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Use the attached article and news to answer the research article's questions attached.

Article Assignment Sheet

-What is the title of the paper?
-What journal was the article published in?
-Who is the lead author and what university are they from?
-Who is the corresponding author and what university are they from? What was the purpose (hypothesis) of this particular research project?

-What is the most relevant background information in this article?

-What is the main conclusion(s) or finding?

-What is the main molecular methodology (if applicable) used in the article? Describe the method and include controls.

-Were the method(s) used appropriate for the question(s) being analyzed? Why or Why not?

-Would you have used additional or alternative methods in this study? If so, which method(s)?

-What are the major results of this project that allowed the authors to come up with their conclusion(s)?

-If relevant, describe each figure in the article (i.e. what is the title of the figure?, what type of data is represented?, are statistics performed on the data? If so, are any of the results statistically significant?).

-If relevant, describe each table in the article (i.e. what is the title of each table?, what type of data is represented?, are statistics performed on the data? If so, are any of the results statistically significant?).

-What are the stated future studies that will follow from this project? If no projected studies are stated in the article, what do you think would be a likely project to follow this?

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Article Assignment Sheet What is the title of the paper? What journal was the article published in? Who is the lead author and what university are they from? Who is the corresponding author and what university are they from? What was the purpose (hypothesis) of this particular research project? What is the most relevant background information in this article? What is the main conclusion(s) or finding? What is the main molecular methodology (if applicable) used in the article? Describe the method and include controls. Were the method(s) used appropriate for the question(s) being analyzed? Why or Why not? Would you have used additional or alternative methods in this study? If so, which method(s)? Article Assignment Sheet What are the major results of this project that allowed the authors to come up with their conclusion(s)? If relevant, describe each figure in the article (i.e. what is the title of the figure?, what type of data is represented?, are statistics performed on the data? If so, are any of the results statistically significant?). If relevant, describe each table in the article (i.e. what is the title of each table?, what type of data is represented?, are statistics performed on the data? If so, are any of the results statistically significant?). What are the stated future studies that will follow from this project? If no projected studies are stated in the article, what do you think would be a likely project to follow this? Research Preliminary Communication Association of Nonmyeloablative Hematopoietic Stem Cell Transplantation With Neurological Disability in Patients With Relapsing-Remitting Multiple Sclerosis Richard K. Burt, MD; Roumen Balabanov, MD; Xiaoqiang Han, MD; Basil Sharrack, MD; Amy Morgan, NP; Kathleeen Quigley, RN; Kim Yaung, RN; Irene B. Helenowski, PhD; Borko Jovanovic, PhD; Dzemila Spahovic, MD; Indira Arnautovic, MD; Daniel C. Lee, MD; Brandon C. Benefield, MS; Stephen Futterer, MD; Maria Carolina Oliveira, MD; Joachim Burman, MD Editorial page 251 IMPORTANCE No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability. Author Audio Interview at jama.com OBJECTIVE To determine the association of nonmyeloablative hematopoietic stem cell Supplemental content at jama.com transplantation with neurological disability and other clinical outcomes in patients with MS. DESIGN, SETTING, AND PARTICIPANTS Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014. INTERVENTIONS Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells. MAIN OUTCOMES AND MEASURES Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan. RESULTS Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ⱖ1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, −0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128). CONCLUSIONS AND RELEVANCE Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials. JAMA. 2015;313(3):275-284. doi:10.1001/jama.2014.17986 Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: Richard K. Burt, MD, Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, 446 E Ontario, Chicago, IL 60611 (rburt@northwestern.edu). (Reprinted) 275 Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a George Washington University User on 01/24/2015 Research Preliminary Communication Hematopoietic Stem Cell Transplantation for Multiple Sclerosis M ultiple sclerosis (MS) is thought to be an immunemediated disorder of the central nervous system that in most patients begins as an inflammatory relapsingremitting disease.1 Despite standard therapies, the majority of patients eventually enter a secondary-progressive phase for which no therapy has demonstrated efficacy. Fifty percent of patients are unable to continue employment by 10 years from diagnosis, require assistance to ambulate by 15 years, or are unable to walk by 25 years.2 Despite an annual cost of approximately US $47 000 per patient3,4 to treat MS, no therapy approved by the US Food and Drug Administration (FDA) has been demonstrated to significantly reverse neurological disability or improve quality of life.5-11 Autologous hematopoietic stem cell transplantation (HSCT) is a form of immune suppression but unlike standard immune-based drugs, it is designed to reset rather than suppress the immune system.12-14 In a previous study, a nonmyeloablative regimen for patients with relapsing-remitting MS was associated with improvement in neurological disability and quality of life in 21 patients.15 This report includes all patients from a single institution treated with a nonmyeloablative regimen with at least 6 months of follow-up, including the 21 patients previously reported.15 Methods Patients All patients who underwent HSCT for MS at Northwestern University (Chicago, Illinois) between July 2003 and February 2014 are included in this report. All patients signed informed consent and were treated and followed up identically per a study protocol approved by the Northwestern University institutional review board. Similar institutional review board approval was obtained for the reporting of patients treated off the study protocol. Race/ethnicity was recorded by the transplant team during the initial history and physical of each patient. Patients who were treated according to the study protocol underwent transplant and met all the following criteria: (1) had relapsing-remitting MS defined as acute relapses followed by partial or complete recovery and stable clinical manifestations between relapses, (2) fulfilled revised McDonald Diagnostic Criteria for MS,16 (3) treatment was unsuccessful with at least 1 FDA-approved drug, (4) had an Extended Disability Status Scale (EDSS) score from 2.0 to 6.0, (5) were aged 18 to 55 years, and (6) during the preceding year, had either at least 2 relapses treated with a corticosteroid or 1 relapse treated with a corticosteroid and additional gadolinium-enhanced lesions on magnetic resonance imaging (MRI) scan at a separate time. In addition, there were also patients treated off the study protocol on a compassionate basis for secondary-progressive MS, which was defined as a gradual progression of disability with or without superimposed relapses, or received HSCT for other reasons, including (1) brainstem, visual, or cognitive impairment with high risk of further paraplegic, quadriplegic, visional, or cognitive impairment, (2) EDSS score greater 276 than 6.0, (3) treatment was unsuccessful with currently available FDA-approved drugs, (4) coexisting autoimmune or neurological disease, (5) allergy to gadolinium, (6) older than 55 years, and (7) tumefactive MS (tumor-like MRI appearance). Most immune-modulation or suppression medications were stopped at the time of mobilization (collection of stem cells), except for natalizumab and fingolimod, which were discontinued 6 and 3 months, respectively, before transplant. After HSCT, patients did not receive immune-based therapies until clinical relapse or when new lesions were detected on an MRI scan. Stem Cell Collection and Transplant Regimen Peripheral blood stem cells were collected 10 days after patients received 2 g/m 2 of cyclophosphamide (administered intravenously) and 5 to 10 μg/kg of filgrastim (administered subcutaneously) daily beginning 5 days after receiving cyclophosphamide. The conditioning (immunoablative) regimen consisted of 50 mg/kg/d of cyclophosphamide (administered intravenously) 5 to 2 days before stem cell infusion (day 0) plus either 20 mg of alemtuzumab given 2 days before stem cell infusion (22 patients) or 0.5 mg/kg of thymoglobulin (administered intravenously) 5 days before stem cell infusion, 1.0 mg/kg 4 days before, and 1.5 mg/kg on 3 days, 2 days, and 1 day before stem cell infusion (129 patients). In addition, 1000 mg of methylprednisolone was infused 30 minutes prior to each antithymocyte globulin infusion. On the day of stem cell infusion, oral prednisone was initiated with a dose of 60 mg/d given for 3 days, 40 mg/d for 2 days, 20 mg/d for 2 days, and 10 mg/d for 2 days. If fever developed, 250 mg of methylprednisolone was administered intravenously. Supportive Care Guidelines Blood products were irradiated and leukocytes were depleted. Filgrastim (5-10 μg/kg/d) was started on day 5 and continued until engraftment. Hyperhydration (150 mL/h of normal saline), diuretics, and intravenous mesna were continued until 24 hours after the last dose of cyclophosphamide. A Foley catheter was placed in patients with a history of urinary retention. Intravenous cefepime or piperacillin-tazobactam was started on the day of stem cell infusion and intravenous vancomycin was added for a febrile episode. Oral daily acyclovir was started at hospital admission and continued for 1 year, oral fluconazole was started 2 days after HSCT and continued for 6 months, and oral trimethoprimsulfamethoxazole (3 times/wk) was started after platelet engraftment and continued for 6 months. Cytomegalovirus was monitored for 90 days and treated preemptively by switching from acyclovir to oral valganciclovir (900 mg twice/d) until a negative result was reached on quantitative polymerase chain reaction. Study End Points The primary end point was disability defined by the EDSS score (range, 0-10 in 0.5 increments). A decrease of 1.0 or greater is considered significant improvement and an increase of 1.0 or greater is considered significant progres- JAMA January 20, 2015 Volume 313, Number 3 (Reprinted) Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a George Washington University User on 01/24/2015 jama.com Hematopoietic Stem Cell Transplantation for Multiple Sclerosis sion (eTable in the Supplement).17-19 Other prespecified and prospectively collected end points included safety, relapsefree survival (no acute relapses), progression-free survival, disease activity–free survival (no acute relapses, no progression, and no gadolinium-enhanced or new T2 lesions on MRI scan), Neurologic Rating Scale (NRS) score,20 Multiple Sclerosis Functional Composite (MSFC) score, Short Form 36 (SF-36) quality-of-life score, new gadolinium-enhanced lesions on MRI scan, and total T2-weighted lesion volume on brain MRI scan. The NRS scores range from 0 to 10019; a decrease of 10 or greater is considered significant progression and an increase of 10 or greater is considered significant improvement (eTable in the Supplement). 19-21 The MSFC measures leg function with the Timed 25-Foot Walk, arm coordination with the 9-Hole Peg Test, and cognitive function with the Paced Auditory Serial Addition Test 3, and reports an integrated score from individual z scores (eTable in the Supplement).18 The SF-36 comprises 8 scales of functional health and well-being and perception of change in health on a scale of 0 to 100 with scores averaged to give a physical, mental, and total health score. Magnetic resonance imaging was obtained on a Siemens 1.5-Tesla scanner, which was used both before and after HSCT. Postcontrast T1-weighted imaging was delayed until 5 minutes after intravenous infusion of gadolinium (single dose of 0.1 mmol/kg). Patient positioning inside the scanner was standardized according to the University of Texas, Houston, MRI Analysis Center imaging acquisition manual. The T2 lesion volume, which correlates with clinical disease severity, was determined using the semiautomated contouring technique with Image J software (National Institutes of Health; http://rsbweb.nih.gov/ij/docs/faqs.html). The same observer (X.H.) marked all lesions, and an experienced reader (S.F.) blinded to MRI chronological order randomly reviewed MRI scans for accuracy. Outcome parameters (MRI scan results and scores on the EDSS, NRS, MSFC, and SF-36) were measured at baseline, 6 months, 1 year, and then annually for 5 years. Thyroid function tests were performed if the patient was symptomatic. Between scheduled assessments, patients and their physicians were instructed to contact the study team to arrange unscheduled visits if any new symptoms were present. Preliminary Communication Research Table 1. Baseline Demographics and Multiple Sclerosis (MS) Disease Characteristics (N=145)a No. (%) of Patients Sex Men Women Race/ethnicity White Black Asian Hispanic Type of MS Relapsing-remitting Secondary-progressive Age group, y 18-25 26-35 36-45 46-60 Prior use of FDA-approved immune-modulation or suppression therapy Corticosteroids Glatiramer acetate Interferon beta-1a (Avenox) Interferon beta-1b Interferon beta-1a (Rebif) Natalizumab Fingolimod Cyclophosphamide Plasmapheresis Angioplasty stenting for chronic cerebrospinal venous insufficiency Otherc No. of different immune-modulation or suppression treatments used before HSCT 2-3 4-5 ≥6 No. of relapses during year before study 0 1 2 >2 Baseline disability scored 6 No. of gadolinium-enhanced lesions on baseline MRI scan 0 1-2 3-4 >4 Statistical Analysis Two-tailed paired t tests (Microsoft Excel 2007) were used for comparison of prespecified primary and secondary outcome measures before and after HSCT. In post hoc analyses, a repeated-measures, mixed-effects model (SAS version 9.4; SAS Institute Inc) was used to calculate the least-squares means and SDs for change in EDSS score, adjusted for disease duration (>10 years or
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Research Article Questions
What is the title of the paper?
Association between Nonmyeloablative Hematopoietic stem cell with neurological disability in
patients with Relapsing-Remitting Multiple Sclerosis.
What journal was the article published in?
It’s a Jama Article published on a website known as Jamanetwork.com with a student from
George Washington University.
Who is the lead author and what university are they from?
Irene B Helenowinsky from the North Western University of Feinberg department of medicine
and the division of Cardiology.
Who is the corresponding author and what universities are they from? What was the
purpose of the particular research?
The lead author is Richard K Burt who comes from the Northwestern University of Feinberg
School of Medicine, Department of Medicine and the division of Immunotherapy. The purpose

Surname 2
of the hypothesis was to obtain information on how the patients who were diagnosed with
Relapsing-Remitting Multiple Sclerosis disease reacted in various medical institutions and how
they reacted to the several medicines that they were given. How the patients responded to the
Hematopoietic stem cell transplantation which is a medicine that is used to suppress the
Relapsing-Remitting Multiple Sclerosis disease. Other corresponding medication are used to
reset Relapsing-Remitting Multiple Sclerosis since there exi...


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