Clients’ Perspectives of Meaningful Healthcare Relationships

The aim of this study was to increase understanding of how clients view meaningful relationships within the healthcare context and how clients respond to differences in approaches or expectations for a meaningful relationship

Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma : results from two phase 3, randomised, double-blind, placebo-controlled trials

BACKGROUND: Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). METHODS: Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count <400 cells/μL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per μL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2). FINDINGS: Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies. INTERPRETATION: Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy. FUNDING: Teva Branded Pharmaceutical Products R&D

Exile Vol. LII No. 2

Title Page 2 Epigraph by Ezra Pound 3 Table of Contents 4 Editor\u27s Note 6 Contributors\u27 Notes 45 Editorial Board 46 ART Wallace Monument by Casey Flax 9 Blind Man by Abbe Wright 18 Untitled by Adrienne Hunter 20 Sentinel by Eric Ahnmark 28 Untitled by Abbe Wright 32 Under Charles by Medha Jaishankar 43 FICTION The Great Lego Wall by Dawson West 12-16 Gods by Nick Wright 21-24 Some Days Hit like Mack Trucks by Sarah Broderick 33-42 POETRY The Liberation from Jack Kerouac by Katie Berta 7-8 Fragmented Grief by Jen Humbert 10 Rauschenberg Painting Iris Clért by Jeremy Heartberg 11 Outgrowing by Sarah Rogers 17 Garden of Eden by Jen Humbert 19 She whispered to the moon by Dave Murrin-von Ebers 25 A Joke by Jeremy Heartberg 26 Retrospective by Casey Flax 27 Ketchup Fetish by Dawson West 29 Winter Raspberries by Jennifer Luebbers 30-31 Knot by Sarah Rogers 44 Editor\u27s Note The process by which Exile comes into being each semester is by no means a quick or simple one, and was further confounded in this instance by having me at its core. I do not necessarily mean to discredit myself ad nauseam as some editors would, but they will all tell you that transitional periods are the toughest on a publication. The collaborative effort of Jeremy Heartberg and Jennifer Humbert over the past several semesters, not to mention the competent and eager editorial staff they have recruited, has seen to it that the transition made in these past few months has not been bulky or awkward, but rather quite seamless. It is appropriate then, that the two of them are both prominently featured in the edition of Exile on which you presently fix your gaze. In recent years, you have benefited from Jeremy\u27s and Jen\u27s dedication to Exile as a whole; this year, enjoy their dedication to the flexibility and nuance of language, to the manipulation of form, to poetry. Jeremy, Jen, Sarah, and Emily, thank you, you will be missed. / April 2006 -6 Front Cover Art by Chris Davis: Reflections / Back Cover Art by Eric Ahnmark: Trucks Only -46 All submissions are reviewed on an anonymous basis, and all editorial decisions are shared equally among the members of the editorial board. -4

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension

Imaging Inflammation - From Whole Body Imaging to Cellular Resolution

Imaging techniques have evolved impressively lately, allowing whole new concepts like multimodal imaging, personal medicine, theranostic therapies, and molecular imaging to increase general awareness of possiblities of imaging to medicine field. Here, we have collected the selected (3D) imaging modalities and evaluated the recent findings on preclinical and clinical inflammation imaging. The focus has been on the feasibility of imaging to aid in inflammation precision medicine, and the key challenges and opportunities of the imaging modalities are presented. Some examples of the current usage in clinics/close to clinics have been brought out as an example. This review evaluates the future prospects of the imaging technologies for clinical applications in precision medicine from the pre-clinical development point of view

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

An Anti-HIV-1 V3 Loop Antibody Fully Protects Cross-Clade and Elicits T-Cell Immunity in Macaques Mucosally Challenged with an R5 Clade C SHIV

Neutralizing antibodies have been shown to protect macaques against SHIV challenge. However, genetically diverse HIV-1 clades have evolved, and a key question left unanswered is whether neutralizing antibodies can confer cross-clade protection in vivo. The novel human monoclonal antibody HGN194 was isolated from an individual infected with an HIV-1 clade AG recombinant circulating recombinant form (CRF). HGN194 targets an epitope in the third hypervariable loop (V3) of HIV-1 gp120 and neutralizes a range of relatively neutralization-sensitive and resistant viruses. We evaluated the potential of HGN194 to protect infant rhesus monkeys against a SHIV encoding a primary CCR5-tropic HIV-1 clade C envelope. After high-dose mucosal challenge, all untreated controls became highly viremic while all HGN194-treated animals (50 mg/kg) were completely protected. When HGN194 was given at 1 mg/kg, one out of two monkeys remained aviremic, whereas the other had delayed, lower peak viremia. Interestingly, all protected monkeys given high-dose HGN194 developed Gag-specific proliferative responses of both CD4+ and CD8+ T cells. To test whether generation of the latter involved cryptic infection, we ablated CD8+ cells after HGN194 clearance. No viremia was detected in any protected monkeys, thus ruling out virus reservoirs. Thus, induction of CD8 T-cell immunity may have resulted from transient “Hit and Run” infection or cross priming via Ag-Ab-mediated cross-presentation. Together, our data identified the HGN194 epitope as protective and provide proof-of-concept that this anti-V3 loop mAb can prevent infection with sterilizing immunity after challenge with virus of a different clade, implying that V3 is a potential vaccine target

Isolation of Monoclonal Antibodies with Predetermined Conformational Epitope Specificity

Existing technologies allow isolating antigen-specific monoclonal antibodies (mAbs) from B cells. We devised a direct approach to isolate mAbs with predetermined conformational epitope specificity, using epitope mimetics (mimotopes) that reflect the three-dimensional structure of given antigen subdomains. We performed differential biopanning using bacteriophages encoding random peptide libraries and polyclonal antibodies (Abs) that had been affinity-purified with either native or denatured antigen. This strategy yielded conformational mimotopes. We then generated mimotope-fluorescent protein fusions, which were used as baits to isolate single memory B cells from rhesus monkeys (RMs). To amplify RM immunoglobulin variable regions, we developed RM-specific PCR primers and generated chimeric simian-human mAbs with predicted epitope specificity. We established proof-of-concept of our strategy by isolating mAbs targeting the conformational V3 loop crown of HIV Env; the new mAbs cross-neutralized viruses of different clades. The novel technology allows isolating mAbs from RMs or other hosts given experimental immunogens or infectious agents

Collage Vol. II

JUDY COCHRAN: Editorial, 4-5 ROBERTA CHAPMEN: Photo, 6 ANITRA CHUGHTAI (Translations): Haikus, 7 CHARLES O\u27KEEFE: Photo, 8 MARK VANDERLINDE-ABERNATHY, ALYSSA LANDRY (Translator): Memories of a Spider (Les souvenirs d\u27une araignee), 9 MARK VANDERLINE-ABERNATHY, AMY NORSKOG (Translator): Tomato Fields (Champ de tomates), 10 SARAH BISHOP, HEFEDH ZANINA (Translator): Dear John (Cher John), 11 RYAN BUTZ (Translator): Basho\u27s Haiku, Issa\u27s Haiku, 12-13 JENNIFER HUMBERT, FADOUA EL BOUAMRAOUI (Translator): Pressed Lips (Levres Serrees), 15 ADELE REEVES (Translator): Contemporary song by Mr. Children, 16-17 BRODY PAGEL, GRACE DUGAR (Translator): The Lizard King (Le Roi Lezard), 18 JIMMY PIPKIN (Translator): In Love with You, 19 MOLLY ROSCOE: Saturday Night at Rusty\u27s (Samedi Soir a Rusty\u27s), 20 CHARLES O\u27KEEFE: Photo, 21 MATT MESSMER (Translator): Waseda University School Song, 22-23 TIMOTHY COOPER: Wenn du grosh bist… (When you\u27re Tall…), 24 DAVID HARMAN: Der Dunkle Stern (The Dark Star), 25 ANN TOWNSEND, JUDY COCHRAN (Translator): From a Window (D\u27une Fenetre), 26-27 SARA CAHILL: El sauce lloron (The Weeping Willow), 28-32 CHARLES O\u27KEEFE: Photo, 30 JENNIFER HUMBERT, MATT BISHOP: Past, Present (passe, present), 33 CAROL GENEYA KAPLAN, FADOUA EL BOUAMRAOUI (Translator): Une Autre Femme (Another Woman), 34-35 CHARLES O\u27KEEFE: Photo, 36 ANN TOWNSEND, JUDY COCHRAN (Translator): The Mowers (Les Faucheurs), 37 PRISCILLA PATON: Photo, 38 GONZALO TUESTA: La Grande Dame De Paris (The Great Lady of Paris), 39 SARAH PILLERDORF (Translator): Japanese Cartoons by Tezuka Osamu, 41-45 DANIELLE GERKEN: Schuhe der Heimat (Boots of Home), 47 CURTIS PLOWGIAN: Le peste de la langue francaise, 48-52 PRISCILLA PATON: Photo, 50 ZANE HOUSEHOLDER: Vive la Republique! (Film), 54 JENNIFER ZIMMER: EL tenis y las frustraciones (Tennis and Frustrations), La tumba de Ben (Ben\u27s Grave), 56-57 AUTUMN LOTZE: Times Square in the rain, 58-59 CHARLES O\u27KEEFE: Photo, 60 STEPHEN M. JULKA: Colors of the Earth, 61 THOMAS BRESSOUD: Java, 62 ERIC NELSON: World, 63 SARAH CLAPP (Translator): At a long day\u27s end (Natsume Soseki), A friend has come and is now leaving, Eating persimmons (Masaoka Shiki), 64 CHARLES O\u27KEEFE: Photo, 65 JOHN BURZYNSKI, MEGAN FETTER (Translator): Home is where the heart is, 66 RICHARD BANAHAN: Photo, 67 KIM FREEMAN: Baltimore, 68 JACOB RIDRIGUEZ-NOBLE: Home (Heimat), 69 SUZANNE KENNEDY: Oft verberge ich mich (Oft I hide myself), 70 RICHARD BANAHAN: Photo, 7