Clinical features, treatment, and outcome of pediatric steroid refractory acute graft-versus-host disease: a multicenter study

Steroid-refractory acute graft-versus-host disease (SR-aGvHD) is a severe complication in pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We aimed to assess clinical course and outcomes of pediatric SR-aGvHD. We performed a retrospective nationwide multicenter cohort study in the Netherlands. All patients aged 0 to 18 years who underwent transplantation between 2010 and 2020 with SR-aGvHD were included. For each patient, weeldy clinical aGvHD grade and stage, immunosuppressive treatment and clinical outcomes were collected. The primary study endpoint was the clinical course of SR-aGvHD over time. As a secondary outcome, factors influencing overall survival and SR-aGvHD remission were identified using a multistate Cox model. 20% of transplanted children developed grade II-IV aGvHD, of which 51% (n = 81) was SR-aGvHD. In these patients, second-line therapy was started at a median of 8 days after initial aGvHD-diagnosis. Forty-nine percent of SR-aGvHD patients received 3 or more lines of therapy. One year after start of second-line therapy, 34 patients (42%) were alive and in remission of aGvHD, 14 patients (17%) had persistent GvHD, and 33 patients (41%) had died. SR-aGvHD remission rate was lower in cord blood graft recipients than in bone marrow (BM) or peripheral blood stem cell (PBSC) recipients (hazard ratio [HR] = 0.51, 0.27-0.94, P = .031). Older age was associated with higher mortality (HR = 2.62, 1.04-6.60, P = .04, fourth quartile [aged 13.9-17.9] versus first quartile [aged 0.175-3.01]). In BM/PBSC recipients older age was also associated with lower remission rates (HR = 0.9, 0.83-0.96, P = .004). Underlying diagnosis, donor matching or choice of second-line therapy were not associated with outcome. Respiratory insufficiency caused by pulmonary GvHD was a prominent cause of death (26% of deceased). Our study demonstrates that SR-aGvHD confers a high mortality risk in pediatric HSCT. Older age and use of CB grafts are associated with an unfavorable outcome. Multicenter studies investigating novel treatment strategies to prevent pediatric SR-aGvHD and inclusion of children in ongoing trials, together with timely initiation of second-line interventions are pivotal to further reduce GvHD-related mortality. (C) 2022 The American Society for Transplantation and Cellular Therapy.Transplantation and immunomodulatio

The residence time of focal adhesion kinase (FAK) and paxillin at focal adhesions in renal epithelial cells is determined by adhesion size, strength and life cycle status

Toxicolog

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan

Obstructing Classification via Projection

Machine learning and data mining techniques are effective tools to classify large amounts of data. But they tend to preserve any inherent bias in the data, for example, with regards to gender or race. Removing such bias from data or the learned representations is quite challenging. In this paper we study a geometric problem which models a possible approach for bias removal. Our input is a set of points P in Euclidean space R^d and each point is labeled with k binary-valued properties. A priori we assume that it is `easy to classify the data according to each property. Our goal is to obstruct the classification according to one property by a suitable projection to a lower-dimensional Euclidean space R^m (m < d), while classification according to all other properties remains easy. What it means for classification to be easy depends on the classification model used. We first consider classification by linear separability as employed by support vector machines. We use Kirchberger's Theorem to show that, under certain conditions, a simple projection to R^(d-1) suffices to eliminate the linear separability of one of the properties whilst maintaining the linear separability of the other properties. We also study the problem of maximizing the linear ``inseparability of the chosen property. Second, we consider more complex forms of separability and prove a connection between the number of projections required to obstruct classification and the Helly-type properties of such separabilities

Heterogeneity of Spina Bifida

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Inter-twin hemoglobin difference at birth in uncomplicated monochorionic twins in relation to the size of the placental anastomoses

Research into fetal development and medicin