A de novo substitution in BCL11B leads to loss of interaction with transcriptional complexes and craniosynostosis

Craniosynostosis, the premature ossification of cranial sutures, is a developmental disorder of the skull vault, occurring in approximately 1 in 2250 births. The causes are heterogeneous, with a monogenic basis identified in ~25% of patients. Using whole-genome sequencing, we identified a novel, de novo variant in BCL11B, c.7C>A, encoding an R3S substitution (p.R3S), in a male patient with coronal suture synostosis. BCL11B is a transcription factor that interacts directly with the nucleosome remodelling and deacetylation complex (NuRD) and polycomb-related complex 2 (PRC2) through the invariant proteins RBBP4 and RBBP7. The p.R3S substitution occurs within a conserved amino-terminal motif (RRKQxxP) of BCL11B and reduces interaction with both transcriptional complexes. Equilibrium binding studies and molecular dynamics simulations show that the p.R3S substitution disrupts ionic coordination between BCL11B and the RBBP4-MTA1 complex, a subassembly of the NuRD complex, and increases the conformational flexibility of Arg-4, Lys-5 and Gln-6 of BCL11B. These alterations collectively reduce the affinity of BCL11B p.R3S for the RBBP4-MTA1 complex by nearly an order of magnitude. We generated a mouse model of the BCL11B p.R3S substitution using a CRISPR-Cas9-based approach, and we report herein that these mice exhibit craniosynostosis of the coronal suture, as well as other cranial sutures. This finding provides strong evidence that the BCL11B p.R3S substitution is causally associated with craniosynostosis and confirms an important role for BCL11B in the maintenance of cranial suture patency

Women’s beliefs about medicines and adherence to pharmacotherapy in pregnancy: Opportunities for community pharmacists?

Background During pregnancy women might weigh benefits of treatment against potential risks to the unborn child. However, non-adherence to necessary treatment can adversely affect both mother and child. To optimize pregnant women’s beliefs and medication adherence, community pharmacists are ideally positioned to play an important role in primary care. Objective This narrative review aimed to summarize the evidence on 1) pregnant women’s beliefs, 2) medication adherence in pregnancy, and 3) community pharmacists’ counselling during pregnancy. Method Three search strategies were used in Medline and Embase to find original studies evaluating women’s beliefs, medication adherence and community pharmacists’ counselling during pregnancy. All original descriptive and analytic epidemiological studies performed in Europe, North America and Australia, written in English and published from 2000 onwards were included. Results We included 14 studies reporting on women’s beliefs, 11 studies on medication adherence and 9 on community pharmacists’ counselling during pregnancy. Women are more reluctant to use medicines during pregnancy and tend to overestimate the teratogenic risk of medicines. Risk perception varies with type of medicine, level of health literacy, education level and occupation. Furthermore, low medication adherence during pregnancy is common. Finally, limited evidence showed current community pharmacists’ counselling is insufficient. Barriers hindering pharmacists are insufficient knowledge and limited access to reliable information. Conclusion Concerns about medication use and non-adherence are widespread among pregnant women. Community pharmacists’ counselling during pregnancy is insufficient. Further education, training and research are required to support community pharmacists in fulfilling all the opportunities they have when counselling pregnant women

A História da Alimentação: balizas historiográficas

Os M. pretenderam traçar um quadro da História da Alimentação, não como um novo ramo epistemológico da disciplina, mas como um campo em desenvolvimento de práticas e atividades especializadas, incluindo pesquisa, formação, publicações, associações, encontros acadêmicos, etc. Um breve relato das condições em que tal campo se assentou faz-se preceder de um panorama dos estudos de alimentação e temas correia tos, em geral, segundo cinco abardagens Ia biológica, a econômica, a social, a cultural e a filosófica!, assim como da identificação das contribuições mais relevantes da Antropologia, Arqueologia, Sociologia e Geografia. A fim de comentar a multiforme e volumosa bibliografia histórica, foi ela organizada segundo critérios morfológicos. A seguir, alguns tópicos importantes mereceram tratamento à parte: a fome, o alimento e o domínio religioso, as descobertas européias e a difusão mundial de alimentos, gosto e gastronomia. O artigo se encerra com um rápido balanço crítico da historiografia brasileira sobre o tema

Exploring what patients think when answering the Interpersonal Skills Questionnaire (ISQ) following a hospital pharmacist consultation: A ‘think-aloud’ study

Background: The Interpersonal Skills Questionnaire (ISQ) was developed to collect patient feedback on consultation skills of practitioners. However, it has not yet been evaluated with pharmacists. Therefore, the aim of this study was to use cognitive interviewing to explore the thinking process of patients as they completed the ISQ following a pharmacist consultation.Methods: A qualitative think-aloud (TA) research methodology combined with retrospective probing was used to uncover the thinking process of patients as they completed the ISQ following a pharmacy consultation. The study was conducted between October-December 2017 in secondary care with outpatients ≥ 18 years old in Norfolk, England. Interviews were carried out in rounds and were informally analysed (i.e. by writing notes while listening to recordings instead of verbatim transcription and analysis) to identify major problems encountered while completing the questionnaire. Discussions were held between researchers to decide whether changes were needed based on patients’ comments. The study received ethical approval by the NHS Health Research Authority.Results: Eight patients in total (4 males and 4 females) were included in this study (mean age: 48 years). Three rounds of TA were conducted (4 in the first, and 2 in the second and third rounds). Most items of the ISQ were interpreted similarly by all respondents, and were not associated with difficulties with respect to its wording, understanding, or its relevance to pharmacy consultations. Most respondents showed a logical sequence of their thinking process as they answered the ISQ and did not reflect any major difficulty that required refining the ISQ with reference to pharmacist consultations.Conclusions: Modification of the ISQ was unnecessary as cognitive interviews conducted demonstrated the lack of major problems with its use in relation to hospital pharmacy consultations. The ISQ is thus a potentially suitable tool to collect patient feedback on pharmacist consultations

THE COMPLEMENTARY USE OF ATOM PROBE FIELD ION MICROSCOPY AND ANALYTICAL TRANSMISSION ELECTRON MICROSCOPY FOR THE STUDY OF A Ni-BASE SUPERALLOY

Les compositions des phases γ, γ' et DO22 dans le superalliage à base Nickel RSR 143 (76Ni-13A1-9Mo-2Ta, % at.) ont été déterminées via la microscopie ionique à sonde à atomes (APFIM) comme étant 76Ni-6A1-18Mo, 67Ni-25A1-4Mo-4Ta et 73Ni-4A1-20Mo-3Ta respectivement. En utilisant la spectroscopie d'énergie dispersive x en microscopie électronique (TEM), la composition de la phase γ' (69Ni-22A1-4Mo-5Ta) s'est avérée similaire à celle déterminée par APFIM. L'écart de la composition DO22 par rapport à Ni3Mo est en accord avec les prévisions tirées d'une récente étude en TEM (Martin et al, 1980, 1982).Compositions of the γ, γ' and DO22 phases in the nickel-base superalloy RSR 143 (76Ni-13A1-9Mo-2Ta, at. %) have been determined via atom probe field-ion microscopy (APFIM) as 76Ni-6A1-18Mo, 67Ni-25A1-4Mo-4Ta and be 73Ni-4A1-20Mo-3Ta respectively. Using energy dispersive x-ray spectroscopy in the analytical transmission electron microscopy (TEM), the composition of the γ' phase (69Ni-22A1-4Mo-5Ta) was found to be similar to that determined by APFIM. The deviation of the DO22 composition from Ni3Mo is in agreement with the prediction of a recent TEM study (Martin et al, 1980, 1982)