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By F. Vibald. Central Christian College of the Bible. 2018.

Women with CD4 T cells above 250/µl have a 12-fold elevated risk (11% versus 0 buy 20mg levitra professional free shipping. In men there is an increased risk above 400 cells/µl (6 order 20 mg levitra professional with amex. Although other studies failed to reveal an association between toxicity and immune status (Manfredi 2006, Wolf 2006, Chu 2010), it is recommended not to use nevirapine in treatment-naïve patients with higher CD4 T cell counts. In con- trast, in ART-experienced patients switching to nevirapine, the risk is not elevated (Mocroft 2007, De Lazzari 2008, Wit 2008). Since 2010, the package information indicates that a switch to nevapirine is possible at a viral load of 50 copies/ml, regard- less of CD4 T cell count. However, there is currently no test available to predict hypersensitivity (Yuan 2011). Gamma-glutamyl transpeptidase (GGT) elevations are very common, which may subject patients to false appearances of excess alcohol consumption. After several studies in both treatment-naïve and –experienced patients (Gathe 2011, Arasteh 2012), a nevapirine extended-release (NVP XR) formulation was approved in 2011, allowing once-daily dosing. The patients should know that the XR tablets are formulated in a non-digestible cellulose-based matrix, which may be seen in the feces. These softened tablet remnants may sometimes resemble whole tablets, but are inactive ingredients. Thus, there is no need to worry when patients observe tablets in their stool. Rilpivirine (RPV, Edurant, also in Complera or Eviplera) was approved in 2011. Like etravirine, it is also a DAPY NNRTI (Janssen 2005). A Phase IIa study on therapy-naïve patients receiving monotherapy for 7 days decreased viral load by 1. The lowest dosage of 25 mg which is far lower than that of other NNRTIs was used in the development program. In treatment naïve patients, rilpivirine has been tested in three large trials against efavirenz. In two Phase III trials (ECHO and THRIVE) on 1,368 patients a compara- ble effect with better tolerability was observed at 48-96 weeks (Cohen 2011, Molina 2011, Behrens 2014). Rilpivirine was associated with lower increases in lipid parameters and fewer dyslipidemia than efavirenz. In the third large trial (STaR), the two single-tablet regimens Complera (rilpivirine plus TDF+FTC) and Atripla (efavirenz plus TDF+FTC) were studied. This randomized, open-label on 786 patients demonstrated non-inferior efficacy and improved tolerability compared to efavirenz. After 48 weeks, 89% versus 82% of the patients had reached an undetectable viral load, respectively. There were fewer discontinuations because of adverse events. However, resistance as well as virological failure were observed more frequently with rilpivirine. In ECHO and THRIVE the rates were 9% vs 5%, in STaR 4% vs. Resistance mutations were mainly seen in the NNRTI loci (mainly E138K or K101E) but also in the NNRTI region (Rimsky 2012). Compared to efavirenz, the risk of resistance-associated virologic failure was significantly elevated in highly viremic patients. Thus, the approval of rilpivirine is restricted to patients with a baseline viral load of less than 100,000 copies/ml. CNS side effects may occur but are less inten- sive than seen with efavirenz. The QT prolongation observed earlier (at a higher dose), seems to occur less frequently at 25 mg (Vanveggel 2009) and the teratogenic risk is small (Desmidt 2009). A parenteral nano-suspension is being investigated, in which ripilvirine levels are achieved via monthly injections, corresponding to a daily dose of 25 mg (Verloes 2008). Rilpivirine currently plays an important role in long- acting strategies. In 2013, rilpivirine was also approved for treatment-experienced patients. In the SPIRIT trial, 476 patients with viral suppression have been randomized to remain on their PI-based regimen or to switch to rilpivirine. The switch was safe and improved lipid changes seen with PIs (Palella 2012). In conclusion, rilpivirine has become an important option in antiretroviral therapy. A certain disadvantage in everyday practice is the requirement that the substance must be taken with food (a fatty meal of at least 500 kcal is necessary) to guarantee 6. Overview of antiretroviral agents 87 sufficient resorption (Crauwels 2013). This can be a problem if patients have irregular daily habits. TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1. Rilpivirine Resistance Mutations in HIV-1+ Patients Failing NNRTI Therapy: Drug- resistance Database, the Spanish AIDS Research Network. Twenty-four-week efficacy and safety of switching virologically suppressed HIV-1-infected patients from nevirapine immediate release 200 mg twice daily to nevirapine extended release 400 mg once daily (TRANxITION).

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In addition cheap levitra professional 20mg on-line, a transcrip- the conclusion that this mutation is not a driver mutation levitra professional 20mg overnight delivery. It is tome sequence will also provide a “digital” expression profile, becoming more and more apparent that a single driver mutation which might point to genes that are overexpressed due to a will, in most cases, not be sufficient to initiate leukemia on its own, translocation or a mutation affecting a regulatory element. Con- but rather that the concerted action of several driver mutations is the versely, mutations present in genes that are expressed at low levels basis of most leukemias. Modeling the interplay of several driver might be overlooked if only the transcriptome of a leukemia is mutations is extremely difficult and time consuming with the sequenced and the coverage in these genes is not adequate. We already have evidence that certain driver mutations are dependent on each other Gene panel sequencing and presumably synergize. For example, normal karyotype AML An alternative to WGS or WES is the deep sequencing of a panel of with a biallelic mutation of the CEBPA gene has very specific zinc genes that is known to be recurringly mutated and have prognostic finger 1 mutations in the transcription factor GATA2. Custom gene panels have the advantage of allowing high read depths of the genes Clinical applications included in the panel. The disadvantages are the relatively high Of course, what we would really like to know is which mutations initial costs in designing a custom gene panel, the fact that adding have an impact on the clinical course of the disease (prognostic additional genes to the panel is cumbersome and expensive, and that significance) and which mutations should guide our treatment one is restricted to analyzing the genes in the panel. Ideally, we would also like to aberrations such as deletions and larger rearrangements cannot identify mutations that are targetable for therapeutic interventions. When one is considering gene The development of algorithms and expert systems that are able to panel sequencing, one also has to keep in mind that the number of provide this kind of information to the physician after the analysis of potential mutational target genes in most malignancies is very large NGS data is still in its infancy. For example, it will become and still not completely known. NGS has also given us a unique insight into the often complicated clonal architecture of leukemias. These analyses showed, for example, that minor clones that were already present at diagnosis WES versus WGS 41 can expand after chemotherapy and lead to a relapse. In the above description of analysis of cancer genomes using NGS, we mainly focused on the information that can be derived from WES experiments. In a WES experiment, one will find missense and Limitations of NGS nonsense mutations in the coding region, as well as splice site It is important to understand that even though NGS is producing an mutations. However, we need to be aware of the fact that the exome enormous amount of data in a single experiment, we will only find constitutes just 1. In WGS projects, many more somatic Therefore, the 10 gigabases of exome sequence from a leukemia aberrations ( 60 times more) can be identified in tumor samples, patient will not allow us to detect a t(8;21)(q22;q22) translocation, including not only point mutations and small indels, but also larger whereas a WGS or transcriptome sequencing experiment would genomic rearrangements such as chromosomal translocations, dele- detect such a rearrangement. Even in the complete genome se- tions, and duplications. Approximately 8% to 9% of the somatic aberrations detected by WGS affect Ethical considerations and future directions conserved or regulatory genomic elements. Occasionally, such The introduction of NGS methodologies into routine tumor diagnos- mutations have been shown to constitute driver mutations. NGS will generate massive amounts of data that have to regions and regulatory elements is very limited, we have a very be stored securely to prevent breaches of patient privacy42 and, at limited capacity to predict or evaluate the functional consequences the same time, a global data-sharing infrastructure has to be put into of these mutations. Close to 90% of the somatic mutations detected place that respects patient privacy and still allows a global data by WGS of tumor samples affect nonconserved single copy exchange on genotype phenotype correlations. In addition, ethically sequences or repetitive elements. Therefore, although WGS does correct procedures (ie, appropriate consent forms and guidelines) detect more somatic aberrations than WES in a tumor sample, have to be developed to adequately address incidental findings that almost all of these additional aberrations are of unknown signifi- are bound to occur (eg, what should be done if a BRCA1 germline cance and can presently not be interpreted properly. It should be mutation is found in the course of WES of a leukemia sample? Whole genome scanning as a exomes can be sequenced in a few hours (Figure 2B). With this cytogenetic tool in hematologic malignancies. DNA sequencing with disease diagnostics to accurately monitor disease burden and NGS chain-terminating inhibitors. Genome sequenc- ing in microfabricated high-density picolitre reactors. Conflict-of-interest disclosure: The author declares no competing 19. Bohlander, Department of Molecular Medicine and whole human genome sequencing using reversible terminator Pathology, Faculty of Medical and Health Sciences, University of chemistry. Auckland, 85 Park Road, Grafton, Private Bag 92019, Auckland 21. Available from: 1142, New Zealand; Phone: 64-9-923-8348; Fax: 64-9-367- http://www. Parla JS, Iossifov I, Grabill I, Spector MS, Kramer M, References McCombie WR. The Sequence Alignment/ ing the euchromatic sequence of the human genome. ENCODE Project Consortium, Bernstein BE, Birney E, Dun- 25. Mortazavi A, Williams BA, McCue K, Schaeffer L, Wold B. Whole genome sequence exome: sequencing the complete human exome. Eur J Hum analysis of 22 MLL rearranged infant acute lymphoblastic Genet. The complete from the St Jude Children’s Research Hospital-Washington genome of an individual by massively parallel DNA sequenc- University Pediatric Cancer Genome Project [abstract]. Initial genome reveals the recent origin of most human protein-coding vari- sequencing and analysis of multiple myeloma. A small-cell lung integrating surveys of structural variation.

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Meta-regression identified study duration and number of study sites purchase 20mg levitra professional fast delivery, male sex 20mg levitra professional with visa, ADHD hyperactive/impulsive subtype, oppositional defiant disorder, baseline ADHD rating scale total score, inattention score, and hyperactivity/impulsivity score to be negatively associated with response. After adjusting for these confounders, atomoxetine remained superior over placebo. Six adverse events were found Attention deficit hyperactivity disorder 59 of 200 Final Update 4 Report Drug Effectiveness Review Project to occur significantly more often with atomoxetine (numbers needed to harm; P value): decrease in appetite (8; P<0. Risk of adverse events was found to be negatively associated with mean age, ADHD inattentive subtype, baseline ADHD rating scale score, and hyperactivity/impulsivity score. Meta-regression identified high ADHD rating scale total and hyperactivity/impulsivity scores at baseline to be significantly associated with adverse events (P<0. Based on the 6 placebo-controlled trials above, with data apparently provided by the manufacturer, meta-analysis was performed to assess differences in response between younger (ages 6-7) and older (ages 8-12) children. Atomoxetine was found statistically significantly superior to placebo on the ADHD–RS and Conners’ scales, in both age groups, although the difference between atomoxetine and placebo was smaller in the older age group compared with 144 the smaller age group. This study also found that abdominal pain, decreased appetite, vomiting, and somnolence occurred significantly more often with atomoxetine than placebo in younger children, and decreased appetite, somnolence, irritability, and fatigue among older children. There was a significant treatment by age effect in abdominal pain (P=0. Statistically significant but small increases in pulse were seen in both younger and older children, and older children experienced increases in both systolic and diastolic blood pressure. In these short-term studies, statistically significant weight decrease was seen in both age groups (–0. Atomoxetine was associated with less rapid times to relapse than placebo under double- blind conditions (218 days compared with 146 days; P<0. The primary outcome measure was the number of days to relapse and relapse was defined as return to 90% of baseline ADHD rating scale score and Clinical Global Impression-Severity Scale score increase of at least 2 points. Similarly, fewer patients on atomoxetine relapsed than on placebo (22% compared with 38%; P<0. As a continuation of that study, subjects initially randomized to atomoxetine were rerandomized to an additional 6 months of either atomoxetine (n=81) or placebo (n=82), with mean time to relapse being 160 days for atomoxetine and 130. A few noncomparative observational studies evaluated 146, 147 duration of effectiveness for atomoxetine. In 1 study, 229 children who had a ≥40% reduction in ADHD rating scale total score after a 7- to 9-week trial of atomoxetine (51% of original sample) were randomly assigned to continue treatment for 8 months at the same or lower 146 dosages. In the other study, stability of treatment response over time was examined in 312 children who had completed 24 months of open treatment with atomoxetine (34% of original 147 sample). Both studies were consistent in finding that improvements in ADHD symptoms and in aspects of health-related quality of life were maintained during longer-term treatment periods, even with reduced dosages of atomoxetine. Although encouraging, findings from these studies must be interpreted with caution, mainly due to the extremely high attrition rates. Attention deficit hyperactivity disorder 60 of 200 Final Update 4 Report Drug Effectiveness Review Project In a pooled analysis of data from 714 children who received atomoxetine for at least 3 years in open-label studies, 1. Clonidine Immediate-release clonidine compared with methylphenidate. Four parallel group randomized controlled trials of immediate-release clonidine compared with immediate-release 149-152 methylphenidate were found. Two small randomized controlled trials of immediate-release clonidine compared with immediate-release methylphenidate measured outcomes using scales or tests that have either been shown to have low validity (e. The remaining small trials (N = 122 and 132) reported no statistically significant differences in Conners’ Abbreviated Symptom Questionnaire Teacher scale from baseline to endpoint (16 weeks) between immediate-release methylphenidate and clonidine. However, this comparison was not the primary aim of either study, and the studies have conflicting findings outside of this comparison. While the studies had similar 2 x 2 factorial designs, 1 enrolled children with both ADHD and Tourette’s disorder and evaluated the effect of drugs on tics, while the other enrolled children without Tourette’s disorder. The study of children with Tourette’s disorder and ADHD enrolled 136 children (mean age 10. All analyses made comparisons of each drug group to placebo, although it is stated that there was no difference between the immediate-release methylphenidate and immediate-release clonidine groups on the primary outcome measure of the Conners’ Abbreviated Symptom Questionnaire Teacher scale (Table 8). Immediate-release clonidine was significantly better than placebo on more Tourette’s outcome measures than immediate-release methylphenidate, and immediate-release methylphenidate was significantly better than placebo on more ADHD outcome measures than clonidine. Summary of differences in results of ADHD/Tourette’s disorder study Immediate-release clonidine vs. Based on the primary outcome measure of mean change in the Conners’ Abbreviated Symptom Questionnaire Teacher scale no difference was found between groups receiving clonidine and those receiving methylphenidate although the change was greater with methylphenidate (‒3. Similar results were found with secondary outcome measures for the direct comparison of the drugs. The difference in results of these 2 studies is shown in Table 9 below. Using the 2x 2 factorial designs, the analysis of treatment effect in groups receiving methylphenidate (alone or with clonidine) was statistically significant compared with groups not receiving methylphenidate (clonidine or placebo groups) in both studies. However, the treatment effect of clonidine (alone or with methylphenidate) was statistically significant only in the Tourette’s syndrome study, and not in the Palumbo 2008 trial. The parent ratings in the Palumbo trial conflict with the results based on teacher ratings – showing methylphenidate to have no effect and clonidine to have an effect. In the Tourette’s syndrome study, the parent and teacher ratings results were similar, finding both drugs beneficial. The reasons for the differences were not clear, but may have been related to differential attrition rates across groups in the Palumbo study, and while the both studies allowed psychological interventions, important variation across the studies may have occurred. Taken together, and considering all efficacy outcomes, we were not able to currently identify a difference in effect between immediate-release clonidine and immediate-release methylphenidate, but it may be that clonidine has a lesser effect. Change in Conners’ Abbreviated Symptom Questionnaire Teacher scale Immediate-release clonidine vs.

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Is the mortality reduction in CAPRICORN different from what would be expected from older trials of beta blockers in post-myocardial infarction patients or in patients with heart failure? The authors of the Lancet paper raised this question purchase levitra professional 20mg overnight delivery, noting that the 23% mortality reduction in CAPRICORN is identical to that found in meta-analyses of the older beta blocker trials buy generic levitra professional 20mg line. Mortality was higher in CAPRICORN than in previous trials of beta blockers in post- myocardial infarction patients. The likeliest explanation is that many earlier trials included a broader mix of patients, including many who had normal left ventricular function and a better prognosis. Unlike many major trials, the CAPRICORN publication did not say how many patients with myocardial infarction were seen at the participating centers during the period of recruitment. It was also not clear what proportion of potentially eligible patients were excluded because they had an ejection fraction greater than 40%. These statistics would be useful in comparing the CAPRICORN subjects to the subjects of previous trials of beta blockers in post- myocardial infarction patients. There was no direct evidence that other beta blockers shown to reduce mortality in post- myocardial infarction patients or in patients with heart failure worked as well as carvedilol in post-myocardial infarction patients with decreased left ventricular function and few or no symptoms of heart failure. While the older trials undoubtedly included some subjects with left ventricular dysfunction, it is difficult to determine how many, or how this subset did compared with post-myocardial infarction patients with normal left ventricular function. This analysis examined the relationship between the mortality reduction reported in each trial and the proportion of patients in the trial who had heart failure. There were few data on the effects of beta blockers after myocardial infarction in patients with documented left ventricular systolic dysfunction, but some studies included subjects with clinical findings of heart failure and reported the proportion of subjects that had these findings. As expected, studies that included patients with heart failure had higher mortality rates. The relative benefit of beta blockers on mortality after a myocardial infarction was similar in the presence or absence of heart failure. Two retrospective subgroup analyses in heart failure patients from individual trials included in this meta analysis provided additional details supporting this hypothesis. One is from the Beta Blocker Heart Attack Trial (BHAT), a large, 3-month trial of propranolol published in 1980. In BHAT, 710 of 1916 subjects had a history of congestive heart failure prior to randomization. The other retrospective subgroup analysis was from a 1980 placebo-controlled trial of metoprolol. At the time of randomization, 262 (19%) of the 1395 subjects had signs or symptoms 65 of mild heart failure. Metoprolol or placebo was administered intravenously once, followed by oral metoprolol or placebo for 3 months, followed by open treatment with metoprolol for up to 2 years in all patients who had signs of ischemia. For patients with heart failure, mortality during the first year of the study was 28%, compared with 10% in subjects without signs of heart failure (P<0. Among the subjects with heart failure at the time of randomization, metoprolol reduced mortality during the 3-month double-blind phase of the trial (14% compared with 27%, P<0. Sudden death 51, 52 Significant reductions in sudden death were reported in 2 of 3 trials of metoprolol tartrate, 1 50 48 trial of propranolol, and in 1 trial of timolol. Reinfarction 52 Significant reductions in reinfarction rates were reported in 1 of 2 trials of metoprolol tartrate 48 and in 1 trial of timolol. Carvedilol was also associated with significantly reduced reinfarction rates in the CAPRICORN trial. Arrhythmias Evidence on the effect of beta blockers on post-myocardial infarction arrhythmias is unclear based on the available evidence. No significant difference in occurrence of post-myocardial infarction arrhythmia (defined as cardiac arrhythmia, fibrillation, or tachycardia) was found in 66 50 placebo-controlled trials of acebutolol (1 trial) or propranolol (1 trial), while 1 placebo- controlled trial of propranolol found a small, but significantly higher, percentage of withdrawals due to serious ventricular arrhythmia in the placebo group (0. One trial of timolol found a significantly higher proportion of patients experiencing ventricular tachycardia with placebo use (20% placebo compared with 8. Two publications comparing carvedilol to placebo presented mixed results. One older trial found no significant difference between the 2 drugs in the rate of cardiac arrhythmias among 60 all enrolled patients. In a subgroup analysis of patients (N=49/151; 32%) with baseline left ventricular ejection fraction <45%, carvedilol was associated with a significant decrease in serious cardiac events, a combined endpoint that included death, reinfarction, unstable angina, congestive heart failure, and ventricular tachycardia (P=0. The second publication, a post- hoc analysis of data from the CAPRICORN trial, compared rates of atrial and ventricular 69 arrhythmias. As stated above, patients enrolled in the CAPRICORN trial had baseline left ventricular ejection fraction ≤40%. Atrial and ventricular arrhythmias were found to be less common with carvedilol use relative to placebo (hazard ratio, 0. These values remained significant when controlling for history of arrhythmias. Carvedilol was also found to reduce the risk of all analyzed combinations of death and arrhythmia outcomes. Beta blockers Page 29 of 122 Final Report Update 4 Drug Effectiveness Review Project Withdrawals Among the major trials, rates of withdrawal ranged from 9. Within studies, rates of withdrawal were generally similar for the beta blocker and placebo groups, with 3 exceptions. Rates of withdrawal were greater for 70 71 67 metoprolol tartrate in 1 of 5 trials, pindolol in 1 trial, and propranolol in 1 trial. Summary of results from placebo-controlled trials of beta blocker therapy following myocardial infarction Study Number Sudden Year Interventions Duration enrolled Total mortality death Reinfarction Withdrawals Acebutolol A: 5. For adult patients with heart failure, do beta blockers differ in efficacy or effectiveness?

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A randomized cheap levitra professional 20 mg with amex, clinical trial comparing the efficacy of continuous nebulized albuterol (15 mg) versus continuous nebulized albuterol (15 mg) plus ipratropium bromide (2 mg) for the treatment of acute asthma order levitra professional 20mg without prescription. Randomized controlled trial of ipratropium bromide and salbutamol versus salbutamol alone in children with acute exacerbation of asthma. Nebulized salbutamol vs salbutamol and ipratropium combination in asthma. Comparison of nebulized ipratropium bromide with salbutamol vs salbutamol alone in acute asthma exacerbation in children. Ralston ME, Euwema MS, Knecht KR, Ziolkowski TJ, Coakley TA, Cline SM. Comparison of levalbuterol and racemic albuterol combined with ipratropium bromide in acute pediatric asthma: a randomized controlled trial. Lack of evidence for beta-2 receptor selectivity: a study of metaproterenol, fenoterol, isoproterenol, and epinephrine in patients with asthma. Comparison of fenoterol and terbutaline administered by intermittent positive pressure breathing. A comparative double-blind study of the bronchodilator effects and side effects of inhaled fenoterol and terbutaline administered in equipotent doses. Fenoterol is as effective as terbutaline in the pear- shaped spacer. A comparison of terbutaline and fenoterol unit dose vials in treating children with acute asthmatic attacks. Comparison of Bricanyl Turbuhaler and Berotec dry powder inhaler. The efficacy of terbutaline and fenoterol aerosols on adult exercise- induced asthma. Comparative effects of pirbuterol acetate, metaproterenol, and placebo aerosols on pulmonary function and incidence of cardiac ectopy. Comparison of safety and efficacy of inhaled pirbuterol with metaproterenol. Chester EH, Doggett WE, Montenegro HD, Schwartz HJ, Jones PK. Quick-relief medications for asthma Page 63 of 113 Final Report Update 1 Drug Effectiveness Review Project 101. A comparative study of the aerosolized bronchodilators, isoproterenol, metaproterenol and terbutaline in asthma. A comparison of levalbuterol with racemic albuterol in the treatment of acute severe asthma exacerbations in adults. Wraight JM, Smith AD, Cowan JO, Flannery EM, Herbison GP, Taylor DR. Adverse effects of short-acting beta-agonists: potential impact when anti-inflammatory therapy is inadequate. Long-term effect of ipratropium bromide and fenoterol on the bronchial hyperresponsiveness to histamine in children with asthma. Therapy with fenoterol and ipratropium bromide powder]. Pharmacological similarities and differences between beta -agonists. Case-control study of severe life threatening asthma (SLTA) in a developing community. Quick-relief medications for asthma Page 64 of 113 Final Report Update 1 Drug Effectiveness Review Project Appendix A. Search strategies Original Search Database: EBM Reviews - Cochrane Central Register of Controlled Trials <1st Quarter 2006> Search Strategy: -------------------------------------------------------------------------------- 1 Salmeterol. Quality assessment methods for drug class reviews for the Drug Effectiveness Review Project This appendix outlines the methods used by the Oregon Evidence-based Practice Center, based at Oregon Health & Science University, and any subcontracting Evidence-based Practice Centers in producing drug class reviews for the Drug Effectiveness Review Project. The procedure outlined in this appendix ensures that the reviews created by using these methods are scientifically defensible, reproducible, and well documented. These methods were adapted from the Procedure Manual developed by the Methods Work Group of the United States Preventive Services Task Force (version 1. All included studies and systematic reviews are assessed for quality and assigned a rating of “good,” “fair,” or “poor”. Studies that have a fatal flaw in 1 or more criteria are rated poor quality. Studies that meet all criteria are rated good quality. As the “fair-quality” category is broad, studies with this rating vary in their strengths and weaknesses: The results of some fair quality studies are likely to be valid, while others are only probably valid. A poor-quality trial is not valid: Its results are at least as likely to reflect flaws in the study design as a true difference between the compared drugs. Controlled Trials Assessment of Internal Validity 1. Was the assignment to treatment groups really random? Adequate approaches to sequence generation: Computer-generated random numbers Random numbers tables Inferior approaches to sequence generation: Useofalternation,caserecordnumber, date of birth, or day of week Not reported 2. Adequateapproachestoconcealmentofrandomization: Centralized or pharmacy-controlled randomization Serially-numbered 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: Useofalternation,caserecordnumber, date of birth, or day of week Open random numbers lists Quick-relief medications for asthma Page 72 of 113 Final Report Update 1 Drug Effectiveness Review Project Serially numbered envelopes (even sealed opaque envelopes can be subject to manipulation) Not reported 3. Were the groups similar at baseline in terms of prognostic factors?

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