Evidence regarding the utility of multiple mini-interview (MMI) for selection to undergraduate health programs: A BEME systematic review: BEME Guide No. 37.

BACKGROUND: In the 11 years since its development at McMaster University Medical School, the multiple mini-interview (MMI) has become a popular selection tool. We aimed to systematically explore, analyze and synthesize the evidence regarding MMIs for selection to undergraduate health programs. METHODS: The review protocol was peer-reviewed and prospectively registered with the Best Evidence Medical Education (BEME) collaboration. Thirteen databases were searched through 34 terms and their Boolean combinations. Seven key journals were hand-searched since 2004. The reference sections of all included studies were screened. Studies meeting the inclusion criteria were coded independently by two reviewers using a modified BEME coding sheet. Extracted data were synthesized through narrative synthesis. RESULTS: A total of 4338 citations were identified and screened, resulting in 41 papers that met inclusion criteria. Thirty-two studies report data for selection to medicine, six for dentistry, three for veterinary medicine, one for pharmacy, one for nursing, one for rehabilitation, and one for health science. Five studies investigated selection to more than one profession. MMIs used for selection to undergraduate health programs appear to have reasonable feasibility, acceptability, validity, and reliability. Reliability is optimized by including 7-12 stations, each with one examiner. The evidence is stronger for face validity, with more research needed to explore content validity and predictive validity. In published studies, MMIs do not appear biased against applicants on the basis of age, gender, or socio-economic status. However, applicants of certain ethnic and social backgrounds did less well in a very small number of published studies. Performance on MMIs does not correlate strongly with other measures of noncognitive attributes, such as personality inventories and measures of emotional intelligence. DISCUSSION: MMI does not automatically mean a more reliable selection process but it can do, if carefully designed. Effective MMIs require careful identification of the noncognitive attributes sought by the program and institution. Attention needs to be given to the number of stations, the blueprint and examiner training. CONCLUSION: More work is required on MMIs as they may disadvantage groups of certain ethnic or social backgrounds. There is a compelling argument for multi-institutional studies to investigate areas such as the relationship of MMI content to curriculum domains, graduate outcomes, and social missions; relationships of applicants' performance on different MMIs; bias in selecting applicants of minority groups; and the long-term outcomes appropriate for studies of predictive validity.

The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors.

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Prosurvival activity for airway neutrophils in severe asthma.

BACKGROUND: Airway neutrophilia is a recognised feature of chronic severe asthma, but the mechanisms that underlie this phenomenon are unknown. Evidence for factors present in airway secretions that prolong neutrophil survival has been sought and it has been hypothesised that these might be augmented in neutrophilic asthma. METHODS: Non-smoking subjects with severe asthma (SA) or mild asthma (MA) and healthy control subjects (HC) underwent sputum induction. The SA group was subdivided into subjects with neutrophil counts above (SA-high) and those within the normal range (SA-low). Apoptotic neutrophils were enumerated in the cellular phase while the fluid phase was assessed for its ability to prolong the in vitro survival of blood-derived neutrophils using morphometric and flow cytometric analyses. RESULTS: There was a significant difference between all four subject groups with respect to the percentage of apoptotic sputum neutrophils (Kruskal-Wallis, p=0.042). Cuzick test showed a highly significant (p=0.008) trend towards decreasing numbers of apoptotic neutrophils across the four groups with increasing asthma severity and neutrophil count. The sputum antiapoptotic activity was also different between the groups (p=0.039), with a highly significant (p=0.005) decreasing trend across the four groups. The survival effect could not be inhibited by blocking selective chemotaxin receptors, neutralising neutrophil survival factors, inhibiting phosphatidylinositol-3-kinase (using LY294002) or with pertussis toxin pretreatment. Similarly, it could not be explained by lipopolysaccharide contamination or by the presence of inhaled corticosteroids in sputum. CONCLUSIONS: These data demonstrate the capacity of as yet unidentified factor(s) in the airways of subjects with asthma to delay human neutrophil apoptosis and extend their lifespan as a potential mechanism contributing to unresolving airways neutrophilia in severe asthma.

Ciclesonide ( Byk Gulden).

Ciclesonide, a non-halogenated inhaled corticosteroid with anti-inflammatory activity, is under development by Byk Gulden, Aventis and Teijin as a potential treatment for asthma [213439]. It was also being developed by Byk Gulden for chronic obstructive pulmonary disease (COPD), but no development had been reported for this indication since 1999; however, Teijin was carrying out clinical trials in this indication at the end of 2000. During 2000, Byk Gulden was carrying out phase III trials in the US and Europe and in March 2001, results were expected in the third quarter of 2001 [312399], [383726], [423659]. Two inhalant formulations (multidose powder and propellant filled) and a nasal formulation of ciclesonide are being developed by Byk Gulden for the treatment of asthma and seasonal allergic rhinitis, respectively [337147]. The compound is formulated for once-daily dosing and demonstrated good efficacy without corticosteroid-associated systemic side effects [409257]. In January 2001, Byk Gulden expected launch of a CFC-free multidose inhaler formulation in 2003 [395596]; in March 1999, launch of a nasal formulation was expected in 2004 and a multidose powder inhaler in 2005 [337147]. By September 2001, the compound was in phase III trials in the US for asthma, with a potential US launch anticipated by Aventis in 2004 [423465]. In November 2001, Aventis expected to submit an NDA to the FDA in 2003 [428057]. Teijin, which has a development and licensing agreement with Byk Gulden for the treatment of asthma and COPD in Japan, commenced phase I trials of ciclesonide in Japan in spring 1999, had completed these during 2000, and began phase II trials by September of that year [383726]. An NDA is expected to befiled in Japan in 2003. In October 2000 and April 2001, Merrill Lynch predicted peak sales of Euro400 million in 2007, with sales of Euro5 million in 2002, rising to Euro150 million in 2004 [395562], [420574]. Deutsche Bank predicted in August 2001, that sales of the product would reach Euro70 million in 2004, rising to Euro150 million in 2005 [420814].

Eosinophil chemotaxis.

Chemotaxis assays have a number of applications in the study of leukocyte biology and immune/inflammatory pathology. Multiwell "blind chamber"-type assays allow a large number of parallel measurements within a single assay. The development of fluorescence assays using microplate-based chemotaxis chambers has permitted a degree of automation to be applied to these assays. Here, a method is described for the quantitative measurement of eosinophil migration using a 96-well assay with numbers of cells that may realistically be obtained from blood samples.

Synergic production of neutrophil chemotactic activity by colonic epithelial cells and eosinophils.

The presence of eosinophils in the lumen and mucosa of the intestine is characteristic of both ulcerative colitis (UC) and Crohn's disease (CD). There is evidence of eosinophil activation in the intestine during acute inflammatory episodes of these diseases; these episodes are also characterized by an influx of neutrophils, which have the potential to cause extensive tissue damage. We undertook a study to determine whether eosinophils in contact with colonic epithelial cells produce factors that may attract neutrophils in response to immunological stimulation. Neutrophil chemotactic activity (NCA) and concentrations of three neutrophil-attracting CXC chemokines - CXCL1 (Groα), CXCL5 (Ena78) and CXCL8 (IL8) - were measured in supernatants of T84 colonic epithelial cells and blood eosinophils or eosinophil-like myeloid leukaemia cells (AML14.3D10), alone or in combination. Cells were stimulated with serum-opsonized zymosan (OZ) particles. NCA (P<0.005) and CXCL5 levels (P<0.05) in the supernatants of OZ-stimulated epithelial/eosinophil co-cultures were significantly higher than in the supernatants of either cell type alone. Release of CXCL1 (P<0.05) and CXCL8 (P<0.01) from OZ-stimulated co-culture supernatants was significantly higher than from OZ-stimulated eosinophils but not higher than from OZ-stimulated epithelial cells. Eosinophils and colonic epithelial cells exhibit synergy in production of neutrophil chemoattractants in response to immunological stimulation. This may represent a mechanism for exaggerated recruitment of neutrophils to the intestine in response to acute infection in conditions that are characterized by the presence of eosinophils in the bowel.

Phosphoinositide 3-kinase gamma mediates chemotactic responses of human eosinophils to platelet-activating factor.

BACKGROUND: Eosinophils are characteristic participants in allergic inflammation. The intracellular signalling mechanisms involved in the migration of eosinophils to sites of allergic inflammation are poorly understood. Chemotactic responses of eosinophils to platelet-activating factor (PAF), but not eotaxin, have been demonstrated to be dependent upon the activation of phosphoinositide 3-kinase (PI3K) but the specific isoform of PI3K involved has not been identified. OBJECTIVE: To determine the roles of the leukocyte-specific PI3K gamma and PI3K delta isoforms of PI3K in PAF-induced chemotaxis of human eosinophils. METHODS: Chemotactic responses of the EoL-1 eosinophilic cell line and human peripheral blood eosinophils were measured. The effects of a PI3K gamma-selective inhibitor (5-[2,2-difluorobenzo(1,3)dioxol-5-ylmethylene]-thiazolidine-2,4-dione; AS604850) and gene knock-down of PI3K gamma and PI3K delta on chemotactic responses were determined. RESULTS: AS604850 caused a concentration-dependent suppression of chemotactic responses of EoL-1 cells and blood eosinophils to PAF but not eotaxin. Specific siRNAs reduced the expression of PI3K gamma and PI3K delta in EoL-1 cells. Knock-down of PI3K gamma by siRNA resulted in a 75% inhibition of the chemotactic response to PAF but had no effect on the response to eotaxin. Knock-down of endogenous PI3K delta by siRNA resulted in a 38% inhibition of the chemotactic response to PAF but had no effect on the response to eotaxin. CONCLUSION: PI3K gamma plays a major role in the induction of chemotaxis in PAF-stimulated eosinophils, while PI3K delta plays a lesser role. Interventions which reduce the activity of PI3K gamma may have therapeutic potential in allergic diseases.

Impaired neutrophil chemotaxis in chronic obstructive pulmonary disease.

RATIONALE: Neutrophilic airway inflammation is considered to be a major factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), with sputum and bronchoalveolar lavage neutrophil counts broadly correlating with disease severity. The mechanisms responsible for neutrophil accumulation are poorly understood, but they could involve increased influx and/or survival of these cells. OBJECTIVES: To investigate whether neutrophil chemotactic responsiveness and/or chemotactic activity in airway secretions are increased in subjects with COPD. METHODS: Chemotaxis experiments were performed using induced sputum supernatants from subjects with and without COPD as a source of chemotactic activity, and neutrophils from healthy donors as responder cells. In addition, chemotactic responses to N-formyl-Met-Leu-Phe (fMLP) and interleukin-8 (IL-8/CXCL8) were studied using neutrophils from healthy subjects and subjects with COPD. MEASUREMENTS AND MAIN RESULTS: As reported in the literature, sputum neutrophil counts were significantly increased in subjects with COPD compared with healthy subjects. However, this was associated with reduced chemotactic activity in sputum in COPD, as judged by reduced chemotaxis to the fluid phase of sputum from subjects with COPD compared with healthy subjects. Furthermore, whereas neutrophils from subjects with stage I COPD had normal responses to fMLP and IL-8, subjects with more severe stage II-IV COPD showed reduced levels of spontaneous migration and chemotaxis to fMLP and IL-8. CONCLUSIONS: Neither increased chemotactic activity in the airways nor increased chemotactic responsiveness of neutrophils explains the increased number of these cells in subjects with stable COPD. The implications of the observed reduction in neutrophil chemotactic activity remain to be established.

Measurement of eotaxin (CCL11) in induced sputum supernatants: validation and detection in asthma.

BACKGROUND: Induced sputum is widely used in asthma research; however, for many mediators, the detection methods have not been validated. OBJECTIVE: We sought to optimize the method of detection of eotaxin, an important chemokine acting through the CCR3 receptor on eosinophils, basophils, and T(H)2 cells. METHODS: Induced sputum from normal and asthmatic subjects was processed with dithioerythritol (DTE) or PBS; recovery of eotaxin was assessed by means of ELISA before and after spiking with recombinant eotaxin. Furthermore, the effects of removing DTE by means of ultrafiltration or the addition of protease inhibitors and high-speed centrifugation on endogenous levels and spiking recovery of eotaxin were assessed. RESULTS: Endogenous eotaxin was undetectable in DTE-processed samples, with a mean of only 30% (SD, 13%) spike recovery. DTE had no effect on the immunoassay capture antibody but dramatically reduced the detection of recombinant eotaxin. Removal of DTE from sputum before immunoassay did not improve detection, although it restored the recovery of a subsequent eotaxin spike. In contrast, PBS-processed sputum resulted in an eotaxin spike recovery of 101% (SD, 20%). Addition of protease inhibitors or high-speed centrifugation had no effect on eotaxin detection. By using this optimized protocol, eotaxin levels in PBS-processed sputum samples were found to be significantly increased in asthmatic sputum (P<.05). CONCLUSION: Measurement of eotaxin by means of immunoassay is adversely affected by DTE, possibly through irreversible denaturation of epitopes, which makes eotaxin undetectable by using the immunoassay antibody. Sputum samples should be processed into PBS for assessment of eotaxin, which is present at increased levels in asthmatic sputum.

Contribution of eotaxin-1 to eosinophil chemotactic activity of moderate and severe asthmatic sputum.

The CC chemokine eotaxin-1 (CCL11) is chemotactic for eosinophils, basophils, and type 2 helper T cells and may play a role in allergic inflammation. We investigated its contribution as an eosinophil chemoattractant in asthmatic airway secretions (sampled as induced sputum), which possess chemotactic activity for eosinophils and T cells. Sputum samples collected from healthy subjects and subjects with mild, stable-moderate, unstable-moderate, and severe asthma were processed with phosphate-buffered saline and assayed for eotaxin by ELISA and for eosinophil chemotactic activity by fluorescence-based chemotaxis assay. The contribution of eotaxin to chemotactic activity was studied by using a high-affinity neutralizing human anti-eotaxin antibody, CAT-213. Sputum eotaxin concentration was significantly raised in moderate and severe asthma (p < 0.05 versus healthy control subjects) but not in mild asthma. Chemotactic activity was significantly increased in all asthmatic groups relative to healthy subjects (p < 0.05) and was significantly inhibited by CAT-213 (100 nM) in subjects with moderate and severe asthma, with median inhibition of 52% (p < 0.05), 78% (p < 0.0001), and 86% (p < 0.0001), respectively, in samples representing stable-moderate, unstable-moderate, and severe asthma. Eotaxin contributed to the eosinophil chemotactic activity of sputum from subjects with more severe forms of asthma but not mild asthma, suggesting that its contribution is more important in more severe disease. This activity is inhibited significantly by CAT-213.

Differential roles of IL-16 and CD28/B7 costimulation in the generation of T-lymphocyte chemotactic activity in the bronchial mucosa of mild and moderate asthmatic individuals.

BACKGROUND: IL-16 is an important T-cell chemotactic cytokine in asthmatic airways; its release from allergen-stimulated bronchial mucosa in mild asthma has been shown to be dependent on CD28/B7 costimulation. OBJECTIVE: We have extended our previous studies to investigate the role of IL-16 and CD28/B7 costimulation in T-lymphocyte chemotactic activity (TLCA) released from the bronchial mucosa in more severe asthma. METHODS: TLCA was determined in the supernatants of induced sputum and allergen-stimulated bronchial mucosal explants from healthy volunteers and volunteers with mild and moderately severe asthma by means of a Boyden chamber technique. The contribution of IL-16 to the activity was evaluated through use of a neutralizing monoclonal antibody; the contribution of CD28/B7 costimulation to allergen-induced release of TLCA was determined through use of CTLA4-Ig fusion protein and neutralizing monoclonal antibodies to CD80 (B7.1) and CD86 (B7.2). RESULTS: Induced sputum and unstimulated explants from asthmatic subjects generated significant spontaneous TLCA (P <.05). Both mild and moderate asthmatic explants showed significantly elevated Dermatophagoides pteronyssinus -induced release of TLCA, but only in mild asthma could sputum and allergen-stimulated explant TLCA be inhibited by anti-IL-16 (median inhibition, 39% and 59%; P <.05). In addition, allergen released significant quantities of IL-16 from mild asthmatic explants (P <.05) but not from moderate asthmatic explants. Antibodies to the CD28 counter-ligands CD80 and CD86 inhibited allergen-induced release of TLCA in mild asthmatic explants by 94% (P <.05) and 62%, but TLCA release from moderate asthmatic explants was unaffected by CTLA4-Ig. CONCLUSION: These results show that TLCA release in moderate asthmatic airways, in contrast to mild asthmatic airways, is not dependent on CD28/B7 costimulation and does not involve IL-16.