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Healthcare-associated transmission of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) has been reported and is of increasing concern. No standardized epidemiologic investigation tool has been published for healthcare-associated NTM outbreak investigations. This report describes the design of an ongoing observational study to standardize the approach to NTM outbreak investigation among pwCF. This is a parallel multi-site study of pwCF within a single Center who have respiratory NTM isolates identified as being highly-similar. Participants have a history of positive airway cultures for NTM, receive care within a single Center, and have been identified as part of a possible outbreak based on genomic analysis of NTM isolates. Participants are enrolled in the study over a 3-year period. Primary endpoints are identification of a shared healthcare-associated encounter(s) among patients in a Center and identification of environmental isolates that are genetically highly-similar to respiratory isolates recovered from pwCF. Secondary endpoints include characterization of potential transmission modes and settings, as well as incidence and prevalence of healthcare-associated environmental NTM species/subspecies by geographical region. We hypothesize that genetically highly-similar strains of NTM among pwCF cared for at the same Center may arise from healthcare sources including patient-to-patient transmission and/or acquisition from environmental sources. This novel study design will establish a standardized, evidence-based epidemiologic investigation tool for healthcare-associated NTM outbreak investigation within CF Care Centers, will broaden the scope of independent outbreak investigations and demonstrate the frequency and nature of healthcare-associated NTM transmission in CF Care Centers nationwide. Furthermore, it will provide valuable insights into modeling risk factors associated with healthcare-associated NTM transmission and better inform future infection prevention and control guidelines. This study will systematically characterize clinically-relevant NTM isolates of CF healthcare environmental dust and water biofilms and set the stage to describe the most common environmental sources within the healthcare setting harboring clinically-relevant NTM isolates. ClinicalTrials.gov NCT04024423. Date of registry July 18, 2019.

Healthcare-associated acquisition and transmission of nontuberculous mycobacteria (NTM) among people with cystic fibrosis (pwCF) has been described, and remains a concern for both patients and providers. This report describes the design of a prospective observational study utilizing the standardized epidemiologic investigation toolkit for healthcare-associated links in transmission of NTM among pwCF. This is a parallel multi-site study of pwCF who have infections with respiratory NTM isolates and receive healthcare within a common CF Care Center. Participants have a history of one or more NTM positive airway cultures and have been identified as having NTM infections suggestive of a possible outbreak within a single Center, based on NTM isolate genomic analysis. Participants are enrolled in the study over a 3-year period. Primary endpoints are identification of shared healthcare-associated source(s) among pwCF in a Center, identification of healthcare environmental dust and water biofilm NTM isolates that are genetically highly-related to respiratory isolates, and identification of common home of residence watersheds among pwCF infected with clustered isolates. Secondary endpoints include characterization of healthcare-associated transmission and/or acquisition modes and settings as well as description of incidence and prevalence of healthcare-associated environmental NTM species/subspecies by geographical region. We hypothesize that genetically highly-related isolates of NTM among pwCF cared for at the same Center may arise from healthcare sources including patient-to-patient transmission and/or acquisition from health-care environmental dust and/or water biofilms. This study design utilizes a published, standardized, evidence-based epidemiologic toolkit to facilitate confidential, independent healthcare-associated NTM outbreak investigations within CF Care Centers. This study will facilitate real-time, rapid detection and mitigation of healthcare-associated NTM outbreaks to reduce NTM risk, inform infection prevention and control guidelines, and characterize the prevalence and origin of NTM outbreaks from healthcare-associated patient-to-patient transmission and/or environmental acquisition. This study will systematically characterize human disease causing NTM isolates from serial collection of healthcare environmental dust and water biofilms and define the most common healthcare environmental sources harboring NTM biofilms. ClinicalTrials.gov NCT05686837.

Nontuberculous mycobacteria (NTM) are ubiquitous, opportunistic pathogens that can cause lung disease in people with non-cystic fibrosis bronchiectasis (NCFB) and cystic fibrosis (CF). The incidence of NTM pulmonary infections and lung disease has continued to increase worldwide over the last decade among both groups. Notably, women with NCFB NTM pulmonary disease (NTM-PD) bear a disproportionate burden with NTM rates increasing in this population as well as having consistently higher incidence of NTM-PD compared to men. In contrast, among people with CF, an overall increased risk among women has not been observed. In the United States, the majority of people with CF are taking highly effective cystic fibrosis transmembrane conductance regulator (CFTR) modulators, and these numbers are increasing worldwide. The long-term impact of CFTR modulator medications on NTM infections is not entirely understood. Guidelines for the screening, diagnosis, and management of NTM-PD exist for people with NCFB and CF, but do not consider unique implications relevant to women. This review highlights aspects of NTM-PD among women with NCFB and CF, including the epidemiology of NTM infection, special considerations for treatment, and unmet research needs relevant to women with NTM-PD. Nontuberculous mycobacterial lung infections in women Nontuberculous mycobacteria (NTM) are bacteria that can cause lung disease in people with non-cystic fibrosis bronchiectasis (NCFB) and cystic fibrosis (CF). The incidence of NTM pulmonary infections and lung disease has continued to increase worldwide over the last decade among both groups. Notably, women with NCFB NTM pulmonary disease (NTM-PD) are more likely than men to get infected with NTM and to get disease. In contrast, among people with CF, women and men are equally likely to get NTM infection and disease. More people with CF across the globe are getting highly effective treatment using CF transmembrane conductance regulator (CFTR) modulators. We don’t understand how these medications will affect the chance of getting NTM infections if people take them for many years. Guidelines for the screening, diagnosis, and management of NTM-PD exist for people with NCFB and CF, but do not consider unique implications relevant to women. This review highlights aspects of NTM-PD among women with NCFB and CF, including the epidemiology of NTM infection, special considerations for treatment, and unmet research needs relevant to women with NTM-PD.

Dust storm exposure may cause or worsen: * Coughing and wheezing * Lower respiratory tract infections (viral, bacterial and fungal including coccidioidomycosis) * Obstructive airway diseases (asthma, bronchitis, COPD) * Lung fibrosis (sand and dust storm-associated silicosis) * Interstitial lung disease * Cardiovascular diseases What is a sandstorm and what are the symptoms following exposure? A sandstorm is created when strong wind lifts sand particles (60 microns or greater) from the ground into the air. [...]upper airway and mucus membrane irritation is the most common health effect. References and Additional Resources: Global Assessment of Sand and Dust Storms * https://library.wmo.int/doc_num.php?explnum_id=3083 National Weather Service * https://www.weather.gov American Lung Association Particle Pollution * http://www.lung.org/our-initiatives/healthy-air/outdoor/airpollution/particle-pollution.html AirNow * https://airnow.gov/index.cfm?action=airnow.main Centers for Disease Control and Prevention Climate Effects on Health * https://www.cdc.gov/climateandhealth/effects/default. htm#factsheets Respirator Fit Testing * Fit testing facts https://www.cdc.gov/niosh/docs/2018-129/ pdfs/2018-129.pdf?id=10.26616/NIOSHPUB2018129 * Fit testing video https://www.osha.gov/video/respiratory_ protection/fittesting.html * Cherrie JW et al.

Key Points TNF family members have a multitude of crucial roles in the immune response, and numerous companies have invested millions of dollars to develop therapeutic drugs that target many of these molecules, including TNF, CD40-L, RANK-L, TRAIL and CD30-L. Two novel TNF family members were discovered several years ago through expressed sequence tag (EST) database searches: APRIL (a proliferation-inducing ligand) and BLyS (B-lymphocyte stimulator), which is also well known as BAFF (B-cell activating factor of the TNF family). It was subsequently shown that both ligands bind to two TNF-R family members, TACI (transmembrane activator and CAML interactor and BCMA (B-cell maturation antigen), and that BLyS also specifically binds to another TNF-R family member, BAFF-R. After a long search for a third TNF-R-like receptor that specifically binds APRIL but not BLyS, two groups recently demonstrated that APRIL also binds to heparan sulfate proteoglycans (HSPG). Although the biological functions of BLyS have been more readily discerned than those of APRIL, especially from studies of transgenic and knockout mice, many recently published experiments have provided more clues about the normal and pathogenic functions of APRIL. APRIL is produced by many of the same cell types that express BLyS, including monocytes, dendritic cells, macrophages and T cells, but is also produced (unlike BLyS) by various carcinomas. Importantly, APRIL is also aberrantly expressed by malignant B cells (normal B cells do not express BLyS or APRIL), and by various cells within the B-cell tumour micro-environment, including 'nurse-like' cells derived from B-chronic lymphocytic leukaemia patients and osteoclasts and stromal cells in the bone marrow from multiple myeloma patients. Becuase these malignant B cells also express at least one of the three BLyS/APRIL receptors (TACI, BCMA and/or BAFF-R), and inhibition of BLyS or APRIL enhances the apoptosis of these tumour cells, many groups have proposed the existence of an autocrine and/or paracrine survival loop mediated by BLyS and APRIL. Some of the normal functions of APRIL are thought to be: co-stimulating antigen-activated B cells; increasing B-cell antigen presentation function via BCMA; enabling isotype switching in B cells; and augmenting plasma cell survival, and possibly affecting plasma cell trafficking. In addition, APRIL may co-stimulate pre-activated T cells, although the data supporting this function are still rather contentious. APRIL and BLyS levels are elevated in the sera of patients suffering from a variety of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and multiple sclerosis. Additionally, it has recently been discovered that certain mutations in TACI in common variable immunodeficiency (CVID) and IgA deficiency (IgAD) patients lead to impaired APRIL binding and consequent inhibition of isotype switching. Based on these and other findings linking APRIL and BLyS to autoimmune disease, immunodeficiency and various cancers, seven biotechnology companies have invested in the development of at least four therapeutic molecules, including a neutralizing anti-BLyS monoclonal antibody and two soluble receptors (BAFF-R and TACI), that target BLyS alone, or BLyS and APRIL together. Two of the newest members of the tumour-necrosis factor family, BLyS and APRIL, are crucial in B-cell development and survival, and are implicated in autoimmune diseases and cancer. Dillon and colleagues review APRIL biology, and compare potential therapeutics that target APRIL and/or BLyS. Since their discovery in 1998, the two TNF family members APRIL and BLyS/BAFF have received increasing attention. In addition to regulating normal B-cell development and immune responses, these molecules might be crucial in a diverse set of diseases, including autoimmunity and cancer. Although more has been published about the general biology of BLyS/BAFF than that of APRIL, many recent articles have described novel APRIL biology. Here we focus on APRIL, exploring its normal and pathological functions, and comparing the therapeutic molecules currently under development that target BLyS/BAFF alone, or APRIL and BLyS/BAFF together.

Although anticapsular antibodies confer serotype-specific immunity to pneumococci, children increase their ability to clear colonization before these antibodies appear, suggesting involvement of other mechanisms. We previously reported that intranasal immunization of mice with pneumococci confers CD4+ T cell-dependent, antibody- and serotype-independent protection against colonization. Here we show that this immunity, rather than preventing initiation of carriage, accelerates clearance over several days, accompanied by neutrophilic infiltration of the nasopharyngeal mucosa. Adoptive transfer of immune CD4+ T cells was sufficient to confer immunity to naïve RAG1(-/-) mice. A critical role of interleukin (IL)-17A was demonstrated: mice lacking interferon-gamma or IL-4 were protected, but not mice lacking IL-17A receptor or mice with neutrophil depletion. In vitro expression of IL-17A in response to pneumococci was assayed: lymphoid tissue from vaccinated mice expressed significantly more IL-17A than controls, and IL-17A expression from peripheral blood samples from immunized mice predicted protection in vivo. IL-17A was elicited by pneumococcal stimulation of tonsillar cells of children or adult blood but not cord blood. IL-17A increased pneumococcal killing by human neutrophils both in the absence and in the presence of antibodies and complement. We conclude that IL-17A mediates pneumococcal immunity in mice and probably in humans; its elicitation in vitro could help in the development of candidate pneumococcal vaccines.

B cells are important in the development of autoimmune disorders by mechanisms involving dysregulated polyclonal B-cell activation, production of pathogenic antibodies, and co-stimulation of autoreactive T cells. zTNF4 (BLyS, BAFF, TALL-1, THANK) is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo. Here we identify two receptors for zTNF4 and demonstrate a relationship between zTNF4 and autoimmune disease. Transgenic animals overexpressing zTNF4 in lymphoid cells develop symptoms characteristic of systemic lupus erythaematosus (SLE) and expand a rare population of splenic B-Ia lymphocytes. In addition, circulating zTNF4 is more abundant in NZBWF1 and MRL-lpr/lpr mice during the onset and progression of SLE. We have identified two TNF receptor family members, TACI and BCMA, that bind zTNF4. Treatment of NZBWF1 mice with soluble TACI-Ig fusion protein inhibits the development of proteinuria and prolongs survival of the animals. These findings demonstrate the involvement of zTNF4 and its receptors in the development of SLE and identify TACI-Ig as a promising treatment of autoimmune disease in humans.

T cell–derived cytokines are important in the development of an effective immune response, but when dysregulated they can promote disease. Here we identify a four-helix bundle cytokine we have called interleukin 31 (IL-31), which is preferentially produced by T helper type 2 cells. IL-31 signals through a receptor composed of IL-31 receptor A and oncostatin M receptor. Expression of IL-31 receptor A and oncostatin M receptor mRNA was induced in activated monocytes, whereas epithelial cells expressed both mRNAs constitutively. Transgenic mice overexpressing IL-31 developed severe pruritis, alopecia and skin lesions. Furthermore, IL-31 receptor expression was increased in diseased tissues derived from an animal model of airway hypersensitivity. These data indicate that IL-31 may be involved in promoting the dermatitis and epithelial responses that characterize allergic and non-allergic diseases.