Implicit and Implicit-Explicit Strong Stability Preserving Runge-Kutta Methods with High Linear Order

When evolving in time the solution of a hyperbolic partial differential equation, it is often desirable to use high order strong stability preserving (SSP) time discretizations. These time discretizations preserve the monotonicity properties satisfied by the spatial discretization when coupled with the first order forward Euler, under a certain time-step restriction. While the allowable time-step depends on both the spatial and temporal discretizations, the contribution of the temporal discretization can be isolated by taking the ratio of the allowable time-step of the high order method to the forward Euler time-step. This ratio is called the strong stability coefficient. The search for high order strong stability time-stepping methods with high order and large allowable time-step had been an active area of research. It is known that implicit SSP Runge-Kutta methods exist only up to sixth order. However, if we restrict ourselves to solving only linear autonomous problems, the order conditions simplify and we can find implicit SSP Runge-Kutta methods of any linear order. In the current work we aim to find very high linear order implicit SSP Runge-Kutta methods that are optimal in terms of allowable time-step. Next, we formulate an optimization problem for implicit-explicit (IMEX) SSP Runge-Kutta methods and find implicit methods with large linear stability regions that pair with known explicit SSP Runge-Kutta methods of orders plin=3,4,6 as well as optimized IMEX SSP Runge-Kutta pairs that have high linear order and nonlinear orders p=2,3,4. These methods are then tested on sample problems to verify order of convergence and to demonstrate the sharpness of the SSP coefficient and the typical behavior of these methods on test problems

Répercussions d’une enfance vécue en institution : le cas des Enfants de Duplessis

Les conséquences négatives d’un placement en institution sur les enfants ont été documentées, mais aucune étude n’a porté sur les orphelins et les enfants placés une fois devenus adultes. Au Québec, les Enfants de Duplessis offrent un témoignage poignant des répercussions à long terme d’une enfance vécue en institution. Les histoires recueillies auprès de 40 hommes et 41 femmes ayant grandi en institution à l’époque de Duplessis font état d’un nombre élevé d’abus et d’expériences adverses, incluant les agressions physiques, psychologiques et sexuelles. Le milieu était peu stimulant et offrait peu d’opportunités de développer des relations d’attachement positives et significatives. Lorsqu’ils sont appariés et comparés à des adultes provenant de l’enquête Santé-Québec, les Enfants de Duplessis devenus adultes rapportent plus de problèmes de santé liés au stress et une détresse psychologique plus importante. Nos résultats indiquent également que les personnes ayant disposé de peu de ressources et d’aptitudes personnelles dans l’enfance sont les plus affectées par les expériences adverses.Whereas the immediate consequences of institutionalized placements on children have been documented, no study has investigated adults who were raised in orphanages or institutions. In Quebec, les enfants de Duplessis offer a unique testimony of the long term consequences of an institutionalized childhood. Stories collected from 40 men and 41 women who grew up in institution in Duplessis’era indicate a high number of abuse and aversive experiences, including physical, psychological and sexual aggressions. In addition, the environment was poor in stimulation and opportunities to develop positive attachment relationships with adults. When matched and compared to adults from the Santé-Québec survey, les enfants de Duplessis report a higher number of health problems associated with stress and more psychological distress. Moreover, our results indicate that those who had fewer strengths and aptitudes in childhood are the most affected by unfavourable experiences.Se han documentado las consecuencias negativas del ingreso de los niños a una institución, pero ningún estudio trata acerca de los adultos que fueron internados cuando eran niños o quedaron huérfanos. En Quebec los niños de Duplessis son un testimonio desgarrador de las repercusiones a largo plazo de una infancia vivida en una institución. Las historias recopiladas de 40 hombres y 41 mujeres que crecieron en una institución en la época de Duplessis constatan el número elevado de abusos y experiencias adversas, incluyendo agresiones físicas, psicológicas y sexuales. El medio era poco estimulante y ofrecía pocas oportunidades de desarrollar relaciones de apego positivas y significativas. Al emparejarlos y compararlos a los adultos provenientes de la encuesta de Salud Quebec, los niños de Duplessis, quienes ya son adultos, reportan más problemas de salud relacionados al estrés y un desasosiego psicológico más importante. Nuestros resultados indican también que las personas que disponen de pocos recursos y aptitudes personales en su infancia son las más afectadas por las experiencias adversas.As conseqüências negativas de uma internação em instituição sobre as crianças foram documentadas, mas nenhum estudo foi realizado sobre os órfãos e as crianças internadas quando já se tornaram adultas. No Quebec, as “crianças de Duplessis” testemunham de maneira profunda das repercussões a longo prazo de uma infância vivida em instituição. As histórias recolhidas junto a 40 homens e 41 mulheres que cresceram em instituição na época do governo de Duplessis relatam um alto número de abusos e de experiências adversas, incluindo agressões físicas, psicológicas e sexuais. O meio era pouco estimulante e oferecia poucas oportunidades de desenvolver relações de apego positivas e significativas. Quando eles foram colocados lado a lado e comparados aos adultos vindos da pesquisa de Santé-Québec, as “crianças de Duplessis” que se tornaram adultas sofrem mais de problemas de saúde ligados ao estresse e a uma depressão psicológica mais importante. Nossos resultados indicam igualmente que as pessoas que dispuseram de poucos recursos e aptidões pessoais na infância são mais afetadas pelas experiências adversas

Les expériences vécues par les enfants de Duplessis institutionnalisés : les conséquences après plus de 50 ans

Dans cet article, les auteurs présentent les résultats qualitatifs recueillis à partir de questionnaires et d’entrevues semi-structurées destinés à documenter les expériences tant actuelles que passées des enfants de Duplessis institutionnalisés (EDI). Des exemples typiques et deux cas représentatifs sont présentés. Les résultats indiquent que les abus et la négligence subis par les EDI pendant l’enfance ont compromis leur ajustement psychosocial à long terme. Ils révèlent aussi que les EDI qui ont rapporté au moins quatre forces pendant leur enfance étaient plus susceptibles d’être protégés à l’âge adulte contre les effets négatifs de leur placement.In this article, the authors present qualitative results, derived from questionnaires and semi-structured interviews, to describe past and present experiences of the Duplessis children. Examples representative of their experience and a detailed description of two cases are provided. Results indicate that childhood abuse and negligence are related to poorer long-term psychological adjustment. The findings also demonstrate that reporting at least four strengths in childhood can have long-term protective effects.En este artículo, los autores presentan los resultados cualitativos recopilados a partir de cuestionarios y entrevistas semiestructuradas destinadas a documentar las experiencias, tanto recientes como pasadas, de los niños de Duplessis que fueron institucionalizados (EDI). Se presentan ejemplos típicos y dos casos representativos. Los resultados indican que los abusos y la negligencia sufridos por los EDI durante la infancia han comprometido su ajuste psicosocial a largo plazo. También revelan que los EDI que han reportado al menos cuatro fuerzas durante su infancia eran más susceptibles de estar protegidos en la edad adulta contra los efectos negativos de su colocación.Neste artigo, os autores apresentam os resultados qualitativos coletados a partir de questionários e entrevistas semi-estruturadas destinados a documentar as experiências tanto atuais quanto passadas das crianças de Duplessis institucionalizadas (CDI). São apresentados exemplos típicos e dois casos representativos. Os resultados indicam que os abusos e a negligência sofridos pelas CDI durante a infância comprometeram seu ajuste psicossocial a longo prazo. Eles revelam também que as CDI que relataram, pelo menos, quatro aspectos positivos durante sua infância eram mais susceptíveis de ser protegidas durante a idade adulta contra os efeitos negativos de sua internação

Eltrombopag for Thrombocytopenia in Patients with Cirrhosis Associated with Hepatitis C

Background Eltrombopag is a new, orally active thrombopoietin-receptor agonist that stimulates thrombopoiesis. We evaluated its ability to increase platelet counts and facilitate treatment for hepatitis C virus (HCV) infection in patients with thrombocytopenia associated with HCV-related cirrhosis. Methods Seventy-four patients with HCV-related cirrhosis and platelet counts of 20,000 to less than 70,000 per cubic millimeter were randomly assigned to receive eltrombopag (30, 50, or 75 mg daily) or placebo daily for 4 weeks. The primary end point was a platelet count of 100,000 per cubic millimeter or more at week 4. Peginterferon and ribavirin could then be initiated, with continuation of eltrombopag or placebo for 12 additional weeks. Results At week 4, platelet counts were increased to 100,000 per cubic millimeter or more in a dose-dependent manner among patients for whom these data were available: in 0 of the 17 patients receiving placebo, in 9 of 12 (75%) receiving 30 mg of eltrombopag, in 15 of 19 (79%) receiving 50 mg of eltrombopag, and in 20 of 21 (95%) receiving 75 mg of eltrombopag (P\u3c0.001). Antiviral therapy was initiated in 49 patients (in 4 of 18 patients receiving placebo, 10 of 14 receiving 30 mg of eltrombopag, 14 of 19 receiving 50 mg of eltrombopag, and 21 of 23 receiving 75 mg of eltrombopag) while the administration of eltrombopag or placebo was continued. Twelve weeks of antiviral therapy, with concurrent receipt of eltrombopag or placebo, were completed by 36%, 53%, and 65% of patients receiving 30 mg, 50 mg, and 75 mg of eltrombopag, respectively, and by 6% of patients in the placebo group. The most common adverse event during the initial 4 weeks was headache; thereafter, the adverse events were those expected with interferon-based therapy. Conclusions Eltrombopag therapy increases platelet counts in patients with thrombocytopenia due to HCV-related cirrhosis, thereby permitting the initiation of antiviral therapy. (ClinicalTrials.gov number, NCT00110799.

HIV-1 Vpr drives a tissue residency-like phenotype during selective infection of resting memory T cells

HIV-1 replicates in CD4+ T cells, leading to AIDS. Determining how HIV-1 shapes its niche to create a permissive environment is central to informing efforts to limit pathogenesis, disturb reservoirs, and achieve a cure. A key roadblock in understanding HIV-T cell interactions is the requirement to activate T cells in vitro to make them permissive to infection. This dramatically alters T cell biology and virus-host interactions. Here we show that HIV-1 cell-to-cell spread permits efficient, productive infection of resting memory T cells without prior activation. Strikingly, we find that HIV-1 infection primes resting T cells to gain characteristics of tissue-resident memory T cells (TRM), including upregulating key surface markers and the transcription factor Blimp-1 and inducing a transcriptional program overlapping the core TRM transcriptional signature. This reprogramming is driven by Vpr and requires Vpr packaging into virions and manipulation of STAT5. Thus, HIV-1 reprograms resting T cells, with implications for viral replication and persistence

T cell derived HIV-1 is present in the CSF in the face of suppressive antiretroviral therapy.

HIV cerebrospinal fluid (CSF) escape, where HIV is suppressed in blood but detectable in CSF, occurs when HIV persists in the CNS despite antiretroviral therapy (ART). To determine the virus producing cell type and whether lowered CSF ART levels are responsible for CSF escape, we collected blood and CSF from 156 neurosymptomatic participants from Durban, South Africa. We observed that 28% of participants with an undetectable HIV blood viral load showed CSF escape. We detected host cell surface markers on the HIV envelope to determine the cellular source of HIV in participants on the first line regimen of efavirenz, emtricitabine, and tenofovir. We confirmed CD26 as a marker which could differentiate between T cells and macrophages and microglia, and quantified CD26 levels on the virion surface, comparing the result to virus from in vitro infected T cells or macrophages. The measured CD26 level was consistent with the presence of T cell produced virus. We found no significant differences in ART concentrations between CSF escape and fully suppressed individuals in CSF or blood, and did not observe a clear association with drug resistance mutations in CSF virus which would allow HIV to replicate. Hence, CSF HIV in the face of ART may at least partly originate in CD4+ T cell populations