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BACKGROUND Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. METHODS We examined whether APS-1 could be classified as a disease mediated by interferon-y. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-/using AirrhIfngh mice and Aire'1' mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. RESULTS Patients with APS-1 had enhanced interferon-y responses in blood and in all examined autoimmunity-affected tissues. Aire1' mice had selectively increased interferon-y production by T cells and enhanced interferon-y, phosphorylated signal transducer and activator of transcription 1 (pSTATl), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Airrh mice normalized interferon-y responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-y, normalized interferon-y and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjogren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. CONCLUSIONS Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-y-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.) [ABSTRACT FROM AUTHOR]

Prototheca wickerhamii is a rare cause of cutaneous and systemic infection that requires long treatment courses with potentially toxic medications. We describe a patient with cutaneous protothecosis refractory to triazole monotherapy who experienced clinical and radiographic improvement with the novel oral lipid nanocrystal formulation of amphotericin B without experiencing toxicity., Competing Interests: Potential conflicts of interest. T.M. is an employee of Matinas Biopharma and has an equity interest and receives support for attending meetings and/or travel and reports a role as board director for Apilli Therapeutics and GoodCap Pharmaceuticals. All other authors report no potential conflicts., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Thymoma presents with several autoimmune manifestations and is associated with secondary autoimmune regulator (AIRE) deficiency. Pneumonitis has recently been described as an autoimmune manifestation associated with thymoma presenting with similar clinical, radiographic, histological, and autoantibody features as seen in patients with inherited AIRE deficiency who suffer from Autoimmune PolyEndocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) syndrome., Objectives: To treat two patients with biopsy-proven thymoma-associated pneumonitis with lymphocyte-directed immunomodulation., Methods: Two patients with thymoma were enrolled on IRB-approved protocols at the NIH Clinical Center. We performed history and physical examination; laboratory, radiographic, histologic and pulmonary function evaluations; and measurement of the lung-directed autoantibodies KCNRG and BPIFB1 prior to and at 1- and 6-months following initiation of lymphocyte-directed immunomodulation with azathioprine with or without rituximab., Results: Combination T- and B-lymphocyte-directed immunomodulation resulted in improvement of clinical, functional, and radiographic parameters at 6-month follow-up evaluations in both patients with sustained remission up to 12-36 months following treatment initiation., Conclusion: Lymphocyte-directed immunomodulation remitted autoimmune pneumonitis in two patients with thymoma., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Introduction: Candida auris is a pathogen of growing public health concern given its rapid spread across the globe, its propensity for long-term skin colonization and healthcare-related outbreaks, its resistance to a variety of antifungal medications, and the high morbidity and mortality associated with invasive disease. Despite that, the host immune response mechanisms that operate during C. auris skin colonization and invasive infection remains poorly understood., Areas Covered: In this manuscript, we review the available literature in the growing research field pertaining to C. auris host defenses and we discuss what is known about the ability of C. auris to thrive on mammalian skin, the role of lymphoid cell-mediated, IL-17-dependent defenses in controlling cutaneous colonization, and the contribution of myeloid phagocytes in curtailing systemic infection., Expert Opinion: Understanding the mechanisms by which the host immune system responds to and controls colonization and infection with C. auris and developing a deeper knowledge of tissue-specific host-C. auris interactions and of C. auris immune-evading mechanisms may help devise improved strategies for decolonization, prognostication, prevention, vaccination, and/or directed antifungal treatment in vulnerable patient populations.

A patient in Virginia, USA, who had previously undergone multiple kidney transplantations showed signs of Bordetella hinzii bacteremia and meningitis. This emerging pathogen has been increasingly identified as a clinically significant pathogen in immunosuppressed and, less frequently, immunocompetent patients. This patient was treated and recovered without further issue.

Interprofessional education (IPE) and collaborative practice (CP) have been prolific areas of inquiry exploring research questions mostly concerned with local program and project assessment. The actual sphere of influence of this research has been limited. Often discussed separately, this article places IPE and CP in the same conceptual space. The interface of these form a nexus where new knowledge creation may be facilitated. Rigorous research on IPE in relation to CP that is relevant to and framed by health system reform in the U.S. is the ultimate research goal of the National Center for Interprofessional Practice and Education at the University of Minnesota. This paper describes the direction and scope for a focused and purposive IPECP research agenda linked to improvement in health outcomes, contextualized by health care reform in the U.S. that has provided a revitalizing energy for this area of inquiry. A research agenda articulates a focus, meaningful and robust questions, and a theory of change within which intervention outcomes are examined. Further, a research agenda identifies the practices the area of inquiry is interested in informing, and the types of study designs and analytic approaches amenable to carrying out the proposed work.

Background: There is currently a resurgence of interest in interprofessional education and collaborative practice (IPECP) and its potential to positively impact health outcomes at both the patient level and population level, healthcare delivery, and health professions education. This resurgence of interest led to the creation of the National Center on Interprofessional Collaborative Practice and Education in October 2012., Methods: This paper describes three intertwined knowledge generation strategies of the National Center on Interprofessional Practice and Education: (1) the development of a Nexus Incubator Network, (2) the undertaking of comparative effectiveness research, and (3) the creation of a National Center Data Repository., Results: As these strategies are implemented over time they will result in the production of empirically grounded knowledge regarding the direction and scope of the impact, if any, of IPECP on well-defined health and healthcare outcomes including the possible improvement of the patient experience of care., Conclusions: Among the motivating factors for the National Center and the three strategies adopted and addressed herein is the need for rigorously produced, scientifically sound evidence regarding IPECP and whether or not it has the capacity to positively affect the patient experience of care, the health of populations, and the per capita cost of healthcare.

Understanding the impact that interprofessional education and collaborative practice (IPECP) might have on triple aim patient outcomes is of high interest to health care providers, educators, administrators, and policy makers. Before the work undertaken by the National Center for Interprofessional Practice and Education at the University of Minnesota, no standard mechanism to acquire and report outcome data related to interprofessional education and collaborative practice and its effect on triple aim outcomes existed. This article describes the development and adoption of the National Center Data Repository (NCDR) designed to capture data related to IPECP processes and outcomes to support analyses of the relationship of IPECP on the Triple Aim. The data collection methods, web-based survey design and implementation process are discussed. The implications of this informatics work to the field of IPECP and health care quality and safety include creating standardized capacity to describe interprofessional practice and measure outcomes connecting interprofessional education and collaborative practice to the triple aim within and across sites/settings, leveraging an accessible data collection process using user friendly web-based survey design to support large data scholarship and instrument testing, and establishing standardized data elements and variables that can potentially lead to enhancements to national/international information system and academic accreditation standards to further team-based, interprofessional, collaborative research in the field.

Background: Impaired signaling in the IFN-γ/IL-12 pathway causes susceptibility to severe disseminated infections with mycobacteria and dimorphic yeasts. Dominant gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1) have been associated with chronic mucocutaneous candidiasis., Objective: We sought to identify the molecular defect in patients with disseminated dimorphic yeast infections., Methods: PBMCs, EBV-transformed B cells, and transfected U3A cell lines were studied for IFN-γ/IL-12 pathway function. STAT1 was sequenced in probands and available relatives. Interferon-induced STAT1 phosphorylation, transcriptional responses, protein-protein interactions, target gene activation, and function were investigated., Results: We identified 5 patients with disseminated Coccidioides immitis or Histoplasma capsulatum with heterozygous missense mutations in the STAT1 coiled-coil or DNA-binding domains. These are dominant gain-of-function mutations causing enhanced STAT1 phosphorylation, delayed dephosphorylation, enhanced DNA binding and transactivation, and enhanced interaction with protein inhibitor of activated STAT1. The mutations caused enhanced IFN-γ-induced gene expression, but we found impaired responses to IFN-γ restimulation., Conclusion: Gain-of-function mutations in STAT1 predispose to invasive, severe, disseminated dimorphic yeast infections, likely through aberrant regulation of IFN-γ-mediated inflammation., (Published by Mosby, Inc.)

Background: Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers., Objective: We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC., Methods: We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX)-like phenotype for STAT1 mutations., Results: We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M [2 patients]). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4(+) IL-17-producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4(+) T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2-induced STAT5 phosphorylation., Conclusions: Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells., (Published by Mosby, Inc.)

STAT1 is a key component of Interferon (IFN)-γ and IFN-α signaling and mediates protection against mycobacteria, fungal, viral infections, and cancer. Dominant negative inhibitory as well as gain of function heterozygous STAT1 mutations demonstrate that IFN-γ driven cellular responses need to be tightly regulated to control infections. We describe an autosomal dominant mutation in the SH2 domain of STAT1 that disrupts protein phosphorylation, c.1961T>A (M654K). The mutant allele does not permit STAT1 phosphorylation, and impairs STAT1 phosphorylation of the wild type allele. Protein dimerization is preserved but DNA binding activity, IFN-γ driven GAS-luciferase activity, and expression of IFN-γ target genes are reduced. IFN-α driven ISRE response, but not IFN-α driven GAS response, are preserved when cells are co-transfected with wild type and the mutant STAT1 constructs. M654K exerts a dominant negative effect on IFN-γ related immunity and is recessive for IFN-α induced immune function.

A 300-bed acute care community hospital used a 2-day "Rapid Process Improvement Workshop" to identify factors contributing to facility-acquired pressure ulcers (PU). The Rapid Process Improvement Workshop included key stakeholders from all procedural areas providing inpatient services and used standard components of rapid process improvement: data analysis, process flow charting, factor identification, and action plan development.On day 1, the discovery process revealed increased PU risk related to prolonged immobility when transporting patients for procedures, during imaging studies, and during the perioperative period. On day 2, action plans were developed that included communication of PU risk or presence of an ulcer,measures to shorten procedure times when clinically appropriate, implementation of prevention techniques during procedures, and recommendations for mattress upgrades. In addition, educational programs about PU prevention were developed, schedules for presentations were established, and an online power point presentation was completed and placed in a learning management system module. Finally, our nursing department amended a hospital wide handoff communication tool to include skin status and PU risk level. This tool is used in all patient handoff situations, including nonnursing departments such as radiology. Patients deemed at risk for ulcers were provided "Braden Risk" armbands to enhance interdepartmental awareness.

Prompted by manager concerns about span of control, a large, integrated health system set out to determine if span of control really mattered. Was there something to it, or was it just an excuse for poor performance? A team of middle managers studied the problem and ultimately demonstrated a strong relationship between span of control and employee engagement. Consequently, it was decided to add 4 management positions to note the effect. One year later, positive changes were observed in employee engagement scores in all 4 areas. This study suggests careful review of manager spans of control to address the untoward effects of large spans of control on employee engagement.