Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

FROM TOTAL INSTITUTION TO EXTITUTION? Discussions on the future of monastic life in the Benedictine women’s monasteries of Catalonia (Spain

On the 50th anniversary of the creation of the Federation of Benedictine Women’s Monasteries of Catalonia (Spain), the five monasteries represented are discussing the following question: what will monastic life be like in the future? This question is added to the debate about “new forms of monasticism”, “urban monastic life” and, in a more general sense, to the modernisations and “the opening up” of the precepts and practices of monastic life at this time. Faced with the ambitious monastic questioning, the author responds with five deliberately provocative debates developed out of a consideration of various chapters of the Rule of St. Benedict that raise profound questions when it comes to responding to the question presented here. Having described these five debates, by way of a summary, the article presents three ideal types of monastery in relation to the current processes of deinstitutionalisation that represent, in an overall way, three provisional responses and serve as a focus for the question discussed here.

Effects of usual nutrient intake and vitamin D status on markers of bone turnover in Swiss adolescents.

OBJECTIVE: To evaluate the effects of nutrient intake and vitamin D status on markers of type I collagen formation and degradation in adolescent boys and girls. DESIGN: Cross-sectional study. SETTING: Canton of Vaud, West Switzerland. SUBJECTS: A total of 92 boys and 104 girls, aged 11-16 y. Data were collected on height, weight, pubertal status (self-assessment of Tanner stage), nutrient intake (3-day dietary record) and fasting serum concentration of 25-hydroxyvitamin D (25OHD), and markers of collagen formation (P1NP) and degradation (serum C-terminal telopeptides: S-CTX). RESULTS: Tanner stage was a significant determinant of P1NP in boys and girls and S-CTX in girls. Of the nutrients examined, only the ratio of calcium to phosphorus (Ca/P) was positively associated with P1NP in boys, after adjustment for pubertal status. 25OHD decreased significantly at each Tanner stage in boys. Overall, 15% of boys and 17% of girls were identified as being vitamin D insufficient (serum 25OHD <30 nmol/l), with the highest proportion of insufficiency at Tanner stage 4-5 (29%) in boys and at Tanner stage 3 (24%) in girls. A significant association was not found between 25OHD and either bone turnover marker, nor was 25OHD insufficiency associated with higher concentrations of the bone turnover markers. CONCLUSIONS: The marked effects of puberty on bone metabolism may have obscured any possible effects of diet and vitamin D status on markers of bone metabolism. The mechanistic basis for the positive association between dietary Ca/P ratio and P1NP in boys is not clear and may be attributable to a higher Ca intake per se, a critical balance between Ca and P intake or higher dairy product consumption. A higher incidence of vitamin D insufficiency in older adolescents may reflect a more sedentary lifestyle or increased utilisation of 25OHD, and suggests that further research is needed to define their requirements. SPONSORSHIP: Nestec Ltd and The Swiss Foundation for Research in Osteoporosis.

Traitement de la d��pression résistante par l'association citalopram-lithium. Méthodologie d'une étude multicentrique en double aveugle et résultats préliminaires [Treatment of resistant depression with the citalopram-lithium combination. Methodology of a double-blind multicenter study and preliminary results].

Citalopram, a new bicyclic antidepressant, is the most selective serotonin reuptake inhibitor. In a number of double-blind controlled studies, citalopram was compared to placebo and to known tricyclic antidepressants. These studies have shown their efficacy and good safety. The inefficacy of a psychotropic treatment in at least 20% of depressives has led a number of authors to propose original drug combinations and associations, like antidepressant/lithium (Li), antidepressant/sleep deprivation (agrypnia), antidepressant/ECT, or antidepressant/LT3. The aim of this investigation is to evaluate the clinical effectiveness and safety of a combined citalopram/lithium treatment in therapy-resistant patients, taking account of serotonergic functions, as tested by the fenfluramine/prolactin test, and of drug pharmacokinetics and pharmacogenetics of metabolism. DESIGN OF THE STUDY: A washout period of 3 days before initiating the treatment is included. After an open treatment phase of 28 days (D) with citalopram (20 mg D1-D3; 40 mg D4-D14; 40 or 60 mg D15-D28; concomitant medication allowed: chloral, chlorazepate), the nonresponding patients [less than 50% improvement in the total score on the 21 item-Hamilton Depression Rating Scale (HDRS)] are selected and treated with or without Li (randomized in double-blind conditions: citalopram/Li or citalopram/placebo) during the treatment (D29-D35). Thereafter, all patients included in the double-blind phase subsequently receive an open treatment with citalopram/Li for 7 days (D36-D42). The hypothesis of a relationship between serotoninergic functions in patients using the fenfluramine/prolactin test (D1) and the clinical response to citalopram (and Li) is assessed. Moreover, it is evaluated whether the pharmacogenetic status of the patients, as determined by the mephenytoin/dextromethorphan test (D0-D28), is related to the metabolism of fenfluramine and citalopram, and also to the clinical response. CLINICAL ASSESSMENT: Patients with a diagnosis of major depressive disorders according to DSM III are submitted to a clinical assessment of D1, D7, D14, D28, D35, D42: HDRS, CGI (clinical global impression), VAS (visual analog scales for self-rating of depression), HDRS (Hamilton depression rating scale, 21 items), UKU (side effects scale), and to clinical laboratory examens, as well as ECG, control of weight, pulse, blood pressure at D1, D28, D35. Fenfluramine/prolactin test: A butterfly needle is inserted in a forearm vein at 7 h 45 and is kept patent with liquemine. Samples for plasma prolactin, and d- and l-fenfluramine determinations are drawn at 8 h 15 (base line). Patients are given 60 mg fenfluramine (as a racemate) at 8 h 30. Kinetic points are determined at 9 h 30, 10 h 30, 11 h 30, 12 h 30, 13 h 30. Plasma levels of d- and l-fenfluramine are determined by gas chromatography and prolactin by IRNA. Mephenytoin/dextromethorphan test: Patients empty their bladders before the test; they are then given 25 mg dextropethorphan and 100 mg mephenytoin (as a racemate) at 8 h 00. They collect all urines during the following 8 hours. The metabolic ratio is determined by gas chromatography (metabolic ratio dextromethorphan/dextrorphan greater than 0.3 = PM (poor metabolizer); mephenytoin/4-OH-mephenytoin greater than 5.6, or mephenytoin S/R greater than 0.8 = PM). Citalopram plasma levels: Plasma levels of citalopram, desmethylcitalopram and didesmethylcitalopram are determined by gas chromatography--mass spectrometry. RESULTS OF THE PILOT STUDY. The investigation has been preceded by a pilot study including 14 patients, using the abovementioned protocol, except that all nonresponders were medicated with citalopram/Li on D28 to D42. The mean total score (n = 14) on the 21 item Hamilton scale was significantly reduced after the treatment, ie from 26.93 +/- 5.80 on D1 to 8.57 +/- 6.90 on D35 (p less than 0.001). A similar patCitalopram, a new bicyclic antidepressant, is the most selective serotonin reu

Association of calcemia and serum vitamin D with 24H-urinary calcium excretion in a swiss population-based study

Background: Elevated urinary calcium excretion is associated with reduced bone mineral density. Population-based data on urinary calcium excretion are scarce. We explored the association of serum calcium and circulating levels of vitamin D (including 25(OH)D2 and 25(OH)D3) with urinary calcium excretion in men and women in a population-based study. Methods: We used data from the "Swiss Survey on Salt" conducted between 2010 and 2012 and including people aged 15 years and over. Twenty-four hour urine collection, blood analysis, clinical examination and anthropometric measures were collected in 11 centres from the 3 linguistic regions of Switzerland. Vitamin D was measured centrally using liquid chromatography - tandem mass spectrometry. Hypercalciuria was defined as urinary calcium excretion >0.1 mmol/kg/24h. Multivariable linear regression was used to explore factors associated with 24-hour urinary calcium excretion (mmol/24h) squared root transformed, taken as the dependant variable. Vitamin D was divided into monthspecific tertiles with the first tertile having the lowest value and the third tertile having the highest value. Results: The 669 men and 624 women had mean (SD) age of 49.2 (18.1) and 47 (17.9) years and a prevalence of hypercalciuria of 8.9% and 8.0%, respectively. In adjusted models, the association of urinary calcium excretion with protein-corrected serum calcium was (β coefficient } standard error, according to urinary calcium squared root transformed) 1.125 } 0.184 mmol/L per square-root (mmol/24h) (P<0.001) in women and 0.374 } 0.224 (P=0.096) in men. Men in the third month-specific vitamin D tertile had higher urinary calcium excretion than men in the first tertile (0.170 } 0.05 nmol/L per mmol/24h, P=0.001) and the corresponding association was 0.048 } 0.043, P= 0.272 in women. Conclusion: About one in eleven person has hypercalciuria in the Swiss population. The positive association of serum calcium with urinary calcium excretion was steeper in women than in men, independently of menopausal status. Circulating vitamin D was associated positively with urinary calcium excretion only in men. The reasons underlying the observed sex differences in the hormonal control of urinary calcium excretion need to be explored in further studies.

Meta-analysis and imputation refines the association of 15q25 with smoking quantity.

Smoking is a leading global cause of disease and mortality. We established the Oxford-GlaxoSmithKline study (Ox-GSK) to perform a genome-wide meta-analysis of SNP association with smoking-related behavioral traits. Our final data set included 41,150 individuals drawn from 20 disease, population and control cohorts. Our analysis confirmed an effect on smoking quantity at a locus on 15q25 (P = 9.45 x 10(-19)) that includes CHRNA5, CHRNA3 and CHRNB4, three genes encoding neuronal nicotinic acetylcholine receptor subunits. We used data from the 1000 Genomes project to investigate the region using imputation, which allowed for analysis of virtually all common SNPs in the region and offered a fivefold increase in marker density over HapMap2 (ref. 2) as an imputation reference panel. Our fine-mapping approach identified a SNP showing the highest significance, rs55853698, located within the promoter region of CHRNA5. Conditional analysis also identified a secondary locus (rs6495308) in CHRNA3.

25-Hydroxyvitamin D in African-origin populations at varying latitudes challenges the construct of a physiologic norm.

BACKGROUND: The vitamin D-endocrine system is thought to play a role in physiologic processes that range from mineral metabolism to immune function. Serum 25-hydroxyvitamin D [25(OH)D] is the accepted biomarker for vitamin D status. Skin color is a key determinant of circulating 25(OH)D concentrations, and genes responsible for melanin content have been shown to be under strong evolutionary selection in populations living in temperate zones. Little is known about the effect of latitude on mean concentrations of 25(OH)D in dark-skinned populations. OBJECTIVE: The objective was to describe the distribution of 25(OH)D and its subcomponents in 5 population samples of African origin from the United States, Jamaica, Ghana, South Africa, and the Seychelles. DESIGN: Participants were drawn from the Modeling of the Epidemiologic Transition Study, a cross-sectional observational study in 2500 adults, ages 25-45 y, enrolled between January 2010 and December 2011. Five hundred participants, ∼50% of whom were female, were enrolled in each of 5 study sites: Chicago, IL (latitude: 41°N); Kingston, Jamaica (17°N); Kumasi, Ghana (6°N); Victoria, Seychelles (4°S); and Cape Town, South Africa (34°S). All participants had an ancestry primarily of African origin; participants from the Seychelles trace their history to East Africa. RESULTS: A negative correlation between 25(OH)D and distance from the equator was observed across population samples. The frequency distribution of 25(OH)D in Ghana was almost perfectly normal (Gaussian), with progressively lower means and increasing skewness observed at higher latitudes. CONCLUSIONS: It is widely assumed that lighter skin color in populations outside the tropics resulted from positive selection, driven in part by the relation between sun exposure, skin melanin content, and 25(OH)D production. Our findings show that robust compensatory mechanisms exist that create tolerance for wide variation in circulating concentrations of 25(OH)D across populations, suggesting a more complex evolutionary relation between skin color and the vitamin D pathway. This trial was registered at clinicaltrials.gov as NCT02111902.

Information sharing in R&D collaboration - Context-dependency and means of governance

Tiedon jakaminen ja kommunikointi ovat tärkeitä toimintoja verkostoituneiden yritysten välillä ja ne käsitetäänkin yhteistyösuhteen yhtenä menestystekijänä ja kulmakivenä. Tiedon jakamiseen liittyviä haasteita ovat mm. yrityksen liiketoiminnalle kriittisen tiedon vuotaminen ja liiketoiminnan vaatima tiedon reaaliaikaisuus ja riittävä määrä. Tuotekehitysyhteistyössä haasteellista on tiedon jäsentymättömyys ja sitä kautta lisääntyvä tiedon jakamisen tarve, minkä lisäksi jaettava tieto on usein monimutkaista ja yksityiskohtaista. Lisäksi tuotteiden elinkaaret lyhenevät, ja ulkoistaminen ja yhteistyö ovat yhä kasvavia trendejä liiketoiminnassa. Yhdessä nämä tekijät johtavat siihen, että tiedon jakaminen on haastavaa eritoten verkostoituneiden yritysten välillä. Tässä tutkimuksessa tiedon jakamisen haasteisiin pyrittiin vastaamaan ottamalla lähtökohdaksi tiedon jakamisen tilanneriippuvuuden ymmärtäminen. Työssä vastattiin kahteen pääkysymykseen: Mikä on tiedon jakamisen tilanneriippuvuus ja miten sitä voidaan hallita? Tilanneriippuvuudella tarkoitetaan työssä niitä tekijöitä, jotka vaikuttavat siihen, miten yritys jakaa tietoa tuotekehityskumppaneidensa kanssa. Tiedon jakamisella puolestaan tarkoitetaan yrityksest�� toiselle siirrettävää tietoa, jota tarvitaan tuotekehitysprojektin aikana. Työn empiirinen aineisto on kerätty laadullisella tutkimusotteella case- eli tapaustutkimuksena yhdessä telekommunikaatioalan yrityksessä jasen eri liiketoimintayksiköissä. Tutkimusjoukko käsitti 19 tuotekehitys- ja toimittajanhallintatehtävissä toimivaa johtajaa tai päällikköä. Työ nojaa pääasiassa hankintojen johtamisen tutkimuskenttään ja tilanneriippuvuuden selvittämiseksi paneuduttiin erityisesti verkostojen tutkimukseen. Työssä kuvattiin tiedon jakaminen yhtenä verkoston toimintona ja yhteistyöhön liittyvättiedon jakamisen hyödyt, haasteet ja riskit identifioitiin. Tämän lisäksi työssä kehitettiin verkoston tutkimismalleja ja yhdistettiin eri tasoilla tapahtuvaa verkoston tutkimusta. Työssä esitettiin malli verkoston toimintojen tutkimiseksija todettiin, että verkostotutkimusta pitäisi tehd�� verkosto, ketju, yrityssuhde- ja yritystasolla. Malliin on myös hyvä yhdist��ä tuote- ja tehtäväkohtaiset ominaispiirteet. Kirjallisuuskatsauksen perusteella huomattiin, että tiedon jakamista on aiemmin tarkasteltu lähinnä tuote- ja yrityssuhteiden tasolla. Väitöskirjassa esitettiin lisää merkittäviä tekijöitä, jotka vaikuttavat tiedon jakamiseen. Näitä olivat mm. tuotekehitystehtävän luonne, teknologia-alueen kypsyys ja toimittajan kyvykkyys. Tiedon jakamisen luonnetta tarkasteltaessa erotettiin operatiivinen, projektin hallintaan ja tuotekehitykseen liittyvä tieto sekä yleinen, toimittajan hallintaan liittyvä strateginen tieto. Tulosten mukaan erityisesti tuotekehityksen määrittelyvaihe ja tapaamiset kasvotusten korostuivat yhteistyössä. Empirian avulla tutkittiin myös niitä tekijöitä, joilla tiedon jakamista voidaan hallita tilanneriippuvuuteen perustuen, koska aiemmin tiedon jakamisen hallintakeinoja tai menestystekijöitä ei ole liitetty suoranaisesti eri olosuhteisiin. Nämä hallintakeinot jaettiin yhteistyötason- ja tuotekehitysprojektitason tekijöihin. Yksi työn keskeisist�� tuloksista on se, että huolimatta tiedon jakamisen haasteista, monet niist�� voidaan eliminoida tunnistamalla vallitsevat olosuhteet ja panostamalla tiedon jakamisen hallintakeinoihin. Työn manageriaalinen hyöty koskee erityisesti yrityksiä, jotka suunnittelevat ja tekevät tuotekehitysyhteistyötä yrityskumppaniensa kanssa. Työssä esitellään keinoja tämän haasteellisen tehtäväkentän hallintaan ja todetaan, että yritysten pitäisikin kiinnittää entist�� enemmän huomiota tiedon jakamisen ja kommunikaation hallintaan jo tuotekehitysyhteistyötä suunniteltaessa.

Vitamin D time profile based on the contribution of non-genetic and genetic factors in HIV-infected individuals of European ancestry.

BACKGROUND: Vitamin D deficiency is prevalent in HIV-infected individuals and vitamin D supplementation is proposed according to standard care. This study aimed at characterizing the kinetics of 25(OH)D in a cohort of HIV-infected individuals of European ancestry to better define the influence of genetic and non-genetic factors on 25(OH)D levels. These data were used for the optimization of vitamin D supplementation in order to reach therapeutic targets. METHODS: 1,397 25(OH)D plasma levels and relevant clinical information were collected in 664 participants during medical routine follow-up visits. They were genotyped for 7 SNPs in 4 genes known to be associated with 25(OH)D levels. 25(OH)D concentrations were analysed using a population pharmacokinetic approach. The percentage of individuals with 25(OH)D concentrations within the recommended range of 20-40 ng/ml during 12 months of follow-up and several dosage regimens were evaluated by simulation. RESULTS: A one-compartment model with linear absorption and elimination was used to describe 25(OH)D pharmacokinetics, while integrating endogenous baseline plasma concentrations. Covariate analyses confirmed the effect of seasonality, body mass index, smoking habits, the analytical method, darunavir/ritonavir and the genetic variant in GC (rs2282679) on 25(OH)D concentrations. 11% of the inter-individual variability in 25(OH)D levels was explained by seasonality and other non-genetic covariates, and 1% by genetics. The optimal supplementation for severe vitamin D deficient patients was 300,000 IU two times per year. CONCLUSIONS: This analysis allowed identifying factors associated with 25(OH)D plasma levels in HIV-infected individuals. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results.

A Population-Based Model to Consider the Effect of Seasonal Variation on Serum 25(OH)D and Vitamin D Status.

Background. We elaborated a model that predicts the centiles of the 25(OH)D distribution taking into account seasonal variation. Methods. Data from two Swiss population-based studies were used to generate (CoLaus) and validate (Bus Santé) the model. Serum 25(OH)D was measured by ultra high pressure LC-MS/MS and immunoassay. Linear regression models on square-root transformed 25(OH)D values were used to predict centiles of the 25(OH)D distribution. Distribution functions of the observations from the replication set predicted with the model were inspected to assess replication. Results. Overall, 4,912 and 2,537 Caucasians were included in original and replication sets, respectively. Mean (SD) 25(OH)D, age, BMI, and % of men were 47.5 (22.1) nmol/L, 49.8 (8.5) years, 25.6 (4.1) kg/m(2), and 49.3% in the original study. The best model included gender, BMI, and sin-cos functions of measurement day. Sex- and BMI-specific 25(OH)D centile curves as a function of measurement date were generated. The model estimates any centile of the 25(OH)D distribution for given values of sex, BMI, and date and the quantile corresponding to a 25(OH)D measurement. Conclusions. We generated and validated centile curves of 25(OH)D in the general adult Caucasian population. These curves can help rank vitamin D centile independently of when 25(OH)D is measured.

Functional and evolutionary analysis of DXL1, a non-essential gene encoding a 1-deoxy-D-xylulose 5-phosphate synthase like protein in Arabidopsis thaliana

The synthesis of 1-deoxy-D-xylulose 5-phosphate (DXP), catalyzed by the enzyme DXP synthase (DXS), represents a key regulatory step of the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway for isoprenoid biosynthesis. In plants DXS is encoded by small multigene families that can be classified into, at least, three specialized subfamilies. Arabidopsis thaliana contains three genes encoding proteins with similarity to DXS, including the well-known DXS1/CLA1 gene, which clusters within subfamily I. The remaining proteins, initially named DXS2 and DXS3, have not yet been characterized. Here we report the expression and functional analysis of A. thaliana DXS2. Unexpectedly, the expression of DXS2 failed to rescue Escherichia coli and A. thaliana mutants defective in DXS activity. Coherently, we found that DXS activity was negligible in vitro, being renamed as DXL1 following recent nomenclature recommendation. DXL1 is targeted to plastids as DXS1, but shows a distinct expression pattern. The phenotypic analysis of a DXL1 defective mutant revealed that the function of the encoded protein is not essential for growth and development. Evolutionary analyses indicated that DXL1 emerged from DXS1 through a recent duplication apparently specific of the Brassicaceae lineage. Divergent selective constraints would have affected a significant fraction of sites after diversification of the paralogues. Furthermore, amino acids subjected to divergent selection and likely critical for functional divergence through the acquisition of a novel, although not yet known, biochemical function, were identified. Our results provide with the first evidences of functional specialization at both the regulatory and biochemical level within the plant DXS family.

Safety of Prasugrel Loading Doses in Patients Pre-Loaded With Clopidogrel in the Setting of Primary Percutaneous Coronary Intervention: Results of a Nonrandomized Observational Study.

OBJECTIVES: The aim of this study was to assess the safety of the concurrent administration of a clopidogrel and prasugrel loading dose in patients undergoing primary percutaneous coronary intervention. BACKGROUND: Prasugrel is one of the preferred P2Y12 platelet receptor antagonists for ST-segment elevation myocardial infarction patients. The use of prasugrel was evaluated clinically in clopidogrel-naive patients. METHODS: Between September 2009 and October 2012, a total of 2,023 STEMI patients were enrolled in the COMFORTABLE (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI]) and the SPUM-ACS (Inflammation and Acute Coronary Syndromes) studies. Patients receiving a prasugrel loading dose were divided into 2 groups: 1) clopidogrel and a subsequent prasugrel loading dose; and 2) a prasugrel loading dose. The primary safety endpoint was Bleeding Academic Research Consortium types 3 to 5 bleeding in hospital at 30 days. RESULTS: Of 2,023 patients undergoing primary percutaneous coronary intervention, 427 (21.1%) received clopidogrel and a subsequent prasugrel loading dose, 447 (22.1%) received a prasugrel loading dose alone, and the remaining received clopidogrel only. At 30 days, the primary safety endpoint was observed in 1.9% of those receiving clopidogrel and a subsequent prasugrel loading dose and 3.4% of those receiving a prasugrel loading dose alone (adjusted hazard ratio [HR]: 0.57; 95% confidence interval [CI]: 0.25 to 1.30, p = 0.18). The HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly) bleeding score tended to be higher in prasugrel-treated patients (p = 0.076). The primary safety endpoint results, however, remained unchanged after adjustment for these differences (clopidogrel and a subsequent prasugrel loading dose vs. prasugrel only; HR: 0.54 [95% CI: 0.23 to 1.27], p = 0.16). No differences in the composite of cardiac death, myocardial infarction, or stroke were observed at 30 days (adjusted HR: 0.66, 95% CI: 0.27 to 1.62, p = 0.36). CONCLUSIONS: This observational, nonrandomized study of ST-segment elevation myocardial infarction patients suggests that the administration of a loading dose of prasugrel in patients pre-treated with a loading dose of clopidogrel is not associated with an excess of major bleeding events. (Comparison of Biomatrix Versus Gazelle in ST-Elevation Myocardial Infarction [STEMI] [COMFORTABLE]; NCT00962416; and Inflammation and Acute Coronary Syndromes [SPUM-ACS]; NCT01000701).

St. Petersburg Court Chant and the Tradition of Eastern Slavic Church Singing

The present study examines the repertory of liturgical chant known as St. Petersburg Court Chant which emerged within the Imperial Court of St. Petersburg, Russia, and appeared in print in a number of revisions during the course of the 19th century, eventually to spread throughout the Russian Empire and even abroad. The study seeks answers to questions on the essence and composition of Court Chant, its history and liturgical background, and most importantly, its musical relationship to other repertories of Eastern Slavic chant. The research questions emerge from previous literary accounts of Court Chant (summarized in the Introduction), which have tended to be inaccurate and generally not based on critical research. The study is divided into eight main chapters. Chapter 1 provides a survey of the history of Eastern Slavic chant and the Imperial Court Chapel of St. Petersburg until 1917, with special emphasis on the history of singing traditional chant in polyphony, the status of the Court Chapel as a government authority, and its endeavours in publishing church music. Chapter 2 deals with the liturgical background of Eastern chant, the chant genres, and main repertories of Eastern Slavic chant. Chapter 3 concentrates on chant sources: it introduces the musical notations utilised, after which a typology of chant books is presented. The discussion continues with a survey of the sources of Court Chant and their content, the specimens selected for closer analysis, the comparative materials from other repertories, and ends with a commentary on some chant sources that have been excluded. The comparative sources include a specimen from around the beginning of the 12th century, a few manuscripts from the 17th century, and printed and manuscript chant books from the early 18th to early 20th century, covering the geographical area that delimits to the western Ukraine, Astrakhan, Nizhny Novgorod, and the Solovetsky Monastery. Chapter 4 presents the approach and methods used in the subsequent analytical comparisons. After a survey of the pitch organization of Eastern Slavic chant, the customary harmonization strategy of traditional chant polyphony is examined, according to which a method for meaningful analysis of the harmony is proposed. The method is based on the observation that the harmonic framework of chant polyphony derives from the standard pitch collection of monodic chant known as the Church Gamut, specific pitches of which form eight harmonic regions that behave like the usual tonalities of major and harmonic minor. Because of the considerable quantity of comparative chant forms, computer-assisted statistical methods are applied to the analysis of chant melodies. The primary chant forms and their respective comparative forms have been pre-processed into reduced chant prototypes and divided into redactions. The analyses are carried out by measuring the formal dissimilarities of the primary chant forms of the Court Chant repertory against each comparative form, and also by measuring the reciprocal dissimilarities of all chant versions in a redaction, the results of which are subjected to agglomerative hierarchical clustering in order to find out how the chant forms relate to each other. The dissimilarities are determined by applying a metric dissimilarity function that is based on the Levenshtein Distance. Chapter 5 provides the melodic and harmonic analyses of generic chants (chants used for multiple texts of different lengths), i.e., chants for stichera samoglasny and troparia, Chapter 6 of pseudo-generic chants (chants that are used for multiple texts but with certain restrictions), i.e., chants for heirmoi, prokeimena, and three other hymns, and Chapter 7 of non-generic chants, covering nine chants that in the Court repertory are not shared by multiple texts. The results are summarized and evaluated in Chapter 8. Accordingly, it can be established that, contrary to previous conceptions, melodically, Court Chant is in effect a full part of the wider Eastern Slavic chant tradition. Even if it is somewhat detached from the chant versions of the Synodal square-note chant books and the local tradition of Moscow, it is particularly close to chant forms of East Ukraine and some vernacular repertories from Russia. Respectively, the harmonization strategies of Court Chant do not show significant individuality in comparison with those of the available polyphonic comparative sources, the main difference being the part-writing, which generally conforms to western common practice standard, whereas the deviations from this tend to be more significant in other analysed repertories of polyphonic chant. Thus, insofar as the subsequent prevalence of Court Chant is not based on its forceful dissemination by authorities (as suggested in previous literature but for which little tangible evidence could be found in Chapter 1), in the present author’s interpretation, Court Chant attained its dominance principally because musically it was considered sufficiently traditional, and as a chant body supported by the government, was conveniently available in print in serviceable harmonizations.

Strategic outsourcing of R&D: The location-specific advantages of India to the pharmaceutical industry

Companies are increasingly under pressure to be more efficient both in terms of costs and overall performance and thus, they seek new ways to develop their products and innovate. For pharmaceutical industry it can take several decades to launch a new drug to the markets. Since pharmaceutical industry is one of the most research-intensive industries, is outsourcing one way to enhance the R&D processes of such companies. It is said that outsourcing to offshore locations is vastly more challenging and complicated than any other exporting activity or inter-company relationship that has evoked a lot of discussion. By outsourcing strategically, companies must also thoroughly focus on transaction costs and core competences. Today, the suppliers are looked for beyond national boundaries and furthermore, the location of the outsourcing activity must also be thoroughly considered. Consequently, the purpose of this study is to analyze what is known of strategic outsourcing of pharmaceutical R&D to India. In order to meet the purpose of the study, this study tries to answer three sub-questions set to it: first, what is strategic outsourcing, second, why pharmaceutical companies utilize strategic outsourcing of R&D and last, why pharmaceutical companies select India as the location for outsourcing their R&D. The study is a qualitative study. The purpose of the study was approached by a literature review with systematic elements and sub-questions were analyzed through different relevant theories, such as theory of transaction costs, core competences and location advantages. Applicable academic journal articles were comprehensively included in the study. The data was collected from electronic journal article databases using key words and almost only peer-reviewed, as new as possible articles were included. Also both the reference list of the included articles and article recommendations from professionals generated more articles for inclusion. The data was analyzed through thematization that resulted in themes that illuminate the purpose of the study and sub-questions. As an outcome of the analysis, each of the theory chapters in the study represents one sub-question. The literature used in this study revealed that strategic outsourcing of R&D is increasingly used in pharmaceutical industry and the major motives to practice it has to do with lowering costs, accessing skilled labor, resources and knowledge and enhancing their quality while speeding up the introduction of new drugs. Mainly for the above-mentioned motives India is frequently chosen as the target location for pharma outsourcers. Still, the literature is somewhat incomplete in this complex phenomenon and more research is needed.