Outcomes of Patients in Long-Term Opioid Maintenance Treatment.
Despite the importance of duration of opioid maintenance treatment (OMT), only few studies have reported outcomes of long-term OMT. To describe outcomes of long-term (> 5 years) OMT patients with respect to substance use, physical and mental health, and socioeconomic characteristics. Patients (n = 160) were recruited from 15 OMT offices in different regions of Germany. Data were collected using a structured interview at baseline, and clinical recordings, including urine drug screenings, during 12 monhts follow-up. Patients had a mean age of 44 years. During follow-up, 23% of patients showed indications of an alcohol problem. Cannabis was used by 56%, often frequently. Heroin was used by 28%, mostly infrequently. Three quarters of patients either had a non-substance related mental disorder (48.1%, most frequently affective and anxiety disorders) or somatic diagnosis (61.3%, frequently hepatitis C, HIV, or cardiovascular diseases), or both. Unemployment rate was 43.1% at baseline (27% for patients without comorbidity) and remained generally stable during follow-up. No arrests or incarcerations were recorded. During follow-up, 2.5% of patients prematurely terminated OMT, 2.5% regularly completed OMT. The sample as a whole was characterized by stable living conditions, high unemployment, low illicit opiate use, and a high retention rate. Continuation of OMT could enable further treatment of comorbidity and prevent resumption of a drug-dominated lifestyle. But it may well be asked how within the context of OMT further improvements can be achieved, especially with regard to further decrease of alcohol use and the treatment of depression.


Alpha 2A adrenergic receptor polymorphism is associated with plasma von Willebrand factor levels in a general population.
High levels of plasma von Willebrand factor are a proposed risk factor for atherothrombotic disorders. Previously, ABO blood type and the von Willebrand factor -1793C/G polymorphism were shown to affect interindividual variations in plasma von Willebrand factor levels. We previously reported that polymorphisms of the alpha 2A adrenergic receptor, an epinephrine receptor, were associated with platelet function as assessed by platelet function analyzer-100. The measurement value of platelet function analyzer-100 has been reportedly associated with plasma von Willebrand factor levels. Also, it was demonstrated that epinephrine administration increases plasma von Willebrand factor levels in vivo. Thus, the present study investigated the association between plasma von Willebrand factor levels and genetic polymorphisms as follows: ABO blood type, von Willebrand factor -1051G/A (linked with -1793C/G), alpha 2A adrenergic receptor 1780A/G, and alpha 2A adrenergic receptor 2372A/G. Study subjects were genetically unrelated Japanese men (n = 277) recruited at their regular medical examinations. Genotyping of the polymorphisms was performed using the single nucleotide primer extension-based method. Plasma von Willebrand factor levels were measured as ristocetin-cofactor activities. The O blood type and alpha 2A adrenergic receptor 2372AA genotype were significantly associated with lower von Willebrand factor levels, though von Willebrand factor -1051G/A polymorphism did not affect them. In stratification analysis of the group according to blood type O and non-O, the significant association between the 2372AA genotype and lower plasma von Willebrand factor levels was observed in non-O subjects, but not O subjects. In conclusion, the alpha 2A adrenergic receptor 2372A/G polymorphism is associated with plasma von Willebrand factor levels in a general population.


Resistance exercise plus to aerobic activities is associated with better lipids' profile among healthy individuals: the ATTICA study.
The influence of different types of exercise on risk factors for cardiovascular diseases has rarely been investigated. The aim of the present work was to evaluate the effect of adding resistance exercise to aerobic activities on lipid-lipoprotein profile, in a representative sample of men and women from the province of Attica, Greece. We randomly enrolled 1514 and 1528 healthy men and women, respectively, stratified by city, age and gender distribution. Participants were classified as inactive (INA), sufficiently active (SA) and highly active for either aerobic activities (HAA) alone or a combination of aerobic plus resistance exercise (HAC). The main outcome measures are lipid-lipoprotein profile [total, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, apolipoprotein-A1, apolipoprotein-B] and anthropometric indices. From those participating in aerobic activities, 480 (31.7%) men and 502 (32.9%) women were classified as SA, 100 men (6.6%) and 93 women (6.1%) as HAA and 90 men (5.9%) and 49 women (3.2%) as HAC. After various adjustments were made, men from the HAC group had an average of 23% lower plasma triacylglycerol concentration (P = 0.04) and 10% lower LDL-cholesterol (P = 0.01) when compared with the HAA group. Moreover, women from the HAC group had 13% lower LDL-cholesterol when compared with HAA group (P = 0.051). These data suggest that combining aerobic and resistance-type activities may confer a better effect on lipoprotein profile in healthy individuals than aerobic activities alone.


Imperfect replacement of native species by non-native species as pollinators of endemic Hawaiian plants.
Native plant species that have lost their mutualist partners may require non-native pollinators or seed dispersers to maintain reproduction. When natives are highly specialized, however, it appears doubtful that introduced generalists will partner effectively with them. We used visitation observations and pollination treatments (experimental manipulations of pollen transfer) to examine relationships between the introduced, generalist Japanese White-eye (Zosterops japonicus) and 3 endemic Hawaiian plant species (Clermontia parviflora, C. montis-loa, and C. hawaiiensis). These plants are characterized by curved, tubular flowers, apparently adapted for pollination by curve-billed Hawaiian honeycreepers. Z. japonicus were responsible for over 80% of visits to flowers of the small-flowered C. parviflora and the midsize-flowered C. montis-loa. Z. japonicus-visited flowers set significantly more seed than did bagged flowers. Z. japonicus also demonstrated the potential to act as an occasional Clermontia seed disperser, although ground-based frugivory by non-native mammals likely dominates seed dispersal. The large-flowered C. hawaiiensis received no visitation by any birds during observations. Unmanipulated and bagged C. hawaiiensis flowers set similar numbers of seeds. Direct examination of Z. japonicus and Clermontia morphologies suggests a mismatch between Z. japonicus bill morphology and C. hawaiiensis flower morphology. In combination, our results suggest that Z. japonicus has established an effective pollination relationship with C. parviflora and C. montis-loa and that the large flowers of C. hawaiiensis preclude effective visitation by Z. japonicus.


Development of geriatric competencies for emergency medicine residents using an expert consensus process.
The emergency department (ED) visit rate for older patients exceeds that of all age groups other than infants. The aging population will increase elder ED patient utilization to 35% to 60% of all visits. Older patients can have complex clinical presentations and be resource-intensive. Evidence indicates that emergency physicians fail to provide consistent high-quality care for elder ED patients, resulting in poor clinical outcomes. The objective was to develop a consensus document, "Geriatric Competencies for Emergency Medicine Residents," by identified experts. This is a minimum set of behaviorally based performance standards that all residents should be able to demonstrate by completion of their residency training. This consensus-based process utilized an inductive, qualitative, multiphase method to determine the minimum geriatric competencies needed by emergency medicine (EM) residents. Assessments of face validity and reliability were used throughout the project. In Phase I, participants (n=363) identified 12 domains and 300 potential competencies. In Phase II, an expert panel (n=24) clustered the Phase I responses, resulting in eight domains and 72 competencies. In Phase III, the expert panel reduced the competencies to 26. In Phase IV, analysis of face validity and reliability yielded a 100% consensus for eight domains and 26 competencies. The domains identified were atypical presentation of disease; trauma, including falls; cognitive and behavioral disorders; emergent intervention modifications; medication management; transitions of care; pain management and palliative care; and effect of comorbid conditions. The Geriatric Competencies for EM Residents is a consensus document that can form the basis for EM residency curricula and assessment to meet the demands of our aging population.


Coinfection with Plasmodium falciparum and Schistosoma haematobium: additional evidence of the protective effect of Schistosomiasis on malaria in Senegalese children.
Parasitic infections are associated with high morbidity and mortality in developing countries. Several studies focused on the influence of helminth infections on malaria but the nature of the biological interaction is under debate. Our objective was to undertake a study to explore the influence of the measure of excreted egg load caused by Schistosoma haematobium on Plasmodium falciparum parasite densities. Ten measures of malaria parasite density and two measures of schistosomiasis egg urinary excretion over a 2-year follow-up period on 178 Senegalese children were considered. A linear mixed-effect model was developed to take data dependence into account. This work showed that children with a light S. haematobium infection (1-9 eggs/mL of urine) presented lower P. falciparum parasite densities than children not infected by S. haematobium (P < 0.04). Possible changes caused by parasite coinfections should be considered in the anti-helminth treatment of children and in malaria vaccination development.


Cannabis sativa L. may reduce aggressive behaviour towards humans in shelter dogs.
Among the phytocomplex components of Cannabis sativa L., cannabidiol (CBD) has a recognised therapeutic effect on chronic pain. Little is known about the veterinary use of CBD in dogs. Even less is known on the effects of CBD on dog behaviour, especially in shelters. The purpose of this study was to determine if CBD affects stress related behaviour in shelter dogs. The sample consisted of 24 dogs divided into two groups that were created by assigning the dogs alternately: 12 dogs were assigned to the treatment group and 12 to the control group. Extra virgin olive oil, titrated to 5% in CBD was given to treated group; the placebo consisted of olive oil only, dispensed daily for 45 days. Behavioural data were collected using the 'focal animal' sampling method with 'all occurrences' and '1/0' methods for 3 h: before (T0), after 15 days (T1), after 45 days of treatment (T2) and after 15 days from the end of the treatment (T3). Treated dogs showed reduced aggressive behaviour toward humans following the treatment (Friedman Test: χ2 = 13.300; df = 3; N = 12; p = .004; adj. sig. p = 0.027), but the difference in the decrease of aggressive behaviour between the two groups was not significant (Mann-Whitney U test, T2-T0: Z = - 1.81; N = 24; p = 0.078). Other behaviours indicative of stress, such as displacing activities and stereotypes, did not decrease. Despite some non-significant results, our findings suggest that it is worth doing more research to further investigate the effect of CBD on dog behaviour; this would be certainly valuable because the potential for improving the welfare of dogs in shelters is priceless.


Ketone bodies mimic the life span extending properties of caloric restriction.
The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP3 ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, d-β-hydroxybutyrate (d-βHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of d-βHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders. © 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(5):305-314, 2017.


Oncogenic MAPK signaling stimulates mTORC1 activity by promoting RSK-mediated raptor phosphorylation.
The mammalian target of rapamycin (mTOR) is a Ser/Thr kinase that controls cell growth in response to mitogens, as well as amino acid and energy sufficiency. The scaffolding protein Raptor binds to mTOR and recruits substrates to the rapamycin-sensitive mTOR complex 1 (mTORC1). Although Raptor has been shown to be essential for mTORC1 activity, the mechanisms regulating Raptor function remain unknown. Here, we demonstrate that Raptor becomes highly phosphorylated on RXRXXpS/T consensus motifs after activation of the Ras/mitogen-activated protein kinase (MAPK) pathway. Using pharmacological inhibitors and RNA interference, we show that the p90 ribosomal S6 kinases (RSKs) 1 and 2 are required for Raptor phosphorylation in vivo and directly phosphorylate Raptor in vitro. Quantitative mass spectrometry and site-directed mutagenesis revealed that RSK specifically phosphorylates Raptor within an evolutionarily conserved region with no previously known function. Interestingly, expression of oncogenic forms of Ras and MEK that elevate mTORC1 activity induced strong and constitutive phosphorylation of Raptor on these residues. Importantly, we demonstrate that expression of Raptor mutants lacking RSK-dependent phosphorylation sites markedly reduced mTOR phosphotransferase activity, indicating that RSK-mediated phosphorylation of Raptor is important for mTORC1 activation by the Ras/MAPK pathway. We propose a unique mode of mTOR regulation in which RSK-mediated phosphorylation of Raptor regulates mTORC1 activity and thus suggest a means by which the Ras/MAPK pathway might promote rapamycin-sensitive signaling independently of the PI3K/Akt pathway.


Characterization of an immunologically conserved epitope from hepatitis C virus E2 glycoprotein recognized by HLA-A2 restricted cytotoxic T lymphocytes.
Identification of epitopes recognized by cytotoxic T lymphocytes (CTL) in hepatitis C virus (HCV) proteins is of importance because they can be used for vaccination, treatment of infection or monitoring of immune responses. Our purpose was to characterize new CTL epitopes in HCV structural proteins. Peptides were synthesized and tested in HLA-A2 binding assays. Binder peptides were used to stimulate peripheral blood mononuclear cells from HCV+ patients and controls, and activity measured in chromium release and ELISPOT assays. Twenty binder peptides were found, and stimulation of HCV+ patient cells with nine peptides showing high binding ability led to the growth of CD8+ CTL recognizing peptide E2(614-622) in association with HLA-A2. Peptide E2(614-622) was recognized by 30% of HLA-A2+ patients with chronic HCV infection, but no responses were observed in control groups. Five peptides derived from region E2(614-622) from 26 different viral isolates bound to HLA-A2 molecules, and all of them but one, containing Phe at position 622, were recognized by E2(614-622) specific CTL. These results show that peptide E2(614-622) belongs to a highly conserved region of HCV E2, and might be a good candidate to induce anti-HCV CTL responses in HLA-A2+ subjects.


A three-dimensional immunocompetent intestine-on-chip model as in vitro platform for functional and microbial interaction studies.
Alterations of the microbial composition in the gut and the concomitant dysregulation of the mucosal immune response are associated with the pathogenesis of opportunistic infections, chronic inflammation, and inflammatory bowel disease. To create a platform for the investigation of the underlying mechanisms, we established a three-dimensional microphysiological model of the human intestine. This model resembles organotypic microanatomical structures and includes tissue resident innate immune cells exhibiting features of mucosal macrophages and dendritic cells. The model displays the physiological immune tolerance of the intestinal lumen to microbial-associated molecular patterns and can, therefore, be colonised with living microorganisms. Functional studies on microbial interaction between probiotic Lactobacillus rhamnosus and the opportunistic pathogen Candida albicans show that pre-colonization of the intestinal lumen of the model by L. rhamnosus reduces C. albicans-induced tissue damage, lowers its translocation, and limits fungal burden. We demonstrate that microbial interactions can be efficiently investigated using the in vitro model creating a more physiological and immunocompetent microenvironment. The intestinal model allows a detailed characterisation of the immune response, microbial pathogenicity mechanisms, and quantification of cellular dysfunction attributed to alterations in the microbial composition.


Easy access to triazolinedione-endcapped peptides for chemical ligation.
An efficient and easy route towards triazolinedione (TAD) endcapped peptides is described, in which a TAD-precursor was coupled to N-terminal amines on a solid support. Modified peptides readily reacted with diene end-functionalized poly(ε-caprolactone) of different molecular weights. The ligation proved to be orthogonal to a variety of functional groups present in natural amino acids.


End-to-end transcription of an Alu family repeat. A new type of polymerase-III-dependent terminator and its evolutionary implication.
Four or more consecutive thymidine residues on the non-template strand and G + C-richness of flanking DNA are the two necessary characteristics of efficient RNA polymerase-III-dependent transcriptional terminators. We have identified, from the study of in vitro transcription of a human Alu family repeat, a new type of RNA polymerase-III-dependent transcriptional terminator. A 258 base-pair Alu repeat located on the 3' side of the human alpha 1 globin gene can be transcribed in a HeLa S-100 extract to generate three RNA species of lengths 404 to 408, 252 to 255 and 173 to 174 nucleotides, respectively. Kinetics, pulse-chase and RNA incubation experiments showed no significant internal processing of the longer transcripts into shorter ones. These data plus detailed RNA mapping demonstrated conclusively that the multiple Alu RNA species resulted from accurate initiation at the first base (5' end) of the repeat, and multiple termination downstream. The 3' end(s) of the major transcript (252 to 255 nucleotides) maps at the 3' end of the Alu repeat sequence where there are not four or more consecutive thymidine residues on the non-template strand. The functional domain of the terminator has been mapped to a 45 base-pair segment that includes 36 base-pairs of the 3' end sequence of the Alu repeat plus nine base-pairs downstream. The high efficiency of termination (greater than 90%), the lack of consecutive T residues, the richness in A + T content, and the proposed ability of the RNA to form an imperfect hairpin structure in the 3' region of the transcript, thus identify a new type of eukaryotic class III terminator. We compare the structure of this class III terminator with that of the bacterial rho-dependent terminator. We also discuss its implication in the mechanism(s) of amplification and dispersion of Alu sequences in the primate genomes.


Elucidation of factors responsible for enhanced thermal stability of proteins: a structural genomics based study.
Understanding the molecular basis for the enhanced stability of proteins from thermophiles has been hindered by a lack of structural data for homologous pairs of proteins from thermophiles and mesophiles. To overcome this difficulty, complete genome sequences from 9 thermophilic and 21 mesophilic bacterial genomes were aligned with protein sequences with known structures from the protein data bank. Sequences with high homology to proteins with known structures were chosen for further analysis. High quality models of these chosen sequences were obtained using homology modeling. The current study is based on a data set of models of 900 mesophilic and 300 thermophilic protein single chains and also includes 178 templates of known structure. Structural comparisons of models of homologous proteins allowed several factors responsible for enhanced thermostability to be identified. Several statistically significant, specific amino acid substitutions that occur going from mesophiles to thermophiles are identified. Most of these are at solvent-exposed sites. Salt bridges occur significantly more often in thermophiles. The additional salt bridges in thermophiles are almost exclusively in solvent-exposed regions, and 35% are in the same element of secondary structure. Helices in thermophiles are stabilized by intrahelical salt bridges and by an increase in negative charge at the N-terminus. There is an approximate decrease of 1% in the overall loop content and a corresponding increase in helical content in thermophiles. Previously overlooked cation-pi interactions, estimated to be twice as strong as ion-pairs, are significantly enriched in thermophiles. At buried sites, statistically significant hydrophobic amino acid substitutions are typically consistent with decreased side chain conformational entropy.


Population Prevalence of Need for Spectacles and Spectacle Ownership Among Urban Migrant Children in Eastern China.
The number of urban migrants in China is 300 million and is increasing rapidly in response to government policies. Urban migrants have poor access to health care, but little is known about rates of correction of refractive error among migrant children. This is of particular significance in light of recent evidence demonstrating the educational impact of providing children with spectacles. To measure prevalence of spectacle need and ownership among Chinese migrant children. Population-based, cross-sectional study among children who failed vision testing (uncorrected visual acuity ≤6/12 in either eye) between September 15 and 30, 2013, at 94 randomly selected primary schools in predominantly migrant communities in Shanghai, Suzhou, and Wuxi, China. Refractive error by cycloplegic refraction; spectacle ownership, defined as producing glasses at school, having been told to bring them; and needing glasses, defined as uncorrected visual acuity of 6/12 or less correctable to greater than 6/12 in either eye, with myopia of -0.5 diopters (D) or less, hyperopia of +2.0 D or greater, or astigmatism of 0.75 D or greater in both eyes. Among 4409 children, 4376 (99.3%) completed vision screening (mean [SD] age, 11.0 [0.81] years; 55.3% boys; 4225 [96.5%] migrant and 151 [3.5%] local). Among 1204 children failing vision testing (total, 27.5%; 1147 migrant children [27.1%] vs 57 local children [37.7%]; P = .003), 850 (70.6%) completed refraction. Spectacle ownership in migrant children needing glasses (147 of 640 children [23.0%]) was less than among local children (12 of 34 children [35.3%]) (odds ratio = 0.55; 95% CI, 0.32-0.95; P = .03). Having uncorrected visual acuity less than 6/18 in both eyes was associated positively with baseline spectacle ownership (odds ratio = 5.73; 95% CI, 3.81-8.62; P < .001), but parental education and family wealth were not. Among urban migrant children, there was a high prevalence of need for spectacles and a very low rate of spectacle ownership. Spectacle distribution programs are needed specifically targeting migrant children.


How to efficiently tune the biradicaloid nature of acenes by chemical doping with boron and nitrogen.
Acenes are fascinating polyaromatic compounds that combine impressive semiconductor properties with an open-shell character by varying their molecular sizes. However, the increasing chemical instabilities related to their biradicaloid structures pose a great challenge for synthetic chemistry. Modifying the π-bond topology through chemical doping allows modulation of the electronic properties of graphene-related materials. In spite of the practical importance of these techniques, remarkably little is known about the basic question - the extent of the radical character created or quenched thereby. In this work, we report a high-level computational study on two acene oligomers doubly-doped with boron and nitrogen, respectively. These calculations demonstrate precisely which the chemical route is in order to either quench or enhance the radical character. Moving the dopants from the terminal rings to the central ones leads to a remarkable variation in the biradicaloid character (and thereby also in the chemical stability). This effect is related to a π-charge transfer involving the dopants and the radical carbon centers at the zigzag edges. This study also provides specific guidelines for a rational design of large polyaromatic compounds with enhanced chemical stability.


Insights into the Kinetics of Supramolecular Comonomer Incorporation in Water.
Multicomponent supramolecular polymers are a versatile platform to prepare functional architectures, but a few studies have been devoted to investigate their noncovalent synthesis. Here, we study supramolecular copolymerizations by examining the mechanism and time scales associated with the incorporation of new monomers in benzene-1,3,5-tricarboxamide (BTA)-based supramolecular polymers. The BTA molecules in this study all contain three tetra(ethylene glycol) chains at the periphery for water solubility but differ in their alkyl chains that feature either 10, 12 or 13 methylene units. C10BTA does not form ordered supramolecular assemblies, whereas C12BTA and C13BTA both form high aspect ratio supramolecular polymers. First, we illustrate that C10BTA can mix into the supramolecular polymers based on either C12BTA or C13BTA by comparing the temperature response of the equilibrated mixtures to the temperature response of the individual components in water. Subsequently, we mix C10BTA with the polymers and follow the copolymerization over time with UV spectroscopy and hydrogen/deuterium exchange mass spectrometry experiments. Interestingly, the time scales obtained in both experiments reveal significant differences in the rates of copolymerization. Coarse-grained simulations are used to study the incorporation pathway and kinetics of the C10BTA monomers into the different polymers. The results demonstrate that the kinetic stability of the host supramolecular polymer controls the rate at which new monomers can enter the existing supramolecular polymers.


Mammography dose in relation to body mass index, race, and menopausal status.
Mammography dose increases with compressed breast thickness (CBT), but few studies have examined other correlates of dose. The purpose of this study was to evaluate the relation between factors such as race, age, body mass index (BMI), CBT, and menopausal status and mammography screening dose, measured for 509 women in a US population. A multiple linear regression model was developed for dose, based on consideration of these factors as well as examination characteristics. BMI and number of films during examination were positively related to dose. After adjusting for these factors, high CBT also leads to higher dose. Whites receive lower doses than black women but differences are slight after controlling for the effects of CBT and BMI, which were significantly higher among black women. Pre-menopausal women receive higher doses, after adjusting for all other factors, than post-menopausal women. Jointly, these factors account for approximately 75% to 80% of the variability in dose among this study population. Because rates of overweight are increasing in the US, average doses from mammography may be increasing as well.


All-optical single-sideband upconversion with an optical interleaver and a semiconductor optical amplifier for radio-over-fiber applications.
We propose and experimentally demonstrate an all-optical upconverter for the generation of an optical single-sideband (OSSB) signal in radio-over-fiber (RoF) systems. The OSSB signal, which is required for overcoming the fiber chromatic dispersion problem in RoF systems, is generated by using an all-optical SSB upconverter consisting of an optical interleaver and a semiconductor optical amplifier. With this upconversion technique, OSSB radio frequency (RF) signals with an RF frequency ranging from 15 GHz to 42.5 GHz are generated by mixing an optical intermediate frequency (IF) signal (1 GHz) with an optical local oscillator signal and transmitted over a 46 km standard single-mode fiber. The OSSB RF signal generated by this upconversion technique shows negligible dispersion-induced carrier suppression effects, which are usually observed for an optical double-sideband RF signal. The all-optical SSB upconverter provides high conversion efficiency of up to 29 dB and a sufficiently large spurious free dynamic range of 82 dB.Hz(2/3) for microcellular personal communication system applications.


8-Oxoguanine causes neurodegeneration during MUTYH-mediated DNA base excision repair.
8-Oxoguanine (8-oxoG), a common DNA lesion caused by reactive oxygen species, is associated with carcinogenesis and neurodegeneration. Although the mechanism by which 8-oxoG causes carcinogenesis is well understood, the mechanism by which it causes neurodegeneration is unknown. Here, we report that neurodegeneration is triggered by MUTYH-mediated excision repair of 8-oxoG-paired adenine. Mutant mice lacking 8-oxo-2'-deoxyguanosine triphosphate-depleting (8-oxo-dGTP-depleting) MTH1 and/or 8-oxoG-excising OGG1 exhibited severe striatal neurodegeneration, whereas mutant mice lacking MUTYH or OGG1/MUTYH were resistant to neurodegeneration under conditions of oxidative stress. These results indicate that OGG1 and MTH1 are protective, while MUTYH promotes neurodegeneration. We observed that 8-oxoG accumulated in the mitochondrial DNA of neurons and caused calpain-dependent neuronal loss, while delayed nuclear accumulation of 8-oxoG in microglia resulted in PARP-dependent activation of apoptosis-inducing factor and exacerbated microgliosis. These results revealed that neurodegeneration is a complex process caused by 8-oxoG accumulation in the genomes of neurons and microglia. Different signaling pathways were triggered by the accumulation of single-strand breaks in each type of DNA generated during base excision repair initiated by MUTYH, suggesting that suppression of MUTYH may protect the brain under conditions of oxidative stress.


Causal chain mapping: a novel method to analyse treatment compliance decisions relating to lymphatic filariasis elimination in Alor, Indonesia.
Many public health programmes require individuals to comply with particular behaviours that are novel to them, for example, acquiring new eating habits, accepting immunizations or taking a new medication. In particular, mass drug administration programmes only work to reduce the prevalence of a disease if significant proportions of the target population take the drug in question. In such cases, knowledge of the factors most likely to lead to high levels of compliance is crucial to the programme's success. Existing models of compliance tend to either address interpersonal, organizational or psychological causes independently. Here, the authors present a formal method for analysing relevant factors in the situational context of the compliant behaviour, identifying how these factors may interact within the individual. This method was developed from semantic network analysis, augmented to include environmental and demographic variables to show causal linkages-hence the name 'causal chain mapping'. The ability of this method to provide significant insight into the actual behaviour of individuals is demonstrated with examples from a mass drug administration for lymphatic filariasis in Alor District, Indonesia. The use of this method is likely to help identify key components influencing compliance, and thus make any public health programme reliant on the adoption of novel behaviours more effective.


Body size and composition of National Football League players.
The purpose of this study was to present a profile of body size and composition of National Football League (NFL) players prior to the start of the regular season. Fifty-three members of the Indianapolis Colts professional football team were measured for height, body mass, and percentage body fat using the BOD POD air-displacement plethysmography system during summer camp of the 2003 football season. These data were categorized by position for comparison with previous studies of NFL football players. The relationships observed were as follows (= represents nonsignificant; > represents p < or = 0.05): Height: Offensive Line = Defensive Line = Quarterbacks/Kickers/Punters = Tight Ends > Linebackers > Running Backs = Wide Receivers = Defensive Backs. Body Mass: Offensive Line = Defensive Line > Tight Ends = Linebackers > Running Backs = Quarterbacks/ Kickers/Punters > Wide Receivers = Defensive Backs. Percentage Body Fat: Offensive Line > Defensive Line > Quarterbacks/ Kickers/Punters = Linebackers = Tight Ends > Running Backs = Wide Receivers = Defensive Backs. Comparisons to teams in the 1970s indicate that body mass has increased only for offensive and defensive linemen; however, height and body fat among player positions have not dramatically changed. Furthermore, the body mass index is not an accurate measure or representation of body fat or obesity in NFL players. These data provide a basic template for size profiles and differences among various positions and allow comparisons with other studies for changes in the NFL over the past 3 decades.


Autoadaptive ER-associated degradation defines a preemptive unfolded protein response pathway.
Folding-defective proteins must be cleared efficiently from the endoplasmic reticulum (ER) to prevent perturbation of the folding environment and to maintain cellular proteostasis. Misfolded proteins engage dislocation machineries (dislocons) built around E3 ubiquitin ligases that promote their transport across the ER membrane, their polyubiquitylation, and their proteasomal degradation. Here, we report on the intrinsic instability of the HRD1 dislocon and the constitutive, rapid turnover of the scaffold protein HERP. We show that HRD1 dislocon integrity relies on the presence of HRD1 clients that interrupt, in a dose-dependent manner, the UBC6e/RNF5/p97/proteasome-controlled relay that controls HERP turnover. We propose that ER-associated degradation (ERAD) deploys autoadaptive regulatory pathways, collectively defined as ERAD tuning, to rapidly adapt degradation activity to misfolded protein load and to preempt the unfolded protein response (UPR) activation.


Electronic damage in S atoms in a native protein crystal induced by an intense X-ray free-electron laser pulse.
Current hard X-ray free-electron laser (XFEL) sources can deliver doses to biological macromolecules well exceeding 1 GGy, in timescales of a few tens of femtoseconds. During the pulse, photoionization can reach the point of saturation in which certain atomic species in the sample lose most of their electrons. This electronic radiation damage causes the atomic scattering factors to change, affecting, in particular, the heavy atoms, due to their higher photoabsorption cross sections. Here, it is shown that experimental serial femtosecond crystallography data collected with an extremely bright XFEL source exhibit a reduction of the effective scattering power of the sulfur atoms in a native protein. Quantitative methods are developed to retrieve information on the effective ionization of the damaged atomic species from experimental data, and the implications of utilizing new phasing methods which can take advantage of this localized radiation damage are discussed.


Exploratory data analysis on the effects of non pharmacological treatment for knee osteoarthritis.
Osteoarthritis (OA) is a chronic rheumatic disease characterized by progressive cartilage destruction mediated by cytokines and other molecules. Chondrocyte activity and metabolism have attracted interest as targets of drug intervention, and spa-therapy can influence the serum levels of several cytokines. We investigated the effects of spa-therapy on clinical and ultrasonographic (US) findings and serum levels of cartilage oligomeric matrix protein (COMP) and several cytokines, chemokines, and growth factors in a prospective cohort of patients with symptomatic knee OA. Patients (n=53) with primary symptomatic knee OA were treated for 12 consecutive days with locally applied mud-packs. Assessments were made at baseline, immediately after completion of the treatment cycle, and 6 and 12 months after completion of treatment. They included visual analogue scale (VAS) ratings of pain, the Lequesne algofunctional index for knee OA, and US with calculation of a semiquantitative score that expressed the severity of the local inflammatory process. Serum levels of 27 cytokines (including interferon--inducible protein-10 [IP-10]), chemokines, and growth factors were measured with multiplex bead-based immunoassays, and COMP levels were determined by ELISA. US scores, VAS pain ratings, and Lequesne indexes indicated significant improvement after spa-therapy and at the 6- and 12-month follow-ups. Serum IP-10 levels also dropped significantly (p=0.0035), and this reduction was positively correlated with improvement of the Lequesne index (p=0.031). In patients with knee OA, spa-therapy can modulate serum levels of proinflammatory cytokines/chemokines and produce improvements in joint pain and function that persists for up to 1 year.


Coupled plasma haemofiltration filtration in severe sepsis: systematic review and meta-analysis.
Coupled plasma filtration and adsorption (CPFA) has been used in the treatment of severe sepsis with the intention of removing the proinflammatory and anti-inflammatory mediators from the systemic circulation. It is believed that this interrupts and moderates the septic cascade, but there is uncertainty about the benefits of this therapy. A systematic review and meta-analysis were performed to estimate the effects of CPFA on mortality in severe sepsis. The Cochrane CENTRAL Register of Controlled Trials, CINAHL, EMBASE, MEDLINE-EBSCO-Host, MEDLINE and ProQuest, were searched from 1997 to 2013. Randomised controlled trials, prospective cohort studies and retrospective cohort studies were included using the Centre for Reviews and Dissemination (CRD) framework. Data were abstracted using standard pro forma, and studies independently reviewed by two authors to confirm inclusion criteria. Quality of studies and risk of bias were assessed using the Grading of Recommendations, Assessment, Development and Evaluation Working Group (GRADE) and Critical Appraisal Skills (CASP) criteria, respectively. Meta-analysis was performed using Review Manager (RevMan V.5.1) software. The primary outcome was 28-day mortality. Secondary outcomes were mediator adsorption (picograms/mL), mean arterial BP (mm Hg) and oxygenation ratio. 17 studies met the inclusion criteria (n=441 patients, 242 CPFA). 14 studies reported the primary outcome of 28-day mortality. There were 88 deaths in CPFA patients versus 118 in those receiving haemofiltration: OR 0.34 (95% CI 0.24 to 0.13). Point estimates of effect on the secondary outcomes of mean arterial pressure and oxygen ratio favoured CPFA. Studies were small and heterogenous. Evidence for CPFA in severe sepsis is sparse, of poor quality and further research is required, however, this meta-analysis noted improvements in survival rates of those patients treated with CPFA.


A genetic analysis of relative growth rate and underlying components in Hordeum spontaneum.
Species from productive and unproductive habitats differ inherently in their relative growth rate (RGR) and a wide range of correlated quantitative traits. We investigated the genetic basis of this trait complex, and specifically assessed whether it is under the control of just one or a few genes that can act as 'master switches' by simultaneously affecting a range of traits in the complex. To address this problem, we crossed two Hordeum spontaneum lines originating from two habitats that differ in productivity. The F3 offspring, in which parental alleles are present in different combinations due to recombination and segregation, was analysed for RGR and its underlying components (leaf area ratio, unit leaf rate, photosynthesis, respiration), as well as a number of other physiological and morphological parameters. For this intra-specific comparison, we found a complex of positively and negatively correlated traits, which was quite similar to what is generally observed across species. A quantitative trait loci (QTL) analysis showed three major and one minor QTL for RGR. Most other variables of the growth-trait complex showed fewer QTLs that were typically scattered over various locations on the genome. Thus, at least in H. spontaneum, we found no evidence for regulation of the trait complex by one or two master switches.


Nonlinear phase correction for navigated diffusion imaging.
Motion during diffusion-weighted imaging (DWI) introduces phase errors that can cause significant artifacts in brain images. One method of correcting these errors uses additional navigator data to measure the phase corruptions. Standard navigator methods correct for rigid-body motion but cannot correct for nonrigid deformations of the brain related to the cardiac cycle. This work derives a generalized reconstruction that corrects for nonrigid motion based on a least-squares formulation. Since this reconstruction has the disadvantage of being computationally expensive, an approximation is presented, called a refocusing reconstruction. The refocusing reconstruction is both efficient and straightforward. Each readout is multiplied in image space by the phase conjugate of the navigator image, and these rephased readouts are then summed. The conditions under which the refocusing reconstruction is sufficient are considered and methods to improve the quality of refocused images are discussed. In particular, synchronization of the acquisition to the cardiac cycle can provide data that is well-conditioned to the refocusing reconstruction without incurring the large time penalty traditionally associated with cardiac gating. These methods are applied to steady-state DWI, a promising pulse sequence that is particularly sensitive to motion-induced phase artifacts. The refocusing reconstruction is shown to significantly improve SS-DWI over standard rigid-body corrections.


Effects of Supplementary Feeding on the Breeding Ecology of the Buff-Throated Partridge in a Tibetan Sacred Site, China.
Our goal was to document effects of year-round supplemental feeding on breeding ecology of the Buff-throated Partridge, Tetraophasis szechenyii, within a Tibetan sacred site. We evaluated effects of supplemental feeding used as religious/cultural practices which could potentially aid conservation of endangered phasianids. We compared fed breeding groups to neighboring nonfed groups. Fed groups initiated first clutches significantly earlier than nonfed groups. Earlier laying groups within fed and nonfed groups showed significantly lower hatching rates than later groups; however, fed groups showed significantly higher hatching rates than nonfed groups laying in the same period. Earlier laying increased opportunities to renest. All six fed groups with clutch failures renested compared to only one of five nonfed groups with clutch failures. Fed female breeders showed significantly greater investment in their young with larger clutches and larger eggs, which likely increased survivability of early hatchlings. We observed no predation on birds at feeding sites and recorded only four cases of predation on incubating females, which showed no detectable difference between fed and nonfed groups. Ground-nesting birds typically face high risks of predation. Ten of the 48 groups nested in trees, which occurs in few phasianid species. Tree nests showed significantly higher hatching rates compared to ground nests; however, we found no significant difference in tree nesting between fed and nonfed groups. This partridge is one of four gallinaceous species with cooperative breeding. Breeding groups with helpers had significantly greater reproductive success than single pairs, and fed female breeders with helpers laid bigger eggs than single pairs. Comparing annual reproductive output per group, fed groups not only produced significantly more independent young (≥ 150 days post-hatching), their young hatched significantly earlier, which likely have greater reproductive value over later hatched young of nonfed groups. Supplemental feeding year-round is likely what enabled the successes of the fed partridges.


Recommendations for the use of bronchial thermoplasty in the management of severe asthma.
There are approximately 3 million asthma suffers in South Africa, and the national death rate is ranked as one of the highest in the world. Approximately 5% have severe asthma (uncontrolled despite being adherent on maximal and optimised therapy). Such uncontrolled asthma is associated with high healthcare expenditure and may require treatment with anti-IgE and/or systemic corticosteroids, in addition to inhaler therapy and oral agents. These treatments may be costly, and those such as oral corticosteroids may have potential serious adverse events. There is therefore a need for more effective, affordable and safe therapies for asthma. A new modality of treatment, bronchial thermoplasty (BT), has recently been developed and approved for the treatment of severe asthma. BT involves delivering radio frequency-generated thermal energy to the airways, with the goal of reducing airway-specific smooth-muscle mass. Several clinical studies have confirmed that BT is effective and safe, that it improves control and quality of life in patients whose asthma remains severe despite optimal medical therapy, and that the beneficial effects are sustained for at least 5 years. We provide recommendations for the management of severe asthma, with an emphasis on the role of BT, and endorse the use of BT in patients with severe persistent asthma who remain uncontrolled despite optimal medical therapy as outlined in steps 4 and 5 of the British Thoracic Society (BTS)/Scottish Intercollegiate Guidelines Network (SIGN), UK National Institute of Clinical Excellence (NICE) and Global Initiative for Asthma (GINA) guidelines. We outline the context in which BT should be used, how it works and associated potential adverse events and contraindications, and also review unanswered questions and controversies.


A Statistical Guide to the Design of Deep Mutational Scanning Experiments.
The characterization of the distribution of mutational effects is a key goal in evolutionary biology. Recently developed deep-sequencing approaches allow for accurate and simultaneous estimation of the fitness effects of hundreds of engineered mutations by monitoring their relative abundance across time points in a single bulk competition. Naturally, the achievable resolution of the estimated fitness effects depends on the specific experimental setup, the organism and type of mutations studied, and the sequencing technology utilized, among other factors. By means of analytical approximations and simulations, we provide guidelines for optimizing time-sampled deep-sequencing bulk competition experiments, focusing on the number of mutants, the sequencing depth, and the number of sampled time points. Our analytical results show that sampling more time points together with extending the duration of the experiment improves the achievable precision disproportionately compared with increasing the sequencing depth or reducing the number of competing mutants. Even if the duration of the experiment is fixed, sampling more time points and clustering these at the beginning and the end of the experiment increase experimental power and allow for efficient and precise assessment of the entire range of selection coefficients. Finally, we provide a formula for calculating the 95%-confidence interval for the measurement error estimate, which we implement as an interactive web tool. This allows for quantification of the maximum expected a priori precision of the experimental setup, as well as for a statistical threshold for determining deviations from neutrality for specific selection coefficient estimates.


Women's knowledge of and attitude towards disability in rural Nepal.
What is perceived to be a disability is both culturally specific and related to levels of development and modernity. This paper explores knowledge and attitudes towards people with disabilities among rural women in Nepal, one of the poorer countries in South Asia. Four hundred and twelve married women of reproductive age (aged 15-49 years), from four villages in two different parts of Nepal, who had delivered a child within the last 24 months preceding the study, completed a standard questionnaire. The majority of the participants only considered physical conditions that limit function of an individual and are visible to naked eyes, such as missing a leg or arm, to be disability. Attitudes towards people with disability were generally positive, for example most women believed that disabled people should have equal rights and should be allowed to sit on committees or get married. Most respondents thought that disability could result from: (i) accidents; (ii) medical conditions; or (iii) genetic inheritance. Fewer women thought that disability was caused by fate or bad spirits. There is need to educate the general population on disability, especially the invisible disabilities. There is also a need for further research on disability and its social impact. • There is need to educate the general population on disability, especially the invisible disabilities and its rehabilitation. There is also a need for further research on disability and its social impact.


The prevalence of depressive symptoms in a white European and South Asian population with impaired glucose regulation and screen-detected Type 2 diabetes mellitus: a comparison of two screening tools.
To compare the identification of prevalent depressive symptoms by the World Health Organization-5 Wellbeing Index (WHO-5) and Centre for Epidemiological Studies Depression Scale (CES-D) for South Asian and white European people, male and female, attending a diabetes screening programme, and to explore the adequacy of the screening tools for this population. An additional aim was to further explore associations of depressive symptoms with impaired glucose regulation (IGR) and Type 2 diabetes mellitus (Type2 DM). Eight hundred and sixty-four white European (40-75 years old) and 290 South Asian people (25-75 years old) underwent an oral glucose tolerance test (OGTT), detailed history and anthropometric measurements and completed the WHO-5 and CES-D. Depressive symptoms were defined by a WHO-5 score <or= 13, and CES-D score >or= 16. Unadjusted prevalence of depressive symptoms with the WHO-5, for people with Type2 DM was 42.3% (47.4% in white European; 28.6% in South Asian) and for IGR 30.7% (26% in white European; 45.8% in South Asian). With the CES-D, the prevalence in Type2 DM was 27.2% (25.4% in white European; 31.8% in South Asian) and for IGR 30.7% (27.8% in white European; 40.7% in South Asian). Statistically significant differences in the prevalence of depressive symptoms for sex or ethnicity were not identified. Odds ratios adjusted for age, sex and ethnicity showed no significant association of depression with Type2 DM or IGR, with either WHO-5 or CES-D. Agreement was moderate (kappa = 0.48, 95% confidence intervals 0.42-0.54), and reduced when identifying depressive symptoms in people with Type2 DM. For this group, a WHO-5 cut-point of <or= 10 was optimal. Depressive symptoms, identified by WHO-5 or CES-D, were not significantly more prevalent in people with Type2 DM or IGR. The WHO-5 and CES-D differed in their identification of depressive symptoms in people with Type2 DM, though discrepancies between sex and ethnicity were not identified.


Pinocembrin protects against β-amyloid-induced toxicity in neurons through inhibiting receptor for advanced glycation end products (RAGE)-independent signaling pathways and regulating mitochondrion-mediated apoptosis.
It is known that amyloid-β peptide (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Interaction between Aβ and the receptor for advanced glycation end products (RAGE) has been implicated in neuronal degeneration associated with this disease. Pinocembrin, a flavonoid abundant in propolis, has been reported to possess numerous biological activities beneficial to health. Our previous studies have demonstrated that pinocembrin has neuroprotective effects on ischemic and vascular dementia in animal models. It has been approved by the State Food and Drug Administration of China for clinical use in stroke patients. Against this background, we investigated the effects of pinocembrin on cognitive function and neuronal protection against Aβ-induced toxicity and explored its potential mechanism. Mice received an intracerebroventricular fusion of Aβ25-35. Pinocembrin was administrated orally at 20 mg/kg/day and 40 mg/kg/day for 8 days. Behavioral performance, cerebral cortex neuropil ultrastructure, neuronal degeneration and RAGE expression were assessed. Further, a RAGE-overexpressing cell model and an AD cell model were used for investigating the mechanisms of pinocembrin. The mechanisms underlying the efficacy of pinocembrin were conducted on target action, mitochondrial function and potential signal transduction using fluorescence-based multiparametric technologies on a high-content analysis platform. Our results showed that oral administration of pinocembrin improved cognitive function, preserved the ultrastructural neuropil and decreased neurodegeneration of the cerebral cortex in Aβ25-35-treated mice. Pinocembrin did not have a significant effect on inhibiting Aβ1-42 production and scavenging intracellular reactive oxygen species (ROS). However, pinocembrin significantly inhibited the upregulation of RAGE transcripts and protein expression both in vivo and in vitro, and also markedly depressed the activation of p38 mitogen-activated protein kinase (MAPK)-MAPKAP kinase-2 (MK2)-heat shock protein 27 (HSP27) and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK)-c-Jun pathways and the downstream nuclear factor κB (NFκB) inflammatory response subsequent to Aβ-RAGE interaction. In addition, pinocembrin significantly alleviated mitochondrial dysfunction through improving mitochondrial membrane potential and inhibiting mitochondrial oxidative stress, and regulated mitochondrion-mediated apoptosis by restoration of B cell lymphoma 2 (Bcl-2) and cytochrome c and inactivation of caspase 3 and caspase 9. Pinocembrin was shown to infer cognitive improvement and neuronal protection in AD models. The mechanisms of action of the compound were illustrated on RAGE-dependent transduction inhibition and mitochondrion protection. It appears to be a promising candidate for the prevention and therapy of AD.


Metabolomics identifies changes in fatty acid and amino acid profiles in serum of overweight older adults following a weight loss intervention.
The application of metabolomics in nutritional research may be a useful tool to analyse and predict the response to a dietary intervention. The aim of this study was to examine metabolic changes in serum samples following exposure to an energy-restricted diet (-15% of daily energy requirements) over a period of 8 weeks in overweight and obese older adults (n = 22) using a gas chromatography/mass spectrometry (GC/MS) metabolomic approach. After 8 weeks, there were significant reductions in weight (7%) and metabolic improvement (glucose and lipid profiles). Metabolomic analysis found that total saturated fatty acids (SFAs), including palmitic acid (C16:0) and stearic acid (C18:0) and monounsaturated fatty acids (MUFAs), were significantly decreased after the 8-week intervention. Furthermore, palmitoleic acid (C16:1) was found to be a negative predictor of change in body fat loss. Both the total ω-6 and ω-3 polyunsaturated fatty acids (PUFAs) significantly decreased, although the overall total amounts of PUFAs did not. The branched chain amino acid (BCAA) isoleucine significantly decreased in the serum samples after the intervention. In conclusion, this study demonstrated that the weight loss intervention based on a hypocaloric diet identified changes in the metabolic profiles of serum in overweight and obese older adults, with a reduction in anthropometric and biochemical parameters also found.


Evaluation of a weighted genetic risk score for the prediction of biomarkers of CYP2A6 activity.
The nicotine metabolite ratio (NMR; 3-hydroxycotinine/cotinine) is an index of CYP2A6 activity. CYP2A6 is responsible for nicotine's metabolic inactivation and variation in the NMR/CYP2A6 is associated with several smoking behaviors. Our aim was to integrate established alleles and novel genome-wide association studies (GWAS) signals to create a weighted genetic risk score (wGRS) for the CYP2A6 gene for European-ancestry populations. The wGRS was compared with a previous CYP2A6 gene scoring approach designed for an alternative phenotype (C2/N2; cotinine-d2/(nicotine-d2 + cotinine-d2)). CYP2A6 genotypes and the NMR were assessed in European-ancestry participants. The wGRS training set included N = 933 smokers recruited to the Pharmacogenetics of Nicotine Addiction and Treatment clinical trial [NCT01314001]. The replication cohort included N = 196 smokers recruited to the Quit 2 Live clinical trial [NCT01836276]. Comparisons between the two CYP2A6 phenotypes and with fractional clearance were made in a laboratory-based pharmacokinetic study (N = 92 participants). In both the training and replication sets, the wGRS, which included seven CYP2A6 variants, explained 33.8% (P < 0.001) of the variance in NMR, providing improved predictive power to the NMR phenotype when compared with other CYP2A6 gene scoring approaches. NMR and C2/N2 were strongly correlated to nicotine clearance (ρ = 0.70 and ρ = 0.79, respectively; P < 0.001), and to one another (ρ = 0.82; P < 0.001); however reduced function genotypes occurred in slow NMR but throughout C2/N2. The wGRS was able to predict smoking quantity and nicotine intake, to discriminate between NMR slow and normal metabolizers (AUC = 0.79; P < 0.001), and to replicate previous NMR-stratified cessation outcomes showing unique treatment outcomes between metabolizer groups.


Rationing just medical care.
U.S. politicians and policymakers have been preoccupied with how to pay for health care. Hardly any thought has been given to what should be paid for--as though health care is a commodity that needs no examination--or what health outcomes should receive priority in a just society, i.e., rationing. I present a rationing proposal, consistent with U.S. culture and traditions, that deals not with "health care," the terminology used in the current debate, but with the more modest and limited topic of medical care. Integral to this rationing proposal--which allows scope to individual choice and at the same time recognizes the interdependence of the individual and society--is a definition of a "decent minimum," the basic package of medical treatments everyone should have access to in a just society. I apply it to a specific example, diabetes mellitus, and track it through a person's life span.


Recognition molecules myelin-associated glycoprotein and tenascin-C inhibit integrin-mediated adhesion of neural cells to collagen.
Because of the importance of collagens in mediating cell-substrate interactions and the association of collagens with neural recognition molecules in the peripheral nervous system, the ability of neural recognition molecules to modify the substrate properties of collagens, in particular collagen type I, for cell adhesion was determined. Two cell lines, the N2A neuroblastoma and PC12 pheochromocytoma, were investigated for their capacity to adhere to different collagen types in the absence or presence of several neural recognition molecules. Adhesion of N2A or PC12 cells and membrane vesicles from PC12 cells to collagen type I was reduced when the collagen had been preincubated prior to its application as substrate with the extracellular domain of myelin-associated glycoprotein (s-MAG) or, as control, fibroblast tenascin-C (F-tenascin). In mixture with other collagen types, s-MAG was only able to reduce the adhesiveness of collagen types III and V, but not of collagen types II and IV. F-tenascin reduced the adhesiveness of all collagen types tested. In contrast to F-tenascin, s-MAG had to be present during fibrillogenesis to exert its effect, indicating that it must be coassembled into the collagen fibril to block the binding site. Cell adhesion to collagen type I was dependent on Mg2+ or Mn2+ and inhibited by a monoclonal antibody to the alpha 1 integrin subunit. The combined observations indicate that s-MAG and F-tenascin interfere with cell binding, most probably by modifying the integrin binding site, and that the two molecules act by different mechanisms, both leading to reduction of adhesion.


Arrhythmic safety of hydroxychloroquine in COVID-19 patients from different clinical settings.
The aim of the study was to describe ECG modifications and arrhythmic events in COVID-19 patients undergoing hydroxychloroquine (HCQ) therapy in different clinical settings. COVID-19 patients at seven institutions receiving HCQ therapy from whom a baseline and at least one ECG at 48+ h were available were enrolled in the study. QT/QTc prolongation, QT-associated and QT-independent arrhythmic events, arrhythmic mortality, and overall mortality during HCQ therapy were assessed. A total of 649 COVID-19 patients (61.9 ± 18.7 years, 46.1% males) were enrolled. HCQ therapy was administrated as a home therapy regimen in 126 (19.4%) patients, and as an in-hospital-treatment to 495 (76.3%) hospitalized and 28 (4.3%) intensive care unit (ICU) patients. At 36-72 and at 96+ h after the first HCQ dose, 358 and 404 ECGs were obtained, respectively. A significant QT/QTc interval prolongation was observed (P < 0.001), but the magnitude of the increase was modest [+13 (9-16) ms]. Baseline QT/QTc length and presence of fever (P = 0.001) at admission represented the most important determinants of QT/QTc prolongation. No arrhythmic-related deaths were reported. The overall major ventricular arrhythmia rate was low (1.1%), with all events found not to be related to QT or HCQ therapy at a centralized event evaluation. No differences in QT/QTc prolongation and QT-related arrhythmias were observed across different clinical settings, with non-QT-related arrhythmias being more common in the intensive care setting. HCQ administration is safe for a short-term treatment for patients with COVID-19 infection regardless of the clinical setting of delivery, causing only modest QTc prolongation and no directly attributable arrhythmic deaths.


Ionic liquids and deep eutectic solvents for the recovery of phenolic compounds: effect of ionic liquids structure and process parameters.
Water pollution is a severe and challenging issue threatening the sustainable development of human civilization. Besides other pollutants, waste fluid streams contain phenolic compounds. These have an adverse effect on the human health and marine ecosystem due to their toxic, mutagenic, and carcinogenic nature. Therefore, it is necessary to remove such phenolic pollutants from waste stream fluids prior to discharging to the environment. Different methods have been proposed to remove phenolic compounds from wastewater, including extraction using ionic liquids (ILs) and deep eutectic solvent (DES), a class of organic salts having melting point below 100 °C and tunable physicochemical properties. The purpose of this review is to present the progress in utilizing ILs and DES for phenolic compound extraction from waste fluid streams. The effects of IL structural characteristics, such as anion type, cation type, alkyl chain length, and functional groups will be discussed. In addition, the impact of key process parameters such as pH, phenol concentration, phase ratio, and temperature will be also described. More importantly, several ideas for addressing the limitations of the treatment process and improving its efficiency and industrial viability will be presented. These ideas may form the basis for future studies on developing more effective IL-based processes for treating wastewaters contaminated with phenolic pollutants, to address a growing worldwide environmental problem.


Ovarian follicular concentrations of activin, follistatin, inhibin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-2 (IGFBP-2), IGFBP-3, and vascular endothelial growth factor in spontaneous menstrual cycles of normal women of advanced reproductive age.
Previous studies indicate that the menstrual cycles of older reproductive age women are characterized by a selective elevation of FSH associated with early development and ovulation of a dominant follicle. Several intraovarian hormones and growth factors have been identified that appear to serve important paracrine roles. The purpose of this study was to examine follicular fluid (FF) hormones and growth factors in the dominant follicle of unstimulated cycles of older, ovulatory women. We aspirated FF from the preovulatory dominant follicle in natural menstrual cycles of older subjects (age, 40-45 yr; n = 20) and younger controls (age, 20-25 yr; n = 19). FF was analyzed for estradiol, progesterone, testosterone, androstenedione, inhibin A and B, total activin A, total follistatin, insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-2 (IGFBP-2), IGFBP-3, and vascular endothelial growth factor (VEGF) concentrations. We found that the dominant follicles from older women contain normal concentrations of steroids, inhibin A and B, IGF-II, IGFBP-2, and IGFBP-3; increased concentrations of follistatin, activin A, and VEGF; and decreased concentrations of IGF-I. Therefore, under the influence of elevated FSH, the dominant follicle in older women is highly competent in terms of hormone and growth factor secretion. We postulate that elevated FF activin may be related to the early ovulation observed in older women, whereas elevated VEGF may be related to the meiotic spindle abnormalities observed in the oocytes of older reproductive age women.


Claiming peaceful embodiment through yoga in the aftermath of trauma.
The purpose of this study was to describe the experiences of practicing yoga and its role within processes of healing for adult women with complex trauma histories. Using a hermeneutic phenomenological method, data were analyzed from interviews with 39 women. Results showed that the core meaning of participants' experience of healing through yoga is claiming peaceful embodiment. This is an ongoing process occurring on a continuum whereby women experienced improved connections with and sense of ownership and control over their bodies, emotions and thoughts, and a greater sense of well-being, calmness, and wholeness in their bodies and minds. A number of interconnected essential themes related to this core meaning were also identified, illuminating processes that supported claiming peaceful embodiment and capabilities that were enabled by being more peacefully embodied. Additional themes were identified highlighting factors that facilitated or impeded participants' engagement with yoga and their experiences of healing through yoga.


Inequality in individual mortality and economic conditions earlier in life.
We analyze the effect of being born in a recession on the mortality rate later in life in conjunction with social class. We use individual data records from Dutch registers of birth, marriage, and death certificates, covering the period 1815-2000, and we merge these with historical data on macro-economic outcomes and health indicators. We estimate duration models and inequality measures. The results indicate that being born in a recession increases the mortality rate later in life for most of the population. Lower social classes suffer disproportionally from being born in recessions. This exacerbates mortality inequality. Upward mobility does not vary much with the business cycle at birth.


Evidence of changes in the immunophenotype and metabolic characteristics (intracellular reactive oxygen radicals) of fetal, but not maternal, monocytes and granulocytes in the fetal inflammatory response syndrome.
The fetal inflammatory response syndrome (FIRS) is present in a fraction of fetuses exposed to intra-amniotic infection and is associated with the impending onset of labor and multisystem organ involvement. Neonates born with funisitis, the histologic counterpart of fetal systemic inflammation, are at increased risk for cerebral palsy and bronchopulmonary dysplasia. The aim of this study was to determine whether fetal and maternal granulocytes and monocytes have the phenotypic and metabolic characteristics of activation in cases with FIRS. A case-control study was conducted with umbilical cord and maternal blood samples obtained from patients who delivered preterm with (n=30) and without funisitis (n=15). The phenotypic characteristics of granulocytes and monocytes were examined using flow cytometry and monoclonal antibodies including CD11b, CD14, CD15, CD16, CD18, CD49d, CD62L, CD64, CD66b, and HLA-DR. Intracellular reactive oxygen species (iROS) were measured at the basal state and after stimulation (oxidative burst). A P<0.01 was considered statistically significant. (1) Funisitis was associated with a significant increase in the median mean channel brightness (MCB) of CD14, CD64, and CD66b on granulocytes and the MCB of CD64 on monocytes collected from umbilical cord blood. (2) The basal iROS production and oxidative burst were higher in the umbilical cord monocytes of neonates with funisitis than in those without funisitis. (3) There were no differences in the immunophenotype, basal iROS production, and oxidative burst in maternal granulocytes or monocytes between the study groups. Fetal systemic inflammation is associated with phenotypic and metabolic changes consistent with activation in fetal immune cells but not in maternal blood.


Evaluation of a patient-initiated review system in rheumatoid arthritis: an implementation trial protocol.
Rheumatoid arthritis is a chronic inflammatory condition that affects the joints causing unpredictable episodes of pain, stiffness and disability. People with rheumatoid arthritis usually require lifelong specialist follow-up but frequently have periods when their disease can be managed through self-care or that provided by their general practitioner. Compared to the traditional clinician-driven care in rheumatoid arthritis, patient-initiated care has proven to be more beneficial in terms of reducing unnecessary medical reviews, providing greater satisfaction to patients and staffs and maintaining the patient's physical and psychological status. We aim to evaluate the implementation of a patient-initiated review system in a routine secondary care rheumatology service in a public hospital in England, where patients get the opportunity to self-manage their disease by requesting specialist reviews at times of need instead of clinician-scheduled appointments. Three hundred and eighty patients attending routine review at Plymouth Hospitals NHS Trust will be randomised to either enrol immediately into a patient-initiated review system (direct access group), or to be seen regularly by a clinician at the hospital (regular clinician-initiated group). Patients (or their general practitioner) in the direct access group can arrange a review by calling a rheumatology nurse-led advice line that enables telephone delivered clinical advice, or where appropriate, an appointment with a rheumatologist within 10 working days. Patients in the regular clinician-initiated group will attend their planned appointments at regular intervals during the intervening period of 12 months. The primary outcome of interest is patient satisfaction; secondary outcomes include service use, waiting times and clinical measures. Semi-structured, in-depth interviews will be conducted with a subset of patients and staff with the aim of identifying facilitators/barriers in implementing patient-initiated clinics. The implementation of a patient-initiated review system in routine care rheumatology will replace the fixed clinician-driven review system with a more flexible patient-driven system where patients usually self-manage their disease, but can request prompt help when required. We believe that this study will enable a comparison of the changes in local services and will be helpful in exploring the benefits/drawbacks of such implementation, thus providing lessons for implementation in other hospitals and for other chronic diseases.


Response to perturbations as a built-in feature in a mathematical model for paced finger tapping.
Paced finger tapping is one of the simplest tasks to study sensorimotor synchronization. The subject is instructed to tap in synchrony with a periodic sequence of brief tones, and the time difference (called asynchrony) between each response and the corresponding stimulus is recorded. Despite its simplicity, this task helps to unveil interesting features of the underlying neural system and the error-correction mechanism responsible for synchronization. Perturbation experiments are usually performed to probe the subject's response, for example, in the form of a "step change," i.e., an unexpected change in tempo. The asynchrony is the usual observable in such experiments and it is chosen as the main variable in many mathematical models that attempt to describe the phenomenon. In this work we show that although asynchrony can be perfectly described in operational terms, it is not well defined as a model variable when tempo perturbations are considered. We introduce an alternative variable and a mathematical model that intrinsically takes into account the perturbation and make theoretical predictions about the response to novel perturbations based on the geometrical organization of the trajectories in phase space. Our proposal is relevant to understand interpersonal synchronization and the synchronization to nonperiodic stimuli.


Safety and efficacy of ubrogepant in participants with major cardiovascular risk factors in two single-attack phase 3 randomized trials: ACHIEVE I and II.
To examine the safety and efficacy of ubrogepant for acute treatment of migraine across cardiovascular (CV) disease risk categories. ACHIEVE I and II were multicenter, double-blind, single-attack, phase 3 trials in adults with migraine, with or without aura. Participants were randomized 1:1:1 to placebo or ubrogepant (50 or 100 mg in ACHIEVE I; 25 or 50 mg in ACHIEVE II), to treat one migraine attack of moderate or severe headache pain intensity. This post-hoc analysis pooled data from ubrogepant 50 mg and placebo groups from the ACHIEVE trials to examine the safety and efficacy of ubrogepant by baseline cardiovascular disease risk factors. Using a cardiovascular risk assessment algorithm, participants were categorized as having no cardiovascular risk, low cardiovascular risk or moderate-high cardiovascular risk at baseline. Treatment-emergent adverse events were documented 48 h and 30 days after taking the trial medication. Co-primary efficacy outcomes were 2-h pain freedom and 2-h absence of most bothersome migraine-associated symptom. Overall, 3358 participants were randomized in the ACHIEVE trials (n = 2901 safety population; n = 2682 modified intent-to-treat population). In the safety population, 11% of participants were categorized as moderate-high (n = 311), 32% low (n = 920), and 58% no cardiovascular risk factors (n = 1670). The proportion of ubrogepant participants reporting a treatment-emergent adverse event was comparable across risk categories and similar to placebo. The treatment effects of ubrogepant versus placebo were consistent across cardiovascular risk categories for all efficacy outcomes. The safety and efficacy of ubrogepant for the acute treatment of a single migraine attack did not differ by the presence of major cardiovascular risk factors. No evidence of increased treatment-emergent adverse events or cardiac system organ class adverse events with ≥2 major cardiovascular risk factors and no safety concerns were identified.Trial Registration: ACHIEVE I ClinicalTrials.gov number, NCT02828020; ACHIEVE II ClinicalTrials.gov number, NCT02867709.


Dipeptidyl peptidases as survival factors in Ewing sarcoma family of tumors: implications for tumor biology and therapy.
Ewing sarcoma family of tumors (ESFT) is a group of aggressive pediatric malignancies driven by the EWS-FLI1 fusion protein, an aberrant transcription factor up-regulating specific target genes, such as neuropeptide Y (NPY) and its Y1 and Y5 receptors (Y5Rs). Previously, we have shown that both exogenous NPY and endogenous NPY stimulate ESFT cell death via its Y1 and Y5Rs. Here, we demonstrate that this effect is prevented by dipeptidyl peptidases (DPPs), which cleave NPY to its shorter form, NPY(3-36), not active at Y1Rs. We have shown that NPY-induced cell death can be abolished by overexpression of DPPs and enhanced by their down-regulation. Both NPY treatment and DPP blockade activated the same cell death pathway mediated by poly(ADP-ribose) polymerase (PARP-1) and apoptosis-inducing factor (AIF). Moreover, the decrease in cell survival induced by DPP inhibition was blocked by Y1 and Y5R antagonists, confirming its dependence on endogenous NPY. Interestingly, similar levels of NPY-driven cell death were achieved by blocking membrane DPPIV and cytosolic DPP8 and DPP9. Thus, this is the first evidence of these intracellular DPPs cleaving releasable peptides, such as NPY, in live cells. In contrast, another membrane DPP, fibroblast activation protein (FAP), did not affect NPY actions. In conclusion, DPPs act as survival factors for ESFT cells and protect them from cell death induced by endogenous NPY. This is the first demonstration that intracellular DPPs are involved in regulation of ESFT growth and may become potential therapeutic targets for these tumors.


Direct to operating room trauma resuscitation decreases mortality among severely injured children.
Expediting evaluation and intervention for severely injured patients has remained a mainstay of advanced trauma care. One technique, direct to operating room (DOR) resuscitation, for selective adult patients has demonstrated decreased mortality. We sought to investigate the application of this protocol in children. All DOR pediatric patients from 2009 to 2016 at a pediatric Level I trauma center were identified. Direct to OR criteria included penetrating injury, chest injuries, amputations, significant blood loss, cardiopulmonary resuscitation, and surgeon discretion. Demographics, injury patterns, interventions, and outcomes were analyzed. Observed mortality was compared with expected mortality, calculated using Trauma Injury Severity Score methodology, with two-tailed t tests, and a p value less than 0.5 was considered significant. Of 2,956 total pediatric trauma activations, 82 (2.8%) patients (age range, 1 month to 17 years) received DOR resuscitation during the study period. The most common indications for DOR were penetrating injuries (62%) and chest injuries (32%). Forty-four percent had Injury Severity Score (ISS) greater than 15, 33% had Glasgow Coma Scale (GCS) score of 8 or less, and 9% were hypotensive. The most commonly injured body regions were external (66%), head (34%), chest (30%), and abdomen (27%). Sixty-seven (82%) patients required emergent procedural intervention, most commonly wound exploration/repair (35%), central venous access (22%), tube thoracostomy (19%), and laparotomy (18%). Predictors of intervention were ISS greater than 15 (odds ratio, 14; p = 0.013) and GCS < 9 (odds ratio = 8.5, p = 0.044). The survival rate to discharge for DOR patients was 84% compared with an expected survival of 79% (Trauma Injury Severity Score) (p = 0.4). The greatest improvement relative to expected mortality was seen in the subgroup with penetrating trauma (84.5% vs 74.4%; p = 0.002). A selective policy of resuscitating the most severely injured children in the OR can decrease mortality. Patients suffering penetrating trauma with the highest ISS, and diminished GCS scores have the greatest benefit. Trauma centers with appropriate resources should evaluate implementing similar policies. Diagnostic tests or criteria, level II.


Effect of polarization purity of cylindrical vector beam on tightly focused spot.
The tightly focused spots of cylindrical vectors (CVs) are dependent on polarization composition. We experimentally demonstrate the effect of polarization purity (PP) of the CV beam on the tightly focused spot quantitatively, which should be strictly controlled for the effective applications of the CV beam. The focal spots measured by a knife-edge scanning method showed that the azimuthally polarized (AP) component increases the transverse field and the size of the focal spots, while the radially polarized component results in a nonzero intensity distribution at the center of the focus even in a high PP AP beam.


Interaction of Escherichia coli ribosomal protein S1 with ribosomes.
The binding affinity of Escherichia coli ribosomal protein S1 for 30S ribosomal particles has been determined by a sucrose gradient band sedimentation technique; the association constant (K) for the binding of one S1 protein per active 30S ribosomal subunit is approximately 2 X 10(8) M-1. The involvement of the two polynucleotide binding sites of S1 protein (site I binding single-stranded DNA or RNA, and site II binding single-stranded RNA only) in the S1--ribosomal interaction have been examined by competition experiments with polynucleotides of known affinity for the two sites. We find that site I does not contribute to the interaction; site II binding appears to provide a major part of the binding free energy, presumably by interaction of S1 with the 16S rRNA of the 30S particle. The remaining binding free energy is probably derived from the interaction of S1 protein with other proteins of the 30S subunit. The affinity of S1 for 70S ribosomes is about the same as that for the 30S subunit; the affinity of S1 for 50S subunits is much less. Binding affinities and stoichiometries of S1 protein with "inactive" 30S ribosomal subunits have also been examined.


Despite obstacles, considerable potential exists for more robust federal policy on community development and health.
The implementation of the Affordable Care Act of 2010 and the Obama administration's urban policy create an opportunity to link community development with health in new and powerful ways. The administration's policy emphasizes improved access to and quality of care through coordinated local and regional approaches, expansion of access to healthy food, and the support of environmental health-including clean air, water, and soil-and healthy homes. New federal programs, such as the Affordable Care Act's Community Transformation Grants, seek to prevent death and disability through policy, environmental, programmatic, and infrastructure changes. But fragmented congressional jurisdiction and budget "scoring" rules pose challenges to needed reform. We argue that government agencies need to adopt so-called systems of innovation, or organizational practices and support mechanisms that seek continuously to test new models, refine promising ones, bring to scale those that work best, and restructure or terminate what does not. We also argue that a strong and well-focused policy advocacy coalition is needed to help drive reform focused on the social determinants of health.


Environmental challenges posed by veld fires in fragile regions: The case of the Bulilima and Mangwe districts in southern Zimbabwe.
This original research confronted challenges to environmental management and sustainability posed by veld fires in the Bulilima and Mangwe Districts of Matabeleland in the South Province in southern Zimbabwe. Veld fires have affected the fauna and flora, polluted air and water, and destroyed livelihoods. The study aimed at establishing challenges to environmental sustainability posed by veld fires, identifying the type of environment upon which veld fires have impacted, analysing legal issues and other interventions surrounding the control of veld fires and suggesting new control measures for veld fires. A qualitative research design and quota sampling were used. The study involved 30 participants. Data was collected through a questionnaire, an interview guide and participant observation. Challenges to environmental management and sustainability posed by veld fires include property damage, reduced soil fertility, destruction of vegetation, air and water pollution and destruction of wildlife. Most veld fires are a result of human actions that emanate from the disposal of cigarettes, the burning of vegetation when preparing fields, the use of fire by hunters, smoking out bees and the making of fires by motorists along highways. The government should consider reviewing the current environmental statues. Fireguards should be wide enough to lessen veld-fire impact. Lastly, veld-fire campaigns and rehearsals should be run on a regular basis. It is hoped that this work would make a significant contribution through improving the current thinking about environmental management and sustainability, thereby benefiting policy makers, practitioners and stakeholders.


The mediating role of sleep, physical activity, and diet in the association between shift work and respiratory infections.
Objectives Shift work may be associated with an increased incidence of respiratory infections. However, underlying mechanisms are unclear. Therefore, our aim was to examine the mediating role of sleep, physical activity, and diet in the association between shift work and respiratory infections. Methods This prospective cohort study included 396 shift and non-shift workers employed in hospitals. At baseline, sleep duration and physical activity were measured using actigraphy and sleep/activity diaries, sleep quality was reported, and frequency of meal and snack consumption was measured using food diaries. In the following six months, participants used a smartphone application to report their influenza-like illness/acute respiratory infection (ILI/ARI) symptoms daily. Mediation analysis of sleep, physical activity, and diet as potential mediators of the effect of shift work on ILI/ARI incidence rate was performed using structural equation modeling with negative binomial and logistic regression. Results Shift workers had a 23% [incidence rate ratio (IRR) 1.23, 95% CI 1.01-1.49] higher incidence rate of ILI/ARI than non-shift workers. After adding the potential mediators to the model, this reduced to 15% (IRR 1.15, 95% CI 0.94-1.40). The largest mediating (ie, indirect) effect was found for poor sleep quality, with shift workers having 29% more ILI/ARI episodes via the pathway of poorer sleep quality (IRR 1.29, 95% CI 1.02-1.95). Conclusions Compared to non-shift workers, shift workers had a higher incidence rate of ILI/ARI that was partly mediated by poorer sleep quality. Therefore, it may be relevant for future research to focus on perceived sleep quality as an underlying mechanism in the relation between shift work and increased infection susceptibility.


Molecular characterization of U3 small nucleolar RNA from the early diverging protist, Euglena gracilis.
U3 small nucleolar RNA (snoRNA) has been isolated from Euglena gracilis, an early diverging protist, and its primary sequence determined. Although this 180-nucleotide-long RNA is considerably smaller than its homolog in vertebrate animals, it contains the conserved sequence blocks (boxes A, Ao, B, C and D) characteristic of U3 snoRNAs from other organisms. A secondary structure can be modelled that displays many of the salient features found in published core structures of vertebrate, yeast and trypanosome U3 snoRNAs. The functional significance of this proposed secondary structure is discussed in relation to the role E. gracilis U3 snoRNA may have in pre-rRNA processing in this organism. Multiple expressed species of E. gracilis U3 snoRNA were found to differ in nucleotide sequence at a number of positions; some of these differences alter pairing in the proposed secondary structure. Analysis of E. gracilis genomic DNA revealed a complex pattern of U3-hybridizing sequences that parallels the multiplicity of expressed species of U3 snoRNA revealed by transcript analysis.


Comparison of diazepam and oxazepam: preference, liking and extent of abuse.
In a residential hospital research ward setting, the effects of and preference for placebo, oxazepam (480 mg) and diazepam (40, 80 and 160 mg) were studied in human volunteers with histories of sedative drug abuse. Doses p.o. were administered every 3rd day under double-blind conditions. After an initial exposure to the letter-coded test drugs, a series of choice days was scheduled on which subjects chose between two available drug alternatives. Compared with oxazepam, diazepam produced greater liking (area under the time-action curve), peak liking and euphoria and was judged to be of greater monetary street value. Diazepam was categorized as producing barbiturate-like subjective effects more frequently than was oxazepam (54 vs. 21%), whereas oxazepam was identified as placebo more often than diazepam (32 vs. 4%). Diazepam was associated with a more rapid onset of effect than was oxazepam, and this rapid onset was repeatedly cited by subjects in poststudy written comments as being a desirable feature of the drug effect. In choice tests, 80 and 160 mg of diazepam were preferred to 480 mg of oxazepam on 62.5 and 91.7% of the choice tests, respectively. In choice tests between placebo and drug, placebo was never preferred to diazepam; however, placebo was preferred to oxazepam on 21.4% of choice tests. Overall, these results extend previous experimental observations suggesting that diazepam has a higher abuse liability than oxazepam. The results are also compatible with an analysis of epidemiological data showing that diazepam abuse uniformly exceeds oxazepam abuse on seven epidemiological measures of drug abuse.


Hemocompatibility and safety of the Carmat Total Artifical Heart hybrid membrane.
The Carmat bioprosthetic total artificial heart (C-TAH) is a biventricular pump developed to minimize drawbacks of current mechanical assist devices and improve quality of life during support. This study aims to evaluate the safety of the hybrid membrane, which plays a pivotal role in this artificial heart. We investigated in particular its blood-contacting surface layer of bovine pericardial tissue, in terms of mechanical aging, risks of calcification, and impact of the hemodynamics shear stress inside the ventricles on blood components. Hybrid membranes were aged in a custom-designed endurance bench. Mechanical, physical and chemical properties were not significantly modified from 9 months up to 4 years of aging using a simulating process. Exploration of erosion areas did not show no risk of oil diffusion through the membrane. Blood contacting materials in the ventricular cavities were subcutaneously implanted in Wistar rats for 30 days as a model for calcification and demonstrated that the in-house anti-calcification pretreatment with Formaldehyde-Ethanol-Tween 80 was able to significantly reduce the calcium concentration from 132 μg/mg to 4.42 μg/mg (p < 0.001). Hemodynamic simulations with a computational model were used to reproduce shear stress in left and right ventricles and no significant stress was able to trigger hemolysis, platelet activation nor degradation of the von Willebrand factor multimers. Moreover, explanted hybrid membranes from patients included in the feasibility clinical study were analyzed confirming preclinical results with the absence of significant membrane calcification. At last, blood plasma bank analysis from the four patients implanted with C-TAH during the feasibility study showed no residual glutaraldehyde increase in plasma and confirmed hemodynamic simulation-based results with the absence of hemolysis and platelet activation associated with normal levels of plasma free hemoglobin and platelet microparticles after C-TAH implantation. These results on mechanical aging, calcification model and hemodynamic simulations predicted the safety of the hybrid membrane used in the C-TAH, and were confirmed in the feasibility study.


SARS-CoV-2 Infection Among Hospitalized Pregnant Women: Reasons for Admission and Pregnancy Characteristics - Eight U.S. Health Care Centers, March 1-May 30, 2020.
Pregnant women might be at increased risk for severe coronavirus disease 2019 (COVID-19), possibly related to changes in their immune system and respiratory physiology* (1). Further, adverse birth outcomes, such as preterm delivery and stillbirth, might be more common among pregnant women infected with SARS-CoV-2, the virus that causes COVID-19 (2,3). Information about SARS-CoV-2 infection during pregnancy is rapidly growing; however, data on reasons for hospital admission, pregnancy-specific characteristics, and birth outcomes among pregnant women hospitalized with SARS-CoV-2 infections are limited. During March 1-May 30, 2020, as part of Vaccine Safety Datalink (VSD)† surveillance of COVID-19 hospitalizations, 105 hospitalized pregnant women with SARS-CoV-2 infection were identified, including 62 (59%) hospitalized for obstetric reasons (i.e., labor and delivery or another pregnancy-related indication) and 43 (41%) hospitalized for COVID-19 illness without an obstetric reason. Overall, 50 (81%) of 62 pregnant women with SARS-CoV-2 infection who were admitted for obstetric reasons were asymptomatic. Among 43 pregnant women hospitalized for COVID-19, 13 (30%) required intensive care unit (ICU) admission, six (14%) required mechanical ventilation, and one died from COVID-19. Prepregnancy obesity was more common (44%) among pregnant women hospitalized for COVID-19 than that among asymptomatic pregnant women hospitalized for obstetric reasons (31%). Likewise, the rate of gestational diabetes (26%) among pregnant women hospitalized for COVID-19 was higher than it was among women hospitalized for obstetric reasons (8%). Preterm delivery occurred in 15% of pregnancies among 93 women who delivered, and stillbirths (fetal death at ≥20 weeks' gestation) occurred in 3%. Antenatal counseling emphasizing preventive measures (e.g., use of masks, frequent hand washing, and social distancing) might help prevent COVID-19 among pregnant women,§ especially those with prepregnancy obesity and gestational diabetes, which might reduce adverse pregnancy outcomes.