A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics

AimsThe aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin.MethodsWe conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88).ResultsIn a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration–time curve (AUC) and peak plasma concentration of rosuvastatin (P = 1.8 × 10−12 and P = 3.2 × 10−15). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P = .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P = .0041 and P = .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6–2.8, P = 4.69 × 10−5) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16–62%; P = .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5–3.0; P = 2.6 × 10−4) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11–42%; P = .01).ConclusionThese data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.</p

Pitkän aikavälin politiikalla läpi murroksen – tahtotiloja työn tulevaisuudesta

Olemme keskellä suurta työn murrosta. Työn tulevaisuuteen liittyviä haasteita on helppoa nimetä, mutta työn muutoksen kaltaiset monimutkaiset pitkäaikaiset muutosilmiöt eivät helposti käänny politiikkatoimiksi ja konkreettisiksi ratkaisuiksi. Muutosta on silti mahdollista ohjata yhteisesti tunnistettujen pitkän aikavälin tahtotilojen avulla. Tämän tutkimuksen tavoitteena on ollut tunnistaa työhön liittyviä toivottavia tulevaisuuksia, päätöksentekotarpeita sekä yhteiskunnallisia ratkaisuja asiantuntijahaastatteluihin ja kansallisen tason kyselytutkimukseen perustuen. Lisäksi raportissa ehdotetaan toimintamallia, jolla pitkän aikavälin keskustelua työn tulevaisuudesta voidaan käydä myös jatkossa. Raportti pohjautuu käsiteltyjen viiden teeman osalta Tulevaisuusselonteon 1. osaan (VNK 2017). Tutkimuksesta vastasi ajatushautomo Demos Helsinki yhteistyössä Teknologian tutkimuskeskus VTT:n kanssa. Tutkimuksesta keskeiset havainnot ovat seuraavat: Työn tekemisen muodot ja työsuhteet moninaistuvat, mikä edellyttää muutoksia esimerkiksi lainsäädännössä ja sosiaaliturvassa. Työn aika- ja paikkasidonnaisuus heikkenee, mutta muutos ei ole yhtä voimakas tai samantahtinen kaikilla aloilla. Koulutuksessa korostuu jatkuva oppiminen: Tarvitsemme Suomeen koko väestön kattavan, laadukkaan elinikäisen oppimisen järjestelmän. Toimeentulo muuttuu niin, että työmarkkinoiden ja koko työelämän joustavuus lisääntyy. Päätöksentekijöiden on tärkeää ymmärtää työn useita erilaisia ja muuttuvia välinearvoja taloudellisten arvojen lisäksi, jotta emme edistä keskenään ristiriitaisia tavoitteit

A comprehensive pharmacogenomic study indicates roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics

Aims The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin. Methods We conducted a genome-wide association study and candidate gene analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88). Results In a genome-wide association meta-analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration-time curve (AUC) and peak plasma concentration of rosuvastatin (P = 1.8 x 10(-12) and P = 3.2 x 10(-15)). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P = .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P = .0041 and P = .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1-fold (90% confidence interval 1.6-2.8, P = 4.69 x 10(-5)) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16-62%; P = .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2-fold (1.5-3.0; P = 2.6 x 10(-4)) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11-42%; P = .01). Conclusion These data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin-induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.Peer reviewe

Social context for workplace health promotion: feasibility considerations in Costa Rica, Finland, Germany, Spain and Sweden

IRETWe constructed a simple, flexible procedure that facilitates the pre-assessment of feasibility of workplace health promotion (WHP) programmes. It evaluates cancer hazards, workers’ need for hazard reduction, acceptability of WHP, and social context. It was tested and applied in 16 workplace communities and among 1085 employees in industry, construction, transport, services, teaching and municipal works in Costa Rica, Finland, Germany, Spain and Sweden. Social context is inseparable from WHP. It covers workers’ organizations and representatives, management, safety committees, occupational health services, health and safety enforcement agencies, general health services, nongovernment organizations, insurance systems, academic and other institutions, regulatory stipulations pertaining WHP, and material resources. Priorities, risk definitions, attitudes, hazard profiles, motivations and assessment methods were highly contextual. Management preferred passive interventions, helping cover expert costs, participating in planning and granting time. Trade unions, workers’ representatives, safety committees and occupational health services appeared to be important operational partners. Occupational health services may however be loaded with curative and screening functions or be non-existent. We advocate participatory, multifaceted WHP based on the needs and empowerment of the workers themselves, integrating occupational and lifestyle hazards. Workforce in irregular and shift work, in agriculture, in small enterprises, in the informal sector, and immigrant, seasonal and temporary workers represent groups in need of particular strategies such as community health promotion. In a more general framework, social context itself may become a target for intervention.Construimos un procedimiento simple y flexible que facilita la evaluación previa de la viabilidad de los programas de promoción de la salud en el lugar de trabajo (WHP). Evalúa los peligros del cáncer, la necesidad de los trabajadores de reducir los peligros, la aceptabilidad de la WHP y el contexto social. Fue probado y aplicado en 16 comunidades laborales y entre 1085 empleados en la industria, construcción, transporte, servicios, docencia y obras municipales en Costa Rica, Finlandia, Alemania, España y Suecia. El contexto social es inseparable de WHP. Abarca las organizaciones y representantes de trabajadores, la dirección, los comités de seguridad, los servicios de salud ocupacional, las agencias de aplicación de la salud y la seguridad, los servicios de salud en general, las organizaciones no gubernamentales, los sistemas de seguros, las instituciones académicas y de otro tipo, las estipulaciones reglamentarias relativas a las WHP y los recursos materiales. Las prioridades, las definiciones de riesgo, las actitudes, los perfiles de peligro, las motivaciones y los métodos de evaluación eran muy contextuales. La gerencia prefirió las intervenciones pasivas, ayudando a cubrir los costos de los expertos, participando en la planificación y otorgando tiempo. Los sindicatos, los representantes de los trabajadores, los comités de seguridad y los servicios de salud en el trabajo parecían ser socios operativos importantes. Sin embargo, los servicios de salud ocupacional pueden estar cargados de funciones curativas y de detección o ser inexistentes. Abogamos por una WHP participativa y multifacética basada en las necesidades y el empoderamiento de los propios trabajadores, integrando los riesgos ocupacionales y de estilo de vida. La mano de obra en el trabajo irregular y por turnos, en la agricultura, en las pequeñas empresas, en el sector informal y los trabajadores inmigrantes, estacionales y temporales representan grupos que necesitan estrategias particulares como la promoción de la salud comunitaria. En un marco más general, el contexto social en sí mismo puede convertirse en un objetivo de intervención.Construímos um procedimento simples e flexível que facilita a pré-avaliação da viabilidade de programas de promoção da saúde no local de trabalho (WHP). Ele avalia os riscos de câncer, a necessidade dos trabalhadores de reduzir os riscos, a aceitabilidade do WHP e o contexto social. Foi testado e aplicado em 16 comunidades de locais de trabalho e entre 1.085 funcionários na indústria, construção, transporte, serviços, ensino e obras municipais na Costa Rica, Finlândia, Alemanha, Espanha e Suécia. O contexto social é inseparável do WHP. Abrange organizações e representantes de trabalhadores, gestão, comitês de segurança, serviços de saúde ocupacional, agências de fiscalização de saúde e segurança, serviços de saúde em geral, organizações não governamentais, sistemas de seguro, instituições acadêmicas e outras, estipulações regulamentares relativas a WHP e recursos materiais. Prioridades, definições de risco, atitudes, perfis de perigo, motivações e métodos de avaliação eram altamente contextuais. A administração preferiu intervenções passivas, ajudando a cobrir os custos de especialistas, participando do planejamento e concedendo tempo. Sindicatos, representantes dos trabalhadores, comitês de segurança e serviços de saúde ocupacional pareciam ser parceiros operacionais importantes. Os serviços de saúde ocupacional podem, entretanto, estar repletos de funções curativas e de triagem ou podem não existir. Defendemos o WHP participativo e multifacetado com base nas necessidades e na capacitação dos próprios trabalhadores, integrando riscos ocupacionais e de estilo de vida. A força de trabalho em trabalho irregular e por turnos, na agricultura, em pequenas empresas, no setor informal e os trabalhadores imigrantes, sazonais e temporários representam grupos que precisam de estratégias específicas, como a promoção da saúde comunitária. Em uma estrutura mais geral, o próprio contexto social pode se tornar um alvo para intervençãoFinnish Institute of Occupational Health, FinlandKarolinska Institute, SwedenBremen Institute for Prevention Research and Social Medicine, GermanyMunicipality of Sabadell, EspañaDirectorate General for Occupational Health, EspañaMunicipal Institute for Medical Research, EspañaNational Institute for Occupational Safety and Hygiene, EspañaUniversidad Nacional, Costa RicaTechnological University of Costa Rica, Costa RicaInstituto Regional de Estudios en Sustancias Tóxica

Observation of the proton emitter 116 57 La59

The quantum tunneling and emission of a single constituent nucleon provide a beautifully simple and unique window into the complex properties of atomic nuclei at the extreme edge of nuclear existence. In particular, for odd-odd proton emitting nuclides, the associated decay energy and partial half-life can be used to probe the correlations between the valence neutrons and protons which have been theoretically predicted to favour a new type of nuclear superfluidity, isoscalar neutron-proton pairing, for which the experimental “smoking gun" remains elusive. In the present work, proton emission from the lanthanum isotope 11657La59, 23 neutrons away from the only stable isotope 13957La82, is reported. 116La nuclei were synthesised in the fusion-evaporation reaction 58Ni(64Zn, p5n)116La and identified via their proton radioactivity using the mass spectrometer MARA (Mass Analysing Recoil Apparatus) and the silicon detectors placed at its focal plane. Comparisons of the measured proton energy (Ep = 718 ± 9 keV) and half-life (T1/2 = 50 ± 22 ms) with values calculated using the Universal Decay Law approach indicate that the proton is emitted with an orbital angular momentum l = 2 and that its emission probability is enhanced relative to its closest, less exotic, odd-even lanthanum isotope (11757La60) while the proton-emission Q-value is lower. We propose this to be a possible signature for the presence of strong neutron-proton pair correlations in this exotic, neutron deficient system. The observations of γ decays from isomeric states in 116La and 117La are also reported.peerReviewe