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Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial purchase imuran on line muscle relaxant norflex. The effects of a nucleoside-sparing antiretroviral regimen on the pharma- cokinetics of ritonavir-boosted darunavir in HIV type-1-infected patients order imuran without prescription muscle relaxant egypt. Efficacy and safety of atazanavir-based HAART in pts with virologic suppression switched from a stable discount imuran 50mg amex muscle relaxant 750, boosted or unboosted PI treatment regimen: the SWAN Study. Non-inferiority of dual-therapy (DT) with lopinavir/ritonavir (LPV/r) plus lamivudine (3TC) vs triple-therapy (TT) with LPV/r plus two nucleos(t)ides (NRTIs) for maintenance of HIV-1 viral suppression: 48-week results of the OLE study. Unboosted atazanavir-based therapy maintains control of HIV type-1 repli- cation as effectively as a ritonavir-boosted regimen. TenofovirDF + efavirenz (TDF+EFV) vs tenofovirDF+ efavirenz + lamivu- dine (TDF+EFV+3TC) maintenance regimen in virologically controlled patients (pts): COOL Trial. Randomized controlled study demonstrating failure of LPV/r monother- apy in HIV: the role of compartment and CD4-nadir. Changes in bone turnover and bone loss in HIV-infected patients changing treatment to tenofovir-emtricitabine or abacavir-lamivudine. Maintenance antiretroviral therapies in HIV infected patients with undetectable plasma HIV RNA after triple-drug therapy. Change to abacavir-lamivudine-tenofovir combination treatment in patients with HIV-1 who had complete virological suppression. A lamivudine (3TC)-based backbone in conjunction with a boosted protease inhibitor (PI) is sufficient to achieve virologic suppression in the presence of M184V mutations. Randomized, controlled, 48 week study of switching stavudine and/or pro- tease inhibitors to Combivir/abacavir to prevent or reverse lipoatrophy in HIV-infected patients. Ritonavir boosted indinavir treatment as a simplified maintenance “mono”- therapy for HIV infection. Maraviroc plus raltegravir failed to maintain virological suppression in HIV-infected patients with lipohypertrophy: results from the ROCnRAL ANRS 157 study. TRIZAL study: switching from successful HAART to Trizivir (abacavir lamivu- dine-zidovudine combination tablet): 48 weeks efficacy, safety and adherence results. Switch to efavirenz (EFV) after protease-inhibitor (PI)-failure: explorative analysis of outcome by baseline viral VS tolerability failure. Factors associated with virological failure in HIV-1-infected patients receiving darunavir/ritonavir monotherapy. Factors associated with virological failure in HIV-1-infected patients receiving darunavir/ritonavir monotherapy. Resistant minority species are rarely observed in patients on darunavir/ritonavir monotherapy. Targeting only reverse transcriptase with zidovudine/lamivudine/abacavir plus tenofovir in HIV-1-infected patients with multidrug-resistant virus: a multicentre pilot study. The safety and efficacy of switching stavudine to tenofovir df in com- bination with lamivudine and efavirenz in hiv-1-infected patients: three-year follow-up after switching therapy. Efficacy and safety of switching from boosted lopinavir to boosted atazanavir in patients with virological suppression receiving a LPV/r-containing HAART: the ATAZIP study. J AIDS 2009, 51:29-36 Marcelin AG, Lambert-Niclot S, Peytavin G, et al. Baseline HIV RNA ultrasensitive assay and viral DNA predict rise in plasma viral load in patients of MONOI-ANRS 136 Trial. Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV- 1-infected patients. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir- lamivudine: a randomized, 96-week trial. Bone mineral density in HIV participants randomized to raltegravir and lopinavir/ritonavir compared with standard second line therapy. HIV lipodystrophy in participants randomised to lopinavir/ritonavir (LPV/r) +2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI) or LPV/r + raltegravir as second-line anti- retroviral therapy. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with HIV infection. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. Effectiveness of protease inhibitor monotherapy versus combination anti- retroviral maintenance therapy: a meta-analysis. PLoS One 2011, 6:e22003 McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons ran- domized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: a randomized, controlled study. Mitochondrial function, inflammation, fat and bone in HIV lipoat- rophy: randomized study of uridine supplementation or switch to tenofovir. Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. Improvement in lipoatrophy associated with HAART in HIV- infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study. Lopinavir/ritonavir monotherapy versus current treatment contin- uation for maintenance therapy of HIV-1 infection: the KALESOLO trial. How to switch ART 221 Milinkovic A, Martinez E, Lopez S, et al. The impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients. Reasons for stopping antiretrovirals used in an initial highly active anti- retroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection. Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a PI-based regimen: a randomized trial. Dual therapy with etravirine plus raltegravir for virologically suppressed HIV- infected patients: a pilot study. J Antimicrob Chemother 2014, 69:742-8 Moyle G, Baldwin C, Langroudi B, Mandalia S, Gazzard BG. A 48 week, randomized, open label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. Early vs deferred HAART switch in heavily pre-treated HIV patients with low viral load level and stable CD4 cell count. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with HIV infection and long-lasting viral suppression.

Adequate approaches to concealment of randomization: Centralized or pharmacy-controlled randomization Serially numbered order cheap imuran online muscle relaxant nursing, identical containers On-site computer based system with a randomization sequence that is not readable until allocation Other approaches sequence to clinicians and patients Inferior approaches to concealment of randomization: Use of alternation purchase imuran mastercard muscle relaxant education, case record number order imuran master card muscle relaxant with painkiller, date of birth, or day of week Open random numbers lists Insomnia Page 60 of 86 Final Report Update 2 Drug Effectiveness Review Project Serially numbered envelopes (Even sealed opaque envelopes can be subject to manipulation. Were the groups similar at baseline in terms of prognostic factors? Were outcome assessors blinded to the treatment allocation? Was the patient kept unaware of the treatment received? Did the article include an intention-to-treat analysis or provide the data needed for one (that is, number of subjects assigned to each group, number of subjects who finished in each group, and the results for all subjects who finished)? Did the article report attrition, crossovers, adherence, and contamination? Was there important differential loss to follow-up or overall high loss to follow-up? How similar is the study population to the population to which the intervention would be applied? What was the funding source and role of funder in the study? Was the selection of patients for inclusion unbiased? Was there important differential loss to follow-up or overall high loss to follow-up? Was there a clear description of the techniques used to identify the events? Was there unbiased and accurate ascertainment of events (independent ascertainer using validated ascertainment technique)? Were potential confounding variables and risk factors identified and examined using accepted statistical techniques? Was the duration of follow-up reasonable with respect to timing of investigated events? How similar is the study population to the population to which the intervention would be applied? What was the funding source and role of funder in the study? Are there a clear review question and inclusion and exclusion criteria reported relating to the primary studies? A good-quality review should focus on a well defined question or set of questions, which ideally will refer to the inclusion/exclusion criteria by which primary studies are included or excluded. The criteria should relate to the 4 components of study design, indications (patient Insomnia Page 62 of 86 Final Report Update 2 Drug Effectiveness Review Project populations), interventions (drugs), and outcomes of interest. In addition, the review should include details of the process of decision-making, that is how many reviewers were involved, whether the studies were examined independently, and how disagreements between reviewers were resolved. Is there evidence of a substantial effort to search for all relevant research? This is usually the case if details of electronic database searches and other identification strategies are given. Ideally, the search terms and the date and language restrictions should be presented. In addition, descriptions of hand searching, attempts to identify unpublished material, and any contact with authors, industry, and research institutes should be provided. The appropriateness of the database(s) searched by the authors should also be considered. For example, if only MEDLINE is searched for a review looking at health education, then it is unlikely that all relevant studies will have been located. Is the validity of included studies adequately assessed? A systematic assessment of the quality of primary studies should include an explanation of the criteria used (for example, method of randomization, whether outcome assessment was blinded, whether analysis was on an intention-to-treat basis). Authors may use either a published checklist or scale or one that they designed specifically for their review. Again, the process relating to the assessment should be explained (that is, how many reviewers were involved, whether the assessment was independent, and how discrepancies between reviewers were resolved). Is sufficient detail of the individual studies presented? This criterion is usually fulfilled in papers that include a table giving information on the design and results of the individual studies or includes a narrative description of the studies within the text. If relevant, the tables or text should include information on study design, sample sizes, patient characteristics, interventions, settings, outcome measures, follow-up, drop-out rate (withdrawals), effectiveness results, and adverse events. The authors should attempt to synthesize the results from individual studies. In all cases, there should be a narrative summary of results, which may or may not be accompanied by a quantitative summary (meta-analysis). For reviews that use a meta-analysis, heterogeneity between studies should be assessed using statistical techniques. If heterogeneity is present, the possible reasons (including chance) should be investigated. In addition, the individual evaluations should be weighted in some way (for example, by sample size or by inverse of the variance) so that studies that are considered to provide the most reliable data have greater impact on the summary statistic. Insomnia Page 63 of 86 Final Report Update 2 Drug Effectiveness Review Project Appendix C. Excluded studies 290 trials were excluded with the exclusion code shown below (new trials from Update 2 are highlighted in gray-scale) Codes: 1 = Foreign language 2 = Wrong outcome 3 = Wrong drug (including combination therapy) 4 = Wrong population 5 = Wrong publication type (letter, editorial, nonsystematic review, etc. Effects on postural oscillation and memory functions of a single dose of zolpidem 5 mg, zopiclone 3. A randomized, cross-over, double- 4 blind study versus placebo. Allain H, Le Breton S, Kleinermans D, Lavoisy J, Klausner J, Gandon JM. Assessment of patients preferences between two hypnotics, zolpidem (10 mg) vs. The effects of single doses of CL284,846, lorazepam, and placebo and psychomotor and memory function in normal male 4 volunteers. A single-site, double-blind, placebo- controlled, dose-ranging study of YKP10A - A putative, new antidepressant. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major 3 depressive disorder. Ansseau M, Pitchot W, Hansenne M, Gonzalez Moreno A. Insomnia Page 64 of 86 Final Report Update 2 Drug Effectiveness Review Project Trials Code Aranko K, Luurila H, Backman JT, Neuvonen PJ, Olkkola KT. The effect of erythromycin on the pharmacokinetics and pharmacodynamics of zopiclone.

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The intercostal structures course under cover of the subcostal The right crus arises from the front of the L1–3 vertebral bodies and groove generic imuran 50 mg mastercard muscle relaxant. Pleural aspiration should be performed close to the upper bor- intervening discs cheap 50mg imuran otc spasms on left side of body. Some fibres from the right crus pass around the lower der of a rib to minimize the risk of injury buy generic imuran 50mg line spasms right flank. Vascular supply and venous drainage of the chest wall The medial arcuate ligament is made up of thickened fascia which The intercostal spaces receive their arterial supply from the anterior overlies psoas major and is attached medially to the body of L1 and lat- and posterior intercostal arteries. The lateral arcuate ligament is • The anterior intercostal arteries are branches of the internal thoracic made up of fascia which overlies quadratus lumborum from the trans- artery and its terminal branch the musculophrenic artery. The lowest verse process of L1 medially to the 12th rib laterally. The median arcuate ligament is a fibrous arch which connects left • The first 2–3 posterior intercostal arteries arise from the superior and right crura. The lower nine posterior inter- •Asternal part: consists of two small slips arising from the deep sur- costal arteries are branches of the thoracic aorta. Openings in the diaphragm The anterior intercostal veins drain anteriorly into the internal thor- Structures traverse the diaphragm at different levels to pass from acic and musculophrenic veins. The posterior intercostal veins drain thoracic to abdominal cavities and vice versa. These levels are as into the azygos and hemiazygos systems (see Fig. Lymph drainage from the: • T10, the oesophageal opening: transmits the oesophagus, vagi and • Anterior chest wall: is to the anterior axillary nodes. The left phrenic nerve passes into the diaphragm as a solitary structure. Only the upper six intercostal nerves run in their inter- • Motor supply: the entire motor supply arises from the phrenic nerves costal spaces, the remainder gaining access to the anterior abdominal (C3,4,5). Diaphragmatic contraction is the mainstay of inspiration. The sensory supply from the • Cutaneous anterior and lateral branches. The thoracic wall II 9 3 The mediastinum Icthe contents of the mediastinum Superior mediastinum Great vessels Trachea Oesophagus Thymus, etc. Middle mediastinum Heart and roots of great vessels Anterior mediastinum Pericardium Thymus Posterior mediastinum Oesophagus Descending thoracic aorta Thoracic duct Fig. The superior mediastinum communicates with the root of the neck The dual drainage of the lower third forms a site of portal-systemic through the ‘thoracic inlet’. The latter opening is bounded anteriorly by anastomosis. In advanced liver cirrhosis, portal pressure rises result- the manubrium, posteriorly by T1 vertebra and laterally by the 1st rib. These veins become distended and fragile (oesophageal varices). They are predisposed to rupture, causing potentially life-threatening • Middle mediastinum: consists of the pericardium and heart. The lower oesophagus also drains into the nodes The contents of the mediastinum (Figs 3. The oesophagus Carcinoma of the oesophagus carries an extremely poor prognosis. In the thorax the oesoph- account for the majority of tumours. The incidence of adenocarcinoma of agus passes initially through the superior and then the posterior medi- the lower third of the oesophagus is currently increasing for unknown astina. Having deviated slightly to the left in the neck the oesophagus reasons. Most tumours are unresectable at the time of diagnosis. The returns to the midline in the thorax at the level of T5. From here, it insertion of stents and use of lasers to pass through tumour obstruction passes downwards and forwards to reach the oesophageal opening in have become the principal methods of palliation. It is situated between the abdom- • A double muscular layeralongitudinal outer layer and circular inal aorta and the right crus of the diaphragm. The muscle is striated in the upper two-thirds and • The thoracic duct carries lymph from the cisterna chyli through the smooth in the lower third. It usually receives • An outer layer of areolar tissue. On trunks, although they may open into the large neck veins directly. After puberty the thymus is gradually replaced by fat. The mediastinum Ibthe contents of the mediastinum 11 4 The mediastinum IIcthe vessels of the thorax Inferior thyroid Inferior laryngeal Superficial cervical Thyroidea ima Suprascapular Costocervical trunk Thyrocervical trunk Vertebral Deep cervical Scalenus anterior Dorsal scapular Superior intercostal Subclavian Upper two posterior Internal thoracic (mammary) intercostals Anterior intercostals Musculophrenic Brachiocephalic Superior epigastric Posterior intercostals (also supply spinal cord) Bronchial Oesophageal branches Mediastinal Subcostal Fig. The internal thoracic artery divides behind the 6th The ascending aorta arises from the aortic vestibule behind the costal cartilage into superior epigastric and musculophrenic branches. It is con- The thyrocervical trunk terminates as the inferior thyroid artery. The arch lies posterior to the lower half of • 2nd part: the part of the artery that lies behind scalenus anterior. It the manubrium and arches from front to back over the left main gives rise to the costocervical trunk (see Fig. The descending thoracic aorta is continuous with the arch • 3rd part: the part of the artery that lies lateral to the lateral border of and begins at the lower border of the body of T4. From here it continues as the abdominal The brachiocephalic veins are formed by the confluence of the subcla- aorta. The The branches of the ascending aorta are the: left brachiocephalic vein traverses diagonally behind the manubrium to • Right and left coronary arteries. The superior vena cava receives only • Brachiocephalic artery: arises from the arch behind the manubrium one tributaryathe azygos vein. It passes through the aortic • Thyroidea ima artery. It receives tributaries from the: lower eight posterior inter- costal arteries. It passes through the aortic opening in the diaphragm and The subclavian arteries become the axillary arteries at the outer bor- up to the level of T9 from where it passes diagonally behind the aorta der of the 1st rib. Each artery is divided into three parts by scalenus and thoracic duct to drain into the azygos vein at the level of T8. It anterior: receives venous blood from the lower four left posterior intercostal • 1st part: the part of the artery that lies medial to the medial border of veins.

These new criteria were designed to aid in the diagnosis of fibromyalgia particularly in the primary care clinic where tender point examination was either not carried out or not performed reliably purchase 50 mg imuran mastercard spasms rib cage, and to recognize the increasing understanding of associated cognitive and 3 somatic symptoms associated with the disorder buy cheap imuran spasms left abdomen. It was also designed to aid in monitoring of patients diagnosed with fibromyalgia imuran 50mg free shipping muscle relaxant eperisone. Previously, as one improved in their condition, they may no longer satisfy the criteria for diagnosis due to reduction in muscle tenderness. With the new definition, the Symptom Severity scale can serve as a monitoring tool for symptom severity without removing the diagnosis. Given the diagnostic challenges and the fact that the criteria for diagnosis have recently changed, it is difficult to obtain accurate prevalence data. Two studies, one in Wichita, Kansas in 1993, and the other in Ontario, Canada in 1999, provided data on the prevalence of 4, 5 fibromyalgia. Both populations were primarily Caucasian which is different from the overall North American population. In Kansas, the overall prevalence among adults was 2% (95% CI, 1. The peak prevalence in men was 1% in the same age group. In the Canadian study, the prevalence was slightly higher among adults at 3. The peak prevalence in women was in the 55-64 year age group at 7. A cohort study of primarily Utah residents was designed to determine the incidence of fibromyalgia and found that the age-adjusted incidence rates were 6. Unlike the prior studies, the female to male ratio was 1. The underlying etiology of fibromyalgia remains unclear but evidence supports complex functional changes to both the peripheral and central nervous system. Current theories include a peripheral tissue sensitization occurring after injury, a pain amplification syndrome that may Drugs for fibromyalgia 7 of 86 Final Original Report Drug Effectiveness Review Project arise from sensitization of the central nervous system and/or peripheral tissue abnormalities, changes in descending noxious inhibitory control, and psychological risk factors that include somatization or increased focus on body symptoms, negative life events, psychological distress, 7-12 and passive pain coping mechanisms. One theory is that nociceptive activity in the peripheral tissue can lead to maintenance of a sustained sensitized state centrally, resulting in chronic pain. The release of substance P, interleukin-1 and 6, tumor necrosis factor, nitric oxide, amino acids, 7, 9-12 and prostaglandin have all been invoked. Given the lack of definitive understanding of the pathophysiology of fibromyalgia and given the constellation of symptoms associated with the disorder, choosing an effective therapy for fibromyalgia has been challenging. A multimodal treatment approach has been recommended, including both pharmacologic and 13 nonpharmacologic therapies. A myriad of pharmacological approaches have been pursued in the hope of finding effective options (Table 1). The objective of this study is to review evidence on the comparative effectiveness/efficacy and comparative harms of the drugs used to treat fibromyalgia, and to determine if there are any subgroups of patients based on demographics, socioeconomic status, other medications, or comorbidities for which any included drugs are more effective or associated with fewer harms. Purpose and Limitations of Systematic Reviews Systematic reviews, also called evidence reviews, are the foundation of evidence-based practice. They focus on the strength and limits of evidence from studies about the effectiveness of a clinical intervention. Systematic reviews begin with careful formulation of research questions. The goal is to select questions that are important to patients and clinicians then to examine how well the scientific literature answers those questions. Terms commonly used in systematic reviews, such as statistical terms, are provided in Appendix B and are defined as they apply to reports produced by the Drug Effectiveness Review Project. Systematic reviews emphasize the patient’s perspective in the choice of outcome measures used to answer research questions. Studies that measure health outcomes (events or conditions that the patient can feel, such as fractures, functional status, and quality of life) are preferred over studies of intermediate outcomes (such as change in bone density). Reviews also emphasize measures that are easily interpreted in a clinical context. Specifically, measures of absolute risk or the probability of disease are preferred to measures such as relative risk. The difference in absolute risk between interventions depends on the number of events in each group, such that the difference (absolute risk reduction) is smaller when there are fewer events. In contrast, the difference in relative risk is fairly constant between groups with different baseline risk for the event, such that the difference (relative risk reduction) is similar across these groups. Relative risk reduction is often more impressive than absolute risk reduction. Another useful measure is the number needed to treat (or harm). The number needed to treat is the number of patients who would need be treated with an intervention for 1 additional patient to benefit (experience a positive outcome or avoid a negative outcome). The absolute risk reduction is used to calculate the number needed to treat. Systematic reviews weigh the quality of the evidence, allowing a greater contribution from studies that meet high methodological standards and, thereby, reducing the likelihood of biased results. In general, for questions about the relative benefit of a drug, the results of well- executed randomized controlled trials are considered better evidence than results of cohort, case- Drugs for fibromyalgia 8 of 86 Final Original Report Drug Effectiveness Review Project control, and cross-sectional studies. In turn, these studies provide better evidence than uncontrolled trials and case series. For questions about tolerability and harms, observational study designs may provide important information that is not available from controlled trials. Within the hierarchy of observational studies, well-conducted cohort designs are preferred for assessing a common outcome. Case-control studies are preferred only when the outcome measure is rare and the study is well conducted. Systematic reviews pay particular attention to whether results of efficacy studies can be generalized to broader applications. Efficacy studies provide the best information about how a drug performs in a controlled setting. These studies attempt to tightly control potential confounding factors and bias; however, for this reason the results of efficacy studies may not be applicable to many, and sometimes to most, patients seen in everyday practice. Most efficacy studies use strict eligibility criteria that may exclude patients based on their age, sex, adherence to treatment, or severity of illness. For many drug classes, including the antipsychotics, unstable or severely impaired patients are often excluded from trials. In addition, efficacy studies frequently exclude patients who have comorbid disease, meaning disease other than the one under study. Efficacy studies may also use dosing regimens and follow-up protocols that are impractical in typical practice settings. These studies often restrict options that are of value in actual practice, such as combination therapies and switching to other drugs. Efficacy studies also often examine the short-term effects of drugs that in practice are used for much longer periods. Finally, efficacy studies tend to assess effects by using objective measures that do not capture all of the benefits and harms of a drug or do not reflect the outcomes that are most important to patients and their families.

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Therefore buy imuran 50mg spasms under right rib cage, also in -thalassemia major purchase imuran overnight delivery muscle relaxant amazon, these drugs have the 14 imuran 50mg cheap quinine spasms. Modulators of erythropoiesis: emerging therapies potential to transform the management of this disease. In conclusion, the focus of many investigators is to identify new 15. Beta-thalassemia and polycythemia vera: mechanisms and strategies to prevent or reverse iron overload and targeting chronic stress erythropoiesis. Hopefully, these investigations will lead to new and 2014;51:89-92. Kautz L, Jung G, Valore EV, Rivella S, Nemeth E, Ganz T. Identifica- mediated by down-regulation of hepcidin and up-regulation of ferropor- tion of erythroferrone as an erythroid regulator of iron metabolism. BMP4 and Madh5 regulate the phenotype in a mouse model of beta-thalassemia. An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe( / ) mice and erythropoiesis in polycythemia vera and beta-thalassemia. Vemula S, Ramdas B, Hanneman P, Martin J, Beggs HE, Kapur R. Essential role for focal adhesion kinase in regulating stress hematopoi- 33. Curr Opin tissue-iron accumulation in disorders of iron overload with anemia. The role of ineffective erythropoiesis in non-transfusion- 35. Roy CN, Mak HH, Akpan I, Losyev G, Zurakowski D, Andrews NC. Decreased differentiation of Hepcidin antimicrobial peptide transgenic mice exhibit features of the erythroid cells exacerbates ineffective erythropoiesis in beta-thalasse- anemia of inflammation. An activin receptor IIA ligand tool to limit iron overload and improve anemia in beta-thalassemic trap corrects ineffective erythropoiesis in beta-thalassemia. Modified activin receptor IIB designed small peptides that mimic hepcidin activity in mice and may be ligand trap mitigates ineffective erythropoiesis and disease complica- useful for the treatment of iron overload. Schmidt P, Racie T, Butler JS, Fitzgerald K, Fleming MD. Minihepcidins prevent iron RNAi-therapeutic targeting tmprss6, in conjunction with oral chelator overload in a hepcidin-deficient mouse model of severe hemochromato- therapy, ameliorates anemia and additively diminishes secondary iron sis. Tmprss6 is a genetic Blood (ASH Annual Meeting Abstracts). Ineffective erythropoiesis beta-thalassemia major: a longitudinal study. Freeman2 1Department of Medical & Molecular Genetics, King’s College London School of Medicine, London, United Kingdom; and 2Department of Clinical Immunology, University of Birmingham Medical School, Edgbaston, Birmingham, United Kingdom The past 40 years have witnessed major advances in defining the cytogenetic aberrations, mutational landscape, epigenetic profiles, and expression changes underlying hematological malignancies. Although it has become apparent that acute myeloid leukemia (AML) is highly heterogeneous at the molecular level, the standard framework for risk stratification guiding transplant practice in this disease remains largely based on pretreatment assessment of cytogenetics and a limited panel of molecular genetic markers, coupled with morphological assessment of bone marrow (BM) blast percentage after induction. However, application of more objective methodology such as multiparameter flow cytometry (MFC) has highlighted the limitations of morphology for reliable determination of remission status. Moreover, there is a growing body of evidence that detection of subclinical levels of leukemia (ie, minimal residual disease, MRD) using MFC or molecular-based approaches provides powerful independent prognostic information. Consequently, there is increasing interest in the use of MRD detection to provide early end points in clinical trials and to inform patient management. However, implementation of MRD assessment into clinical practice remains a major challenge, hampered by differences in the assays and preferred analytical methods employed between routine laboratories. Although this should be addressed through adoption of standardized assays with external quality control, it is clear that the molecular heterogeneity of AML coupled with increasing understanding of its clonal architecture dictates that a “one size fits all” approach to MRD detection in this disease is not feasible. However, with the range of platforms now available, there is considerable scope to realistically track treatment response in every patient. Although cytogenet- Learning Objectives ics continues to provide the framework for risk stratification used to ● Consideration of technical aspects of flow cytometry and guide the management of AML, there has been inconsistency in the molecular-based approaches to minimal residual disease classification systems employed by different trial groups, with (MRD) detection in acute myeloid leukemia (AML). After advances in sequencing technology that led to the discovery of ● Appreciation of the assays that are now ready for clinical a number of novel recurrent mutational targets in AML, there has implementation and those which are currently investigational. It is reprinted with permission from Blood 2014, Volume 124. The prognostic impact of MFC-MRD is strong enough to Although pretreatment characterization of AML based on cytoge- have emerged despite study differences in the MFC assays and the netic analysis and molecular profiling can evidently distinguish limitations of now-outdated restricted antibody panels. Its clinical broad subgroups of patients with relatively favorable, unfavorable, value as a biomarker to inform therapy is therefore difficult to or intermediate prognosis, major drawbacks are that it lacks the ignore, particularly with its applicability to the majority of patients. Because replica- to reliably identify those most likely to benefit from early transplan- tion of this requires the organization of specialized core laborato- tation. Importantly, although cytogenetics and molecular profiling ries, the implementation of flow cytometric measurement of MRD can provide a snapshot of the genetic makeup of each case of has lagged behind that of real-time quantitative PCR. These may in some instances reflect differences in the cellular Assay approaches origins of the leukemia and sensitivity of the leukemic clone to Continued improvements in multiparameter flow technology and therapy, which may be influenced by the biology of the neoplastic reagents enable simultaneous measurement of up to 20 antigens/ cells, interaction with the marrow microenvironment, and interpa- markers per cell compared with 3 in initial AML MFC-MRD reports,16 allowing higher resolution detection per tube of BM cells. This capability is potentially further increased by mass cytometry (up to 45 parameters, but with slower cell acquisition). Visualiza- Despite the major advances in understanding the molecular patho- tion and analysis of immunophenotypic data may be transformed in genesis of AML, assessment of bone marrow (BM) morphology the near future by clinical use of automated analysis algorithms such as SPADE17 and ViSNE18 but at present, defining and detecting remains the standard approach to gauge treatment response in routine care and in the clinical trial setting, and is used to inform abnormal leukemic cells from the data produced by flow cytometry decisions concerning allogeneic transplantation. However, determi- still rely on manual inspection of cells by 2 parameters at a time on nation of blast percentage by light microscopy is hampered by biaxial plots with multiple gating steps of selected cell populations. Indeed, a recent This MFC-MRD analysis becomes more complex with increased study conducted in a large cohort of pediatric AML patients (n numbers of simultaneous fluorochrome parameters (ie, colors), as 203) reported marked discrepancies in evaluation of remission do the technical issues (eg, compensation, fluorescence overlap status as determined by standard morphology and flow cytometry. Conversely, 67% of patients classified on morphological grounds to have a partial There are 2 main analysis strategies for detecting MFC-MRD. The response (5% to 15% blasts) and 26% of those classified as having first, using a screening antibody panel (Figure 1), selects antigen resistant disease ( 15% blasts) actually had an excellent response combinations at diagnosis (termed leukemia-associated immunophe- according to flow cytometry, with no detectable minimal residual notypes [LAIPs]), each displayed by at least 5% to 10% of leukemic disease (MRD). Subsequent MFC-MRD monitoring tracks previously, together with the problems in using morphology to these diagnostic LAIPs (sometimes using tailored antibody combi- reliably assess remission status, there is clearly a very strong nations), with a cluster of 20 cell events in the LAIP gate being rationale for use of MRD detection methods to provide a more potentially sufficient to identify MRD—resulting in a maximum objective assessment of treatment response to develop a more sensitivity of between 10 4 and 10 5 when 500 000 nucleated cells individualized approach to management. Identifying specific LAIPs at diagnosis may be the various platforms available at present or in the near future, take improved by incorporation of more colors, thereby allowing the account of their relative advantages and limitations, and discuss the addition of further simultaneous markers required to define an most informative approach depending on the subtype of AML and abnormal cell. However, this is a double-edged sword because clinical scenario, recognizing the challenges for the laboratory instability of even 1 of the LAIP markers after treatment increases involved in the successful delivery of MRD-directed therapy. Experience of which phenotypic Hematology 2014 223 Figure 1. Outline of antibody groups used in panels for identification of AML-aberrant immunophenotypes (both for LAIP and “different- from-normal” approaches) and subsequent residual disease monitoring. Core markers are those selected for the backbone of the panel to identify myeloid blast populations.

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Sensitivity analysis: An analysis used to determine how sensitive the results of a study or systematic review are to changes in how it was done purchase imuran 50 mg spasms gerd. Sensitivity analyses are used to assess how robust the results are to uncertain decisions or assumptions about the data and the methods that were used purchase genuine imuran online spasms or twitches. Side effect: Any unintended effect of an intervention imuran 50 mg without a prescription spasms of the esophagus. Side effects are most commonly associated with pharmaceutical products, in which case they are related to the pharmacological properties of the drug at doses normally used for therapeutic purposes in humans. Standard deviation (SD): A measure of the spread or dispersion of a set of observations, calculated as the average difference from the mean value in the sample. Standard error (SE): A measure of the variation in the sample statistic over all possible samples of the same size. The standard error decreases as the sample size increases. Standard treatment: The treatment or procedure that is most commonly used to treat a disease or condition. In clinical trials, new or experimental treatments sometimes are compared to standard treatments to measure whether the new treatment is better. Statistically significant: A result that is unlikely to have happened by chance. Study: A research process in which information is recorded for a group of people. The data are used to answer questions about a health care problem. Study population: The group of people participating in a clinical research study. The study population often includes people with a particular problem or disease. It may also include people who have no known diseases. Subgroup analysis: An analysis in which an intervention is evaluated in a defined subset of the participants in a trial, such as all females or adults older than 65 years. Superiority trial: A trial designed to test whether one intervention is superior to another. Surrogate outcome: Outcome measures that are not of direct practical importance but are believed to reflect outcomes that are important; for example, blood pressure is not directly important to patients but it is often used as an outcome in clinical trials because it is a risk factor for stroke and heart attacks. Surrogate endpoints are often physiological or biochemical markers that can be relatively quickly and easily measured, and that are taken as being predictive of important clinical outcomes. They are often used when observation of clinical outcomes requires long follow-up. Targeted immune modulators 149 of 195 Final Update 3 Report Drug Effectiveness Review Project Survival analysis: Analysis of data that correspond to the time from a well-defined time origin until the occurrence of some particular event or end-point; same as time-to-event analysis. Systematic review: A review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant research and to collect and analyze data from the studies that are included in the review. The extent to which a drug’s adverse effects impact the patient’s ability or willingness to continue taking the drug as prescribed. These adverse effects are often referred to as nuisance side effects, because they are generally considered to not have long-term effects but can seriously impact compliance and adherence to a medication regimen. Treatment regimen: The magnitude of effect of a treatment versus no treatment or placebo; similar to “effect size”. Can be calculated in terms of relative risk (or risk ratio), odds ratio, or risk difference. Two-tailed test (two-sided test): A hypothesis test in which the values that reject the null hypothesis are located in both tails of the probability distribution. For example, testing whether one treatment is different than another (rather than testing whether one treatment is either better than another). Type I error: A conclusion that there is evidence that a treatment works, when it actually does not work (false-positive). Type II error: A conclusion that there is no evidence that a treatment works, when it actually does work (false-negative). Validity: The degree to which a result (of a measurement or study) is likely to be true and free of bias (systematic errors). Variable: A measurable attribute that varies over time or between individuals. Variables can be • Discrete: taking values from a finite set of possible values (e. Washout period: [In a cross-over trial] The stage after the first treatment is withdrawn, but before the second treatment is started. The washout period aims to allow time for any active effects of the first treatment to wear off before the new one gets started. Targeted immune modulators 150 of 195 Final Update 3 Report Drug Effectiveness Review Project Appendix B. Component studies of included systematic reviews The following full-text publications were included in this report but were not described fully if outcomes were well-described in an included systematic review. Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-related quality of life. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double- blind, randomized, placebo-controlled trial. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment. The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial. Improved health-related quality of life for rheumatoid arthritis patients treated with abatacept who have inadequate response to anti-TNF therapy in a double-blind, placebo-controlled, multicentre randomized clinical trial. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate Targeted immune modulators 160 of 195 Final Update 3 Report Drug Effectiveness Review Project therapy: a randomized, placebo-controlled, 52-week trial.

There are also different approaches to defining MRD positivity/negativity purchase generic imuran on line spasms hands, either by using cutoff values Standardization of MFC-MRD derived from combined data of multiple phenotypic aberrancies at Despite the powerful prognostic value of MFC-MRD generic imuran 50 mg on-line muscle relaxant medications, standardiza- postinduction/consolidation time points or by defining MRD positiv- tion and therefore comparability of results between laboratories ity as any level of MRD detectable above the relevant aberrant combination sensitivity threshold purchase imuran amex muscle relaxant herniated disc. Although MFC-MRD can be applied to most AML patients, this involves multiple aberrant antigen combinations first approach tested different MFC-MRD cutoff values by relapse detected by evolving antibody panels developed separately by probability and showed significant differences in relapse for MFC- laboratories. This is analogous to standardizing quantitative polymer- MRD detected above 0. The cutoff value was similar whether or not the MFC-MRD laboratories using different primers for each target. There is value incorporated a correction for LAIP frequency in the presenta- variation in the quantitation of MFC-MRD (ie, % of total nucleated tion sample and was not improved by using log reduction values. Proportion of AML patients informative for MRD detection by RT-qPCR for leukemia-specific MRD targets (ie, fusion genes, NPM1 mutation) according to age. Integration of flow cytometric and genetic different variable primers to cover the common isoform types data will allow optimization of predictive cutoffs for specific LAIPs encountered in primary patient samples. Specific probes (rather than when these are associated with different genetic abnormalities—for SYBR green I) were used to detect target amplicons to enhance example, aberrant CD7 in AML with CEBPA or FLT3-ITD assay sensitivity and specificity. Incorporation of a correction factor for hemodilution34 is protocols that included reaction conditions for all steps of the another consideration for standardized reporting as well as reduc- RT-qPCR procedure, a key achievement of the EAC program was tion of false negatives. This process identified ABL as the most reliable control between pediatric and adult AML for the specificity and frequency 40 gene. Although some laboratories prefer to use alternative house- of aberrancies. Improved selection and analysis of leukemic aberran- keeping genes, there is no evidence that these are superior; cies could be achieved by Web-based access to international therefore, consistent use of ABL for assay normalization would interlaboratory shared resources of the most useful robust LAIPs/ greatly facilitate comparison of MRD data between laboratories. Data from samples, together in triplicate wells, provided guidance concerning acceptable sample with control BM processed by standardized flow cytometric proto- quality indicated by the level of housekeeping gene expression and cols in different laboratories, could be analyzed remotely, thereby accessing a core facility of appropriate expertise. It is feasible that established clear criteria used to define PCR positivity (ie, specific further development of automated analysis algorithms combined amplification in the MRD assay in at least 2 of 3 replicate wells with with high-dimensional cytometry applied as a different-from- average cycle threshold value 40). Although some laboratories still use conventional RT-PCR with nested primers for MRD detection, this approach has a number of Real-time quantitative PCR limitations and should be abandoned in favor of RT-qPCR, The development of these assays in the 1990s provided a major step which is more reliable and readily standardized. Performance of forward in establishing standardized approaches for MRD detection the same RT-qPCR platform is highly reproducible between in a range of leukemias. In AML, they can be applied in cases with laboratories, turnaround time is more rapid, and risk of PCR chimeric fusion genes generated by balanced chromosomal rearrange- contamination is substantially reduced. A further key advantage ments—for example, PML-RARA/t(15;17), RUNX1-RUNX1T1/t(8; of RT-qPCR is the capacity to quantify an independent housekeep- 21), CBFB-MYH11/(inv(16)/t(16;16), DEK-CAN(NUP214)/t(6;9), ing gene in parallel, enabling suboptimal follow-up samples that t(11q23)/MLL fusions, t(5;11)/NUP98-NSD1 or NPM1 mutations, collectively covering 60% of AML presenting in children and could potentially have given rise to false-negative PCR results to younger adults (Figure 3). Importantly, qualitative end- generate complementary DNA before the quantitative PCR (qPCR) point assays lack the capacity to measure the absolute level of step. This allows a relatively limited panel of optimized standard- leukemic transcripts or determine whether they are rising or ized assays to be used, circumventing the need to characterize falling, which is invaluable information for clinical decision- translocation breakpoints at the genomic level, which can be making. The EAC program laid the groundwork for defining challenging and not realistic in routine laboratories. Use of MRD monitoring to inform clinical prognostic information. The standardized EAC level after 2 courses of chemotherapy being at significantly in- PML-RARA RT-qPCR assay has been shown to improve MRD creased risk of subsequent relapse. Therefore, marrow is toring using the standardized EAC assays as a tool to distinguish the recommended sample source for serial MRD monitoring where more precisely those CBF leukemia patients destined to relapse the goal is to detect recurrent disease promptly—allowing a from those who can be cured with chemotherapy alone. Clinically sufficient window of time to confirm PCR positivity in an indepen- relevant threshold transcript levels were defined, with studies dent sample and to initiate preemptive therapy to prevent progres- consistently showing that relapse can be predicted by persistently sion to frank relapse with its associated risk of fatal bleeding. MRD monitoring to guide early intervention has been shown to reduce the risk of induction of hyperleukocytosis and the associated NPM1 mutant AML. Frameshift mutations in exon 12 of the differentiation syndrome as compared with treatment in the context NPM1 gene are found in approximately one-third of AML cases, of frank relapse. Mutation-specific prim- been recommended in the National Comprehensive Cancer Network ers can be readily designed to allow MRD detection in AML guidelines to inform treatment approach. The NPM1 mutant transcript is typically highly treated in clinical trials, particularly those including ATO as expressed in diagnostic AML samples, affording sensitivities typi- frontline therapy, the value of routine sequential monitoring for cally higher (median 1 in 105) than observed with RT-qPCR assays PML-RARA transcripts beyond the postconsolidation time point has for other molecular subtypes of AML, with RNA-based assays been increasingly questioned. In APL (presenting WBC 10 109/L) who rapidly achieve molecu- accordance with the findings in CBF leukemia, RT-qPCR assess- lar remission, based on current evidence there appears to be limited ment of MRD can distinguish patients at markedly differing risk of benefit for sequential MRD monitoring beyond the end of treatment relapse based on response kinetics. On the other hand, there remains a predicted in individual patients based on persistent high level PCR case for stringent assessment of MRD in the subgroup of patients positivity after frontline therapy or by a rising NPM1 mutant presenting with high-risk disease (WBC 10 109/L), who have a transcript level after an initial molecular response (Figure 4D). The significant risk of relapse ( 25%) after conventional all-trans recent study by Shayegi and colleagues also highlighted the retinoic acid and anthracycline-based therapy and can benefit from potential of serial MRD monitoring to predict outcome after serial molecular monitoring to guide early salvage with ATO. Considering that a RUNX1-RUNX1T1 and CBFB-MYH11 detection in CBF significant proportion of AML cases lack an informative leukemia- leukemias. Established EAC RT-qPCR assays have also been specific target (ie, chimeric fusion gene, NPM1 mutation, Figure 3), evaluated in large cohorts of clinical trial patients with core-binding there has been interest as to whether WT1, which is overexpressed in Hematology 2014 227 228 American Society of Hematology the majority of AML cases, could provide a universal molecular of applicability and sensitivity in the substantial proportion of AML MRD marker. However, there has been inconsistency in the patients in whom MRD tracking is not feasible using an established literature concerning the utility of this approach to MRD assess- leukemia-specific RT-qPCR assay. This issue has been addressed by an ELN study that systematically evaluated 9 WT1 Defining the mutational landscape by high-throughput sequencing RT-qPCR assays, leading to selection of an assay that amplified a of AML genomes has broadened the scope of potential molecular region outside the mutational hot spots and exhibited the best methods for MRD detection. Although it is possible to design performance profile. Moreover, because of the marked level MRD from normal background. In contrast to leukemia- heterogeneity of mutations already described in AML, developing a specific markers (eg, PML-RARA, NPM1 mutation) in which BM catalog of standardized assays to cover every patient would be generally provides a more sensitive and reliable sample source for completely unrealistic. Therefore, several groups have started to MRD assessment (Figure 4D), in the case of WT1 PB is more explore the use of next-generation sequencing (NGS) technologies informative because of the much higher background level of as a further platform to detect MRD. To provide proof of principle, expression in normal marrow. Taking this into account, based on the Heuser and colleagues used targeted sequencing to successfully analysis of a large cohort of diagnostic AML samples (n 620), the detect FLT3-ITD and NPM1 mutations in remission samples and to track the emergence of relapsing disease. Measurement of kinetics of WT1 response after approaches to enable detection of subclinical disease in subsets of induction therapy in informative patients can provide independent AML that are not informative for one of the established leukemia- prognostic information. Because this approach is scalable, ment, this platform seems unlikely to be widely adopted into routine with increasing read depth, it may be possible to achieve further clinical practice, particularly because flow cytometry (see previous improvements in sensitivity. However, there are several other sections) and, potentially, newer sequencing-based approaches (see technical issues that need to be taken into consideration in the the following section) are expected to be more informative in terms application of NGS for MRD detection, including background Figure 4. Development of leukemia-specific RT-qPCR assays to track treatment response is dependent upon molecular characterization of diagnostic material to determine the most appropriate assay, with MRD monitoring strategies informed by maximal achievable sensitivity, optimal sample type, and typical kinetics of disease relapse. For example, in 5% of acute promyelocytic leukemia cases, the standard EAC assays are not suitable because of occurrence of rarer breakpoints within the PML locus requiring design of patient-specific forward primers to be used in conjunction with the standard EAC probe and reverse primer (both located in RARA). This can be measured as the difference in the number of PCR cycles ( Ct) to detect fluorescence above background from amplification of the leukemic transcript and the control gene at the threshold (set at 0. The detection limit of PCR is taken as 40 cycles (equivalent to 1 copy), with 1-log being equivalent to 3. Assuming ABL amplification at cycle threshold (Ct) value of 24, the observed Ct value for amplification of the leukemic target in blasts at diagnosis indicates the maximal theoretical sensitivity for detection of MRD in that particular patient.