These findings highlight the need to understand the temporal and spatial components of thermotolerance variation better, including plasticity and rapid seasonal selection, and the potential for this variation to affect species responses to climate change. With summers becoming longer and increasing winter nighttime temperatures, we expect increasing tropicalization of species thermal tolerances in both space and time.We report three babies from two families with a severe lethal form of congenital cutis laxa. All three had redundant and doughy-textured skin and two siblings from one family had facial dysmorphism. Echocardiograms showed thickened and poorly contractile hearts, arterial dilatation and tortuosity. Post-mortem examination in two of the babies further revealed widespread ectasia and tortuosity of medium and large sized arteries, myocardial hypertrophy, rib and skull fractures. The presence of fractures initially suggested a diagnosis of osteogenesis imperfecta. Under light microscopy bony matrices were abnormal and arterial wall architecture was grossly abnormal showing fragmented elastic fibres. Molecular analysis of known cutis laxa genes did not yield any pathogenic defects. Whole exome sequencing of DNA following informed consent identified two separate homozygous variants in the LOX (Lysyl Oxidase) gene. LOX belongs to the 5-lysyl oxidase gene family involved in initiation of cross-linking of elastin and collagen. A mouse model of a different variant in this gene recapitulates the phenotype seen in the three babies. Our findings suggest that the LOX gene is a novel cause of severe congenital cutis laxa with arterial tortuosity, bone fragility and respiratory failure.A method for generalized linear regression with interval-censored covariates is described, extending previous approaches. A scenario is considered in which an interval-censored covariate of interest is defined as a function of other variables. Instead of directly modeling the distribution of the interval-censored covariate of interest, the distributions of the variables which determine that covariate are modeled, and the distribution of the covariate of interest is inferred indirectly. This approach leads to an estimation procedure using the Expectation-Maximization (EM) algorithm. The performance of this approach is compared to two alternative approaches, one in which the censoring interval midpoints are used as estimates of the censored covariate values, and another in which the censored values are multiply imputed using uniform distributions over the censoring intervals. Entinostat A simulation framework is constructed to assess these methods' accuracies across a range of scenarios. The proposed approach is found to have less bias than midpoint analysis and uniform imputation, at the cost of small increases in standard error. Life-sustaining treatment limitation (LSTL) on the intensive care unit (ICU) may affect the rate of organ donation after brain death (DBD). The primary aim of this study was to examine whether there is a relationship between LSTL and DBD. Furthermore, we aimed to determine the rate of LSTL involved in ICU deaths and to describe technical and procedural characteristics of LSTL on Swedish ICUs. This was an observational cohort study on all ICU deaths (n=13156) in Sweden between 2014 and 2017. We analysed differences in DBD rates between deaths in ICU with and those without LSTL, using descriptive statistics and logistic regression. After excluding 1084 deaths on specialised ICUs and units not registering goals of treatment, the study population comprised 12072 deaths including 615 DBDs, of which 7865 had LSTL, 1706 had no LSTL and 2501 had no stated goals of treatment. The final cohort on which the relationship between DBD and LSTL was analysed comprised 9571 deaths including 419 DBDs. When no LSTL was documented, the rate of organ donation was 9.5% compared to 3.3% when LSTL was documented (P<.001). LSTL was associated with a lower DBD rate after adjusting for patient- and ICU-related factors (OR 0.41, 95% CI 0.31-0.53, P<.001). There was an inverse relationship between LSTL and DBD amongst patients who died on the ICU. This relationship remained after adjusting for factors known to influence organ donation. The reason remains to be determined.There was an inverse relationship between LSTL and DBD amongst patients who died on the ICU. This relationship remained after adjusting for factors known to influence organ donation. The reason remains to be determined.Sepsis is a complex syndrome related to an infection-induced exaggerated inflammatory response, which is associated with a high mortality. Granzymes (Gzm) are proteases mainly found in cytotoxic lymphocytes that not only have a role in target cell death, but also as mediators of infection and inflammation. In this study we sought to analyse the intracellular expression of GzmA, B, M and K by flow cytometry in diverse blood lymphocyte populations from 22 sepsis patients, 12 non-infected intensive care unit (ICU) patients and 32 healthy controls. Additionally, we measured GzmA and B plasma levels. Both groups of patients presented decreased percentage of natural killer (NK) cells expressing GzmA, B and M relative to healthy controls, while sepsis patients showed an increased proportion of CD8+ T cells expressing GzmB compared to controls. Expression of GzmK remained relatively unaltered between groups. Extracellular levels of GzmB were increased in non-infected ICU patients relative to sepsis patients and healthy controls. Our results show differential alterations in intracellular expression of Gzm in sepsis patients and non-infected critically ill patients compared to healthy individuals depending on the lymphocyte population and on the Gzm.Ageing dramatically affects number and function of both innate and adaptive arms of immune system, particularly T cell subsets, contributing to reduced vaccination efficacy, decreased resistance to infections and increased prevalence of cancer in older people. In the present paper, we analysed the age-related changes in the absolute number of lymphocytes in 214 Sicilian subjects, and in the percentages of T and natural killer (NK) cells in a subcohort of donors. We compared these results with the immunophenotype of the oldest living Italian supercentenarian (aged 111 years). The results were also sorted by gender. The correlation between number/percentage of cells and age in all individuals. and separately in males and females, was examined using a simple linear regression analysis. We did not record the increase in the rate of inversion of the CD4/CD8 ratio, frequently reported as being associated with ageing in literature. Our observation was the direct consequence of a flat average trend of CD4+ and CD8+ T cell percentages in ageing donors, even when gender differences were included.