Project description:BackgroundOutcomes among acute kidney injury (AKI) patients are poor in United Kingdom (UK) hospitals, and electronic alerts and care bundles may improve them. We implemented such a system at West Suffolk Hospital (WSH) called the 'AKI order set'. We aimed to assess its impact on all-cause mortality, length of stay (LOS) and renal function among AKI patients, and its utilization.MethodsRetrospective, single-center cohort study of patients ≥ 18 years old with AKI at WSH, a 430-bed general hospital serving a rural UK population of approximately 280,000. 7243 unique AKI events representing 5728 patients with full data were identified automatically from our electronic health record (EHR) between 02 September 2018 and 1 July 2021 (median age 78 years, 51% male). All-cause mortality, LOS and improvement in AKI stage, demographic and comorbidity data, medications and AKI order set use were automatically collected from the EHR.ResultsThe AKI order set was used in 9.8% of AKI events and was associated with 28% lower odds of all-cause mortality (multivariable odds ratio [OR] 0.72, 95% confidence interval [CI] 0.57-0.91). Median LOS was longer when the AKI order set was utilized than when not (11.8 versus 8.8 days, p < .001), but was independently associated with improvement in the AKI stage (28.9% versus 8.7%, p < .001; univariable OR 4.25, 95% CI 3.53-5.10, multivariable OR 4.27, 95% CI 3.54-5.14).ConclusionsAKI order set use led to improvements in all-cause mortality and renal function, but longer LOS, among AKI patients at WSH.
Project description:Antibodies that block T cell inhibition via the immune checkpoints CTLA-4 and PD-1 have revolutionized cancer therapy during the last 15 years. T cells express additional inhibitory surface receptors that are considered to have potential as targets in cancer immunotherapy. Antibodies against LAG-3 and TIM-3 are currently clinically tested to evaluate their effectiveness in patients suffering from advanced solid tumors or hematologic malignancies. In addition, blockade of the inhibitory BTLA receptors on human T cells may have potential to unleash T cells to effectively combat cancer cells. Much research on these immune checkpoints has focused on mouse models. The analysis of animals that lack individual inhibitory receptors has shed some light on the role of these molecules in regulating T cells, but also immune responses in general. There are current intensive efforts to gauge the efficacy of antibodies targeting these molecules called immune checkpoint inhibitors alone or in different combinations in preclinical models of cancer. Differences between mouse and human immunology warrant studies on human immune cells to appreciate the potential of individual pathways in enhancing T cell responses. Results from clinical studies are not only highlighting the great benefit of immune checkpoint inhibitors for treating cancer but also yield precious information on their role in regulating T cells and other cells of the immune system. However, despite the clinical relevance of CTLA-4 and PD-1 and the high potential of the emerging immune checkpoints, there are still substantial gaps in our understanding of the biology of these molecules, which might prevent the full realization of their therapeutic potential. This review addresses PD-1, CTLA-4, BTLA, LAG-3, and TIM-3, which are considered major inhibitory immune checkpoints expressed on T cells. It provides summaries of our current conception of the role of these molecules in regulating T cell responses, and discussions about major ambiguities and gaps in our knowledge. We emphasize that each of these molecules harbors unique properties that set it apart from the others. Their distinct functional profiles should be taken into account in therapeutic strategies that aim to exploit these pathways to enhance immune responses to combat cancer.
Project description:A biological molecule, e.g., an enzyme, tends to interact with its many cognate substrates, targets, or partners differentially. Such a property is termed relative specificity and has been proposed to regulate important physiological functions, even though it has not been examined explicitly in most complex biochemical systems. This essay reviews several recent large-scale studies that investigate protein folding, signal transduction, RNA binding, translation and transcription in the context of relative specificity. These results and others support a pervasive role of relative specificity in diverse biological processes. It is becoming clear that relative specificity contributes fundamentally to the diversity and complexity of biological systems, which has significant implications in disease processes as well.
Project description:The need to assess the randomness of a single sequence, especially a finite sequence, is ubiquitous, yet is unaddressed by axiomatic probability theory. Here, we assess randomness via approximate entropy (ApEn), a computable measure of sequential irregularity, applicable to single sequences of both (even very short) finite and infinite length. We indicate the novelty and facility of the multidimensional viewpoint taken by ApEn, in contrast to classical measures. Furthermore and notably, for finite length, finite state sequences, one can identify maximally irregular sequences, and then apply ApEn to quantify the extent to which given sequences differ from maximal irregularity, via a set of deficit (def(m)) functions. The utility of these def(m) functions which we show allows one to considerably refine the notions of probabilistic independence and normality, is featured in several studies, including (i) digits of e, pi, radical2, and radical3, both in base 2 and in base 10, and (ii) sequences given by fractional parts of multiples of irrationals. We prove companion analytic results, which also feature in a discussion of the role and validity of the almost sure properties from axiomatic probability theory insofar as they apply to specified sequences and sets of sequences (in the physical world). We conclude by relating the present results and perspective to both previous and subsequent studies.
Project description:The harnessing in clinical practice of cyclin-dependent kinases 4/6 inhibitors, namely palbociclib, ribociclib, and abemaciclib, has substantially changed the therapeutic approach for hormone receptor-positive metastatic breast cancer (BC). Phase II-III clinical trials evaluating the addition of these agents to standard endocrine therapy reported consistent improvements in response rates and progression-free survival as well as manageable toxicity profiles and excellent impact on patients' quality of life. Hence, pivotal trials provided comparable results among different cyclin-dependent kinases 4/6 inhibitors, there is an increasing interest in finding substantial differences in order to implement their use in clinical practice. The aim of this paper is to summarize the current evidences raised from preclinical and clinical studies on cyclin-dependent kinases 4/6 inhibitors in BC, focusing on differences in terms of pharmacological properties, toxicity profile, and patients' quality of life.
Project description:Many prospective studies and a recent randomized controlled trial have shown that the B-cell-depleting monoclonal antibody, rituximab, safely promotes the remission of nephrotic syndrome in approximately 65% of patients with membranous nephropathy (MN). Mechanistic studies have indicated that rituximab-induced proteinuria reduction is associated with clearance of anti-podocyte antigens phospholipase 2 receptor autoantibodies and subepithelial immune complexes, the hallmarks of the disease. A recently published study reported results which, at first sight, looked less favorable and implied that, due to a publication bias against negative results, the efficacy of rituximab in MN might be overestimated. Since patients received only one or 2 rituximab administrations, the authors suggest that when rituximab is used, higher doses and longer treatments should be considered. In this study, we highlight limitations of the study and warn against an oversimplified interpretation of the data. Though information on the optimal dose of rituximab to use in MN is still limited, available data from studies with predefined rituximab administration protocols collectively support the concept of titrating rituximab to the number of circulating B-cells that are invariably depleted after the first or second administration. Additional doses may increase the risk of adverse effects and related costs without augmenting efficacy. Importantly, underpowered studies with inconclusive results should not be confused with negative studies formally proving a neutral effect of a treatment. Until data from ad hoc designed clinical trials are available, the B-cell-driven protocol should be the preferred regimen, since it is similarly effective, but safer and more cost effective than other protocols employing multiple rituximab administrations.
Project description:Secretory granules carrying fluorescent cargo proteins are widely used to study granule biogenesis, maturation, and regulated exocytosis. We fused the soluble secretory protein peptidylglycine alpha-hydroxylating monooxygenase (PHM) to green fluorescent protein (GFP) to study granule formation. When expressed in AtT-20 or GH3 cells, the PHM-GFP fusion protein partitioned from endogenous hormone (adrenocorticotropic hormone, growth hormone) into separate secretory granule pools. Both exogenous and endogenous granule proteins were stored and released in response to secretagogue. Importantly, we found that segregation of content proteins is not an artifact of overexpression nor peculiar to GFP-tagged proteins. Neither luminal acidification nor cholesterol-rich membrane microdomains play essential roles in soluble content protein segregation. Our data suggest that intrinsic biophysical properties of cargo proteins govern their differential sorting, with segregation occurring during the process of granule maturation. Proteins that can self-aggregate are likely to partition into separate granules, which can accommodate only a few thousand copies of any content protein; proteins that lack tertiary structure are more likely to distribute homogeneously into secretory granules. Therefore, a simple "self-aggregation default" theory may explain the little acknowledged, but commonly observed, tendency for both naturally occurring and exogenous content proteins to segregate from each other into distinct secretory granules.
Project description:The rise in drug overdose deaths in the United States since the turn of the millennium has been extraordinary. A popular narrative paints a picture whereby opioid overdoses among white, male, less-educated, rural workers have been caused by reduced economic opportunities borne by such people. In this article, we causally test the validity of this theory by using Bartik-type variables to explore the relationship between local economic conditions and county opioid overdose death rates. We add to the literature by exploring how both employment and wage growth in different types of industries are related to opioid overdose deaths for the population as a whole, as well as for rural (vs. urban), male (vs. female) and white (vs. black) populations. We find mixed evidence. Our results confirm that wage and employment growth in industries more likely to employ low-skill workers are important protective factors for rural, white males. However, we also find evidence that economic improvements in low-skill industries are just as important in protecting blacks and women against opioid overdoses, and for workers in metro counties. We also find evidence that employment growth in high-paying industries has led to increases in opioid overdoes rates.