Acquired resistance to anti-PD1 therapy: checkmate to checkpoint blockade?

Editorial summary Anti-programmed cell death 1 (PD1) immunotherapies are among the most effective anti-cancer immunotherapies available; however, a large number of patients present with or develop resistance to them. Unfortunately, very little is known regarding the mechanisms of resistance to such therapies. A recent study sought to identify mutations associated with resistance to anti-PD1 therapy. Results from this study demonstrated that mutations which affected the sensitivity of tumor cells to T-cell-derived interferons, and mutations limiting tumor-cell antigen presentation, could cause acquired resistance. These findings have significant implications for understanding the mechanisms by which anti-PD1 therapies exert their efficacy, comprehending why and how some patients acquire resistance over time, and ultimately guiding the development of combination therapies designed to overcome, or potentially prevent, the development of acquired immunotherapeutic resistance

Gender Bias: An Analysis of the Distribution of Institutional Aid

This study is based on the premise that equity in the distribution of institutional student aid is related to a student\u27s academic ability and need. Thus, to establish evidence of gender bias, this study examined the influence of gender on students\u27 institutional aid awards while controlling for these two factors, as well as other related student and institutional characteristics. This study found no direct evidence of gender bias when examining the relationship between student characteristics and institutional aid. However, when examining institutional characteristics, indirect implications suggested that gender was related to the relationship between academic ability as measured by SAT/ ACT and institutional aid

Planning Implementation Success of Syncope Clinical Practice Guidelines in the Emergency Department Using CFIR Framework

Background and Objectives: Overuse and inappropriate use of testing and hospital admission are common in syncope evaluation and management. Though guidelines are available to optimize syncope care, research indicates that current clinical guidelines have not significantly impacted resource utilization surrounding emergency department (ED) evaluation of syncope. Matching implementation strategies to barriers and facilitators and tailoring strategies to local context hold significant promise for a successful implementation of clinical practice guidelines (CPG). Our team applied implementation science principles to develop a stakeholder-based implementation strategy. Methods and Materials: We partnered with patients, family caregivers, frontline clinicians and staff, and health system administrators at four health systems to conduct quantitative surveys and qualitative interviews for context assessment. The identification of implementation strategies was done by applying the CFIR-ERIC Implementation Strategy Matching Tool and soliciting stakeholders’ inputs. We then co-designed with patients and frontline teams, and developed and tested specific strategies. Results: A total of 114 clinicians completed surveys and 32 clinicians and stakeholders participated in interviews. Results from the surveys and interviews indicated low awareness of syncope guidelines, communication challenges with patients, lack of CPG protocol integration into ED workflows, and organizational process to change as major barriers to CPG implementation. Thirty-one patients and their family caregivers participated in interviews and expressed their expectations: clarity regarding their diagnosis, context surrounding care plan and diagnostic testing, and a desire to feel cared about. Identifying change methods to address the clinician barriers and patients and family caregivers expectations informed development of the multilevel, multicomponent implementation strategy, MISSION, which includes patient educational materials, mentored implementation, academic detailing, Syncope Optimal Care Pathway and a corresponding mobile app, and Lean quality improvement methods. The pilot of MISSION demonstrated feasibility, acceptability and initial success on appropriate testing. Conclusions: Effective multifaceted implementation strategies that target individuals, teams, and healthcare systems can be employed to plan successful implementation and promote adherence to syncope CPGs

Regulation of Carcinogenesis by IL-5 and CCL11: A Potential Role for Eosinophils in Tumor Immune Surveillance

The role of the immune system in the surveillance of transformed cells has seen a resurgence of interest in the last 10 years, with a substantial body of data in mice and humans supporting a role for the immune system in host protection from tumor development and in shaping tumor immunogenicity. A number of earlier studies have demonstrated that eosinophils, when recruited into tumors, can very effectively eradicate transplantable tumors. In this study, we investigated whether eosinophils also play a role in tumor immune surveillance by determining the incidence of methylcholanthrene (MCA)-induced flbrosarcomas in IL-5 transgenic mice that have greatly enhanced levels of circulating eosinophils, CCL11 (eotaxin-l)-deficient mice that lack a key chemokine that recruits eosinophils into tissues, and the eosinophil-deficient mouse strains, IL-5/CCL11-/- and ΔdblGATA. It was found that MCA-induced tumor incidence and growth were significantly attenuated in IL-5 transgenic mice of both the BALB/c and C57BL/6 backgrounds. Histological examination revealed that the protective effect of IL-5 was associated with massively enhanced numbers of eosinophils within and surrounding tumors. Conversely, there was a higher tumor incidence in CCL11-/- BALB/c mice, which was associated with a reduced eosinophil influx into tumors. This correlation was confirmed in the eosinephil-deficient IL-5/CCL11-/- and ΔdblGATA mouse strains, where tumor incidence was greatly increased in the total absence of eosinophils. In addition, subsequent in vitro studies found that eosinophils could directly kill MCA-induced fibrosarcoma cells. Collectively, our data support a potential role for the eosinophil as an effector cell in tumor immune surveillance

Improving SWE Estimation with Data Assimilation: The Influence of Snow Depth Observation Timing and Uncertainty

Snow depth observations can be leveraged with data assimilation (DA) to improve estimation of snow density and snow water equivalent (SWE). A key consideration for mission and campaign design is how snow depth retrieval characteristics (including observation timing/frequency and sampling error) influence SWE accuracy and uncertainty in a DA framework. To quantify these effects, we implement a particle filter (PF) assimilation technique to assimilate depth and validate this approach against observed snow density and SWE at 49 snow telemetry sites across 9 years. We sample from continuous in-situ snow depth records to test a range of measurement timing scenarios and two sampling error scenarios representative of remote sensing capabilities. Assimilation reduces density bias by over 40% and SWE bias by over 70% across climate zones and in both wet and dry years. There is little incremental benefit to SWE accuracy when assimilating more than one depth observation near peak accumulation. SWE estimates are less sensitive to observation timing than sampling error. Alternatively, more frequent depth observations improve melt-out date timing and reduce SWE uncertainty, a key consideration when evaluating the operational utility of DA. In matching depth observations, the PF mostly acts to increase precipitation inputs to the model, while not systematically shifting other parameter values or forcings across the climate zones represented with the study sites. This demonstrates that precipitation is the largest source of model error. With DA, density errors are still nontrivial, illuminating the need for further improvements to modeled density to achieve SWE error targets.</div

BK polyomavirus: clinical aspects, immune regulation, and emerging therapies

BK polyomavirus (BKV) causes frequent infections during childhood and establishes persistent infections within renal tubular cells and the uroepithelium, with minimal clinical implications. However, reactivation of BKV in immunocompromised individuals following renal or hematopoietic stem cell transplantation may cause serious complications, including BKV-associated nephropathy (BKVAN), ureteric stenosis, or hemorrhagic cystitis. Implementation of more potent immunosuppression and increased posttransplant surveillance has resulted in a higher incidence of BKVAN. Antiviral immunity plays a crucial role in controlling BKV replication, and our increasing knowledge about host-virus interactions has led to the development of improved diagnostic tools and clinical management strategies. Currently, there are no effective antiviral agents for BKV infection, and the mainstay of managing reactivation is reduction of immunosuppression. Development of immune-based therapies to combat BKV may provide new and exciting opportunities for the successful treatment of BKV-associated complications

Development of the Liverpool Adverse Drug Reaction Avoidability Assessment Tool

Aim To develop and test a new tool to assess the avoidability of adverse drug reactions that is suitable for use in paediatrics but which is also applicable to a variety of other settings. Methods The study involved multiple phases. Preliminary work involved using the Hallas scale and a modification of the existing Hallas scale, to assess two different sets of adverse drug reaction (ADR) case reports. Phase 1 defined, modified and refined a new tool using multidisciplinary teams. Phase 2 involved the assessment of 50 ADR case reports from a prospective study of paediatric inpatients by individual assessors. Phase 3 compared assessments with the new tool for individuals and groups in comparison to the ‘gold standard’ (the avoidability outcome set by a panel of senior investigators: an experienced clinical pharmacologist, paediatrician and pharmacist). Main Outcome Measures Inter-rater reliability (IRR), measure of disagreement and utilization of avoidability categories. Results Preliminary work—Pilot phase: results for the original Hallas cases were fair and pairwise kappa scores ranged from 0.21 to 0.36. Results for the modified Hallas cases were poor, pairwise kappa scores ranged from 0.06 to 0.16. Phase 1: on initial use of the new tool, agreement between the two multidisciplinary groups was found on 13/20 cases with a kappa score of 0.29 (95% CI -0.04 to 0.62). Phase 2: the assessment of 50 ADR case reports by six individual reviewers yielded pairwise kappa scores ranging from poor to good 0.12 to 0.75 and percentage exact agreement (%EA) ranged from 52–90%. Phase 3: Percentage exact agreement ranged from 35–70%. Overall, individuals had better agreement with the ‘gold standard’. Conclusion Avoidability assessment is feasible but needs careful attention to methods. The Liverpool ADR avoidability assessment tool showed mixed IRR. We have developed and validated a method for assessing the avoidability of ADRs that is transparent, more objective than previous methods and that can be used by individuals or groups

A structural basis for selection and cross-species reactivity of the semi-invariant NKT cell receptor in CD1d/glycolipid recognition

Little is known regarding the basis for selection of the semi-invariant αβ T cell receptor (TCR) expressed by natural killer T (NKT) cells or how this mediates recognition of CD1d–glycolipid complexes. We have determined the structures of two human NKT TCRs that differ in their CDR3β composition and length. Both TCRs contain a conserved, positively charged pocket at the ligand interface that is lined by residues from the invariant TCR α- and semi-invariant β-chains. The cavity is centrally located and ideally suited to interact with the exposed glycosyl head group of glycolipid antigens. Sequences common to mouse and human invariant NKT TCRs reveal a contiguous conserved “hot spot” that provides a basis for the reactivity of NKT cells across species. Structural and functional data suggest that the CDR3β loop provides a plasticity mechanism that accommodates recognition of a variety of glycolipid antigens presented by CD1d. We propose a model of NKT TCR–CD1d–glycolipid interaction in which the invariant CDR3α loop is predicted to play a major role in determining the inherent bias toward CD1d. The findings define a structural basis for the selection of the semi-invariant αβ TCR and the unique antigen specificity of NKT cells

Influence of permanent night work on the circadian rhythm of blood pressure

Abstract. Night workers exercise their labours activities and rest in contrary schedules to the chronobiological standards. This inversion leads the body to several adaptations, including changes in the circadian rhythm of blood pressure (BP). Objectives: To evaluate the BP in individuals who perform work at night, in order to objectively detail the BP circadian rhythm adaptations infixed night workers. Methods: A cross-sectional study enrolling 23 fixed night workers, both genders, was performed, with 24h BP measured with ambulatory blood pressure monitoring (ABPM) during a normal working day. Risk factors, anthropometric and lifestyle information were collected using a standard questionnaire. Results: Ambulatory BP demonstrated a pattern of adaptation to the sleep/activity cycle in all participants. BP dropped during the sleeping period (mean drop: -11.35±6.85) and was higher during the awakening period, reaching the highest results and greater BP variability during the working period. The chronobiological adaptation of the 24h BP was not dependent on sociodemographic or clinical characteristics. In addition, age, male gender, obesity, and those working less time were associated with higher BP mean values. Conclu-sions: The circadian rhythm of BP follows the working circadian profile of the individual.info:eu-repo/semantics/publishedVersio