Disaster plans should incorporate public health messaging and regional PCCs for public health promotion and toxicological surveillance.


Analysis and design of prisms using the derivatives of a ray. Part I: derivatives of a ray with respect to boundary variable vector.
A computational scheme based on differential geometry is proposed for determining the first- and second-order derivative matrices of a skew ray as it is reflected/refracted at a flat boundary surface. In the proposed approach, the position and orientation of the boundary surface in 3D space are described using just four variables. As a result, the proposed method is more computationally efficient than existing schemes based on all six variables. The derivative matrices enable the cross-coupling effects of the system variables on the exit ray to be fully understood. Furthermore, the proposed method provides a convenient means of determining the search direction used by existing gradient-based schemes to minimize the merit function during the optimization stage of the optical system design process. The validity of the proposed approach as an analysis and design tool is demonstrated using a corner-cube mirror and laser tracking system for illustration purposes.


Home-Applied Dual-Light Photodynamic Therapy in the Treatment of Stable Chronic Periodontitis (HOPE-CP)-Three-Month Interim Results.
A single-site, randomized clinical trial was designed to determine the efficacy of regular home use of Lumoral® dual-light antibacterial aPDT in periodontitis patients. For the study, 200 patients were randomized to receive non-surgical periodontal treatment (NSPT), including standardized hygiene instructions and electric toothbrush, scaling and root planing, or NSPT with adjunctive Lumoral® treatment. A complete clinical intraoral examination was conducted in the beginning, at three months, and at six months. This report presents the three-month results of the first 59 consecutive randomized subjects. At three months, bleeding on probing (BOP) was lower in the NSPT + Lumoral®-group than in the NSPT group (p = 0.045), and more patients in the NSPT + Lumoral®-group had their BOP below 10% (54% vs. 22%, respectively, p = 0.008). In addition, patients in the NSPT + Lumoral®-group improved their oral hygiene by visible-plaque-index (p = 0.0003), while the NSPT group showed no statistical improvement compared to the baseline. Both groups significantly reduced the number of deep periodontal pockets, but more patients with a reduction in their deep pocket number were found in the NSPT + Lumoral® group (92% vs. 63%, p = 0.02). Patients whose number of deep pockets was reduced by 50% or more were also more frequent in the NSPT + Lumoral®-group (71% vs. 33%, p = 0.01). Patients with initially less than ten deep pockets had fewer deep pockets at the three-month follow-up in the Lumoral® group (p = 0.01). In conclusion, adjunctive use of Lumoral® in NSPT results in improved treatment outcomes at three months post-therapy.


Biomaterial and implant induced ossification: in vitro and in vivo findings.
Material-induced ossification is suggested as a suitable approach to heal large bone defects. Fiber-reinforced composite-bioactive glasses (FRC-BGs) display properties that could enhance the ossification of calvarial defects. Here, we analyzed the healing processes of a FRC-BG implant in vivo from the perspective of material-induced ossification. Histological analysis of the implant, which was removed 5 months after insertion, showed the formation of viable, noninflammatory mesenchymal tissue with newly-formed mineralized woven bone, as well as nonmineralized connective tissue with capillaries and larger blood vessels. The presence of osteocytes was detected within the newly generated bone matrix. To expand our understanding on the osteogenic properties of FRC-BG, we cultured human adipose tissue-derived mesenchymal stromal cells (AD-MSCs) in the presence of two different BGs (45S5 and S53P4) and Al2 O3 control. AD-MSCs grew and proliferated on all the scaffolds tested, as well as secreted abundant extracellular matrix, when osteogenic differentiation was appropriately stimulated. 45S5 and S53P4 induced enhanced expression of COL2A1, COL10A1, COL5A1 collagen subunits, and pro-osteogenic genes BMP2 and BMP4. The concomitant downregulation of BMP3 was also detected. Our findings show that FRC-BG can support the vascularization of the implant and the formation of abundant connective tissue in vivo. Specifically, BG 45S5 and BG S53P4 are suited to evoke the osteogenic potential of host mesenchymal stromal cells. In conclusion, FRC-BG implant demonstrated material-induced ossification both in vitro and in vivo.


Melanocytes and pigmentation are affected in dopachrome tautomerase knockout mice.
The tyrosinase family comprises three members, tyrosinase (Tyr), tyrosinase-related protein 1 (Tyrp1), and dopachrome tautomerase (Dct). Null mutations and deletions at the Tyr and Tyrp1 loci are known and phenotypically affect coat color due to the absence of enzyme or intracellular mislocalization. At the Dct locus, three mutations are known that lead to pigmentation phenotype. However, these mutations are not null mutations, and we therefore set out to generate a null allele at the Dct gene locus by removing exon 1 of the mouse Dct gene. Mice deficient in Dct [Dct(tm1(Cre)Bee)] lack Dct mRNA and dopachrome tautomerase protein. They are viable and do not show any abnormalities in Dct-expressing sites such as skin, retinal pigment epithelium, or brain. However, the mice show a diluted coat color phenotype, which is due to reduced melanin content in hair. Primary melanocytes from Dct knockout mice are viable in culture and show a normal distribution of tyrosinase and tyrosinase-related protein 1. In comparison to the knockout, the slaty mutation (Dct(slt)/Dct(slt)) has less melanin and affects growth of primary melanocytes severely. In summary, we have generated a knockout of the Dct gene in mice with effects restricted to pigment production and coat color.


Predictive factors for the development of renal insufficiency following partial nephrectomy and subsequent renal function recovery: A multicenter retrospective study.
Patients who undergo partial nephrectomy (PN) may exhibit renal function insufficiency, and a subset of these patients achieves renal function recovery. We evaluated the predictors of renal insufficiency and subsequent renal function recovery following PN. Data on 393 patients who underwent PN for solid renal tumors between March 2001 and November 2013, obtained from 6 institutions, were retrospectively reviewed. Renal insufficiency was defined as new onset of chronic kidney disease stage ≥3 postoperatively on the second of 2 consecutive tests. Renal function recovery was defined as an estimated glomerular filtration rate ≥60 ml/minute/1.73 m following renal insufficiency. Tumor complexity was stratified according to the RENAL classification system. The median (interquartile range) age, tumor size, and follow-up period were 53 (45-63) years, 2.6 (1.9-3.8) cm, and 36 (12-48) months, respectively. Tumors were of low complexity in 258/393 (65.6%) of cases. Renal insufficiency developed in 54/393 (13.5%) patients, in which age ≥60 years and preoperative creatinine ≥1.1 mg/ml were independent predictors. Tumor complexity, clamp type, and operative method were not significant prognostic factors. Among patients with newly developed renal insufficiency, 18/54 (33.3%) patients exhibited renal function recovery within a median period of 18 months, of which preoperative creatinine <1.1 mg/ml was an independent predictor. Age ≥60 years and preoperative creatinine ≥1.1 mg/ml were risk factors for renal insufficiency following PN. Patients with renal insufficiency whose preoperative creatinine was <1.1 mg/ml were likely to have renal function recovery.


A review of quality of care evaluation for the palliation of dyspnea.
Assessment and management of dyspnea has emerged as a priority topic for quality evaluation and improvement. Evaluating dyspnea quality of care requires valid, reliable, and responsive measures of the care provided to patients across settings and diseases. As part of an Agency for Healthcare Research and Quality Symposium, we reviewed quality of care measures for dyspnea by compiling quality measures identified in systematic searches and reviews. Systematic reviews identified only three existing quality measurement sets that included quality measures for dyspnea care. The existing dyspnea quality measures reported by retrospective evaluations of care assess only four aspects: dyspnea assessment within 48 hours of hospital admission, use of objective scales to rate dyspnea severity, identification of management plans, and evidence of dyspnea reduction. To begin to improve care, clinicians need to assess and regularly document patient's experiences of dyspnea. There is no consensus on how dyspnea should be characterized for quality measurement, and although over 40 tools exist to assess dyspnea, no rating scale or instrument is ideal for palliative care. The panel recommended that dyspnea assessment should include a measure of intensity and some inquiry into the associated bother or distress experienced by the patient. A simple question into the presence or absence of dyspnea would be unlikely to help guide therapy, as complete relief of dyspnea in advanced disease would not be anticipated. Additional knowledge gaps include standards for clinical dyspnea care, assessment in the cognitively impaired, and evaluation of effectiveness of dyspnea care for patients with advanced disease.


Transport characteristics of mammalian Rh and Rh glycoproteins expressed in heterologous systems.
The development and use of heterologous expression systems is critical for deciphering the function of mammalian Rh and Rh-glycoproteins. The studies here use Xenopus oocytes, well known for their ability to readily traffic and express difficult membrane proteins, and S. cerevisiae wild-type strains and mutants that are defective in ammonium transport. Data obtained in both of these expression systems revealed that mammalian Rh-glycoprotein-mediated transport (RhAG, RhBG, and RhCG) is an electroneutral process that is driven by the NH4+ concentration and the transmembrane H+ gradient, effectively exchanging NH4+ for H+ in a process that results in transport of net NH3. Homology modeling and functional studies suggest that the more recently evolved erythrocyte blood group proteins, RhCE and RhD, may not function directly in ammonia transport and may be evolving a new function in the RBC membrane. The relationship of Rh and Rh-glycoproteins to the Amt/Mep ammonium transporters is substantiated with functional transport data and structural modeling.


Dietary protein-to-carbohydrate ratio and added sugar as determinants of excessive gestational weight gain: a prospective cohort study.
To examine the relation between the protein:carbohydrate (P/C) ratio and added sugar intake in pregnancy and gestational weight gain (GWG). A prebirth cohort including 103 119 pregnancies enrolled between 1996 and 2003. All women in Denmark were eligible to participate if they spoke Danish and were planning to carry to term.The pregnant women were recruited and enrolled during their first antenatal visit (6-10 weeks of gestation). Participants included women with live-born singletons and complete data on dietary intake and GWG, leaving 46 262 women for the analysis. Macronutrient intake was quantified using a validated food frequency questionnaire administered in the 25th week of gestation. The P/C ratio and added sugar intake were examined in quintiles. GWG was based on self-reported weight in gestational weeks 12 and 30 and defined as gain in g/week. We used multivariable linear regression, including adjusting for pre-pregnancy body mass index, to calculate relative change in GWG and 95% CI. Average GWG was 471(224) g/week. The adjusted weight gain was 16 g/week lower (95% CI 9 to 22, p for trend <0.001) in the highest (Q5) versus lowest (Q1) quintile of the P/C ratio (∼3% average reduction across the entire pregnancy). Weight gain for those with >20%E vs <12%E from protein was 36 g/week lower (95% CI 20 to 53, p for trend <0.0001; ∼8% average reduction). A high P/C ratio was inversely related to intake of added sugars. Added sugar consumption was strongly associated with GWG (Q5 vs Q1: 34, 95% CI 28 to 40 g/week, p for trend <0.0001). A high P/C ratio was associated with reduced GWG. This association appeared to be partly driven by a decrease in intake of added sugar. These results are consistent with randomised trials in non-pregnant participants. A dietary intervention targeting an increased P/C ratio with emphasis on reducing added sugar can contribute to reducing excessive GWG.


Haloarchaeobius iranensis gen. nov., sp. nov., an extremely halophilic archaeon isolated from a saline lake.
Strain EB21(T) was isolated from a brine sample from Aran-Bidgol salt lake, a saline playa in Iran. Strain EB21(T) was an orange-red-pigmented, motile rod and required at least 2 M NaCl but not MgCl(2) for growth. Optimal growth was achieved at 3.5 M NaCl and 0.2 M MgCl(2). The optimum pH and temperature for growth were pH 7.5 and 40 °C, while it was able to grow at pH 6.0-8.0 and 25-55 °C. Analysis of the 16S rRNA gene sequence revealed that strain EB21(T) is a member of the family Halobacteriaceae, showing low levels of similarity to other members of the family. The highest sequence similarities, 91.8, 91.7 and 91.5 %, were obtained with the 16S rRNA gene sequences of the type strains of Halobiforma lacisalsi, Haloterrigena thermotolerans and Halalkalicoccus tibetensis, respectively. Polar lipid analyses revealed that strain EB21(T) contains phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and phosphatidylglycerol sulfate. Three unidentified glycolipids and one minor phospholipid were also observed. The only quinone present was MK-8(II-H(2)). The G+C content of its DNA was 67.7 mol%. On the basis of the data obtained, the new isolate could not be classified in any recognized genus. Strain EB21(T) is thus considered to represent a novel species in a new genus within the family Halobacteriaceae, order Halobacteriales, for which the name Haloarchaeobius iranensis gen. nov., sp. nov. is proposed. The type strain of Haloarchaeobius iranensis is EB21(T) ( = IBRC-M 10013(T) = KCTC 4048(T)).


Mapping main, epistatic and sex-specific QTL for body composition in a chicken population divergently selected for low or high growth rate.
Delineating the genetic basis of body composition is important to agriculture and medicine. In addition, the incorporation of gene-gene interactions in the statistical model provides further insight into the genetic factors that underlie body composition traits. We used Bayesian model selection to comprehensively map main, epistatic and sex-specific QTL in an F2 reciprocal intercross between two chicken lines divergently selected for high or low growth rate. We identified 17 QTL with main effects across 13 chromosomes and several sex-specific and sex-antagonistic QTL for breast meat yield, thigh + drumstick yield and abdominal fatness. Different sets of QTL were found for both breast muscles [Pectoralis (P) major and P. minor], which suggests that they could be controlled by different regulatory mechanisms. Significant interactions of QTL by sex allowed detection of sex-specific and sex-antagonistic QTL for body composition and abdominal fat. We found several female-specific P. major QTL and sex-antagonistic P. minor and abdominal fatness QTL. Also, several QTL on different chromosomes interact with each other to affect body composition and abdominal fatness. The detection of main effects, epistasis and sex-dimorphic QTL suggest complex genetic regulation of somatic growth. An understanding of such regulatory mechanisms is key to mapping specific genes that underlie QTL controlling somatic growth in an avian model.


Genetic determinants of in vivo fitness and diet responsiveness in multiple human gut Bacteroides.
Libraries of tens of thousands of transposon mutants generated from each of four human gut Bacteroides strains, two representing the same species, were introduced simultaneously into gnotobiotic mice together with 11 other wild-type strains to generate a 15-member artificial human gut microbiota. Mice received one of two distinct diets monotonously, or both in different ordered sequences. Quantifying the abundance of mutants in different diet contexts allowed gene-level characterization of fitness determinants, niche, stability, and resilience and yielded a prebiotic (arabinoxylan) that allowed targeted manipulation of the community. The approach described is generalizable and should be useful for defining mechanisms critical for sustaining and/or approaches for deliberately reconfiguring the highly adaptive and durable relationship between the human gut microbiota and host in ways that promote wellness.


Immunobiology of gestational zinc deficiency.
The trace element zinc is an essential micronutrient for the proper functioning of the immune system. Zinc deficiency leads to impaired function of the unspecific and specific immune response and consequently to an increased susceptibility to bacterial, viral and fungal infections. Immunological defects are not only seen in pronounced but even in marginal and moderate zinc deficiency. Lack of zinc is especially harmful for the development of the immune system, which stresses the importance of a balanced zinc level during pregnancy. However, gestational zinc deficiency due to an imbalance between intake and increased requirements is a common problem world-wide. In animals, gestational zinc deficiency results in reduced thymic and spleen size and depressed active and passive immunity in the infant. For example, depressed immunoglobulin levels, altered antibody repertoire, reduced proliferative response of lymphocytes and diminished neutrophil functions have been reported. Interestingly, immune defects caused by prenatal zinc deficiency, such as depressed antibody levels and lymphocyte proliferation, may even persist in subsequent generations and are not reversible by postnatal zinc administration. Since gestational zinc deficiency is a common problem throughout all cultures and socioeconomic levels, it might have immense consequences for the health status of the population. Based on a summary of the immunobiology of zinc, this article reviews the significance of zinc deficiency during pregnancy and the effect of gestational zinc deficiency on passive and active immunity in the infant. It provides a rational basis for both immunological laboratory investigations and field studies, such as large community-based zinc supplementation trials in pregnant women.


Differences in the effects of selenite and biological selenium on the chemical form and distribution of mercury after the simultaneous administration of HgCl2 and selenium to rats.
The interaction was compared between inorganic (HgCl2) mercury and selenite (Na2SeO3) vs. the interaction between inorganic mercury and biological selenium (a freeze-dried preparation of liver from rats treated with selenite). Organ concentrations of selenium were always significantly lower after biological selenium than after selenite. Biological selenium affected the organ distribution of inorganic mercury differently than selenite. Furthermore, the speciation of mercury was affected by this form of selenium. A mercury-selenide compound (presumably HgSe) accounted for a greater proportion of total mercury in tissues after selenite than after a dose of biological selenium. Administration of selenomethionine had a similar effect on the speciation of mercury to that seen after biological selenium. As the forms of selenium in selenomethionine or selenium deposited in the liver are most likely nearer than selenite to selenium present in food, our results suggest that, as far as the reaction of mercury with selenide is concerned, experiments with selenite overestimate the protective effect of dietary selenium against inorganic mercury and possibly against methylmercury.


Bibliometric analysis of global migration health research in peer-reviewed literature (2000-2016).
The health of migrants has become an important issue in global health and foreign policy. Assessing the current status of research activity and identifying gaps in global migration health (GMH) is an important step in mapping the evidence-base and on advocating health needs of migrants and mobile populations. The aim of this study was to analyze globally published peer-reviewed literature in GMH. A bibliometric analysis methodology was used. The Scopus database was used to retrieve documents in peer-reviewed journals in GMH for the study period from 2000 to 2016. A group of experts in GMH developed the needed keywords and validated the final search strategy. The number of retrieved documents was 21,457. Approximately one third (6878; 32.1%) of the retrieved documents were published in the last three years of the study period. In total, 5451 (25.4%) documents were about refugees and asylum seekers, while 1328 (6.2%) were about migrant workers, 440 (2.1%) were about international students, 679 (3.2%) were about victims of human trafficking/smuggling, 26 (0.1%) were about patients' mobility across international borders, and the remaining documents were about unspecified categories of migrants. The majority of the retrieved documents (10,086; 47.0%) were in psychosocial and mental health domain, while 2945 (13.7%) documents were in infectious diseases, 6819 (31.8%) documents were in health policy and systems, 2759 (12.8%) documents were in maternal and reproductive health, and 1918 (8.9%) were in non-communicable diseases. The contribution of authors and institutions in Asian countries, Latin America, Africa, Middle East, and Eastern European countries was low. Literature in GMH represents the perspectives of high-income migrant destination countries. Our heat map of research output shows that despite the ever-growing prominence of human mobility across the globe, and Sustainable Development Goals of leaving no one behind, research output on migrants' health is not consistent with the global migration pattern. A stronger evidence base is needed to enable authorities to make evidence-informed decisions on migration health policy and practice. Research collaboration and networks should be encouraged to prioritize research in GMH.


Interleukin-6 gene promoter-572 C allele may play a role in rate of disease progression in multiple sclerosis.
Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system. Although the exact pathogenesis of MS is unknown, it is generally considered to be an autoimmune disease, with numerous genetic and environmental factors determining disease susceptibility and severity. One important mediator of immune responses and inflammation is interleukin-6 (IL-6). Previously, elevated levels of IL-6 in mononuclear cells in blood and in brain tissue from MS patients have been reported. Various polymorphisms in the promoter region of the IL6 gene have also been linked with IL-6 protein levels. In MS, several small studies have investigated whether two IL6 promoter polymorphisms (-597 G>A and -174 G>C) correlate with MS susceptibility, but with varying results. In the present study, we analyzed these polymorphisms, together with an additional polymorphism (-572 G>C) in 279 healthy controls and 509 patients with MS. We found no significant differences between MS patients and healthy controls for the different -597 or -174 IL6 promoter alleles or genotypes. There was a slight reduction in the percentage of individuals with MS who carried a C allele at position -572, although this was not significant after correction for multiple comparisons. Interestingly, however, the -572 C allele showed a significant correlation with the MS severity score, suggesting a possible role in disease progression.


Explaining the Gender Gap in the Caregiving Burden of Partner Caregivers.
We examine gender differences in the experienced burden of partner caregivers using the stress-appraisal model. Gender differences can be explained by differences in conditions of burden (primary stressors, help from others, hours of caregiving, and secondary stressors) and how strong their effects are. The data are from the Netherlands' Older Persons and Informal Caregivers Survey-Minimum Data Set (N = 1,611 caregivers). We examine mediation and moderation effects using structural equation modeling. Women experience greater partner caregiver burden than men, which is related to women experiencing more secondary stressors (relational and financial problems, problems combining different tasks). For women and men alike, there is a positive association between burden and more primary stressors (partner's care need indicated by health impairment), help from other caregivers, and secondary stressors. For male caregivers, caregiving intensity also contributes to a greater burden. This study corroborates the structural impact of gender on the conditions of as well as their effects on the partner caregiver burden. Reducing the hours of caregiving for male caregivers in severe care situations and helping female and male caregivers deal emotionally with the caregiving situation can reduce the partner caregiver burden.


Management of pediatric tachyarrhythmias on mechanical support.
Pediatric patients with persistent arrhythmias may require mechanical cardiopulmonary support. We sought to classify the population, spectrum, and success of current treatment strategies. A multicenter retrospective chart review was undertaken at 11 sites. Inclusion criteria were (1) patients <21 years, (2) initiation of mechanical support for a primary diagnosis of arrhythmias, and (3) actively treated on mechanical support. A total of 39 patients were identified with a median age of 5.5 months and median weight of 6 kg. A total of 69% of patients were cannulated for supraventricular tachycardia with a median rate of 230 beats per minute. A total of 90% of patients were supported with extracorporeal membrane oxygenation for an average of 5 days. The remaining 10% were supported with ventricular assist devices for an average of 38 (20-60) days. A total of 95% of patients were treated with antiarrhythmics, with 43% requiring >1 antiarrhythmic. Amiodarone was the most frequently used medication alone or in combination. A total of 33% patients underwent electrophysiology study/transcatheter ablation. Radiofrequency ablation was successful in 9 patients on full flow extracorporeal membrane oxygenation with 3 radiofrequency-failures/conversion to cryoablation. One patient underwent primary cryoablation. A total of 15% of complications were related to electrophysiology study/ablation. At follow-up, 23 patients were alive, 8 expired, and 8 transplanted. Younger patients were more likely to require support in the presented population. Most patients were treated with antiarrhythmics and one third required electrophysiology study/ablation. Radiofrequency ablation is feasible without altering extracorporeal membrane oxygenation flows. There was a low frequency of acute adverse events in patients undergoing electrophysiology study/ablation, while on extracorporeal membrane oxygenation.


The brain cytoplasmic RNA BC1 regulates dopamine D2 receptor-mediated transmission in the striatum.
Dopamine D(2) receptor (D(2)DR)-mediated transmission in the striatum is remarkably flexible, and changes in its efficacy have been heavily implicated in a variety of physiological and pathological conditions. Although receptor-associated proteins are clearly involved in specific forms of synaptic plasticity, the molecular mechanisms regulating the sensitivity of D(2) receptors in this brain area are essentially obscure. We have studied the physiological responses of the D(2)DR stimulations in mice lacking the brain cytoplasmic RNA BC1, a small noncoding dendritically localized RNA that is supposed to play a role in mRNA translation. We show that the efficiency of D(2)-mediated transmission regulating striatal GABA synapses is under the control of BC1 RNA, through a negative influence on D(2) receptor protein level affecting the functional pool of receptors. Ablation of the BC1 gene did not result in widespread dysregulation of synaptic transmission, because the sensitivity of cannabinoid CB(1) receptors was intact in the striatum of BC1 knock-out (KO) mice despite D(2) and CB(1) receptors mediated similar electrophysiological actions. Interestingly, the fragile X mental retardation protein FMRP, one of the multiple BC1 partners, is not involved in the BC1 effects on the D(2)-mediated transmission. Because D(2)DR mRNA is apparently equally translated in the BC1-KO and wild-type mice, whereas the protein level is higher in BC1-KO mice, we suggest that BC1 RNA controls D(2)DR indirectly, probably regulating translation of molecules involved in D(2)DR turnover and/or stability.


The use of solid-phase fluorescence spectroscopy in the characterisation of organic matter transformations.
Given its high sensitivity and non-destructive nature, fluorescence excitation-emission matrix (EEM) spectroscopy is widely used to differentiate changes and transformations of dissolved or water-extracted organic matter (OM) in natural environments. The same technique applied directly on solid samples (solid-phase fluorescence spectroscopy, SPF-EEM) provides accurate results when used with pharmaceutical products or food samples, but only a few studies have considered natural OM. This study reports on the use of SPF-EEM on solid compost samples and emphasises the way the different maturation phases can be distinguished with fluorophores closely resembling those found in dissolved samples. A very good correlation has been found with data from Rock-Eval pyrolysis, nuclear magnetic resonance ((13)C CPMAS NMR), and humic-fulvic acid ratios determined by conventional NaOH-extraction. SPF-EEM appears as a much simpler method than the conventional ones to detect transformations in natural OM samples with low mineral contents. However, direct application to soil samples requires some additional studies.


The neglected role of insulin-like growth factors in the maternal circulation regulating fetal growth.
Maternal insulin-like growth factors (IGFs) play a pivotal role in modulating fetal growth via their actions on both the mother and the placenta. Circulating IGFs influence maternal tissue growth and metabolism, thereby regulating nutrient availability for the growth of the conceptus. Maternal IGFs also regulate placental morphogenesis, substrate transport and hormone secretion, all of which influence fetal growth either via indirect effects on maternal substrate availability, or through direct effects on the placenta and its capacity to supply nutrients to the fetus. The extent to which IGFs influence the mother and/or placenta are dependent on the species and maternal factors, including age and nutrition. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing degenerative diseases in adult life, understanding the role of maternal IGFs during pregnancy is essential in order to identify mechanisms underlying altered fetal growth and offspring programming.


Craniofacial characteristics of fragile X syndrome in mouse and man.
For a disorder as common as fragile X syndrome, the most common hereditary form of cognitive impairment, the facial features are relatively ill defined. An elongated face and prominent ears are the most commonly accepted dysmorphic hallmarks. We analysed 3D facial photographs of 51 males and 15 females with full FMR1 mutations and 9 females with a premutation using dense-surface modelling techniques and a new technique that forms a directed graph with normalized face shapes as nodes and edges linking those with closest dysmorphism. In addition to reconfirming known features, we confirmed the occurrence of some at an earlier age than previously recorded. We also identified as yet unrecorded facial characteristics such as reduced facial depth, hypoplasticity of the nasal bone-cartilage interface and narrow mid-facial width exaggerating ear prominence. As no consistent craniofacial abnormalities had been reported in animal models, we analysed micro-CT images of the fragile X mouse model. Results indicated altered dimensions in the mandible and both outer and inner skull, with the latter potentially reflecting differences in neuroanatomy. We extrapolated the mouse results to face shape differences of the human fragile X face.


RGD-QD-MoS2 nanosheets for targeted fluorescent imaging and photothermal therapy of cancer.
The fast-developing field of nanotechnology provides unprecedented opportunities for the increasing demands of biomedicine, especially for cancer diagnostics and treatment. Here, novel multifunctional zero-dimensional-two-dimensional (0D-2D) RGD-QD-MoS2 nanosheets (NSs) with excellent fluorescence, photothermal conversion, and cancer-targeting properties were successfully prepared by functionalizing single-layer MoS2 NSs with fluorescent quantum dots (QDs) and arginine-glycine-aspartic (RGD) containing peptides. By using RGD-QD-MoS2 NSs as a multifunctional theranostic agent, targeted fluorescent imaging and photothermal therapy (PTT) of human cervical carcinoma (HeLa) cells were achieved. Moreover, HeLa tumors in mouse models can be fluorescently imaged and completely eradicated by photothermal irradiation using a low power NIR laser, due to the effective accumulation of RGD-QD-MoS2 NSs at the tumor sites through the RGD-integrin targeting and the enhanced penetration and retention (EPR) effect. Without exhibiting any appreciable toxicity to treated cells or animals, RGD-QD-MoS2 NSs have been demonstrated as promising multifunctional theranostic agents for cancer imaging and therapy.


Exploring functional cyclophellitol analogues as human retaining beta-glucosidase inhibitors.
The natural product, cyclophellitol and its aziridine analogue are potent mechanism-based retaining β-glucosidase inhibitors. In this paper we explore the inhibitory potency of a number of cyclophellitol analogues against the three human retaining β-glucosidases, GBA, GBA2 and GBA3. We demonstrate that N-alkyl cyclophellitol aziridine is at least equally potent in inhibiting the enzymes evaluated as its N-acyl congener, whereas the N-sulfonyl analogue is a considerably weaker inhibitor. Our results complement the literature on the inhibitory potency of cyclophellitol analogues and hold promise for the future design of more effective activity-based retaining glycosidase probes with respect to probe stability in physiological media.


Combining longitudinal studies showed prevalence of disease differed throughout older adulthood.
Disease prevalence rates are often generalized across the older adult age range. By pooling self-reported health data from five Australian longitudinal studies of aging, we were able to present disease prevalence rates by 5-year age bands and sex. We also investigated the influence of education on prevalence at each age range and compared our observed prevalence rates with those from the 2001 National Health Survey (NHS) to see if existing data could be used to augment national estimates. We used data on 12,718 adults between 60 and 105 years of age from the Dynamic Analyses to Optimise Ageing (DYNOPTA) project. Hypertension and arthritis were the most prevalent diseases, with approximately 30% of males and 45% of females having either condition. Nearly all diseases were most prevalent amongst older adults in their 70s and lower for individuals in their 60s, and 80s and older. The effect of education varied by disease and older age group. Prevalence rates from DYNOPTA were generally similar to those reported by the NHS. Disease prevalence is not consistent across older adulthood. Combining longitudinal studies provided a sufficient sample to estimate precise age divisions and can be used to supplement national estimates for specific populations.


The process, outcomes, and challenges of feasibility studies conducted in partnership with stakeholders: a health intervention for women survivors of intimate partner violence.
Feasibility studies play a crucial role in determining whether complex, community-based interventions should be subject to efficacy testing. Reports of such studies often focus on efficacy potential but less often examine other elements of feasibility, such as acceptance by clients and professionals, practicality, and system integration, which are critical to decisions for proceeding with controlled efficacy testing. Although stakeholder partnership in feasibility studies is widely suggested to facilitate the research process, strengthen relevance, and increase knowledge transfer, little is written about how this occurs or its consequences and outcomes. We began to address these gaps in knowledge in a feasibility study of a health intervention for women survivors of intimate partner violence (IPV) conducted in partnership with policy, community and practitioner stakeholders. We employed a mixed-method design, combining a single-group, pre-post intervention study with 52 survivors of IPV, of whom 42 completed data collection, with chart review data and interviews of 18 purposefully sampled participants and all 9 interventionists. We assessed intervention feasibility in terms of acceptability, demand, practicality, implementation, adaptation, integration, and efficacy potential. Our findings demonstrate the scope of knowledge attainable when diverse elements of feasibility are considered, as well as the benefits and challenges of partnership. The implications of diverse perspectives on knowledge transfer are discussed. Our findings show the importance of examining elements of feasibility for complex community-based health interventions as a basis for determining whether controlled intervention efficacy testing is justified and for refining both the intervention and the research design.


Rheum palmatum extract exerts anti-hepatocellular carcinoma effects by inhibiting signal transducer and activator of transcription 3 signaling.
Hepatocellular carcinoma (HCC) is among the most common malignancies. Signal transducer and activator of transcription 3 (STAT3), with abnormal expression and constitutive activation, has been reported to promote proliferation, metastasis, survival and angiogenesis of HCC cells. Rheum palmatum (RP), a traditional Chinese medicinal herb, exhibited tumor-suppressing effects in multiple human cancers, but its potential functions in HCC remain unexplored. This study aimed to examine the involvement of STAT3 signaling in the anti-HCC effects of RP extract. SMMC-7721 and HepG2 HCC cell lines were treated with RP extract for 24 h, and then viability, migration, and invasion of HCC cells and angiogenesis of human umbilical vein endothelial cells (HUVECs) were analyzed using MTS, wound-healing, Transwell invasion and tube formation assays, respectively. Western blotting and immunohistochemistry (IHC) were used to examine the activation of key molecules in STAT3 signaling, including STAT3, JAK2, and Src. Additionally, we explored the in vivo antitumor effects of RP extract in a xenograft tumor nude mouse model of HCC. The result showed that RP extract reduced viability, migration, and invasion of SMMC-7721 and HepG2 cells and angiogenesis of HUVECs. It suppressed the phosphorylation of STAT3 and its upstream kinases including JAK2 and Src. In addition, RP extract treatment downregulated STAT3 target genes, including survivin, Bcl-xL, Mcl-1, Bcl-2, MMP-2, MMP-9, Cyclin D1, CDK4, c-Myc, and VEGF-C. Furthermore, RP extract suppressed the xenograft tumor growth and activation of STAT3 in xenograft tumor mice. Collectively, the results showed that RP extract prevented HCC progression by inhibiting STAT3, and might be useful for the treatment of HCC.


Gene expression variation in the adult human retina.
Despite evidence that differences in gene expression levels contribute significantly to phenotypic variation across individuals, there has been only limited effort to study gene expression variation in human tissue. To characterize expression variation in the normal human retina, we utilized a custom retinal microarray to analyze 33 normal retinas from 19 donors, aged 29-90 years. Statistical models were designed to separate and quantify biological and technical sources of variation, including age, gender, eye laterality, gene function and age-by-gender interaction. Although the majority of the 9406 genes analyzed showed relatively stable expression levels across different donors (for an average gene the expression level value of 95 out of a 100 individuals fell within a 1.23-fold range), 2.6% of genes showed significant donor-to-donor variation, with a false discovery rate of 10%. The mean expression ratio standard deviation was 0.15+/-0.8, log2, with a range of 0.09-0.99. Genes selectively expressed in photoreceptors showed higher expression variation than other gene classes. Gender, age and other donor-specific factors contributed significantly to the expression variation of multiple genes, and groups of genes with an age- and gender-associated expression pattern were identified. Our findings show that a significant fraction of gene expression variation in the normal human retina is attributable to identifiable biological factors. The greater expression variability of many genes central to retinal function (including photoreceptor-specific genes) may be partially explained by the dynamics of the vision process, and raises the possibility that photoreceptor gene expression levels may contribute to phenotypic diversity across normal adult retinas. In addition, as such diversity may result in different levels of disease susceptibility, exploring its sources may provide insights into the pathogenesis of retinal disease.


The effect of volume-of-interest misregistration on quantitative planar activity and dose estimation.
In targeted radionuclide therapy (TRT), dose estimation is essential for treatment planning and tumor dose response studies. Dose estimates are typically based on a time series of whole-body conjugate view planar or SPECT scans of the patient acquired after administration of a planning dose. Quantifying the activity in the organs from these studies is an essential part of dose estimation. The quantitative planar (QPlanar) processing method involves accurate compensation for image degrading factors and correction for organ and background overlap via the combination of computational models of the image formation process and 3D volumes of interest defining the organs to be quantified. When the organ VOIs are accurately defined, the method intrinsically compensates for attenuation, scatter and partial volume effects, as well as overlap with other organs and the background. However, alignment between the 3D organ volume of interest (VOIs) used in QPlanar processing and the true organ projections in the planar images is required. The aim of this research was to study the effects of VOI misregistration on the accuracy and precision of organ activity estimates obtained using the QPlanar method. In this work, we modeled the degree of residual misregistration that would be expected after an automated registration procedure by randomly misaligning 3D SPECT/CT images, from which the VOI information was derived, and planar images. Mutual information-based image registration was used to align the realistic simulated 3D SPECT images with the 2D planar images. The residual image misregistration was used to simulate realistic levels of misregistration and allow investigation of the effects of misregistration on the accuracy and precision of the QPlanar method. We observed that accurate registration is especially important for small organs or ones with low activity concentrations compared to neighboring organs. In addition, residual misregistration gave rise to a loss of precision in the activity estimates that was on the order of the loss of precision due to Poisson noise in the projection data. These results serve as a lower bound on the effects of misregistration on the accuracy and precision of QPlanar activity estimate and demonstrate that misregistration errors must be taken into account when assessing the overall precision of organ dose estimates.


HAART receipt and viral suppression among HIV-infected patients with co-occurring mental illness and illicit drug use.
Mental illness (MI) and illicit drug use (DU) frequently co-occur. We sought to determine the individual and combined effects of MI and DU on highly active antiretroviral therapy (HAART) receipt and HIV-RNA suppression among individuals engaged in HIV care. Using 2004 data from the HIV Research Network (HIVRN), we performed a cross-sectional study of HIV-infected patients followed at seven primary care sites. Outcomes of interest were HAART receipt and virological suppression, defined as an HIV-RNA <400 copies/ml. Independent variables of interest were: (1) MI/DU; (2) DU only; (3) MI only; and (4) Neither. We used chi-squared analysis for comparison of categorical variables, and logistic regression to adjust for age, race, sex, frequency of outpatient visits, years in clinical care, CD4 nadir, and study site. During 2004, 10,284 individuals in the HIVRN were either on HAART or HAART eligible defined as a CD4 cell count < or =350. Nearly half had neither MI nor DU (41%), 22% MI only, 15% DU only, and 22% both MI and DU. In multivariate analysis, co-occurring MI/DU was associated with the lowest odds of HAART receipt (Adjusted Odds Ratio: 0.63 (95% CI: (0.55-0.72]), followed by those with DU only (0.75(0.63-0.87)), compared to those with neither. Among those on HAART, concurrent MI/DU (0.66 (0.58-0.75)), DU only (0.77 (0.67-0.88)), were also associated with a decreased odds of HIV-RNA suppression compared to those with neither. MI only was not associated with a statistically significant decrease in HAART receipt (0.93(0.81-1.07)) or viral suppression (0.93 (0.82-1.05)) compared to those with neither. Post-estimation testing revealed a significant difference between those with MI/DU and DU only, and MI/DU and MI only. Co-occurring MI and DU is associated with lower HAART receipt and viral suppression compared to individuals with either MI or DU or neither. Integrating HIV, substance abuse, and mental healthcare may improve outcomes in this population.


Association between frequency of primary care provider visits and evidence-based statin prescribing and statin adherence: Findings from the Veterans Affairs system.
Statin use remains suboptimal in patients with atherosclerotic cardiovascular disease (ASCVD). We assessed if the frequency of visits with primary care providers (PCPs) is associated with higher use of evidence-based statin prescriptions and adherence among patients with ASCVD. We identified patients with ASCVD aged ≥18 years receiving care in 130 facilities and associated community-based outpatient clinics in the entire Veterans Affairs Health Care System between October 1, 2013 and September 30, 2014. Patients were divided into frequent PCP visitors (annual PCP visits ≥ median number of PCP visits for the entire cohort) and infrequent PCP visitors (annual PCP visits < median number of patient visits). We assessed any- and high-intensity statin prescription as well as statin adherence which was defined by proportion of days covered (PDC). We included 1,249,061 patients with ASCVD (mean age was 71.9 years; 98.0% male). Median number of annual PCP visits was 3. Approximately 80.1% patients were on statins with 23.8% on high-intensity statins. Mean PDC was 0.715 ± 0.336 with 58.3% patients with PDC ≥0.8. Frequent PCP visitors had higher frequency of statin use (82.2% vs 77.4%), high-intensity statin use (26.4% vs 20.3%), and statin adherence (mean PDC 0.73 vs 0.68; P < .01) compared to infrequent PCP visitors. After adjusting for covariates, frequent PCP visits was associated with greater odds of being on any statin, high intensity statin, and higher statin adherence. Frequent visits with PCPs is associated with a higher likelihood of any statin use, high intensity statin use, and statin adherence. Further research endeavors are needed to understand the reasons behind these associations.


Health related quality of life of people with non-epileptic seizures: The role of socio-demographic characteristics and stigma.
People with non-epileptic seizures (NES) consistently report poorer Health-Related Quality of Life (HRQoL) than people with epilepsy. Yet, unlike in epilepsy, knowledge of how social factors influence the HRQoL of adults with NES is limited. To add to the evidence base, this study explores the relationship between HRQoL and perceived stigma among adults with NES, and the role of socio-demographic characteristics. Data was gathered from a survey of 115 people living with the condition, recruited from online support groups. Participants provided socio-demographic and health-related data and completed a series of questions investigating their HRQoL (QOLIE-31) and stigma perceptions (10-item Epilepsy Stigma Scale). Participants were found to experience high levels of perceived stigma (median 5.2, mean 4.9). A significant and moderate inverse correlation was observed between HRQoL and stigma (rs - 0.474, p = < 0.001); suggesting higher perceptions of stigma contribute to poorer HRQoL among adults with NES. Stigma perceptions were found to be most strongly associated with the seizure worry (rs = - 0.479), emotional wellbeing (rs = - 0.421), and social functioning (rs = 0.407) HRQoL domains. Participants who reported being in employment or education were found to have significantly better HRQoL than those who were not (p = < 0.001). More (qualitative and quantitative) research is justified to understand how - and why - those with the condition experience stigmatisation, and the factors that impede and help facilitate the participation of people with NES in education and employment.


Adolescent environmental tobacco smoke exposure predicts academic achievement test failure.
Research has linked prenatal tobacco exposure to neurocognitive and behavioral problems that can disrupt learning and school performance in childhood. Less is known about its effects on academic achievement in adolescence when controlling for known confounding factors (e.g., environmental tobacco smoke [ETS]). We hypothesized that prenatal tobacco exposure would decrease the likelihood of passing academic achievement tests taken at 16 and 18 years of age. This study was a longitudinal analysis of birth cohort data including 6,380 pregnant women and offspring from the 1958 National Child Development Study (NCDS). Academic pass/fail performance was measured on British standardized achievement tests ("Ordinary Level" [O-Level] and Advanced Level: [A-Level]). Prenatal tobacco exposure plus controlling variables (ETS, teen offspring smoking and gender, maternal age at pregnancy, maternal smoking before pregnancy, and socioeconomic status) were included in regression models predicting O- and A-Level test failure. Significant predictors of test failure in the O-Level model included exposure to maternal (OR = 0.71, p < .0001) and paternal (OR = 0.70, p < .0001) ETS, as well as teen smoking, female gender, and lower SES. Prenatal tobacco exposure did not influence failure. Similar factors emerged in the A-Level model except that male gender contributed to likelihood of failure. Prenatal exposure remained nonsignificant. Our model suggests that adolescent exposure to ETS, not prenatal tobacco exposure, predicted failure on both O- and A-Level achievement tests when controlling for other factors known to influence achievement. Although this study has limitations, results bolster growing evidence of academic-related ETS consequences in adolescence.


Environmental determinants of active travel in youth: a review and framework for future research.
Many youth fail to meet the recommended guidelines for physical activity. Walking and cycling, forms of active travel, have the potential to contribute significantly towards overall physical activity levels. Recent research examining the associations between physical activity and the environment has shown that environmental factors play a role in determining behaviour in children and adolescents. However, links between the environment and active travel have received less attention. Twenty four studies were identified which examined the associations between the environment (perceived or objectively measured) and active travel among youth aged 5-18 years. Findings were categorised according to the location of the environmental measure examined; attributes of the neighbourhood, destination and the route between home and destination. Results from the reviewed studies indicated that youth active travel is positively associated with social interactions, facilities to assist active travel and urban form in the neighbourhood as well as shorter route length and road safety en-route. A conceptual framework is presented which highlights the associations between active travel behaviours and environmental factors, drawing upon both existing and hypothesised relationships. We provide a review of the available literature and present a novel theoretical framework that integrates the environment into the wider decision making process around travel choices for children and adolescents. Further work should explore associations where gaps in understanding have been identified, and account for the main moderators of behaviour so hypothesised associations can be confirmed.


Uncovering the Role of p38 Family Members in Adipose Tissue Physiology.
The complex functions of adipose tissue have been a focus of research interest over the past twenty years. Adipose tissue is not only the main energy storage depot, but also one of the largest endocrine organs in the body and carries out crucial metabolic functions. Moreover, brown and beige adipose depots are major sites of energy expenditure through the activation of adaptive, non-shivering thermogenesis. In recent years, numerous signaling molecules and pathways have emerged as critical regulators of adipose tissue, in both homeostasis and obesity-related disease. Among the best characterized are members of the p38 kinase family. The activity of these kinases has emerged as a key contributor to the biology of the white and brown adipose tissues, and their modulation could provide new therapeutic approaches against obesity. Here, we give an overview of the roles of the distinct p38 family members in adipose tissue, focusing on their actions in adipogenesis, thermogenic activity, and secretory function.


Ketamine and rapid-acting antidepressants: a new era in the battle against depression and suicide.
Therapeutic medications for the treatment of depression have serious limitations, particularly delayed onset and low rates of efficacy. However, the discovery that a single subanesthetic dose of ketamine, a glutamate NMDA receptor channel blocker, can produce a rapid (within hours) antidepressant response that is sustained (about 1 week), even in patients considered treatment-resistant, has invigorated the field. In addition to these remarkable actions, ketamine has proven effective for the treatment of suicidal ideation. Efforts are under way to develop ketamine-like drugs with fewer side effects as well as agents that act at other sites within the glutamate neurotransmitter system. This includes ketamine metabolites and stereoisomers, drugs that act as NMDA allosteric modulators or that block mGluR2/3 autoreceptors. In addition, targets that enhance glutamate neurotransmission or synaptic function (or both), which are essential for the rapid and sustained antidepressant actions of ketamine in rodent models, are being investigated; examples are the muscarinic cholinergic antagonist scopolamine and activators of mechanistic target of rapamycin complex 1 (mTORC1) signaling, which is required for the actions of ketamine. The discovery of ketamine and its unique mechanisms heralds a new era with tremendous promise for the development of novel, rapid, and efficacious antidepressant medications.


Comparison of the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology Systemic Lupus Erythematosus Classification Criteria With Two Sets of Earlier Systemic Lupus Erythematosus Classification Criteria.
The Systemic Lupus International Collaborating Clinics (SLICC) 2012 systemic lupus erythematosus (SLE) classification criteria and the revised American College of Rheumatology (ACR) 1997 criteria are list based, counting each SLE manifestation equally. We derived a classification rule based on giving variable weights to the SLICC criteria and compared its performance to the revised ACR 1997, the unweighted SLICC 2012, and the newly reported European Alliance of Associations for Rheumatology (EULAR)/ACR 2019 criteria sets. The physician-rated patient scenarios used to develop the SLICC 2012 classification criteria were reemployed to devise a new weighted classification rule using multiple linear regression. The performance of the rule was evaluated on an independent set of expert-diagnosed patient scenarios and compared to the performance of the previously reported classification rules. The weighted SLICC criteria and the EULAR/ACR 2019 criteria had less sensitivity but better specificity compared to the list-based revised ACR 1997 and SLICC 2012 classification criteria. There were no statistically significant differences between any pair of rules with respect to overall agreement with the physician diagnosis. The 2 new weighted classification rules did not perform better than the existing list-based rules in terms of overall agreement on a data set originally generated to assess the SLICC criteria. Given the added complexity of summing weights, researchers may prefer the unweighted SLICC criteria. However, the performance of a classification rule will always depend on the populations from which the cases and non-cases are derived and whether the goal is to prioritize sensitivity or specificity.


Optimizing sgRNA position markedly improves the efficiency of CRISPR/dCas9-mediated transcriptional repression.
CRISPR interference (CRISPRi) represents a newly developed tool for targeted gene repression. It has great application potential for studying gene function and mapping gene regulatory elements. However, the optimal parameters for efficient single guide RNA (sgRNA) design for CRISPRi are not fully defined. In this study, we systematically assessed how sgRNA position affects the efficiency of CRISPRi in human cells. We analyzed 155 sgRNAs targeting 41 genes and found that CRISPRi efficiency relies heavily on the precise recruitment of the effector complex to the target gene transcription start site (TSS). Importantly, we demonstrate that the FANTOM5/CAGE promoter atlas represents the most reliable source of TSS annotations for this purpose. We also show that the proximity to the FANTOM5/CAGE-defined TSS predicts sgRNA functionality on a genome-wide scale. Moreover, we found that once the correct TSS is identified, CRISPRi efficiency can be further improved by considering sgRNA sequence preferences. Lastly, we demonstrate that CRISPRi sgRNA functionality largely depends on the chromatin accessibility of a target site, with high efficiency focused in the regions of open chromatin. In summary, our work provides a framework for efficient CRISPRi assay design based on functionally defined TSSs and features of the target site chromatin.


A numerical simulation of flow in a two-dimensional end-to-side anastomosis model.
In order to understand the possible role that hemodynamic factors may play in the pathogenesis of distal anastomotic intimal hyperplasia, we carried out numerical simulations of the flow field within a two-dimensional 45 degree rigid-walled end-to-side model anastomosis. The numerical code was tested and compared with experimental (photochromic dye tracer) studies using steady and near-sinusoidal waveforms, and agreement was generally very good. Using a normal human superficial femoral artery waveform, numerical simulations indicated elevated instantaneous wall shear stress magnitudes at the toe and heel of the graft-host junction and along the host artery bed. These sites also experienced highly variable wall shear stress behavior over the cardiac cycle, as well as elevated spatial gradients of wall shear stress. These observations provide additional evidence that intimal hyperplasia may be correlated to wall shear stresses over the cardiac cycle, high wall shear stress gradients, or a combination of the three. The limitations of the present work (especially in regard to the two-dimensional nature of the flow simulations) are discussed, and results are compared to previous observations about distal anastomotic intimal hyperplasia.


Communicable diseases in the South-East Asia Region of the World Health Organization: towards a more effective response.
This article looks at the current burden of communicable diseases in the South-East Asia Region of the World Health Organization and analyses whether the current levels and trends in funding are adequate to meet the needs of control, prevention and treatment. Our analysis considers the Millennium Development Goals (MDGs) for health and indicators of economic progress in each country, as well as the impact of the global financial crisis on progress towards MDGs for communicable diseases in the region. The analysis indicates that the current focus of funding may need to be expanded to include less-discussed but high-burden diseases often related to inadequacies in the health sector and the particular development paths that countries pursue. Scarce funding during times of global economic recession could be used more effectively if informed by a careful analysis of the complex set of factors, including behavioural, environmental and health systems factors, that determine the burden of communicable diseases. Significant gaps in funding as well as varying regional needs warrant a more diverse set of national and international aid measures. Although regional and global collaboration is critical, the effectiveness of future policies to deal with the burden of communicable diseases in the region will only be assured if these policies are based on evidence and developed by policy-makers familiar with each country's needs and priorities.


A checklist for evaluating the methodological quality of validation studies on self-report instruments for physical activity and sedentary behavior.
The quality of methodological papers assessing physical activity instruments depends upon the rigor of a study's design. We present a checklist to assess key criteria for instrument validation studies. A Medline/PubMed search was performed to identify guidelines for evaluating the methodological quality of instrument validation studies. Based upon the literature, a pilot version of a checklist was developed consisting of 21 items with 3 subscales: 1) quality of the reported data (9 items: assess whether the reported information is sufficient to make an unbiased assessment of the findings); 2) external validity of the results (3 items: assess the extent to which the findings are generalizable); 3) internal validity of the study (9 items: assess the rigor of the study design). The checklist was tested for interrater reliability and feasibility with 6 raters. Raters viewed the checklist as helpful for reviewing studies. They suggested minor wording changes for 8 items to clarify intent. One item was divided into 2 items for a total of 22 items. Checklists may be useful to assess the quality of studies designed to validate physical activity instruments. Future research should test checklist internal consistency, test-retest reliability, and criterion validity.


Coherent cortical and muscle discharge in cortical myoclonus.
There is increasing evidence in man that the cortical drive to motor neurons is rhythmic. This oscillatory drive may be exaggerated in patients with cortical myoclonus. Spectral analysis of surface bipolar EEG and EMG activity was performed in eight such patients. Only three cases had evidence of giant cortical evoked potentials or a cortical correlate on back-averaging at the time of study. In six subjects, significant coherence between contralateral and vertex EEG and EMG was observed in ranges similar to that previously reported for normal subjects (15-30 and 30-60 Hz). Three out of these six subjects also had significant coherence at higher frequencies (up to 175 Hz). All eight patients had a correlate in the cumulant density estimate between EEG and contralateral EMG. EMG lagged EEG by about 14, 25 and 35 ms for the muscles of the forearm, hand and foot, respectively. These delays were estimated from the slope of the phase curves and the timing of the peaks in the cumulant density estimates, and are appropriate for conduction in fast pyramidal pathways. The results provide clear evidence of a cortical drive synchronizing muscle discharge over a broad range of frequencies in patients with cortical myoclonus. Fourier analysis is a promising technique in the diagnosis and investigation of such patients.


Nickel carcinogenesis: epigenetics and hypoxia signaling.
Both water soluble and insoluble nickel compounds have been implicated in the etiology of human lung and nasal cancers. Water insoluble nickel compounds have been shown to enter cells by phagocytosis and are contained in cytoplasmic vacuoles, which are acidified thus accelerating the dissolution of soluble nickel from the particles. Using Newport Green, a dye that fluoresces when ionic nickel is bound, we have shown that following exposure (48-72 h) of human lung (A549) cells to NiS particles, most of the nickel is contained in the nucleus, while cells exposed to soluble NiCl2 exhibit most of the ions localized in the cytoplasm. This effect is consistent with previously published reports showing that short-term exposure of cells to crystalline nickel particles (1-3 days) is able to epigenetically silence target genes placed near heterochromatin, while similar short-term exposure to soluble nickel compounds are not able to induce silencing of genes placed near heterochromatin. However, a 3 week exposure of cells to soluble NiCl2 is also able to induce gene silencing. A similar effect was found in yeast cells where nickel was able to silence the URA-3 gene placed near (1.3 kb) a telomere silencing element, but not when the gene was placed farther away from the silencing element (2.0 kb). In addition to epigenetic effects, nickel compounds activate hypoxia signaling pathways. The mechanism of this effect involves the ability of either soluble or insoluble nickel compounds to block iron uptake leading to cellular iron depletion, directly affect iron containing enzymes, or both. This results in the inhibition of a variety of iron-dependent enzymes, such as aconitase and the HIF proline hydroxylases (PHD1-3). The inhibition of the HIF proline hydroxylases stabilizes the HIF protein and activates hypoxic signaling. Additional studies have shown that nickel and hypoxia decrease histone acetylation and increase the methylation of H3 lysine 9. These events are involved in gene silencing and hypoxia can also cause these effects in human cells. It is hypothesised that the state of hypoxia either by low oxygen tension or as a result of agents that signal hypoxia under normal oxygen tension (iron chelation, nickel and cobalt) results in low levels of acetyl CoA, which is a substrate for histone and other protein acetylation. This effect may in part be responsible for the gene silencing following nickel exposure and during hypoxia.


Solid state properties and drug release behavior of co-amorphous indomethacin-arginine tablets coated with Kollicoat® Protect.
A promising approach to improve the solubility of poorly water-soluble drugs and to overcome the stability issues related to the plain amorphous form of the drugs, is the formulation of drugs as co-amorphous systems. Although polymer coatings have been proven very useful with regard to tablet stability and modifying drug release, there is little known on coating co-amorphous formulations. Hence, the aim of the present study was to investigate whether polymer coating of co-amorphous formulations is possible without inducing recrystallization. Tablets containing either a physical mixture of crystalline indomethacin and arginine or co-amorphous indomethacin-arginine were coated with a water soluble polyvinyl alcohol-polyethylene glycol graft copolymer (Kollicoat® Protect) and stored at 23°C/0% RH and 23°C/75% RH. The solid state properties of the coated tablets were analyzed by XRPD and FTIR and the drug release behavior was tested for up to 4h in phosphate buffer pH 4.5. The results showed that the co-amorphous formulation did not recrystallize during the coating process or during storage at both storage conditions for up to three months, which confirmed the high physical stability of this co-amorphous system. Furthermore, the applied coating could partially inhibit recrystallization of indomethacin during drug release testing, as coated tablets reached a higher level of supersaturation compared to the respective uncoated formulations and showed a lower decrease of the dissolved indomethacin concentration upon precipitation. Thus, the applied coating enhanced the AUC of the dissolution curve of the co-amorphous tablets by about 30%. In conclusion, coatings might improve the bioavailability of co-amorphous formulations.


Invasive cervical cancer and screening: what are the rates of unscreened and underscreened women in the modern era?
It has been reported that approximately 50% of invasive cervical malignancies are diagnosed in patients who have never been screened and that 10% of the remaining cervical cancer patients have not had a Pap smear in the 5 years before diagnosis. We sought to determine whether this holds true among a university-based gynecologic oncology patient population. After institutional review board approval, a retrospective chart review of women in a university-based gynecologic oncology group with cervical cancer from 2002 to 2007 was conducted. Patients' demographics, referral Pap smear, method of diagnosis, histology, clinical stage, treatment, and time since last Pap smear were collected. Descriptive statistics were used during data analysis. A total of 419 women with cervical cancer were identified. Of these women, 67% of patients were white, 18% Hispanic, and 6% African-American. The most common referral Pap smear to our institution was high-grade squamous intraepithelial lesion (21%). Diagnosis was primarily made by cervical punch biopsy (47%). The most common histologic type was squamous cell carcinoma (70%). Of all patients, 80% were diagnosed with stage I and 9% with stage II cervical cancer, whereas stage III and IV were uncommon. The most common therapy was radical hysterectomy with lymph node dissection performed in 250 patients (60%). The length of time from last reported Pap smear to diagnosis of invasive cervical cancer ranged from 1 to 65 years, with a median of 3 years. Stage IA1 patients ranged from 1 to 12 years from last reported Pap with a median of 1 year (SD = 3.38), whereas stage III/IV patients ranged from 1 to 20 years since last screening, with a median of 4 years (SD = 6.39). Regarding length of time since last reported Pap smear, 235 patients (56%) were unable to report the length of time since their last Pap smear. Of those who reported their last Pap smear, 4 patients (1%) reported never having a Pap smear, 39 patients (9%) reported last Pap smear more than 10 years ago, and 10 patients (2%) reported a Pap smear more than 20 years ago. Of all patients, 85 (20%) reported a Pap smear within 2 years. Of these 85 patients, 71 patients (84%) were diagnosed at stage I, whereas more advanced stages were uncommon. Traditionally, patients diagnosed with an invasive cervical malignancy are either unscreened or underscreened with cervical cytology. Our patient population was noncompliant with the screening measures. A fraction of our patients were compliant with screening within the last 2 years, yet still developed a cervical malignancy--albeit early stage disease. As such, our data suggest that compliance continues to be an issue. However, even with adherence to screening guidelines, cervical cancer continues to develop.


Decomposition of gendered income-related inequalities in multiple biological cardiovascular risk factors in a middle-aged population.
Socioeconomic inequalities in cardiovascular disease seem to widen or endure in Sweden. However, research on inequalities in antecedent cardiovascular risk factors (CVRFs), and particularly what underpins them, is scarce. The present study aimed 1) to estimate income-related inequalities in eight biological cardiovascular risk factors in Swedish middle-aged women and men; and 2) to examine the contribution of demographic, socioeconomic, behavioural and psychosocial determinants to the observed inequalities. Participants (N = 12,481) comprised all 40- and 50-years old women and men who participated in the regional Västerbotten Intervention Programme in Northern Sweden during 2008, 2009 and 2010. All participants completed a questionnaire on behavioural and psychosocial conditions, and underwent measurements with respect to eight CVRFs (body mass index; waist circumference; total cholesterol; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol; triglycerides; systolic/diastolic blood pressure; glucose tolerance). Data on cardiovascular risk, psychosocial and health behaviours were linked to national register data on income and other socioeconomic and demographic factors. To estimate income inequalities in each CVRF concentration indexes were calculated, and to examine the contribution of the underlying determinants to the observed inequalities a Wagstaff-type decomposition analysis was performed separately for women and men. Health inequalities ranged from small to substantial with generally greater magnitude in women. The highest inequalities among women were seen in BMI, triglycerides and HDL-cholesterol (Concentration index = - 0.1850; - 0.1683 and - 0.1479 respectively). Among men the largest inequalities were seen in glucose regulation, BMI and abdominal obesity (Concentration index = - 0.1661; - 0.1259 and - 0.1172). The main explanatory factors were, for both women and men socioeconomic conditions (contributions ranging from 54.8 to 76.7% in women and 34.0-72.6% in men) and health behaviours (contributions ranging from 6.9 to 20.5% in women and 9.2 to 26.9% in men). However, the patterns of specific dominant explanatory factors differed between CVRFs and genders. Taken together, the results suggest that the magnitude of income-related inequalities in CVRFs and their determinants differ importantly between the risk factors and genders, a variation that should be taken into consideration in population interventions aiming to prevent inequalities in manifest cardiovascular disease.


Measurement of mRNA therapeutics: method development and validation challenges.
The progression of chemically modified mRNA therapeutics through development pipelines is accelerating for many disease indications and the need to assess these analytes is becoming more routine for the pharmaceutical industry and contract research organizations. This article describes some of the challenges and strategies for performing regulated bioanalysis of modified mRNA therapeutics by comparing the two main analytical approaches - quantitative reverse transcription PCR and branched DNA.


Understanding emotional prosody activates right hemisphere regions.
Defects in expressing or understanding the affective or emotional tone of speech (aprosodias) have been associated with right hemisphere dysfunction, while defects of propositional language have been linked to left hemisphere disease. The brain regions involved in recognition of emotional prosody in healthy subjects is less clear. To investigate the brain regions involved in understanding emotional prosody and to determine whether these differ from those involved in understanding emotion based on propositional content. We studied 13 healthy subjects using water labeled with radioactive oxygen 15 and positron emission tomography while they listened to 3 similar sets of spoken English sentences. In different tasks, their responses were based on the emotional propositional content, on the emotional intonation of the sentence (prosody), or on their ability to repeat the second word in the sentence (control). Understanding propositional content activated the prefrontal cortex bilaterally, on the left more than on the right. In contrast, responding to the emotional prosody activated the right prefrontal cortex. Neurologically healthy subjects activate right hemisphere regions during emotional prosody recognition.


High-temperature bulk metallic glasses developed by combinatorial methods.
Since their discovery in 19601, metallic glasses based on a wide range of elements have been developed2. However, the theoretical prediction of glass-forming compositions is challenging and the discovery of alloys with specific properties has so far largely been the result of trial and error3-8. Bulk metallic glasses can exhibit strength and elasticity surpassing those of conventional structural alloys9-11, but the mechanical properties of these glasses are critically dependent on the glass transition temperature. At temperatures approaching the glass transition, bulk metallic glasses undergo plastic flow, resulting in a substantial decrease in quasi-static strength. Bulk metallic glasses with glass transition temperatures greater than 1,000 kelvin have been developed, but the supercooled liquid region (between the glass transition and the crystallization temperature) is narrow, resulting in very little thermoplastic formability, which limits their practical applicability. Here we report the design of iridium/nickel/tantalum metallic glasses (and others also containing boron) with a glass transition temperature of up to 1,162 kelvin and a supercooled liquid region of 136 kelvin that is wider than that of most existing metallic glasses12. Our Ir-Ni-Ta-(B) glasses exhibit high strength at high temperatures compared to existing alloys: 3.7 gigapascals at 1,000 kelvin9,13. Their glass-forming ability is characterized by a critical casting thickness of three millimetres, suggesting that small-scale components for applications at high temperatures or in harsh environments can readily be obtained by thermoplastic forming14. To identify alloys of interest, we used a simplified combinatorial approach6-8 harnessing a previously reported correlation between glass-forming ability and electrical resistivity15-17. This method is non-destructive, allowing subsequent testing of a range of physical properties on the same library of samples. The practicality of our design and discovery approach, exemplified by the identification of high-strength, high-temperature bulk metallic glasses, bodes well for enabling the discovery of other glassy alloys with exciting properties.


Estimating transmission intensity for a measles epidemic in Niamey, Niger: lessons for intervention.
The objective of this study is to estimate the effective reproductive ratio for the 2003-2004 measles epidemic in Niamey, Niger. Using the results of a retrospective and prospective study of reported cases within Niamey during the 2003-2004 epidemic, we estimate the basic reproductive ratio, effective reproductive ratio (RE) and minimal vaccination coverage necessary to avert future epidemics using a recent method allowing for estimation based on the epidemic case series. We provide these estimates for geographic areas within Niamey, thereby identifying neighbourhoods at high risk. The estimated citywide RE was 2.8, considerably lower than previous estimates, which may help explain the long duration of the epidemic. Transmission intensity varied during the course of the epidemic and within different neighbourhoods (RE range: 1.4-4.7). Our results indicate that vaccination coverage in currently susceptible children should be increased by at least 67% (vaccine efficacy 90%) to produce a citywide vaccine coverage of 90%. This research highlights the importance of local differences in vaccination coverage on the potential impact of epidemic control measures. The spatial-temporal spread of the epidemic from district to district in Niamey over 30 weeks suggests that targeted interventions within the city could have an impact.


Direct interaction with filamins modulates the stability and plasma membrane expression of CFTR.
The role of the cystic fibrosis transmembrane conductance regulator (CFTR) as a cAMP-dependent chloride channel on the apical membrane of epithelia is well established. However, the processes by which CFTR is regulated on the cell surface are not clear. Here we report the identification of a protein-protein interaction between CFTR and the cytoskeletal filamin proteins. Using proteomic approaches, we identified filamins as proteins that associate with the extreme CFTR N terminus. Furthermore, we identified a disease-causing missense mutation in CFTR, serine 13 to phenylalanine (S13F), which disrupted this interaction. In cells, filamins tethered plasma membrane CFTR to the underlying actin network. This interaction stabilized CFTR at the cell surface and regulated the plasma membrane dynamics and confinement of the channel. In the absence of filamin binding, CFTR was internalized from the cell surface, where it prematurely accumulated in lysosomes and was ultimately degraded. Our data demonstrate what we believe to be a previously unrecognized role for the CFTR N terminus in the regulation of the plasma membrane stability and metabolic stability of CFTR. In addition, we elucidate the molecular defect associated with the S13F mutation.