America Foundation Research Articles

Clinical trials for myasthenia gravis: a historical perspective.

Symposia dedicated to myasthenia gravis and related disorders date back to 1947 and serve as markers of the progress for the field. We provide a brief historical review of therapy development through the lens of the publications that arose from the close to quinquennial meetings that have been supported nearly since their inception by the Myasthenia Gravis Foundation of America and the New York Academy of Sciences. One can appreciate great advances, false starts, and dead ends that are found in all fields of medicine. We tally up the score card for MG and find points scored, but the win is not yet close.

P170 A NOVEL PATIENT REPORTED QUALITY OF LIFE MEASURE CORRELATES WELL WITH THE SHORT INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE IN A LARGE INTERNET BASED COHORT OF PATIENTS WITH INFLAMMATORY BOWEL DISEASE

The Short Inflammatory Bowel Disease Questionnaire (SIBDQ), a validated inflammatory bowel disease (IBD) specific measure of health related quality of life (HRQOL), is a proprietary instrument. We aimed to create and evaluate a novel measure of HRQOL among patients with Crohn’s disease (CD) or ulcerative colitis (UC) utilizing widely available patient reported outcomes (PROs). Utilizing longitudinal data collected in the Crohn’s and Colitis Foundation of America (CCFA) Partners internet cohort, we analyzed baseline and follow-up responses including the SIBDQ (licensed from McMaster University, Hamilton, Ontario), questions selected from several Patient-Reported Outcomes Measurement Information System domains, and other PROs, including disease activity assessments. The population was separated into training and test sets. Potential questions were compared to the 4 SIBDQ domains and the composite SIBDQ score using Wilcoxon Rank Sum and Pearson correlation analysis. Responsiveness of the measure to changes in disease activity was assessed using Wilcoxon Rank Sum testing. Among 7,670 patients (63% CD, 37% UC), we identified candidate PRO questions based on correlations with each SIBDQ domain, with 5 PRO questions selected (Pearson correlation coefficient r ranging from 0.560–0.738, Table 1). The 5-question measure correlated well with the composite SIBDQ in the training (r=0.883, p<0.001) and test set (r=0.879, p<0.001). The 5-question measure also demonstrated significant responsiveness to changes in disease activity over time, in both CD and UC (Table 2). We created a novel measure of HRQOL that is composed of freely available PROs and demonstrates responsiveness to changes in disease activity among patients with both CD and UC. This potential new measure of HRQOL among patients with IBD decreases patient burden, and may offer substantial benefits as a new assessment tool in research settings and in clinical practice.

DOP032 Crohn’s disease patients’ perspectives towards de-escalating immunosuppressive therapy: a comparative French and American survey

When patients with Crohn’s disease (CD) are in remission on combination therapy including an anti-tumour necrosis factor (TNF) agent and an immunomodulator (IM), a frequent question is whether it is appropriate to stop one of these medications. The aim of this study was to understand patients’ perspectives on stopping therapy for CD when in remission, and to identify differences between French and US patient groups. To develop a questionnaire about stopping therapy, a focus group of patients with CD was conducted in the USA. The questionnaire was then distributed to patients from France and the USA. Patients from France were identified from both the St-Antoine cohort and the Association Francois Aupetit (AFA) database. Patients from the US were identified from the Crohn’s and Colitis Foundation of America (CCFA) Partners cohort. A total of 410 patients with CD from the USA (113) and France (297) completed the questionnaire. Their median age was 37, and 75% of respondents were women. The majority of patients from France and the USA had CD for longer than 10 years. French patients were more likely than those in the USA to consider stopping combination therapy if recommended by their doctor (69% vs. 48%, p < 0.01). When asked which prescription they would prefer to stop, most patients in the USA and France preferred to stop the IM (53% US, 47% France) as opposed to anti-TNF (26% US, 28% France). About a quarter of patients (26%) are unwilling to accept any chance of a disease flare when de-escalating therapy. Additionally, over a quarter of patients (27%) responded that they would be unwilling to de-escalate therapy if there is any risk of not getting back into remission when restarting treatment for a flare. A majority of patients (56%) responded that they are more concerned about their CD than the risk of cancer associated with treatment. Over 90% of USA and French patients would be willing to have blood work every 3 months and over 60% were willing to have an annual MRI to monitor for disease recurrence. Patients in the USA were more willing than those in France to have annual colonoscopy to detect early disease recurrence (p < 0.01). French patients are more willing to de-escalate therapy than US patients, and patients in both the USA and France prefer de-escalating from combination therapy to biologic monotherapy. However, a sizeable minority of patients is not willing to accept any risk of future flares or loss of response to therapy when considering de-escalation. Both patient groups are open to regular testing to assess for disease recurrence after de-escalation.

The Profit of the Earth: The Global Seeds of American Agriculture by Courtney Fullilove

Reviewed by: The Profit of the Earth: The Global Seeds of American Agriculture by Courtney Fullilove Rebecca Egli (bio) The Profit of the Earth: The Global Seeds of American Agriculture. By Courtney Fullilove. (Chicago: University of Chicago Press, 2017. Pp 288. $38.00 cloth; $31.20 ebook) In The Profit of the Earth: The Global Seeds of American Agriculture, Courtney Fullilove offers an instrumental history of American agriculture through its arguably most fundamental and complex unit—the mighty seed. She demonstrates that seeds are anything but static. Indeed, through their distribution, preservation, and improvement, seeds reveal themselves to be both practical and political artifacts of [End Page 542] central importance to human history. Dividing her analysis into three parts, she documents the collection, migration, and preservation of seeds bound for the United States in the nineteenth century. In "Collection," Fullilove begins with the history of seed collection and distribution by the U.S. Patent Office. Not only did the office serve as a storehouse for seeds gathered on expeditions, it dispensed seeds—with little reference to their origins or methods of cultivation—with the hope of improving the nation's farms. "Migration" examines German Mennonites and their efforts to grow a variety of Turkish wheat on Kansas prairies. She looks critically at the wealth and land ownership that allowed these immigrants to successfully cultivate the iconic "amber waves of grain" on Midwestern plains. A final section on "Preservation" surveys the impact of changing patterns of land use. Following a pharmacist's efforts to obtain and market the native purple coneflower (Echinacea) for its medicinal benefits, she considers the impact of vast monocultures on biological diversity. Between each of these parts Fullilove has included "Field Notes" from her travels with plant genetic resource specialists in the North and South Caucasus. These sections reorient readers to the global nature of environmental knowledge and the far-flung origins of most American crops. As readers follow Fullilove on unexpected paths across time and international borders, she demonstrates the need for more global histories of plants and the knowledge that has shaped their cultivation. The Profit of the Earth resists dominant narratives about modern biological innovation that emphasize American creativity and rapid progress, revealing instead the "incremental and checkered legacies of improvement" (p. 12). Seeds, she argues "are always in a state of becoming, never fixable" (p. 211). Fullilove invites us to reconsider seeds as artifacts of prolonged human effort, deep-time technologies that contain complex social and ecological relations within. Yet the global movement of seeds has often obscured these relations. By moving a resource from its point of origin for the sake of improvement or preservation, plant collectors separated them from their human [End Page 543] histories "rendering non-Western and indigenous progenitors invisible" as stewards of knowledge (p. 65). Stripping seeds of their context paved the way for new proprietary claims. Fullilove's analysis raises valuable questions about the foundations of America's agricultural development and opens new fields of inquiry into the history of crop biodiversity and preservation. Agricultural innovation, she explains, is not only a process of creation but also one of destruction and loss. While the introduction of new and exotic varieties into the United States might ostensibly have contributed to greater agricultural diversity, modern plant breeders often eschewed those possibilities for the production of pest resistant, high-yielding monocultures. In light of modern-day concerns over input-intensive forms of production, single-crop agriculture, and biodiversity, Fullilove reminds us that for all of our knowledge, we are not masters of nature, not even those environments we create for ourselves. Instructively drawing together histories of agriculture, environment, and science, this narrative history will certainly appeal to a wide range of scholars and students, alike. Rebecca Egli REBECCA EGLI is a doctoral candidate at the University of California-Davis. She is currently writing a dissertation about American plant explorers and their impact on agricultural science in the twentieth century. Copyright © 2018 Kentucky Historical Society

Juvenile Myasthenia Gravis- A rare case report

Background : It is an acquired autoimmune mediated postsynaptic disorder that is rare in childhood with prevalence of 5 in 1,00,000. First case was reported in the year 1644 in USA of an Indian chief Opechankanough. The disease is due to circulating antibodies which bind to acetylcholine receptors at neuromuscular junction and prevent a normal action of acetylcholine in opening the calcium channel in muscle fibers. There are two types of the disease: ocular (corresponding to 10% of cases) [1] or generalized (90% of cases), although both may occur under different temporal evolution in the same patient. Myasthenia gravis geoepidemiology shows that it is a rare disorder with similar incidence and prevalence in the world, except for infantile MG, which is more common in Asia. Methods : With progressive ptosis towards the end of the day, Juvenile Myasthenia gravis was suspected. Anti cholinesterase (AChE) test was done under ECG monitoring using intravenous injection of neostigmine (Prostigmine test) which showed a dramatic response i.e. immediate elevation of both upper eyelids with resolution of ptosis[Fig. 1 and 2]. Bed side icepack test was also performed which was positive. Computerized tomography (CT scan) of thorax was done to rule out thymic hyperplasia or thymoma. We diagnosed this child as a case of juvenile myasthenia gravis and treated with intravenous neostigmine(0.04mg/ kg/dose) 4 hourly followed by atropine(0.05mg/kg/dose) to counteract ill muscarinic side effects of neostigmine. Intravenous methylprednisolone was also given as pulse therapy (30mg/ kg/day for 3 consecutive days) with multipara monitoring (for hypertension and hyperglycemia). Plasma anti-AChR antibodies though advised was not affordable. Results : The cardinal symptom in MG is muscle weakness that is typically fluctuating and fatigable. The most common initial presentation involves a specific muscle weakness, and not a generalized weakness. Symptoms are exacerbated with exercise (it may be caused by sustained muscle action) and heat, and decreased with relaxation and cooling. The disease involves striated or voluntary muscles, with a typical anatomical distribution. The weakness is usually ocular, bulbar, proximal muscle groups (most commonly the upper limbs) and neck, but may also in some patients involve the respiratory muscles. The disease can progress from mild to moderate to severe in weeks and months with episodes of exacerbations and remissions. The Myasthenia Gravis Foundation of America# proposed a clinical classification of the disease into five main classes and several subclasses, according to the location of muscle weakness and its intensity. Ptosis or extra ocular muscle weakness is the initial presentation in 75% of patients [1] and occurs during the course of the disease in 90% of cases (remaining exclusively ocular only 16% of cases [2-4]). When anti AChR antibodies are negative, MuSK receptor antibodies should be advised. Table 1 : Classification of MG according to Ossermann Scale Type 1 Ocular myasthenia characterized by ptosis and diplopia Type 2a Slow onset, frequently ocular, with gradual evolution to skeletal musculature Type 2b Slow onset with dysarthria, dysphagia, and change in mastication Type 3 Fast onset with severe bulbar and skeletal muscle fatigue with respiratory muscle compromise Type 4 Severe MG that manfests in two years Conclusion : Repetitive ulnar nerve stimulation (RNS) studies show significant decremental response in abductor digiti minimi suggestive of post synaptic neuromuscular junction (NMJ) receptor disorder[5]. Other differentials which should be considered include neuroparalytic snake bite, Miller-Fischer type of GBS and botulism. Our patient was classified as type III i.e. fast onset with severe bulbar and skeletal muscle fatigue with respiratory muscle compromise, so he had to be ventilated for 3 days. He was weaned from IPPV to T-piece over 12 hours and then to CPAP for 6 hours maintaining normal saturations and vitals. Thereafter he was referred to higher center for plasmapharesis but since then he is lost to follow up.

Independent long-term result of robotic thymectomy for myasthenia gravis, a single center experience

Robotic thymectomy has been suggested a feasible and safe approach for myasthenia gravis (MG). Few investigations have revealed the independent effect of robotic thymectomy without the confounding impact of immunosuppressive (IM) therapy. Between May 2009 and December 2012, robotic extended thymectomy was carried out for patients with diagnosis of MG. The clinical data, subsequent neurological therapy and postintervention status were collected. Data of 37 cases was available for analysis. The mean follow-up was 70.0±13.3 months. The median age was 40 years. Twelve (32.4%) patients kept free of IM therapy, and 25 (67.6%) patients accepted postoperatively. The overall 5-year complete stable remission (CSR) rate was 40.6% and improvement rate was 81.6%. The young (age ≤40) displayed a significant better CSR rate (P=0.015) and a trend of better improvement rate (P=0.050) compared to the old (age >40). Patients without usage of IM therapy showed significant higher CSR rate (P=0.014) and improvement rate (P=0.024) compared to those with usage of IM therapy. Patients with Myasthenia Gravis Foundation of America (MGFA) classes I showed a trend of higher remission rate by multivariate analysis. No significant differences were found for the remission rate according to gender, pathology, and the duration of symptoms. The mono-therapy of robotic thymectomy may bring with a satisfactory long-term result for part of MG patients. Precision selection and individualized therapy are of the most importance.

Editorial introductions

Editorial introductions

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Alexion Pharmaceuticals.

Different neurologic outcomes of myasthenia gravis with thymic hyperplasia and thymoma after extended thymectomy: A single center experience

This study aimed to reveal the clinical course and outcomes of myasthenia gravis (MG) in patients with thymic lymphoid hyperplasia and thymoma undergoing extended thymectomy and to identify the clinical prognostic factors of remission for MG. In total, 73 patients undergoing extended thymectomy were divided into two groups: group A with lymphoid hyperplasia (n=39) and group B with thymoma (n=34). According to the MG Foundation of America (MGFA) post-intervention status, the primary endpoint was a composite measure defined as achievement of complete stable remission (CSR), pharmacologic remission (PR), minimal manifestations (MM) or improvement (IM). The secondary endpoint was CSR. The cumulative probabilities of reaching the primary endpoint were 71.8% in group A and 85.3% in group B (p=0.164), respectively. Using Kaplan-Meier survival analysis, the probability of reaching the primary endpoint in group B was remarkably greater than group A (p=0.036). Cox multivariate analysis indicated that pre-operative MGFA class I (HR: 3.019, 95% CI: 1.084–8.410) and MGFA II (2.665, 95% CI: 1.033–6.873) compared to MGFA III and presence of thymoma (HR: 2.229, 95% CI: 1.079–4.606), showed the most consistent association with remission of MG after thymectomy. Finally, thymic lymphoid hyperplasia and severe symptoms may negatively affect prognosis of MG following thymectomy.

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial

Patients with advanced sarcomas have a poor prognosis and few treatment options that improve overall survival. Chemotherapy and targeted therapies offer short-lived disease control. We assessed pembrolizumab, an anti-PD-1 antibody, for safety and activity in patients with advanced soft-tissue sarcoma or bone sarcoma. In this two-cohort, single-arm, open-label, phase 2 study, we enrolled patients with soft-tissue sarcoma or bone sarcoma from 12 academic centres in the USA that were members of the Sarcoma Alliance for Research through Collaboration (SARC). Patients with soft-tissue sarcoma had to be aged 18 years or older to enrol; patients with bone sarcoma could enrol if they were aged 12 years or older. Patients had histological evidence of metastatic or surgically unresectable locally advanced sarcoma, had received up to three previous lines of systemic anticancer therapy, had at least one measurable lesion according to the Response Evaluation Criteria In Solid Tumors version 1.1, and had at least one lesion accessible for biopsy. All patients were treated with 200 mg intravenous pembrolizumab every 3 weeks. The primary endpoint was investigator-assessed objective response. Patients who received at least one dose of pembrolizumab were included in the safety analysis and patients who progressed or reached at least one scan assessment were included in the activity analysis. Accrual is ongoing in some disease cohorts. This trial is registered with ClinicalTrials.gov, number NCT02301039. Between March 13, 2015, and Feb 18, 2016, we enrolled 86 patients, 84 of whom received pembrolizumab (42 in each disease cohort) and 80 of whom were evaluable for response (40 in each disease cohort). Median follow-up was 17·8 months (IQR 12·3-19·3). Seven (18%) of 40 patients with soft-tissue sarcoma had an objective response, including four (40%) of ten patients with undifferentiated pleomorphic sarcoma, two (20%) of ten patients with liposarcoma, and one (10%) of ten patients with synovial sarcoma. No patients with leiomyosarcoma (n=10) had an objective response. Two (5%) of 40 patients with bone sarcoma had an objective response, including one (5%) of 22 patients with osteosarcoma and one (20%) of five patients with chondrosarcoma. None of the 13 patients with Ewing's sarcoma had an objective response. The most frequent grade 3 or worse adverse events were anaemia (six [14%]), decreased lymphocyte count (five [12%]), prolonged activated partial thromboplastin time (four [10%]), and decreased platelet count (three [7%]) in the bone sarcoma group, and anaemia, decreased lymphocyte count, and prolonged activated partial thromboplastin time in the soft-tissue sarcoma group (three [7%] each). Nine (11%) patients (five [12%] in the bone sarcoma group and four [10%] in the soft-tissue sarcoma group) had treatment-emergent serious adverse events (SAEs), five of whom had immune-related SAEs, including two with adrenal insufficiency, two with pneumonitis, and one with nephritis. The primary endpoint of overall response was not met for either cohort. However, pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. Enrolment to expanded cohorts of those subtypes is ongoing to confirm and characterise the activity of pembrolizumab. Merck, SARC, Sarcoma Foundation of America, QuadW Foundation, Pittsburgh Cure Sarcoma, and Ewan McGregor.

Inflammatory Bowel Diseases Dedicated Gastroenterologists Have Greater Adherence to Clinical Care Quality Indicators Than General Gastroenterologists

Introduction: The wide variation of care received by patients with inflammatory bowel disease (IBD) is a surrogate for poor clinical outcomes. Physician performance measures and quality of care indicators for IBD were developed by the American Gastroenterological Association (AGA) and the Crohn's and Colitis Foundation of America (CCFA) with the goal to improve clinical outcomes, quality of life, and decrease healthcare costs. The aim of our study was to assess adherence to IBD quality of care indicators at a tertiary academic center by IBD-dedicated gastroenterologists (IBD-GIs) compared to general gastroenterologists practicing in the community that manage IBD patients (Gen-GIs). Methods: A prospective review (January 1, 2017 to April 30, 2017) was conducted of consecutive outpatient visits at the gastroenterology clinic at Washington University in Saint Louis. Demographics and established quality of care indicators in IBD as published by AGA and CCFA were collected: documentation of IBD phenotype, vaccination status, and appropriate endoscopic evaluation. We compared adherence to quality of care indicators by IBD-GIs managing established IBD patients vs referred patients with IBD managed by community Gen-GIs using t-test and Chi square (Prism, Irving CA). Results: Over the study period, 478 patients (median age 42 years, 51% female, 14% African American) were evaluated in the clinic. Disease duration was a median of 14 years, and 55% had Crohn's disease. 235 patients were managed by IBD-GIs and 248 were managed by Gen-GIs with similar demographics among the two groups. IBD-GIs were significantly more compliant with recommended quality of care indicators compared to Gen-GIs, including IBD phenotype documentation, vaccination practices, corticosteroid usage, colonoscopy for colon cancer surveillance, and endoscopy as part of treat-to-target therapy or to detect post-surgical recurrence (Table 1).Table: Table. Comparison of adherence to IBD quality of care indicatorsConclusion: IBD-GIs compared to Gen-GIs are consistently and significantly more adherent in the implementation of quality of care indicators for IBD. Our data suggest that patients with IBD might benefit from focused and comprehensive clinical care by IBD-dedicated gastroenterologists. Furthermore, the study highlights the need for further training and education of Gen-GI physicians in areas where specialized IBD care is not currently available.

Evaluation of Gastrointestinal Patient Reported Outcomes Measurement Information System (GI-PROMIS) Symptom Scales in Subjects With Inflammatory Bowel Diseases.

Patient reported outcomes (PROs) are important treatment endpoints in inflammatory bowel diseases (IBD). We evaluated the gastrointestinal (GI) PRO Measurement Information System (PROMIS) in IBD subjects. Crohn's and Colitis Foundation of America's Partners is an Internet-based cohort of IBD subjects. Participants complete surveys, including demographics, disease characteristics, PROMIS domains, disease activity (short Crohn's disease activity index or simple clinical colitis activity index) and quality of life (QoL) indices. In a nested cross-sectional study, we used univariate and bivariate analyses to assess associations between 8 GI-PROMIS domains (reflux, swallowing, diarrhea, nausea, belly pain, gas, incontinence, and constipation) and QoL and disease activity indices. The study included 2,378 Crohn's Disease (CD) and 1,455 ulcerative colitis (UC) respondents with a median age of 41 years. Median disease duration was 11 years for CD subjects and 8 years for UC subjects; 57% of CD subjects and 42% of UC subjects were in remission. Among symptomatic CD subjects, those with active CD reported significantly worse symptoms on all 8 domains than those in remission. The same was observed for UC subjects with the exception of disrupted swallowing. IBD subjects with worse QoL reported significantly worse symptoms on all 8 domains compared to those with better QoL. In IBD subjects experiencing GI symptoms, GI-PROMIS domains were strongly associated with disease activity and QoL indices. GI-PROMIS holds potential as PRO measures in IBD and correlates with other validated indices in this population.

Optimizing the quality of endoscopy in inflammatory bowel disease: focus on surveillance and management of colorectal dysplasia using interactive image- and video-based teaching

Varying recommendations regarding the detection and management of dysplasia can lead to uncertainty and may impede the uptake of strategies that could improve surveillance in patients with inflammatory bowel disease (IBD). An educational event was held to assist in disseminating the recently published Surveillance for Colorectal Endoscopic Neoplasia Detection and Management in Inflammatory Bowel Disease Patients: International Consensus Recommendations (SCENIC). Specialists in IBD and endoscopy led the Optimizing Quality of Endoscopy in IBD course. The American Society for Gastrointestinal Endoscopy (ASGE) organized the course, and the Crohn's and Colitis Foundation of America (CCFA) provided endorsement. One was held in March 2015 at the ASGE Institute for Training and Technology in Chicago, Illinois, and the second in September 2016 preceding the ASGE Endofest in Chandler, Arizona. The program included interactive case-based discussions and didactic presentations on topics including the rationale and current approach of surveillance in IBD; endoscopic characterization and nomenclature of active and quiescent disease; detection of dysplasia during IBD surveillance; role of image-enhanced endoscopy in IBD surveillance, with a focus on chromoendoscopy technique; and management of dysplasia in IBD. Participants were surveyed before and after the course to assess their perspectives and practice. Eighteen presenters or panel members and approximately 92 IBD and endoscopist physician leaders attended the meeting. Most attendees were aged 30 to 49 years (88.1%), had been in practice less than 10 years (89.7%), were from academic medical centers (90.7%), and spent >50% of their time caring for patients with IBD (59.7%). Recommended quality improvements for endoscopy in IBD included the use of endoscopic scoring systems to describe disease activity, the use of a modified Paris classification to characterize visible dysplastic lesions (polypoid, nonpolypoid with description of presence of ulcer and distinct or indistinct borders), the use of chromoendoscopy for dysplasia detection, and the endoscopic removal of visible dysplastic lesions. In the follow-up survey, participants were asked to indicate whether they had changed their practice as a result of attending the course. Ninety-three percent (93%) indicated they had changed their practice. For dysplasia detection, the use of chromoendoscopy increased: 51.7% of respondents reported using chromoendoscopy in most surveillance colonoscopies compared with 34.3% before the course. For dysplasia management, the use of EMR increased for polypoid and nonpolypoid lesions 10 to 20mm in size; and the referral of dysplastic lesions 20mm or larger that appeared endoscopically resectable shifted toward removal by an experienced endoscopist. Evidence-based advances in endoscopy have occurred in the characterization and nomenclature of active and quiescent disease, polypoid and nonpolypoid dysplasia in IBD, and in the detection and management of dysplasia in colonic IBD. Implementation of updated guidelines and recommendations into clinical practice may be facilitated by interactive image- and video-based courses on the topic.

Rituximab as treatment for anti-MuSK myasthenia gravis: Multicenter blinded prospective review.

To evaluate the efficacy of rituximab in treatment of anti-muscle-specific kinase (MuSK) myasthenia gravis (MG). This was a multicenter, blinded, prospective review, comparing anti-MuSK-positive patients with MG treated with rituximab to those not treated with rituximab. The primary clinical endpoint was the Myasthenia Gravis Status and Treatment Intensity (MGSTI), a novel outcome that combines the Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) and the number and dosages of other immunosuppressant therapies used. A priori, an MGSTI of level ≤2 was used to define a favorable outcome. Secondary outcomes included modified MGFA PIS of minimal manifestations or better, mean/median prednisone dose, and mean/median doses of other immunosuppressant drugs. Seventy-seven of 119 patients with anti-MuSK MG evaluated between January 1, 2005, and January 1, 2015, at 10 neuromuscular centers were selected for analysis after review of limited clinical data by a blinded expert panel. An additional 22 patients were excluded due to insufficient follow-up. Baseline characteristics were similar between the rituximab-treated patients (n = 24) and the controls (n = 31). Median follow-up duration was >3.5 years. At last visit, 58% (14/24) of rituximab-treated patients reached the primary outcome compared to 16% (5/31) of controls (p = 0.002). Number needed to treat for the primary outcome is 2.4. At last visit, 29% of rituximab-treated patients were taking prednisone (mean dose 4.5 mg/day) compared to 74% of controls (mean dose 13 mg/day) (p = 0.001 and p = 0.005). This study provides Class IV evidence that for patients with anti-MuSK MG, rituximab increased the probability of a favorable outcome.

Predictive factors of prolonged mechanical ventilation, overall survival, and quality of life in patients with post-thymectomy myasthenic crisis

BackgroundThymectomy is the primary approach for the treatment of myasthenia gravis (MG). This retrospective study aimed to identify the clinical and demographical features that may impact the duration of mechanical ventilation (DMV), the long-term survival, and the quality of life (QOL) in patients with post-thymectomy myasthenic crisis (PTMC).MethodsWe reviewed the patients who suffered from PTMC from June 2008 to November 2015. Cox proportional hazard regression analysis was used to identify potential prognostic factors that may impact DMV and long-term survival. Spearman bivariate correlation analysis was used to analyze the relationship between DMV and QOL. Statistical powers were calculated.ResultsIn total, 70 patients with PTMC were enrolled. Alcohol abuse, high scores of Myasthenia Gravis Foundation of America (MGFA) classification and Clavien-Dindo classification were critical factors that remarkably delayed early extubation. High scores of Osserman’s classification, MGFA classification, and Clavien-Dindo classification predicted a poor prognosis in PTMC patients. Occupational skills and job status were observed to be negatively affected in PTMC patients.ConclusionsTo decrease the duration of mechanical ventilation, we suggest alcohol abstinence before the operation, appropriate preoperative treatment to decrease MGFA classification, and greater attention to the treatment of postoperative complications.

2016 Giving USA data show record donations

Nonprofit Business AdvisorVolume 2017, Issue 335 p. 6-8 Industry News 2016 Giving USA data show record donations First published: 21 July 2017 https://doi.org/10.1002/nba.30346Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Abstract Donations from America's individuals, estates, foundations and corporations reached a record $390.05 billion in 2016, according to the latest Giving USA report compiled by the Giving USA Foundation. That marks the third year in a row that giving, in inflation-adjusted dollars, has set a record. Volume2017, Issue335August 2017Pages 6-8 RelatedInformation

Factors affecting outcome in ocular myasthenia gravis

ABSTRACTAim of the study: 50%–60% of patients with ocular myasthenia gravis (OMG) progress to generalized myasthenia gravis (GMG) within two years. The aim of our study was to explore factors affecting prognosis of OMG and to test the predictive role of several independent clinical variables.Materials and methods: We reviewed a cohort of 168 Caucasian patients followed from September 2000 to January 2016. Several independent variables were considered as prognostic factors: gender, age of onset, results on electrophysiological tests, presence and level of antibodies against acetylcholine receptors (AChR Abs), treatments, thymic abnormalities. The primary outcome was the progression to GMG and/or the presence of bulbar symptoms. Secondary outcomes were either achievement of sustained minimal manifestation status or worsening in ocular quantitative MG subscore (O-QMGS) or worsening in total QMG score (T-QMGS), assessed by Myasthenia Gravis Foundation of America (MGFA) quantitative scores. Changes in mental and physical subscores of health-related quality of life (HRQoL) were assessed with SF-36 questionnaire. Variance analysis was used to interpret the differences between AChR Ab titers at different times of follow up among the generalized and non-generalized patients.Results: Conversion to GMG occurred in 18.4% of patients; it was significantly associated with sex, later onset of disease and anti-AChR Ab positivity. Antibody titer above the mean value of 25.8 pmol/mL showed no significant effect on generalization. Sex and late onset of disease significantly affected T-QMGS worsening. None of the other independent variables significantly affected O-QMGS and HRQoL.Conclusions: Sex, later onset and anti-AChR Ab positivity were significantly associated with clinical worsening.

The correlation of neutrophil-to-lymphocyte ratio with the presence and activity of myasthenia gravis.

Though the pathogenesis of myasthenia gravis (MG) is not fully understood, the role of inflammation has been well appreciated in the development of MG. We aimed to investigate the role of neutrophil-to-lymphocyte ratio (NLR) in MG patients and the relationship between the NLR and the activity of the disease. A total number of 172 MG patients and 207 healthy controls (HC) were enrolled in this study. The MG patients were divided into tertiles according to NLR (low NLR < 1.58, n = 57; intermediate NLR 1.58–2.33, n = 57 and high NLR > 2.33, n = 58). The disease activity assessment was performed according to the standard criteria established by the Myasthenia Gravis Foundation of America. Patients with MG had significantly higher NLR when compared with the HC group (P < 0.0001). The NLR levels were higher in the MG patients with severe disease activity than those with mild disease activity (P < 0.001), meanwhile, median NLR was statistically higher in MG patients with myasthenic crisis (MC) than those without MC (P < 0.001). Incidences of severe disease activity and MC were both higher in the high NLR group, compared to low and intermediate NLR groups (both P < 0.001). Multivariate logistic regression analysis suggested that elevated NLR was an independent predictor of severe disease activity (odds ratio = 13.201, CI% = 1.418–122.938, P = 0.023). These results indicate that NLR may be a simple and useful potential marker in indicating disease activity in patients with MG.

Tissue-specific requirements for IL-10 in maintaining homeostasis in response to chronic virus infection

Abstract Herpesviruses have co-evolved with their hosts for million of years, establishing an intimate balancing act of lifelong infection with minimal damage to the host. Interleukin (IL)-10 is a major inhibitory cytokine that has been usurped by many herpesviruses to facilitate infection. Here we tested the consequence of IL-10 deficiency on the outcome of murine gammaherpesvirus 68 (γHV68) infection, a small animal model of γHV pathogenesis. While IL-10 deficiency had minimal impact on the control of virus infection, IL-10 deficient mice showed hyper-activation of the immune response with increased levels of T cell activation, effector T cells and prolonged neutrophilia in the infected lung. IL-10 further had a non-redundant role in limiting intestinal inflammation with chronically infected mice showing a prolonged failure to thrive following infection, associated with enhanced colonic Th1 responses. CD4 T cells were a prominent source of IL10 during acute and chronic infection, with IL10+ interferon-gamma+ FoxP3- type 1 regulatory CD4 T cells as the major early source of IL10. High-dimensional mass cytometric analysis of IL10 expressing cells, and IL10 responsive cells, identified a constellation of phenotypes that correlate with robust IL10 expression, and further identified direct and indirect targets of IL10. In total, these data demonstrate the context dependent role of IL10 in constraining the antiviral host response and identify IL10-dependent and –independent regulatory pathways in regulating chronic herpesvirus infection. This research was funded by grants from the American Heart Association, Crohn’s and Colitis Foundation of America and the UC Department of Anesthesiology (ETC).

A Motivational Interviewing Intervention by Pharmacy Students to Improve Medication Adherence.

Diabetes mellitus (DM) patients with comorbid hypertension (HTN) are at a higher risk of developing microvascular and macrovascular DM complications. Through guideline-driven recommendations, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are highly recommended for these patients. Unfortunately, medication adherence to these products, though crucial to achieving therapeutic benefit, is frequently suboptimal. Motivational interviewing (MI) is a patient-centered collaborative communication style that is used to strengthen internal motivation for change that may prove effective in enhancing adherence. To examine the effect of an MI telephone intervention conducted by pharmacy students in improving adherence to ACEIs/ARBs among Medicare Advantage Plan (MAP) patients with both DM and HTN. A prospective study was conducted among patients enrolled in a Texas MAP. Medical claims data were used to identify patients with DM and HTN, and pharmacy claims were observed to recognize those who filled either an ACEI or an ARB during June 2014. Patients with a 6-month proportion of days covered (PDC) < 0.80 in the previous 6 months were determined nonadherent, and 75% of those were randomly selected to serve as potential subjects for the intervention, while 25% were randomly selected to serve as potential subjects for the control group. The intervention was a telephone call by a pharmacy student on rotation at the health plan, and 5 monthly follow-up calls. Before implementing calls, participating students attended a 3-day MI training course, where their proficiency for MI skills was evaluated. Refill data during the 6-month postintervention were evaluated to examine the intervention effect measured on 3 outcomes: PDC; PDC ≥ 0.80 versus < 0.80; and discontinuation versus continuation. Multivariate linear and logistic regression models were constructed to adjust for any imbalances in baseline characteristics, including age, gender, number of other medications, regimen complexity, health low-income subsidy status, prescriber specialty, comorbidities, 6-month previous hospitalization, baseline 6-month PDC, and Centers for Medicare & Medicaid Services risk score. A total of 11 students participated in the intervention implementation. Patients receiving calls were randomly selected from those potential subjects for the intervention arm until a target of 250 was reached; 500 controls were randomly selected from the potential subjects for the control arm. The final cohort included in multivariate models consisted of 743 patients. Patients completing the initial call and at least 2 follow-ups were less likely to discontinue (OR = 0.29; 95% CI = 0.15-0.54; P < 0.001) and more likely to be adherent in the linear regression model (β = 0.0604, P < 0.001) and the logistic regression model (OR = 1.53; 95% CI = 1.02-2.28; P = 0.009). Other factors significantly associated with better adherence included higher baseline PDC and number of medications. Depression status was significantly associated with lower adherence. Patients receiving 2 or more calls had significantly better adherence and less discontinuation during the 6 months following initial calls compared with those who did not receive calls. This finding indicates that an MI-based telephone intervention by pharmacy students may be a promising intervention to improve adherence. Future research should examine the sustainability of the intervention effect for longer time periods and its influence on associated clinical outcomes. This project was supported by the Pharmaceutical Research and Manufacturers of America Foundation (PhRMA). The content is solely the responsibility of the authors and does not necessarily represent the official views of PhRMA. The funding agency was not involved in research design, analysis, or reporting results. Funding was obtained by Abughosh. Holstad provided a consultation regarding the MI guide and provided the MI training. Study concept and design were contributed by Abughosh and Fleming, along with Serna, Esse, and Holstad. Serna, Esse, Mann, Holstad, and Masilamani collected the data, and data interpretation was performed by Abughosh, Wong, and Esse. The manuscript was written by Abughosh, Wong, and Esse and revised by Masilamani and Holstad, along with the other authors.