Browsing by Author "Sevin, Carla M."

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    Blockade of the programmed death-1 pathway restores sarcoidosis CD4(+) T-cell proliferative capacity
    (American Thoracic Society, 2014-09-01) Braun, Nicole A.; Celada, Lindsay J.; Herazo-Maya, Jose D.; Abraham, Susamma; Shaginurova, Guzel; Sevin, Carla M.; Grutters, Jan; Culver, Daniel A.; Dworski, Ryszard; Sheller, James; Massion, Pierre P.; Polosukhin, Vasiliy V.; Johnson, Joyce E.; Kaminski, Naftali; Wilkes, David S.; Oswald-Richter, Kyra A.; Drake, Wonder P.; Department of Medicine, IU School of Medicine
    RATIONALE: Effective therapeutic interventions for chronic, idiopathic lung diseases remain elusive. Normalized T-cell function is an important contributor to spontaneous resolution of pulmonary sarcoidosis. Up-regulation of inhibitor receptors, such as programmed death-1 (PD-1) and its ligand, PD-L1, are important inhibitors of T-cell function. OBJECTIVES: To determine the effects of PD-1 pathway blockade on sarcoidosis CD4(+) T-cell proliferative capacity. METHODS: Gene expression profiles of sarcoidosis and healthy control peripheral blood mononuclear cells were analyzed at baseline and follow-up. Flow cytometry was used to measure ex vivo expression of PD-1 and PD-L1 on systemic and bronchoalveolar lavage-derived cells of subjects with sarcoidosis and control subjects, as well as the effects of PD-1 pathway blockade on cellular proliferation after T-cell receptor stimulation. Immunohistochemistry analysis for PD-1/PD-L1 expression was conducted on sarcoidosis, malignant, and healthy control lung specimens. MEASUREMENTS AND MAIN RESULTS: Microarray analysis demonstrates longitudinal increase in PDCD1 gene expression in sarcoidosis peripheral blood mononuclear cells. Immunohistochemistry analysis revealed increased PD-L1 expression within sarcoidosis granulomas and lung malignancy, but this was absent in healthy lungs. Increased numbers of sarcoidosis PD-1(+) CD4(+) T cells are present systemically, compared with healthy control subjects (P < 0.0001). Lymphocytes with reduced proliferative capacity exhibited increased proliferation with PD-1 pathway blockade. Longitudinal analysis of subjects with sarcoidosis revealed reduced PD-1(+) CD4(+) T cells with spontaneous clinical resolution but not with disease progression. CONCLUSIONS: Analogous to the effects in other chronic lung diseases, these findings demonstrate that the PD-1 pathway is an important contributor to sarcoidosis CD4(+) T-cell proliferative capacity and clinical outcome. Blockade of the PD-1 pathway may be a viable therapeutic target to optimize clinical outcomes.
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    Enablers and Barriers to Implementing ICU Follow-Up Clinics and Peer Support Groups Following Critical Illness: The Thrive Collaboratives
    (Wolters Kluwer, 2019-09) Haines, Kimberley J.; McPeake, Joanne; Hibbert, Elizabeth; Boehm, Leanne M.; Aparanji, Krishna; Bakhru, Rita N.; Bastin, Anthony J.; Beesley, Sarah J.; Beveridge, Lynne; Butcher, Brad W.; Drumright, Kelly; Eaton, Tammy L.; Farley, Thomas; Firshman, Penelope; Fritschle, Andrew; Holdsworth, Clare; Hope, Aluko A.; Johnson, Annie; Kenes, Michael T.; Khan, Babar A.; Kloos, Janet A.; Kross, Erin K.; Mactavish, Pamela; Meyer, Joel; Montgomery-Yates, Ashley; Quasim, Tara; Saft, Howard L.; Slack, Andrew; Stollings, Joanna; Weinhouse, Gerald; Whitten, Jessica; Netzer, Giora; Hopkins, Ramona O.; Mikkelsen, Mark E.; Iwashyna, Theodore J.; Sevin, Carla M.; Medicine, School of Medicine
    OBJECTIVES: Data are lacking regarding implementation of novel strategies such as follow-up clinics and peer support groups, to reduce the burden of postintensive care syndrome. We sought to discover enablers that helped hospital-based clinicians establish post-ICU clinics and peer support programs, and identify barriers that challenged them. DESIGN: Qualitative inquiry. The Consolidated Framework for Implementation Research was used to organize and analyze data. SETTING: Two learning collaboratives (ICU follow-up clinics and peer support groups), representing 21 sites, across three continents. SUBJECTS: Clinicians from 21 sites. MEASUREMENT AND MAIN RESULTS: Ten enablers and nine barriers to implementation of "ICU follow-up clinics" were described. A key enabler to generate support for clinics was providing insight into the human experience of survivorship, to obtain interest from hospital administrators. Significant barriers included patient and family lack of access to clinics and clinic funding. Nine enablers and five barriers to the implementation of "peer support groups" were identified. Key enablers included developing infrastructure to support successful operationalization of this complex intervention, flexibility about when peer support should be offered, belonging to the international learning collaborative. Significant barriers related to limited attendance by patients and families due to challenges in creating awareness, and uncertainty about who might be appropriate to attend and target in advertising. CONCLUSIONS: Several enablers and barriers to implementing ICU follow-up clinics and peer support groups should be taken into account and leveraged to improve ICU recovery. Among the most important enablers are motivated clinician leaders who persist to find a path forward despite obstacles.