Parental perception of pediatric clinical exome sequencing in a Latino population

Clinical exome sequencing (CES) is an established method for genetic diagnosis that is commonly used in clinical practices. Studies examining the CES experience for families have primarily been non-Latino white participants who speak English. To begin to address how these experiences may differ in other populations, we conducted in-depth semi-structured interviews. Interviews were completed with 22 Latino parents (14 in English; 8 in Spanish) of children who had pediatric CES at Columbia University Medical Center and received results within three to 20 months of the interview. We also measured acculturation with a standardized scale. Similar to prior studies, parents reported varied emotional reactions to their child’s results. Parents largely understood their child’s CES results though were not always able to correctly recall recurrence risk. The majority of participants reported feelings of anxiety while waiting for CES results. Some parents, particularly those not fluent in English with lower acculturation scores, reported language barriers to their understanding of the testing and their child’s care. Faith appeared to be a positive coping mechanism that was more frequently reported by participants with lower acculturation scores. Our findings are consistent with many of the previous studies of parental experience of CES but highlight some key findings that warrant further study and potentially inform practice. Larger studies should explore potential associations between acculturation and parental understanding or emotional response to results. The minimal language barriers reported by Spanish-speaking patients reiterates the importance of a Spanish-speaking provider, when possible, and bilingual resources

Global prevalence and genotype distribution of hepatitis C virus infection in 2015 : A modelling study

Publisher Copyright: © 2017 Elsevier LtdBackground The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of—and expansion on—the 2014 analysis, which reported 80 million (95% CI 64–103) viraemic infections in 2013. Methods We developed country-level disease burden models following a systematic review of HCV prevalence (number of studies, n=6754) and genotype (n=11 342) studies published after 2013. A Delphi process was used to gain country expert consensus and validate inputs. Published estimates alone were used for countries where expert panel meetings could not be scheduled. Global prevalence was estimated using regional averages for countries without data. Findings Models were built for 100 countries, 59 of which were approved by country experts, with the remaining 41 estimated using published data alone. The remaining countries had insufficient data to create a model. The global prevalence of viraemic HCV is estimated to be 1·0% (95% uncertainty interval 0·8–1·1) in 2015, corresponding to 71·1 million (62·5–79·4) viraemic infections. Genotypes 1 and 3 were the most common cause of infections (44% and 25%, respectively). Interpretation The global estimate of viraemic infections is lower than previous estimates, largely due to more recent (lower) prevalence estimates in Africa. Additionally, increased mortality due to liver-related causes and an ageing population may have contributed to a reduction in infections. Funding John C Martin Foundation.publishersversionPeer reviewe

Global wealth disparities drive adherence to COVID-safe pathways in head and neck cancer surgery

Peer reviewe

Bases teóricas do pluralismo jurídico

Tese de Doutoramento em Ciências Jurídicas (Especialidade em Ciências Jurídicas Gerais)Abordar las bases teóricas de un objeto de conocimiento cualquiera, equivale a establecer los fundamentos que dan explicación a sus existencia y a razonar acerca de la racionalidad y deseabilidad de sus propósitos. En la presente tesis, los objetos de análisis son: el Pluralismo Jurídico y sus fundamentos, en conexión con la Teoría del Discurso de Jürgen Habermas. Dentro del análisis de esos objetos, se han identificado y examinado dos constataciones fácticas: 1) Que el Pluralismo Jurídico es un hecho, presente en muchas sociedades contemporáneas y 2) Que allí donde hay sociedades jurídicamente plurales ocurren tensiones entre los distintos ordenamientos jurídicos que conforman esos escenarios jurídicamente plurales, dando lugar a problemas de aplicación del Derecho y a cierto grado de irracionalidad en el funcionamiento del Derecho (o los Derechos, de esas sociedades) pues, las personas componentes de esas sociedades tienen más de una referencia jurídica. Dadas tales constataciones de hecho y en virtud a ellas, se ha reconocido la necesidad de que el hecho del pluralismo jurídico tenga algún tipo de fundamentación racional. En ese cometido, la presente investigación pretende establecer una vía de armonización y equilibrio que alivie las tensiones y problemas entre ordenamientos jurídicos en contextos plurales. Entiende que la Ética del Discurso de Jürgen Habermas es una teoría que puede dar las respuestas precisas a la necesidad de aliviar las tensiones entre los ordenamientos componentes de las realidades sociales, jurídicamente plurales; con lo que se sentarían las bases teóricas que otorguen racionalidad a dichas realidades. Así, el hecho del pluralismo jurídico, con el soporte de la Ética del Discurso, quedaría fundamentado y por lo tanto su racionalidad asegurada, convirtiéndolo no solamente en un hecho presente en las sociedades sino en una realidad regulada y deseable. En efecto, la tesis analiza el pluralismo jurídico como un hecho común en las sociedades actuales, dando por asumido, no obstante, que la Teoría General del Derecho acepta mayoritariamente que una de las características esenciales del Derecho de los Estados, es la Unidad de sistema jurídico (siguiendo la corriente del monismo jurídico). La investigación no entra a cuestionar dicha corriente pero describe las posiciones jurídicamente pluralistas que la colocan en entredicho, afirmando que el pluralismo jurídico es un hecho real que no está exento de tensiones y que no deja de ser un escenario que genera conflictos entre sus componentes y entre ellos y el Derecho estatal. En base a ese análisis, la tesis hace hincapié en que las tales tensiones pueden ser resueltas racionalmente y en que la racionalidad del pluralismo jurídico es una tarea pendiente. Tarea que puede ser encarada con la mediación de la Teoría del Discurso. En efecto, describe y analiza la teoría del discurso como conjunto regulativo del que emerge la racionalidad argumentativa y el consenso racional en materia ética y luego traslada las posturas de la Teoría del Discurso del ámbito de la Moral al del Derecho a través de una concepción particular de derechos humanos, que hace viable el concepto de derechos colectivos. De ese modo, desarrolla el concepto de derechos humanos cuyos titulares son tanto individuos como colectivos de individuos, atribuyendo a éstos últimos la posibilidad de ser sujetos de la argumentación dialogada que da lugar al discurso racional, que, cuando trata de los derechos vinculados en su ejercicio, al desarrollo de un ordenamiento jurídico particular y propio de un colectivo concreto, entonces produce la emergencia de un pluralismo jurídico como materia de la argumentación –y del discurso mismo-. Finalmente, presenta el modelo de pluralismo jurídico vigente en Bolivia y aboga por que la teoría del discurso es apta para servir de base teórica para el funcionamiento armónico de dicho esquema de derecho plural, aun en pleno proceso de construcción.To approach the theoretical bases of any object of knowledge is to establish the foundations that explain its existence and to reason about the rationality and desirability of its purposes. In this thesis, the objects of analysis are: Legal Pluralism and its foundations, in connection with Jürgen Habermas' Theory of Discourse. Within the analysis of these objects, two factual findings have been identified and examined: 1) That, Legal Pluralism is a fact, present in many contemporary societies and 2) That, wherever there are legally plural societies, there are tensions between the different legal systems that make up those diversely legal scenarios, giving rise to problems of application of the law and to a certain degree of irrationality in the functioning of the law (or the various “Laws” of such societies), since people who are members of those societies, have more than one legal reference. Given those factual findings and due to them, the need for legal pluralism to have some kind of rational foundation has been recognized. In that task, the present research aims to establish a path of harmonization and balance that could relieve the tensions and the problems taking place between legal systems in plural contexts. The thesis sustains that Jürgen Habermas's Discourse Ethics is a theory that can provide the precise and basic answers to the need lessening the tensions between the constituent Legal Orders of juridically plural realities; with which, theoretical bases that grant rationality to those realities, would be established. Thus, the fact of legal pluralism, with the support of the Discourse Ethics, would be justified and therefore, its rationality assured; making it not only a fact present in societies but a regulated and desirable reality. The thesis investigates juridical pluralism as a common fact in today's societies, assuming, however, that the General Theory of Law accepts mostly that one of the essential characteristics of the Law of States, is the System Unit (following the movement of legal monism). This investigation does not repudiate that movement, but describes the legally pluralistic positions that put it into question, affirming that legal pluralism is a real fact that is not free of tensions and that is a scenario that generates conflicts between its components and between them and the State Law. On the basis of that analysis, the thesis emphasizes that such tensions can be resolved rationally giving that the rationality of legal pluralism is a pending task. Task that can be faced with the mediation of Discourse Theory. In fact, the thesis describes and analyses the Discourse Theory as a regulative set from which argumentative rationality in ethical matters emerge, as well as rational consensus in those matters, and then moves the positions of Discourse Theory from the scope of the Moral to the Law one, through a particular conception Human rights which makes the concept of collective rights viable. In that way, the thesis develops a concept of human rights whose holders are both individuals and collectives of individuals, attributing to the latter the possibility of being subjects of the dialogical argumentation that gives rise to rational discourse, which, when dealing with human rights related (in its exercise) to the development of a particular legal order that belongs to a specific group, then gives rise to a legal pluralism conceived as a matter of argumentation - and discourse itself-. Finally, the thesis approaches the model of legal pluralism presently in force in Bolivia and argues that the Theory of Discourse is suitable to serve as a theoretical basis for the harmonious functioning of that pluralist legal system, even though it is still in the midst of its construction process.Apontar a base teórica de qualquer objeto de conhecimento, é lançar as bases que dão explicação para sua existência e para raciocinar sobre racionalidade e conveniência de seus propósitos. Nesta tese, os objetos de análise são o pluralismo jurídico e as suas fundações, em conexão com a Teoria do Discurso de Jürgen Habermas. Na análise desses objetos, foram identificadas e examinadas duas constatações factuais: 1) O Pluralismo jurídico é um fato, presente em muitas sociedades contemporâneas e 2) Que, onde há sociedades legalmente pluralistas, tensões ocorrem entre os diferentes sistemas legais que fazem parte desse cenários juridicamente plurais, levando a problemas de aplicação da lei e a algum grau de irracionalidade no funcionamento do Direito (ou dos “direitos” de tais sociedades), dado que, as pessoas dessas sociedades têm mais de uma referência legal. Dadas as constatações referidas e sob elas, a tese reconheceu a necessidade para o fato do pluralismo legal de ter algum tipo de fundamento racional. Nessa tarefa, a Tese visa a estabelecer um meio de harmonizar e equilibrar, para aliviar as tensões e problemas entre os sistemas jurídicos em contextos plurais. Ela entende que a ética do discurso de Jürgen Habermas é uma teoria que pode dar as respostas precisas e necessárias para aliviar as tensões entre os componentes das realidades sociais legalmente plurais; com o qual se definiam as bases teóricas para dar racionalidade a tais realidades. Assim, o pluralismo jurídico, com o apoio da Ética do Discurso, ficaria fundado e, por conseguinte, a sua racionalidade assegurada, tornando-o não apenas num fato presente nas sociedades mas numa realidade controlada e desejável. De fato, a tese analisa o pluralismo jurídico como uma ocorrência comum nas sociedades de hoje, assumindo no entanto, que a Teoria Geral do Direito esmagadoramente concorda que uma das características essenciais do Direito dos Estados é a Unidade do sistema legal (seguindo a tendência do monismo jurídico). A investigação não vem para questionar essa corrente, mas descreve as posições legalmente pluralistas que a colocam em questão, afirmando que o pluralismo jurídico é um fato que não é livre de tensões e que é um cenário que gera conflitos entre seus componentes e entre eles e o Direito do estadual. Com base nesta análise, a tese enfatiza que tais tensões podem ser resolvidas de forma racional e que a racionalidade do pluralismo jurídico é uma tarefa pendente. Tarefas que podem ser tratadas com a mediação da teoria do discurso. Na verdade, a tese descreve e analisa a teoria do discurso como um conjunto regulador que gera a racionalidade argumentativa e consenso racional sobre questões éticas e então desloca as posições de teoria do discurso do campo da moral para o Direito através de uma concepção particular dos direitos humanos que torna o conceito de direitos coletivos, viável. Dessa forma, desenvolve um conceito de direitos humanos cujos titulares não são apenas os indivíduos mas também os grupos de indivíduos, atribuindo a estes últimos a possibilidade de ser sujeitos da argumentação dialógica que leva ao discurso racional, que, quando se lida com os direitos relacionados, no seu exercício, com o desenvolvimento dum determinado sistema jurídico dum grupo particular, em seguida, surge o pluralismo jurídico como a questão da argumentação –e mesmo do discurso racional-. Finalmente, apresenta-se o modelo de pluralismo jurídico existente na Bolívia e defende-se que a teoria do discurso é adequada para servir como uma base teórica para o bom funcionamento do esquema de Direito plural, mesmo que agora está ainda em construção

Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3

Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development

De Novo Mutations in NALCN Cause a Syndrome Characterized by Congenital Contractures of the Limbs and Face, Hypotonia, and Developmental Delay

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s)

Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030 : a modelling study

Background Hepatitis C virus (HCV) is a leading cause of liver-related morbidity and mortality worldwide. In the European Union (EU), treatment and cure of HCV with direct-acting antiviral therapies began in 2014. WHO targets are to achieve a 65% reduction in liver-related deaths, a 90% reduction of new viral hepatitis infections, and 90% of patients with viral hepatitis infections being diagnosed by 2030. This study assessed the prevalence of HCV in the EU and the level of intervention required to achieve WHO targets for HCV elimination. Methods We populated country Markov models for the 28 EU countries through a literature search of PubMed and Embase between Jan 1, 2000, and March 31, 2016, and a Delphi process to gain expert consensus and validate inputs. We aggregated country models to create a regional EU model. We used the EU model to forecast HCV disease progression (considering the effect of immigration) and developed a strategy to acehive WHO targets. We used weighted average sustained viral response rates and fibrosis restrictions to model the effect of current therapeutic guidelines. We used the EU model to forecast HCV disease progression (considering the effect of immigration) under current screening and therapeutic guidelines. Additionally, we back-calculated the total number of patients needing to be screened and treated to achieve WHO targets. Findings We estimated the number of viraemic HCV infections in 2015 to be 3\ue2\u80\u88238\ue2\u80\u88000 (95% uncertainty interval [UI] 2\ue2\u80\u88106\ue2\u80\u88000\ue2\u80\u933\ue2\u80\u88795\ue2\u80\u88000) of a total population of 509\ue2\u80\u88868\ue2\u80\u88000 in the EU, equating to a prevalence of viraemic HCV of 0\uc2\ub764% (95% UI 0\uc2\ub741\ue2\u80\u930\uc2\ub774). We estimated that 1\ue2\u80\u88180\ue2\u80\u88000 (95% UI 1\ue2\u80\u88003\ue2\u80\u88000\ue2\u80\u931\ue2\u80\u88357\ue2\u80\u88000) people were diagnosed with viraemia (36\uc2\ub74%), 150\ue2\u80\u88000 (12\ue2\u80\u88000\ue2\u80\u93180\ue2\u80\u88000) were treated (4\uc2\ub76% of the total infected population or 12\uc2\ub77% of the diagnosed population), 133\ue2\u80\u88000 (106\ue2\u80\u88000\ue2\u80\u93160\ue2\u80\u88000) were cured (4\uc2\ub71%), and 57\ue2\u80\u88900 (43\ue2\u80\u88900\ue2\u80\u9367\ue2\u80\u88300) were newly infected (1\uc2\ub78%) in 2015. Additionally, 30\ue2\u80\u88400 (26\ue2\u80\u88600\ue2\u80\u9342\ue2\u80\u88500) HCV-positive immigrants entered the EU. To achieve WHO targets, unrestricted treatment needs to increase from 150\ue2\u80\u88000 patients in 2015 to 187\ue2\u80\u88000 patients in 2025 and diagnosis needs to increase from 88\ue2\u80\u88800 new cases annually in 2015 to 180\ue2\u80\u88000 in 2025. Interpretation Given its advanced health-care infrastructure, the EU is uniquely poised to eliminate HCV; however, expansion of screening programmes is essential to increase treatment to achieve the WHO targets. A united effort, grounded in sound epidemiological evidence, will also be necessary. Funding Gilead Sciences