Diagnosis and management of systemic mastocytosis in a community hematology setting.

BACKGROUND: Systemic mastocytosis (SM) is a rare and potentially severe hematologic disorder characterized by the clonal proliferation of mast cells (MCs) into various organs. The clinical manifestations of advanced SM are caused by the uncontrolled release of cytokines and vasoactive amines from MC and disease-induced organ dysfunction. Patients with SM typically present with symptoms such as flushing, pruritus, diarrhea, and headaches, but outcomes following active treatment have not been well characterized. In this study, the clinical characteristics, treatment patterns, and natural history of an SM patient cohort diagnosed and treated within a community hematology network in the United States is described. METHODS: We identified 105 patients who were diagnosed and managed in one of 19 community hematology clinics up to an index date of 1 October 2022. Data collection included patient and disease characteristics, baseline biochemistry and hematology, SM diagnostic criteria being met, biomarkers tested, CD2 and/or CD25 expression in MCs as well as serum tryptase levels at presentation. Data abstraction also included supportive care drugs and anticancer therapy used, treatment response, reason for discontinuation, and overall survival by disease subtype. RESULTS: A total of 105 SM patients were identified who met the inclusion criteria. The specific SM subtypes were indolent (47.6%), aggressive (9.5%), SM with an associated hematological neoplasm (19.0%), MC leukemia (1.9%), and subtype not documented (21.9%). Regardless of subtype, approximately 62% of patients did not receive SM-directed active therapy. Only 26% of patients with indolent systemic mastocytosis (ISM) received treatment compared to 65.6% with advanced subtypes. Relative to ISM cohort, the relative risk of death in patients with the advanced SM subtypes was approximately 15 times greater (hazard ratio = 15.0; 95% confidence interval: 3.3 to 66.5). CONCLUSIONS: SM patients present with multiple underlying symptoms, within various disease subtypes that are difficult to diagnose in a timely manner. As a result, many patients do not receive active drug therapy for their disease. Therefore, greater disease awareness is required as well as new tools for earlier disease detection.

Revisiting the Digital Plumber: Modifying the Installation Process of an Established Commercial IoT Alarm System.

The 'digital plumber' is a conceptualisation in ubicomp research that describes the work of installing and maintaining IoT devices. But an important and often understated element of commercial IoT solutions is their long-term socio-technical infrastructural nature, and therefore long-term installation and maintenance needs. This adds complexity to both the practice of digital plumbing and to the work of design that supports it. In this paper we study a commercial company producing and installing IoT alarm systems. We examine video recordings that capture how a digital plumbing representative and software development team members make changes to both the installation process and supporting technology. Our data enables us to critically reflect on concepts of infrastructuring, and uncover the ways in which the team methodically foreground hidden elements of the infrastructure to address a point of failure experienced during field trials of a new version of their product. The contributions from this paper are twofold. Firstly, our findings build on previous examples of infrastructuring in practice by demonstrating the use of notions of elemental states to support design reasoning through the continual foregrounding and assessment of tensions identified as key factors at the point of failure. Secondly, we build on current notions of digital plumbing work. We argue that additional responsibilities of 'reporting failure' and 'facilitation of change' are part of the professional digital plumbing role and that commercial teams should support these additional responsibilities through collaborative troubleshooting and design sessions alongside solid communication channels with related stakeholders within the product team.

Regulation of mucin secretion and inflammation in asthma: a role for MARCKS protein?

BACKGROUND: A major characteristic of asthmatic airways is an increase in mucin (the glycoprotein component of mucus) producing and secreting cells, which leads to increased mucin release that further clogs constricted airways and contributes markedly to airway obstruction and, in the most severe cases, to status asthmaticus. Asthmatic airways show both a hyperplasia and metaplasia of goblet cells, mucin-producing cells in the epithelium; hyperplasia refers to enhanced numbers of goblet cells in larger airways, while metaplasia refers to the appearance of these cells in smaller airways where they normally are not seen. With the number of mucin-producing and secreting cells increased, there is a coincident hypersecretion of mucin which characterizes asthma. On a cellular level, a major regulator of airway mucin secretion in both in vitro and in vivo studies has been shown to be MARCKS (myristoylated alanine-rich C kinase substrate) protein, a ubiquitous substrate of protein kinase C (PKC). GENERAL SIGNIFICANCE: In this review, properties of MARCKS and how the protein may regulate mucin secretion at a cellular level will be discussed. In addition, the roles of MARCKS in airway inflammation related to both influx of inflammatory cells into the lung and release of granules containing inflammatory mediators by these cells will be explored. This article is part of a Special Issue entitled: Biochemistry of Asthma.

Antipsychotic Medication Adherence and Healthcare Services Utilization in Two Cohorts of Patients with Serious Mental Illness.

OBJECTIVE: To evaluate differences in patient characteristics and real-world outcomes in two distinct high-risk cohorts of patients with serious mental illness (SMI). METHODS: Retrospective cross-sectional analysis using a national multi-payer claims database. Two SMI cohorts identified by a technical expert panel-patients recently discharged (RD) from an SMI-related hospitalization and early episode (EE) patients-were evaluated for antipsychotic medication adherence, healthcare utilization, and spending patterns. RESULTS: The analysis included 51,705 patients with bipolar disorder, major depressive disorder, and schizophrenia. More than half were over age 46 and >60% were female. Adherence to psychiatric medications was low (52.5% RD and 16.1% EE). More than half of RD and 100% of EE patients switched medications at least once annually, but 19% of RD patients switched ≥2 times compared to 14% of EE. The RD cohort (generally older and sicker) had higher psychiatric related utilization and higher annual costs (US$21,171 versus US$15,398). In both cohorts, women were more likely to have an emergency department (ED) and primary care provider (PCP) visit, but less likely to be hospitalized. Patients age <46 were less likely to have a PCP visit and more likely to have an ED visit, but younger patients age 18-24 were less likely to be hospitalized. CONCLUSION: Efforts to manage SMI are confounded by heterogeneity and low adherence to treatment. By better understanding which patients are at higher risk for specific adverse outcomes, clinicians can target interventions more appropriately to reduce the significant burden of SMI.

Distinguishing motive through perception of emotions.

The question of whether people use perceived expressions of emotion to infer motive is tested in this study. Naïve observers viewed target subjects performing a simple "tower building" task under more or less motivating conditions. Observers ranked target effort levels and ticked emotions displayed of four targets. Motive rankings matched target motive conditions well. Emotion checklist scores also showed high accuracy when compared with target self-reports of emotions experienced. Regression showed that most of the variance in motivation ratings was accounted for by emotions observed. Discussion centers on applications of this understanding of emotive perception in organizations, and the relation between the first two components of Salovey and Mayer's (1990) model of emotional intelligence.

Directed migration of mouse macrophages in vitro involves myristoylated alanine-rich C-kinase substrate (MARCKS) protein.

A role for MARCKS protein in directed migration of macrophages toward a chemoattractant was investigated. A peptide identical to the N-terminus of MARCKS (the MANS peptide), shown previously to inhibit the function of MARCKS in various cell types, was used. We investigated whether this MARCKS-related peptide could affect migration of macrophages, using the mouse macrophage-like J774A.1 cell line and primary murine macrophages. Both of these cell types migrated in response to the chemoattractants macrophage/MCPs, MCP-1 (25-100 ng/ml) or C5a (5-20 ng/ml). Cells were preincubated (15 min) with MANS or a mis-sense control peptide (RNS), both at 50 µM, and effects on migration determined 3 h after addition of chemoattractants. The movement and interactions of MARCKS and actin also were followed visually via confocal microscopy using a fluorescently labeled antibody to MARCKS and fluorescently tagged phalloidin to identify actin. MANS, but not RNS, attenuated migration of J774A.1 cells and primary macrophages in response to MCP-1 or C5a, implicating MARCKS in the cellular mechanism of directed migration. Exposure of cells to MCP-1 resulted in rapid phosphorylation and translocation of MARCKS from plasma membrane to cytosol, whereas actin appeared to spread through the cell and into cell protrusions; there was visual and biochemical evidence of a transient interaction between MARCKS and actin during the process of migration. These results suggest that MARCKS is involved in directed migration of macrophages via a process involving its phosphorylation, cytoplasmic translocation, and interaction with actin.