Patients with severe acute‐on‐chronic liver failure are disadvantaged by model for end‐stage liver disease‐based organ allocation policy

Background: Mortality for patients with acute‐on‐chronic liver failure (ACLF) may be underestimated by the model for end‐stage liver disease‐sodium (MELD‐Na) score. / Aim: To assess waitlist outcomes across varying grades of ACLF among a cohort of patients listed with a MELD‐Na score ≥35, and therefore having similar priority for liver transplantation. / Methods: We analysed the United Network for Organ Sharing (UNOS) database, years 2010‐2017. Waitlist outcomes were evaluated using Fine and Gray's competing risks regression. / Results: We identified 6342 candidates at listing with a MELD‐Na score ≥35, of whom 3122 had ACLF‐3. Extra‐hepatic organ failures were present primarily in patients with four to six organ failures. Competing risks regression revealed that candidates listed with ACLF‐3 had a significantly higher risk for 90‐day waitlist mortality (Sub‐hazard ratio (SHR) = 1.41; 95% confidence interval [CI] 1.12‐1.78) relative to patients with lower ACLF grades. Subgroup analysis of ACLF‐3 revealed that both the presence of three organ failures (SHR = 1.40, 95% CI 1.20‐1.63) or four to six organ failures at listing (SHR = 3.01; 95% CI 2.54‐3.58) was associated with increased waitlist death. Candidates with four to six organ failures also had the lowest likelihood of receiving liver transplantation (SHR = 0.61, 95% CI 0.54‐0.68). The Share 35 rule was associated with reduced 90‐day waitlist mortality among the full cohort of patients listed with ACLF‐3 and MELD‐Na score ≥35 (SHR = 0.59; 95% CI 0.49‐0.70). However, Share 35 rule implementation was not associated with reduced waitlist mortality among patients with four to six organ failures (SHR = 0.76; 95% CI 0.58‐1.02). / Conclusion: The MELD‐Na score disadvantages patients with ACLF‐3, both with and without extra‐hepatic organ failures. Incorporation of organ failures into allocation policy warrants further exploration

Leukocytes Breach Endothelial Barriers by Insertion of Nuclear Lobes and Disassembly of Endothelial Actin Filaments

Israel Science Foundation (grant 87/12) Flight Attendant Medical Research Institute Foundation (FAMRI) (grant FAMRI032001_CoE), USA Minerva Foundation, Germany Wellcome Trust (grant 098291/Z/12/Z to S.N.

Beyond motivation: Job and work design for development, health, ambidexterity, and more

Much research shows it is possible to design motivating work, which has positive consequences for individuals and their organizations. This article reviews research that adopts this motivational perspective on work design, and it emphasizes that it is important to continue to refine motivational theories. In light of continued large numbers of poor-quality jobs, attention must also be given to influencing practice and policy to promote the effective implementation of enriched work designs. Nevertheless, current and future work-based challenges mean that designing work for motivation is necessary but insufficient. This review argues that work design can be a powerful vehicle for learning and development, for maintaining and enhancing employees' physical and mental health, and for achieving control and flexibility simultaneously (for example, in the form of ambidexterity); all these outcomes are important given the challenges in today's workplaces. The review concludes by suggesting methodological directions

Constraints on Non-Newtonian Gravity from Recent Casimir Force Measurements

Corrections to Newton's gravitational law inspired by extra dimensional physics and by the exchange of light and massless elementary particles between the atoms of two macrobodies are considered. These corrections can be described by the potentials of Yukawa-type and by the power-type potentials with different powers. The strongest up to date constraints on the corrections to Newton's gravitational law are reviewed following from the E\"{o}tvos- and Cavendish-type experiments and from the measurements of the Casimir and van der Waals force. We show that the recent measurements of the Casimir force gave the possibility to strengthen the previously known constraints on the constants of hypothetical interactions up to several thousand times in a wide interaction range. Further strengthening is expected in near future that makes Casimir force measurements a prospective test for the predictions of fundamental physical theories.Comment: 20 pages, crckbked.cls is used, to be published in: Proceedings of the 18th Course of the School on Cosmology and Gravitation: The Gravitational Constant. Generalized Gravitational Theories and Experiments (30 April- 10 May 2003, Erice). Ed. by G. T. Gillies, V. N. Melnikov and V. de Sabbata, 20pp. (Kluwer, in print, 2003

Comparison of age-specific cataract prevalence in two population-based surveys 6 years apart

BACKGROUND: In this study, we aimed to compare age-specific cortical, nuclear and posterior subcapsular (PSC) cataract prevalence in two surveys 6 years apart. METHODS: The Blue Mountains Eye Study examined 3654 participants (82.4% of those eligible) in cross-section I (1992–4) and 3509 participants (75.1% of survivors and 85.2% of newly eligible) in cross-section II (1997–2000, 66.5% overlap with cross-section I). Cataract was assessed from lens photographs following the Wisconsin Cataract Grading System. Cortical cataract was defined if cortical opacity comprised ≥ 5% of lens area. Nuclear cataract was defined if nuclear opacity ≥ Wisconsin standard 4. PSC was defined if any present. Any cataract was defined to include persons who had previous cataract surgery. Weighted kappa for inter-grader reliability was 0.82, 0.55 and 0.82 for cortical, nuclear and PSC cataract, respectively. We assessed age-specific prevalence using an interval of 5 years, so that participants within each age group were independent between the two surveys. RESULTS: Age and gender distributions were similar between the two populations. The age-specific prevalence of cortical (23.8% in 1(st), 23.7% in 2(nd)) and PSC cataract (6.3%, 6.0%) was similar. The prevalence of nuclear cataract increased slightly from 18.7% to 23.9%. After age standardization, the similar prevalence of cortical (23.8%, 23.5%) and PSC cataract (6.3%, 5.9%), and the increased prevalence of nuclear cataract (18.7%, 24.2%) remained. CONCLUSION: In two surveys of two population-based samples with similar age and gender distributions, we found a relatively stable cortical and PSC cataract prevalence over a 6-year period. The increased prevalence of nuclear cataract deserves further study

Molecular heterogeneity and immunosuppressive microenvironment in Glioblastoma

Copyright © 2020 DeCordova, Shastri, Tsolaki, Yasmin, Klein, Singh and Kishore. Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, with a poor prognosis, despite surgical resection combined with radio- and chemotherapy. The major clinical obstacles contributing to poor GBM prognosis are late diagnosis, diffuse infiltration, pseudo-palisading necrosis, microvascular proliferation, and resistance to conventional therapy. These challenges are further compounded by extensive inter- and intra-tumor heterogeneity and the dynamic plasticity of GBM cells. The complex heterogeneous nature of GBM cells is facilitated by the local inflammatory tumor microenvironment, which mostly induces tumor aggressiveness and drug resistance. An immunosuppressive tumor microenvironment of GBM provides multiple pathways for tumor immune evasion. Infiltrating immune cells, mostly tumor-associated macrophages, comprise much of the non-neoplastic population in GBM. Further understanding of the immune microenvironment of GBM is essential to make advances in the development of immunotherapeutics. Recently, whole-genome sequencing, epigenomics and transcriptional profiling have significantly helped improve the prognostic and therapeutic outcomes of GBM patients. Here, we discuss recent genomic advances, the role of innate and adaptive immune mechanisms, and the presence of an established immunosuppressive GBM microenvironment that suppresses and/or prevents the anti-tumor host response

Power analysis for genome-wide association studies

Abstract Background Genome-wide association studies are a promising new tool for deciphering the genetics of complex diseases. To choose the proper sample size and genotyping platform for such studies, power calculations that take into account genetic model, tag SNP selection, and the population of interest are required. Results The power of genome-wide association studies can be computed using a set of tag SNPs and a large number of genotyped SNPs in a representative population, such as available through the HapMap project. As expected, power increases with increasing sample size and effect size. Power also depends on the tag SNPs selected. In some cases, more power is obtained by genotyping more individuals at fewer SNPs than fewer individuals at more SNPs. Conclusion Genome-wide association studies should be designed thoughtfully, with the choice of genotyping platform and sample size being determined from careful power calculations.</p

Increased RPA1 gene dosage affects genomic stability potentially contributing to 17p13.3 duplication syndrome

A novel microduplication syndrome involving various-sized contiguous duplications in 17p13.3 has recently been described, suggesting that increased copy number of genes in 17p13.3, particularly PAFAH1B1, is associated with clinical features including facial dysmorphism, developmental delay, and autism spectrum disorder. We have previously shown that patient-derived cell lines from individuals with haploinsufficiency of RPA1, a gene within 17p13.3, exhibit an impaired ATR-dependent DNA damage response (DDR). Here, we show that cell lines from patients with duplications specifically incorporating RPA1 exhibit a different although characteristic spectrum of DDR defects including abnormal S phase distribution, attenuated DNA double strand break (DSB)-induced RAD51 chromatin retention, elevated genomic instability, and increased sensitivity to DNA damaging agents. Using controlled conditional over-expression of RPA1 in a human model cell system, we also see attenuated DSB-induced RAD51 chromatin retention. Furthermore, we find that transient over-expression of RPA1 can impact on homologous recombination (HR) pathways following DSB formation, favouring engagement in aberrant forms of recombination and repair. Our data identifies unanticipated defects in the DDR associated with duplications in 17p13.3 in humans involving modest RPA1 over-expression

EPHA2 Is Associated with Age-Related Cortical Cataract in Mice and Humans

Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of age-related cataract. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. We report that homozygous deletion of Epha2 in two independent strains of mice developed progressive cortical cataract. Retroillumination revealed development of cortical vacuoles at one month of age; visible cataract appeared around three months, which progressed to mature cataract by six months. EPHA2 protein expression in the lens is spatially and temporally regulated. It is low in anterior epithelial cells, upregulated as the cells enter differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. Deletion of Epha2 caused a significant increase in the expression of HSP25 (murine homologue of human HSP27) before the onset of cataract. The overexpressed HSP25 was in an underphosphorylated form, indicating excessive cellular stress and protein misfolding. The orthologous human EPHA2 gene on chromosome 1p36 was tested in three independent worldwide Caucasian populations for allelic association with cortical cataract. Common variants in EPHA2 were found that showed significant association with cortical cataract, and rs6678616 was the most significant in meta-analyses. In addition, we sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln, in the protein kinase domain that significantly alters EPHA2 functions in cellular and biochemical assays. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with age

Design principles for riboswitch function

Scientific and technological advances that enable the tuning of integrated regulatory components to match network and system requirements are critical to reliably control the function of biological systems. RNA provides a promising building block for the construction of tunable regulatory components based on its rich regulatory capacity and our current understanding of the sequence–function relationship. One prominent example of RNA-based regulatory components is riboswitches, genetic elements that mediate ligand control of gene expression through diverse regulatory mechanisms. While characterization of natural and synthetic riboswitches has revealed that riboswitch function can be modulated through sequence alteration, no quantitative frameworks exist to investigate or guide riboswitch tuning. Here, we combined mathematical modeling and experimental approaches to investigate the relationship between riboswitch function and performance. Model results demonstrated that the competition between reversible and irreversible rate constants dictates performance for different regulatory mechanisms. We also found that practical system restrictions, such as an upper limit on ligand concentration, can significantly alter the requirements for riboswitch performance, necessitating alternative tuning strategies. Previous experimental data for natural and synthetic riboswitches as well as experiments conducted in this work support model predictions. From our results, we developed a set of general design principles for synthetic riboswitches. Our results also provide a foundation from which to investigate how natural riboswitches are tuned to meet systems-level regulatory demands