By D. Frithjof. California Institute of Integral Studies.
However order top avana from india, although this test is able to detect HIV-1 infec- tion much earlier than all previously developed tests top avana 80mg with mastercard, a second diagnostic false neg- ative window can occur when equal levels of p24 antigen and anti-p24 antibody are present purchase top avana overnight. The most substantiated diagnosis of acute HIV-1 infection is based on the detection of HIV-1 replication in the absence of HIV-1 antibodies (pre-seroconver- sion). The most sensitive test is therefore based on detection of plasma HIV-1 RNA. All assays for HIV-1 RNA that have been compared (branched chain DNA, PCR and GenProbe) have a sensitivity of 100%, but occasionally (in 2–5% of cases) can lead to false positive results (Hecht 2002). False positive results from these tests are usually below 2,000 copies HIV-1 RNA per ml, and therefore are far below the high titers of viral load normally seen during acute HIV-1 infection (in our own studies subjects average 13 x 106 copies HIV-1 RNA/ml with a range of 0. Repetition of the assay for HIV-1 RNA from the same sample with the same test led to a negative result in all false positive cases. Measurement of HIV-1 RNA from duplicate samples therefore results in a sensitivity of 100% with 100% specificity. In contrast, detection of p24 antigen has a sensitivity of only 79% with a specificity of 99. The diagnosis of acute infection must be subsequently confirmed with a positive HIV-1 antibody test (seroconversion) within the follow- ing weeks. During acute HIV-1 infection, there is frequently a marked decrease of the CD4 cell count, which later increases again, but usually does not normalize to initial levels. Acute HIV-1 Infection 55 Figure 2: Algorithm for the diagnosis of acute HIV-1 infection In contrast, the CD8 cell count rises initially, which may result in a CD4/CD8 ratio of <1. Infectious mononucleosis is the most important diagnosis to be aware of, but the differential diagnosis also includes cytomegalovirus, toxoplasmosis, rubella, syphilis, viral hepatitis, disseminated gonococcal infection, other viral infections and side effects of medications. In summary, the most important step in the diagnosis of acute HIV-1 infection is to keep it in mind during diagnosis. The clinical hypothesis of acute infection requires performance of an HIV-1 antibody test and possibly repeated testing of HIV-1 viral load, as shown in the algorithm in Figure 1 (adapted from Hecht 2002). Immunological and virological events during AHI Transmission of HIV-1 generally results from viral exposure at mucosal surfaces fol- lowed by viral replication in submucosal and locoregional lymphoid tissues, and subsequently through overt systemic infection. Studies have estimated that most infections occur with a single virus (transmitted founder virus, TF) but in some instances it can occur with two or more viruses. There is the notion that an infec- tion with more viruses is associated with higher viral loads. Moreover, recent studies have demonstrated that the TF is on average different compared to the majority of circulating viruses – higher env content, enhanced cell-free infectivity, improved dendritic cell interaction, and relative IFN- resistance (Parrish 2013). The virus expo- nentially replicates in the absence of any detectable adaptive immune response, reaching levels of more than 100 million copies HIV-1 RNA/ml. It is during this initial cycle of viral replication that important pathogenic processes are thought to occur. These include the seeding of virus to a range of tissue reservoirs and the cellular 56 The Basics reservoir. Indeed, studies in rhesus macaques have demonstrated that the latent cellular reservoir is already established on day 3 and predominantly found in central memory and stem cell like memory CD4 T cells (Whitney 2014). Simultaneously to viral dissemination the destruction of CD4+ T lymphocytes, in particular within the lymphoid tissues of the gut occurs. Early on in infection, the very high levels of HIV- 1 viremia are normally short-lived, indicating that the host is able to generate an immune response that can control viral replication. Over the following weeks, viremia declines by several orders of magnitude before reaching a viral setpoint. This setpoint following resolution of the acute infection is a strong predictor of long-term disease progression rates (Mellors 1995 & 2007). It is therefore of critical importance to characterize and understand the immune responses induced in the initial stages of HIV-1 infection as these first responses appear responsible for the initial control of viral replication. In contrast to hepatitis B and C infection, acute phase HIV replication is associated with the activationof a dramatic cytokine cascade, with plasma levels of some ofthe most rapidly induced innate cytokines peaking 7 days after the first detection of plasma viremia and many other cytokines being upregulated as viral titers increase to their peak. Although some of the cytokines/chemokines produced in acute HIV infection may contribute to the control of viral replication,the exaggerated cytokine response likely also contributes to the early immunopathology of the infection and associated long-term consequences (Stacey 2009). Also, a specific activation and expansion of natural killer (NK) cells has been noted during the acute phase of infection (Alter 2007). Indeed, it has been shown that NK cells can recognize and kill HIV-infected cells (Alter 2011). Several factors can influence viral replication during acute infection and the establishment of a viral setpoint. These include the fitness of the infecting virus, host genetic factors and host immune responses. While it has been shown that the transmitted/founder virus population has intact principal gene open reading frames and encodes replication-competent viruses (Salazar-Gonzalez 2009), the envelope (env) gene of elite controllers has been demonstrated to mediate less efficient entry than the envelope protein of chronic progressors (Troyer 2009). Interestingly, acute infection envs exhibit an intermediate phenotypic pattern not distinctly different from chronic progressor envs. These findings imply that lower env fitness may be established early and may directly contribute to viral suppression in elite controllers. Antibodies against HIV-1 with neutralizing capacities are rarely detectable during primary HIV-1 infection and are therefore less likely to be major contributors to the initial control of viral replication. However, broadly neutralizing antibodies develop over time in a rare subset of HIV-infected individuals and the expression of specific markers on CD4 T cells is modestly associated with the development of these responses (Mikell 2011). In addition, several studies have demonstrated a crucial role of HIV-1-specific cellular immune responses for the initial control of viral replica- tion. A massive, oligoclonal expansion of CD8 T cell responses has been described during acute HIV-1 infection (Pantaleo 1994), and the appearance of HIV-1-specific CD8 T cells has been temporally associated with the initial decline of viremia (Koup 1994, Borrow 1994). These CD8 T cells have the ability to eliminate HIV-1-infected cells directly by MHC class I-restricted cytolysis or indirectly by producing cytokines, chemokines or other soluble factors, thus curtailing the generation of new viral progeny (Yang 1997). The biological relevance of HIV-1-specific cytotoxic T cells (CTL) in acute HIV-1 infection was highlighted in in vivo studies demonstrating a dramatic rise of SIV viremia and an accelerated clinical disease progression in macaques after the artificial depletion of CD8 T cells (Schmitz 1999, Jin 1999). Additional evidence for the antiviral pressure of HIV-1-specific CTLs during primary Acute HIV-1 Infection 57 HIV-1 infection was provided by the rapid selection of viral species with CTL epitope mutations that were detected within a few weeks of HIV-1 infection (Price 1997). A study assessing the impact of early HIV-1-specific CD8 T cell responses on the early viral set point in a cohort of over 420 subjects was able to demonstrate that the ability to mount a strong early CD8 T cell response during primary HIV-1 infection is moderately associated with a lower viral setpoint (Streeck 2009). Furthermore, the assessment of the CD8 T cell responses against autologous patient-virus-derived peptides in three subjects suggest that even more, yet undetectable, responses are present during the acute phase of the infection contributing up to 15% each to the initial control of viral replication (Goonetilleke 2009). Many of the early immunodominant CD8 T cell responses have been shown to be restricted by HLA class I alleles, which have been previously associated with slower disease progression such as HLA-B57 or -B27. Moreover, these HLA-restricted responses preferentially target epitopes within a short highly conserved region of p24/Gag (Streeck 2007). This region encodes the HIV-1 capsid, which has been shown to be crucial for the stability of HIV-1 (Schneidewind 2007).
Nevertheless discount top avana master card, the strength of evidence of these results for comparing different drugs must be rated lower than results from the most preferred type of trial discount top avana online mastercard. If no head-to-head evidence was published purchase top avana 80mg amex, we reviewed placebo-controlled trials for indications of interest. We reviewed all placebo-controlled trials to provide an overview of efficacy without taking drug equivalency into account. Study populations, disease severity, and concomitant treatments can differ considerably across placebo-controlled trials. Comparisons of treatment effects across trials must, therefore, be made with caution. We included meta-analyses in the evidence report if they were relevant to a key question 31 and of good or fair methodological quality. For each section, we included results from the most recent and best-quality systematic review and meta-analysis and did not include data from older meta-analyses where these had been superseded in terms of included studies and analysis. We did not summarize individual studies in evidence tables if they were included in a high-quality meta-analysis (listed in Appendix C). We excluded meta-analyses that were not based on a comprehensive systematic literature search or did not maintain the units of the studies in their statistical analyses. We checked our database to guarantee that our literature search had detected trials included in any meta-analyses that we discarded and obtained any missing articles. For adverse events we included both experimental and observational studies. For observational studies we included those with large sample sizes (> 1000 patients) that lasted at least 6 months and reported an included outcome. We initially reviewed studies with health outcomes as the primary outcome measures. Outcomes were, among others, quality of life, functional capacity, alleviation of symptoms, hospitalizations, or mortality. For head-to-head studies we also included radiological changes. Targeted immune modulators 23 of 195 Final Update 3 Report Drug Effectiveness Review Project Safety outcomes included overall and specific adverse events (e. Data Abstraction We designed and used a structured data abstraction form to ensure consistency in appraisal for each study. Trained reviewers abstracted data from each study and assigned an initial quality rating. A senior reviewer read each abstracted article, evaluated the completeness of the data abstraction, and confirmed the quality rating. We abstracted the following data from included trials: study design, eligibility criteria, intervention (drugs, dose, and duration), additional medications allowed, methods of outcome assessment, population characteristics, sample size, loss to follow-up, withdrawals attributed to adverse events, results, and adverse events reported. Validity Assessment We assessed the internal validity (quality) of trials based on predefined criteria developed by the 32 United States Preventive Services Task Force (ratings: good-fair-poor) and the National Health 33 Service Centre for Reviews and Dissemination. External validity (generalizability) was assessed and reported but did not influence quality ratings. We did not rate the quality of pooled data-analyses. Two independent reviewers assigned quality ratings; they resolved any disagreements by discussion and consensus or by consulting a third, independent party. Elements of internal validity assessment included, among others, randomization and allocation concealment, similarity of compared groups at baseline, whether eligibility criteria were specified, use of intent-to-treat analysis, and overall and differential loss to follow-up. Loss to follow-up was defined as the number of persons randomized who did not reach 34 the endpoint of the study, independent of the reason and the use of intent-to-treat analysis. We adopted no formal cut-off point of loss to follow-up because some studies defined withdrawals due to acute worsening of the disease as an outcome measure. Trials that had a fatal flaw in one or more categories were rated poor quality and not included in the analysis of the evidence report; trials that met all criteria were rated good quality. The majority of trials received a quality rating of fair. This includes studies that presumably fulfilled all quality criteria but did not report their methods to an extent that answered all of our questions. Therefore, the “fair quality” category includes trials with quite different strengths and weaknesses and a range of validity. Data Synthesis Throughout this report we synthesized the literature qualitatively. If data were sufficient, we augmented findings with quantitative analyses (meta-analyses of placebo-controlled trials or indirect comparisons). Because only limited head-to-head evidence on targeted immune modulators was available, we conducted adjusted indirect comparisons when data was sufficient and trials were of similar design, conducted in similar settings with a comparable patient population. We used metaregressions as a statistical method for adjusted indirect comparisons. Evidence suggests that adjusted indirect comparisons agree with head-to-head trials if Targeted immune modulators 24 of 195 Final Update 3 Report Drug Effectiveness Review Project component studies are similar and treatment effects are expected to be consistent in patients 35,36 included in different trials. Nevertheless, findings must be interpreted cautiously. To conduct indirect comparisons we employed random effects meta-analyses of data from placebo-controlled trials that were fairly homogenous in study populations and outcome assessments. Our outcome measure of choice for rheumatoid arthritis was the relative risk of achieving an American College of Rheumatology 50 response (numbers refer to percentage improvement [see Appendix D for a summary of different scales]). We did not find sufficient data to pool results of the Health Assessment Questionnaire or other measures of health-related quality of life. We chose the American College of Rheumatology 50 outcome measure because response to treatment can be viewed as a close proxy to health outcomes. Therefore, such an outcome measure has more clinical significance than a comparison of mean changes of scores on rating scales. A 50% improvement on the American College of Rheumatology scale is commonly viewed as a clinically significant response. We used random effects metaregressions to determine the relative risk of achieving American College of Rheumatology 50 response between two drugs. All statistical analyses were conducted using Stata, version 11. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011). Peer Review We requested and received peer review of the report from four content or methodology experts. Their comments were reviewed and, where possible, incorporated into the final document. All comments and the authors’ proposed actions were reviewed by representatives of the participating organizations of the Drug Effectiveness Review Project before finalization of the report. Names of peer reviewers for the Drug Effectiveness Review Project are listed at: http://www.
Unfortunately purchase top avana 80mg online, for many drugs there exist few or no effectiveness studies and many efficacy studies cheap top avana 80 mg free shipping. Yet clinicians must decide on treatment for many patients who would not have been included in controlled trials and for whom the effectiveness and tolerability of different drugs are uncertain buy top avana 80 mg amex. Systematic reviews indicate whether or not there exists evidence that drugs differ in their effects in various subgroups of patients, but they do not attempt to set a standard for how results of controlled trials should be applied to patients who would not have been eligible for them. With or without an evidence report, these decisions must be informed by clinical judgment. In the context of development of recommendations for clinical practice, systematic reviews are useful because they define the strengths and limits of the evidence, clarifying whether assertions about the value of an intervention are based on strong evidence from clinical studies. Judgment, reasoning, and applying one’s values under conditions of uncertainty must also play a role in decision making. Users of an Overactive bladder Page 7 of 73 Final Report Update 4 Drug Effectiveness Review Project evidence report must also keep in mind that not proven does not mean proven not; that is, if the evidence supporting an assertion is insufficient, it does not mean the assertion is untrue. The quality of the evidence on effectiveness is a key component, but not the only component, in making decisions about clinical policy. Additional criteria include acceptability to physicians and patients, potential for unrecognized harm, applicability of the evidence to practice, and consideration of equity and justice. Scope and Key Questions The scope of the review and key questions were originally developed and refined by the Oregon Evidence-based Practice Center with input from a statewide committee of experts. Subsequently, the key questions were reviewed and revised by representatives of organizations participating in the Drug Effectiveness Review Project. The participating organizations of the Drug Effectiveness Review Project are responsible for ensuring that the scope of the review reflects the populations, drugs, and outcome measures of interest to clinicians and patients. The scope of the current review was approved in June 2008. The participating organizations approved the following key questions to guide this review: 1. For adult patients with overactive bladder, do anticholinergic drugs differ in effectiveness? Is there a difference in effectiveness between long-acting and short-acting formulations? For adult patients with overactive bladder, do anticholinergic drugs differ in safety or adverse effects? Is there a difference in safety or adverse effects between long-acting and short- acting formulations? Are there subgroups of patients based on demographics (age, racial groups, gender), other medications, or comorbidities for which one anticholinergic drug is more effective or is associated with fewer adverse effects? Are there differences in adverse event profiles in older patients between the drugs, particularly long-acting compared with short-acting, and newer drugs compared with the older drug oxybutynin? Overactive bladder Page 8 of 73 Final Report Update 4 Drug Effectiveness Review Project METHODS Inclusion Criteria Populations Adult patients with symptoms of urge incontinence/overactive bladder (urgency, frequency, leakage, dysuria). Interventions Included interventions are listed in Table 1. Included interventions Active ingredient Form Brand name Darifenacin Oral Extended-release tablet Enablex Flavoxate hydrochloride Oral tablet Urispas Hyoscyamine sulfate Oral tablet Levsin Oxybutynin chloride Oral tablet and syrup Ditropan Oxybutynin chloride Extended release oral tablet Ditropan XL Oxybutynin Transdermal system Oxytrol Scopolamine (hyoscine) Oral tablet Buscopan butylbromide Solifenacin succinate Oral tablet Vesicare Tolterodine tartrate Oral tablet Detrol Tolterodine tartrate Extended release oral capsule Detrol LA Sanctura (USA), Trospium chloride Oral tablet Trosec (Canada) a Trospium chloride Extended release oral capsule Sanctura XR a Not available in Canada. Effectiveness outcomes • Change in mean number of incontinence episodes per 24 hours • Change in mean number of micturitions per 24 hours • Change in mean number of pads per 24 hours • Subjective patient assessments of symptoms (severity of ‘problems’ caused by bladder symptoms, severity of urgency, global evaluation of treatment) • Quality of life Safety outcomes • Overall adverse effects • Withdrawals due to overall adverse effects • Serious adverse events reported • Specific adverse events or withdrawals due to specific adverse events (dry mouth, effects on cognition, blurred vision, and cardiac conduction abnormalities) Overactive bladder Page 9 of 73 Final Report Update 4 Drug Effectiveness Review Project Study Designs For effectiveness, the study is a randomized controlled trial or good-quality systematic review of an anticholinergic incontinence drug compared with another anticholinergic incontinence drug, another drug, or placebo. For adverse effects, the study is a controlled clinical trial or observational study of at least 6 months’ duration. Literature Search To identify articles relevant to each key question for each version of this report, we searched Medline, the Cochrane Library, and reference lists of review articles. For the original report we also searched EMBASE (1980-July week 3 2005). For the current update, we searched Medline and the Cochrane Library through December 2008. In electronic searches, we used broad searches, only combining terms for drug names with terms for relevant research designs. We have attempted to identify additional studies through searches of reference lists of included studies and reviews, the US Food and Drug Administration website, and dossiers submitted by pharmaceutical companies for the current review. All citations were imported into an electronic database (EndNote XI). Study Selection Selection of included studies was based on the inclusion criteria created by the Drug Effectiveness Review Project participants, as described above. Two reviewers independently assessed titles and abstracts of citations identified through literature searches for inclusion using the criteria below. Full-text articles of potentially relevant citations were retrieved and again were assessed for inclusion by 2 reviewers. Results published only in abstract form were not included because lack of detail prevented quality assessment. Trials that evaluate one anticholinergic drug against another provide direct evidence of comparative effectiveness and adverse event rates. In theory, trials that compare these drugs with placebos or with other drugs used to treat overactive bladder can also provide evidence about efficacy. However, the efficacy of drugs in different trials can be difficult to interpret because of significant differences in key characteristics of the patient populations. Comparison of results across trials (direct comparisons or indirect comparisons) is difficult due to differing outcome measures. Data Abstraction The following data were abstracted from included trials: study design; setting; population characteristics (including sex, age, ethnicity, diagnosis); eligibility and exclusion criteria; interventions (dose and duration); comparisons; numbers screened, eligible, enrolled, and lost to follow-up; method of outcome ascertainment; and results for each outcome. We recorded intention-to-treat results if they were available and the trial did not report high overall loss to follow-up. Data were abstracted by one reviewer and checked for accuracy by a second. Overactive bladder Page 10 of 73 Final Report Update 4 Drug Effectiveness Review Project Validity Assessment We assessed the internal validity (quality) of trials based on the predefined criteria listed in Appendix C. These criteria were based on the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (United Kingdom) criteria for assessing study quality. In rating the internal validity of each trial we assessed the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw were rated poor-quality; trials that met all criteria were rated good-quality. As the fair-quality category was broad, studies with this rating varied in their strengths and weaknesses; the results of some fair-quality studies were likely to be valid, while others were only possibly valid. Poor-quality trials were not valid: The results were at least as likely to reflect flaws in the study design as a true difference between the compared drugs. A fatal flaw is reflected by failure to meet combinations of items on the quality assessment checklist. Appendix C also shows the criteria we used to rate observational studies of adverse events.
Effect of pramlintide on weight in overweight and obese insulin-treated type 2 diabetes patients buy top avana 80mg overnight delivery. Addition of pramlintide to insulin therapy lowers HbA1c in conjunction with weight loss in patients with type 2 diabetes approaching glycaemic targets purchase top avana mastercard. Davis S top avana 80 mg without a prescription, Johns D, Maggs D, Northrup J, Xu H, Brodows R. Exploring the substitution of Exenatide for Insulin in patients with Type 2 Diabetes treated with insulin in combination with oral antidiabetic agents. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Nauck MA DS, Kim D, Johns D, Northrup J, Festa A, Brodows R, Trautmann M. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non- inferiority study. 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The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double- blind, placebo-controlled trials. Nelson P, Poon T, Guan X, Schnabel C, Wintle M, Fineman M. The incretin mimetic exenatide as a monotherapy in patients with type 2 diabetes. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformin-treated patients with type 2 diabetes mellitus. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. A review of the effects of antihyperglycaemic agents on body weight: the potential of incretin targeted therapies. Validation of an index of the quality of review articles. Diabetes Page 82 of 99 Final Report Drug Effectiveness Review Project 45. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Efficacy and tolerability of the dipeptidyl peptidase- 4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Effect of intial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. 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Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Page 83 of 99 Final Report Drug Effectiveness Review Project 59. Diabetes Page 84 of 99 Final Report Drug Effectiveness Review Project Appendix A. Search strategies Pramlintide Database: Ovid MEDLINE(R) <1950 to September Week 1 2007> and updated on <1996 to April Week 3 2008> Search Strategy: -------------------------------------------------------------------------------- 1 196078-30-5. Quality assessment methods for drug class reviews for the Drug Effectiveness Review Project Study quality is objectively assessed using predetermined criteria for internal validity which are based on the US Preventive Services Task Force and the National Health Service Center for 1 2 Reviews and Dissemination criteria. All included studies, regardless of design, are assessed for quality and assigned a rating of “good,” “fair,” or “poor. A fatal flow is failure to meet combinations of criteria that together are consistent with absence of systematic bias. An example would be inadequate procedures for randomization and/or allocation concealment combined with important differences in prognostic factors at baseline. Studies that meet all criteria are rated good quality and the remainder is rated fair quality. As the “fair” 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.