Polymorphism in TGFB1 is associated with worse non-relapse mortality and overall survival after stem cell transplantation with unrelated donors.

Transforming growth factor beta-1, encoded by the TGFB1 gene, is a cytokine that plays a central role in many physiological and pathogenic processes. We have sequenced TGFB1 regulatory region and assigned allelic genotypes in a large cohort of hematopoietic stem cell transplantation patients and donors. In this study, we analyzed 522 unrelated donor-patient pairs and examined the combined effect of all the common polymorphisms in this genomic region. In univariate analysis, we found that patients carrying a specific allele, 'p001', showed significantly reduced overall survival (5-year overall survival 30.7% for p001/ p001 patients vs. 41.6% others; P=0.032) and increased non-relapse mortality (1-year nonrelapse mortality: 39.0% vs. 25.4%; P=0.039) after transplantation. In multivariate analysis, the presence of a p001/ p001 genotype in patients was confirmed as an independent factor for reduced overall survival [hazard ratio=1.53 (1.04-2.24); P=0.031], and increased non-relapse mortality [hazard ratio=1.73 (1.06-2.83); P=0.030]. In functional experiments we found a trend towards a higher percentage of surface transforming growth factor beta-1-positive regulatory T cells after activation when the cells had a p001 allele (P=0.07). Higher or lower production of transforming growth factor beta-1 in the inflammatory context of hematopoietic stem cell transplantation may influence the development of complications in these patients. Findings indicate that TGFB1 genotype could potentially be of use as a prognostic factor in hematopoietic stem cell transplantation risk assessment algorithms

Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations

Abstract Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidence-based guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline

The efficacy of chemotherapy is limited by intratumoral senescent cells expressing PD-L2

Chemotherapy often generates intratumoral senescent cancer cells that strongly modify the tumor microenvironment, favoring immunosuppression and tumor growth. We discovered, through an unbiased proteomics screen, that the immune checkpoint inhibitor programmed cell death 1 ligand 2 (PD-L2) is highly upregulated upon induction of senescence in different types of cancer cells. PD-L2 is not required for cells to undergo senescence, but it is critical for senescent cells to evade the immune system and persist intratumorally. Indeed, after chemotherapy, PD-L2-deficient senescent cancer cells are rapidly eliminated and tumors do not produce the senescence-associated chemokines CXCL1 and CXCL2. Accordingly, PD-L2-deficient pancreatic tumors fail to recruit myeloid-derived suppressor cells and undergo regression driven by CD8 T cells after chemotherapy. Finally, antibody-mediated blockade of PD-L2 strongly synergizes with chemotherapy causing remission of mammary tumors in mice. The combination of chemotherapy with anti-PD-L2 provides a therapeutic strategy that exploits vulnerabilities arising from therapy-induced senescence. © 2024, The Author(s)

Direct medical costs of adverse events in Dutch hospitals

Background: Various international studies have shown that a substantial number of patients suffer from injuries or even die as a result of care delivered in hospitals. The occurrence of injuries among patients caused by health care management in Dutch hospitals has never been studied systematically. Therefore, an epidemiological study was initiated to determine the incidence, type and impact of adverse events among discharged and deceased patients in Dutch hospitals. Methods/Design: Three stage retrospective patient record review study in 21 hospitals of 8400 patient records of discharged or deceased patients in 2004. The records were reviewed by trained nurses and physicians between August 2005 and October 2006. In addition to the determination of presence, the degree of preventability, and causes of adverse events, also location, timing, classification, and most responsible specialty of the adverse events were measured. Moreover, patient and admission characteristics and the quality of the patient records were recorded. Discussion: In this paper we report on the design of the retrospective patient record study on the occurrence of adverse events in Dutch hospitals. Attention is paid to the strengths and limitations of the study design. Furthermore, alterations made in the original research protocol in comparison with former international studies are described in detail.

Toxicity Testing in the 21st Century: Defining New Risk Assessment Approaches Based on Perturbation of Intracellular Toxicity Pathways

The approaches to quantitatively assessing the health risks of chemical exposure have not changed appreciably in the past 50 to 80 years, the focus remaining on high-dose studies that measure adverse outcomes in homogeneous animal populations. This expensive, low-throughput approach relies on conservative extrapolations to relate animal studies to much lower-dose human exposures and is of questionable relevance to predicting risks to humans at their typical low exposures. It makes little use of a mechanistic understanding of the mode of action by which chemicals perturb biological processes in human cells and tissues. An alternative vision, proposed by the U.S. National Research Council (NRC) report Toxicity Testing in the 21st Century: A Vision and a Strategy, called for moving away from traditional high-dose animal studies to an approach based on perturbation of cellular responses using well-designed in vitro assays. Central to this vision are (a) “toxicity pathways” (the innate cellular pathways that may be perturbed by chemicals) and (b) the determination of chemical concentration ranges where those perturbations are likely to be excessive, thereby leading to adverse health effects if present for a prolonged duration in an intact organism. In this paper we briefly review the original NRC report and responses to that report over the past 3 years, and discuss how the change in testing might be achieved in the U.S. and in the European Union (EU). EU initiatives in developing alternatives to animal testing of cosmetic ingredients have run very much in parallel with the NRC report. Moving from current practice to the NRC vision would require using prototype toxicity pathways to develop case studies showing the new vision in action. In this vein, we also discuss how the proposed strategy for toxicity testing might be applied to the toxicity pathways associated with DNA damage and repair

Species Interactions during Diversification and Community Assembly in an Island Radiation of Shrews

Closely related, ecologically similar species often have adjacent distributions, suggesting competitive exclusion may contribute to the structure of some natural communities. In systems such as island archipelagos, where speciation is often tightly associated with dispersal over oceanic barriers, competitive exclusion may prevent population establishment following inter-island dispersal and subsequent cladogenesis.) species in the Philippines are the result of competitive exclusion preventing secondary invasion of occupied islands. We first compare ecological niche models between two widespread, allopatric species and find statistical support for their ecological similarity, implying that competition for habitat between these species is possible. We then examine dispersion patterns among sympatric species and find some signal for overdispersion of body size, but not for phylogenetic branch length. Finally, we simulate the process of inter-island colonization under a stochastic model of dispersal lacking ecological forces. Results are dependent on the geographic scope and colonization probability employed. However, some combinations suggest that the number of inter-island dispersal events necessary to populate the archipelago may be much higher than the minimum number of colonization events necessary to explain current estimates of species richness and phylogenetic relationships. If our model is appropriate, these results imply that alternative factors, such as competitive exclusion, may have influenced the process of inter-island colonization and subsequent cladogenesis.We interpret the combined results as providing tenuous evidence that similarity in body size may prevent co-occurrence in Philippine shrews and that competitive exclusion among ecologically similar species, rather than an inability to disperse among islands, may have limited diversification in this group, and, possibly other clades endemic to island archipelagos

Gap Junction Mediated Intercellular Metabolite Transfer in the Cochlea Is Compromised in Connexin30 Null Mice

Connexin26 (Cx26) and connexin30 (Cx30) are two major protein subunits that co-assemble to form gap junctions (GJs) in the cochlea. Mutations in either one of them are the major cause of non-syndromic prelingual deafness in humans. Because the mechanisms of cochlear pathogenesis caused by Cx mutations are unclear, we investigated effects of Cx30 null mutation on GJ-mediated ionic and metabolic coupling in the cochlea of mice. A novel flattened cochlear preparation was used to directly assess intercellular coupling in the sensory epithelium of the cochlea. Double-electrode patch clamp recordings revealed that the absence of Cx30 did not significantly change GJ conductance among the cochlear supporting cells. The preserved electrical coupling is consistent with immunolabeling data showing extensive Cx26 GJs in the cochlea of the mutant mice. In contrast, dye diffusion assays showed that the rate and extent of intercellular transfer of multiple fluorescent dyes (including a non-metabolizable D-glucose analogue, 2-NBDG) among cochlear supporting cells were severely reduced in Cx30 null mice. Since the sensory epithelium in the cochlea is an avascular organ, GJ-facilitated intercellular transfer of nutrient and signaling molecules may play essential roles in cellular homeostasis. To test this possibility, NBDG was used as a tracer to study the contribution of GJs in transporting glucose into the cochlear sensory epithelium when delivered systemically. NBDG uptake in cochlear supporting cells was significantly reduced in Cx30 null mice. The decrease was also observed with GJ blockers or glucose competition, supporting the specificity of our tests. These data indicate that GJs facilitate efficient uptake of glucose in the supporting cells. This study provides the first direct experimental evidence showing that the transfer of metabolically-important molecules in cochlear supporting cells is dependent on the normal function of GJs, thereby suggesting a novel pathogenesis process in the cochlea for Cx-mutation-linked deafness

Bone Marrow Cells in Murine Colitis: Multi-Signal Analysis Confirms Pericryptal Myofibroblast Engraftment without Epithelial Involvement

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The first oviraptorosaur (Dinosauria: Theropoda) bonebed: Evidence of gregarious behaviour in a maniraptoran theropod

A monodominant bonebed of Avimimus from the Nemegt Formation of Mongolia is the first oviraptorosaur bonebed described and the only recorded maniraptoran bonebed from the Late Cretaceous. Cranial elements recovered from the bonebed provide insights on the anatomy of the facial region, which was formerly unknown in Avimimus. Both adult and subadult material was recovered from the bonebed, but small juveniles are underrepresented. The taphonomic and sedimentological evidence suggests that the Avimimus bonebed represents a perimortem gregarious assemblage. The near absence of juveniles in the bonebed may be evidence of a transient age-segregated herd or ‘flock’, but the behaviour responsible for this assemblage is unclear. Regardless, the Avimimus bonebed is the first evidence of gregarious behaviour in oviraptorosaurs, and highlights a potential trend of increasing gregariousness in dinosaurs towards the end of the Mesozoic