FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies.

The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p.Arg85Cys and p.Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca(2) (+) pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition

Nonparametric Information Geometry

The differential-geometric structure of the set of positive densities on a given measure space has raised the interest of many mathematicians after the discovery by C.R. Rao of the geometric meaning of the Fisher information. Most of the research is focused on parametric statistical models. In series of papers by author and coworkers a particular version of the nonparametric case has been discussed. It consists of a minimalistic structure modeled according the theory of exponential families: given a reference density other densities are represented by the centered log likelihood which is an element of an Orlicz space. This mappings give a system of charts of a Banach manifold. It has been observed that, while the construction is natural, the practical applicability is limited by the technical difficulty to deal with such a class of Banach spaces. It has been suggested recently to replace the exponential function with other functions with similar behavior but polynomial growth at infinity in order to obtain more tractable Banach spaces, e.g. Hilbert spaces. We give first a review of our theory with special emphasis on the specific issues of the infinite dimensional setting. In a second part we discuss two specific topics, differential equations and the metric connection. The position of this line of research with respect to other approaches is briefly discussed.Comment: Submitted for publication in the Proceedings od GSI2013 Aug 28-30 2013 Pari

The effectiveness of ibrutinib in chronic lymphocytic leukaemia: a nationwide, population-based study in the Netherlands

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Selected liver grafts from donation after circulatory death can be safely used for retransplantation – a multicenter retrospective study

Due to the growing number of liver transplantations (LTs), there is an increasing number of patients requiring retransplantation (reLT). Data on the use of grafts from extended criteria donors (ECD), especially donation after circulatory death (DCD), for reLT are lacking. We aimed to assess the outcome of patients undergoing reLT using a DCD graft in the Netherlands between 2001 and July 2018. Propensity score matching was used to match each DCD-reLT with three DBD-reLT cases. Primary outcomes were patient and graft survival. Secondary outcome was the incidence of biliary complications, especially nonanastomotic strictures (NAS). 21 DCD-reLT were compared with 63 matched DBD-reLTs. Donors in the DCD-reLT group had a significantly lower BMI (22.4 vs. 24.7 kg/m2, P-value = 0.02). Comparison of recipient demographics and ischemia times yielded no significant differences. Patient and graft survival rates were comparable between the two groups. However, the occurrence of nonanastomotic strictures after DCD-reLT was significantly higher (38.1% vs. 12.7%, P-value = 0.02). ReLT with DCD grafts does not result in inferior patient and graft survival compared with DBD grafts in selected patients. Therefore, DCD liver grafts should not routinely be declined for patients awaiting reLT

Pregnancy outcomes in women with cardiovascular disease: evolving trends over 10 years in the ESC Registry Of Pregnancy And Cardiac disease (ROPAC)

Aims Reducing maternal mortality is a World Health Organization (WHO) global health goal. Although maternal deaths due to haemorrhage and infection are declining, those related to heart disease are increasing and are now the most important cause in western countries. The aim is to define contemporary diagnosis-specific outcomes in pregnant women with heart disease. Methods and results From 2007 to 2018, pregnant women with heart disease were prospectively enrolled in the Registry Of Pregnancy And Cardiac disease (ROPAC). Primary outcome was maternal mortality or heart failure, secondary outcomes were other cardiac, obstetric, and foetal complications. We enrolled 5739 pregnancies; the mean age was 29.5. Prevalent diagnoses were congenital (57%) and valvular heart disease (29%). Mortality (overall 0.6%) was highest in the pulmonary arterial hypertension (PAH) group (9%). Heart failure occurred in 11%, arrhythmias in 2%. Delivery was by Caesarean section in 44%. Obstetric and foetal complications occurred in 17% and 21%, respectively. The number of high-risk pregnancies (mWHO Class IV) increased from 0.7% in 2007–2010 to 10.9% in 2015–2018. Determinants for maternal complications were pre-pregnancy heart failure or New York Heart Association >II, systemic ejection fraction <40%, mWHO Class 4, and anticoagulants use. After an increase from 2007 to 2009, complication rates fell from 13.2% in 2010 to 9.3% in 2017. Conclusion Rates of maternal mortality or heart failure were high in women with heart disease. However, from 2010, these rates declined despite the inclusion of more high-risk pregnancies. Highest complication rates occurred in women with PAH

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter

Donor hepatectomy time influences ischemia-reperfusion injury of the biliary tree in donation after circulatory death liver transplantation

Background: Donor hepatectomy time is associated with graft survival after liver transplantation. The aim of this study was to identify the impact of donor hepatectomy time on biliary injury during donation after circulatory death liver transplantation. Methods: First, bile duct biopsies of livers included in (pre)clinical machine perfusion research were analyzed. Secondly, of the same livers, bile samples were collected during normothermic machine perfusion. Lastly, a nationwide retrospective cohort study was performed including 273 adult patients undergoing donation after circulatory death liver transplantation between January 1, 2002 and January 1, 2017. Primary endpoint was development of non-anastomotic biliary strictures within 2 years of donation after circulatory death liver transplantation. Cox proportiona

Faixas normais de nutrientes em cana-de-açúcar pelos métodos ChM, DRIS e CND e nível crítico pela distribuição normal reduzida

Existem diversos métodos para a interpretação da diagnose foliar; o nível crítico ou as faixas de suficiência descritas na literatura são os mais utilizados. Porém, o uso de métodos de determinação de faixas normais de nutrientes que contemplam regiões específicas (localidades) aumenta a eficiência da interpretação. O objetivo deste trabalho foi determinar as faixas normais de nutrientes para a cultura da cana-de-açúcar, mediante a utilização dos métodos Chance Matemática (ChM), Sistema Integrado de Diagnose e Recomendação (DRIS) e Diagnose da Composição Nutricional (CND), além do Nível Crítico determinado pelo método de distribuição normal reduzida. O trabalho foi realizado tomando-se como base dados relativos a teores de nutrientes em amostras foliares e de produtividade de lavouras comerciais de cana-de-açúcar, localizadas no município de Campos de Goytacazes, RJ. Com o método da ChM, foram obtidas faixas de suficiência semelhantes aos métodos DRIS e CND, para N, Ca, S e Mn, enquanto para P, K, Mg, Cu e Zn os valores obtidos pela ChM foram superiores. A utilização dos métodos ChM, DRIS e CND, em lavouras comerciais de cana-de-açúcar em geral, possibilitou a obtenção de menor amplitude da faixa normal dos nutrientes, em comparação com os valores alcançados pelos métodos nível crítico e faixa de suficiência