Systematic review: hand activity and ultrasound of the median nerve.

BACKGROUND: Ultrasound is an established method of viewing the median nerve in the carpal tunnel syndrome (CTS). There is some evidence to suggest that immediate changes may occur in the median nerve before and after hand activity. The evidence for the validity and reliability of ultrasound for testing acute changes in the median nerve has not been systematically reviewed to date. AIMS: To evaluate the evidence for visible change in ultrasound appearance of the median nerve after hand activity. METHODS: A literature search was designed, and three reviewers independently selected published research for inclusion. Two reviewers independently appraised papers using the Evidence Based Library and Information Practice (EBLIP) appraisal checklist, while the third reviewer resolved discrepancies between appraisals. RESULTS: Ten studies were appraised and the results showed an increase in median nerve cross-sectional area following activity, with a return to normal size within 1 h following activity. Both healthy individuals and those diagnosed with CTS participated, all were small convenience samples. Ultrasonographic measurements of the median nerve were reliable in the four studies reporting this, and the studies demonstrated high quality. CONCLUSIONS: Good-quality evidence as identified by the EBLIP appraisal checklist suggests that following hand activity, the median nerve changes in size in the carpal tunnel. The results may not be generalizable to all people and activities due to the use of small convenience sampling and narrow range of activities studied, in all of the studies appraised.

Grading quality of evidence and strength of recommendations in clinical practice guidelines part 3 of 3. The GRADE approach to developing recommendations.

This is the third and last article in the series about the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to grading the quality of evidence and the strength of recommendations in clinical practice guidelines and its application in the field of allergy. We describe the factors that influence the strength of recommendations about the use of diagnostic, preventive and therapeutic interventions: the balance of desirable and undesirable consequences, the quality of a body of evidence related to a decision, patients' values and preferences, and considerations of resource use. We provide examples from two recently developed guidelines in the field of allergy that applied the GRADE approach. The main advantages of this approach are the focus on patient important outcomes, explicit consideration of patients' values and preferences, the systematic approach to collecting the evidence, the clear separation of the concepts of quality of evidence and strength of recommendations, and transparent reporting of the decision process. The focus on transparency facilitates understanding and implementation and should empower patients, clinicians and other health care professionals to make informed choices.

Criteria for the differential indication of asthma education versus asthma instruction for families of preschoolers: results from the randomized DIAT2 study (Differential Indication of Asthma Trainings in Toddlers).

BACKGROUND: Asthma management of preschoolers is more improved by a family oriented psycho-educational program provided by a multi-professional team than by a short instruction alone. For some families however an instruction could be sufficient. Criteria to assign education or instruction to asthmatic schoolchildren (DIA) have been evaluated . This paper describes the use of those criteria in the Preschoolers' and parents' asthma education trial (P (2)AET) . PATIENTS: DIA at study entry were available of 233 children (aged 2-5 [mean 3.9] years) participating in the randomised controlled P (2)AET (education, instruction, waiting group). Children had been included after having at least 3 obstructive episodes in their life plus chronic or recurrent wheeze in the 6 months before the start of the study. 74 % were on inhaled corticosteroids. METHODS: Logistic regression procedures were used to assess the predictive value of DIA and possible confounders on the success of the interventions (education and instruction). RESULTS: Regarding the outcome "better in asthma management test" education is superior to instruction (OR 5.2; CI 1.7-16). DIA "quarrel about inhalation" indicates an even greater advantage of education (OR 19; CI 2-176). An equal high advantage was found, when there was NO "need for peer support" (OR 11; CI 2-64). CONCLUSION: Families with asthmatic preschoolers displaying dysfunctional interaction, which can only be corrected in an educational process, should be provided with the psycho-educational program promptly.

Preschoolers' and parents' asthma education trial (P2AET)--a randomized controlled study.

We aimed to evaluate a family-oriented psycho-educational asthma training program for the age group of 2-5 years, involving both parents and children. Children were included after having at least 3 obstructive episodes in their life plus chronic or recurrent wheeze in the 6 months before the start of the study. In the multicenter randomized trial we had (1) a waiting group (WG), (2) an instruction group (IG) trained in a structured way according to the national asthma guideline, and (3) an education group (EG), having a standardized multiprofessional psycho-educational program, according to the national licensed asthma education for the age group of 6-18 years. All were assessed after 6 months. A subgroup analysis was performed on those being on regular inhaled corticosteroids at study entry (74.3%). A total of 338 children were randomized, and 288 (85%) completed the study. In the asthma emergency management, test scores increased most in EG, less in IG, and not in WG. For emergency visits the risk ratio for EG was 0.68 compared to IG: Patients regularly inhaling corticosteroids (74.3%) had an increased risk for emergency visits when having only an instruction (OR 3.99 [1.89-8.40]) or had been waiting (OR 2.5 [1.16-5.37]) when compared to those having an asthma education. We conclude that in the German health system, the family oriented psycho-educational program provided in a standardized manner by a multiprofessional team is effective also in the age group of 2-5 years. It should be made accessible to each asthmatic child.

Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions.

The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach provides guidance to grading the quality of underlying evidence and the strength of recommendations in health care. The GRADE system's conceptual underpinnings allow for a detailed stepwise process that defines what role the quality of the available evidence plays in the development of health care recommendations. The merit of GRADE is not that it eliminates judgments or disagreements about evidence and recommendations, but rather that it makes them transparent. This first article in a three-part series describes the GRADE framework in relation to grading the quality of evidence about interventions based on examples from the field of allergy and asthma. In the GRADE system, the quality of evidence reflects the extent to which a guideline panel's confidence in an estimate of the effect is adequate to support a particular recommendation. The system classifies quality of evidence as high, moderate, low, or very low according to factors that include the study methodology, consistency and precision of the results, and directness of the evidence.

Grading quality of evidence and strength of recommendations in clinical practice guidelines: Part 2 of 3. The GRADE approach to grading quality of evidence about diagnostic tests and strategies.

The GRADE approach to grading the quality of evidence and strength of recommendations provides a comprehensive and transparent approach for developing clinical recommendations about using diagnostic tests or diagnostic strategies. Although grading the quality of evidence and strength of recommendations about using tests shares the logic of grading recommendations for treatment, it presents unique challenges. Guideline panels and clinicians should be alert to these special challenges when using the evidence about the accuracy of tests as the basis for clinical decisions. In the GRADE system, valid diagnostic accuracy studies can provide high quality evidence of test accuracy. However, such studies often provide only low quality evidence for the development of recommendations about diagnostic testing, as test accuracy is a surrogate for patient-important outcomes at best. Inferring from data on accuracy that using a test improves outcomes that are important to patients requires availability of an effective treatment, improved patients' wellbeing through prognostic information, or - by excluding an ominous diagnosis - reduction of anxiety and the opportunity for earlier search for an alternative diagnosis for which beneficial treatment can be available. Assessing the directness of evidence supporting the use of a diagnostic test requires judgments about the relationship between test results and patient-important consequences. Well-designed and conducted studies of allergy tests in parallel with efforts to evaluate allergy treatments critically will encourage improved guideline development for allergic diseases.

Updated European Consensus Statement on diagnosis and treatment of adult ADHD.

Background Attention-deficit/hyperactivity disorder (ADHD) is among the most common psychiatric disorders of childhood that often persists into adulthood and old age. Yet ADHD is currently underdiagnosed and undertreated in many European countries, leading to chronicity of symptoms and impairment, due to lack of, or ineffective treatment, and higher costs of illness. Methods The European Network Adult ADHD and the Section for Neurodevelopmental Disorders Across the Lifespan (NDAL) of the European Psychiatric Association (EPA), aim to increase awareness and knowledge of adult ADHD in and outside Europe. This Updated European Consensus Statement aims to support clinicians with research evidence and clinical experience from 63 experts of European and other countries in which ADHD in adults is recognized and treated. Results Besides reviewing the latest research on prevalence, persistence, genetics and neurobiology of ADHD, three major questions are addressed: (1) What is the clinical picture of ADHD in adults? (2) How should ADHD be properly diagnosed in adults? (3) How should adult ADHDbe effectively treated? Conclusions ADHD often presents as a lifelong impairing condition. The stigma surrounding ADHD, mainly due to lack of knowledge, increases the suffering of patients. Education on the lifespan perspective, diagnostic assessment, and treatment of ADHD must increase for students of general and mental health, and for psychiatry professionals. Instruments for screening and diagnosis of ADHD in adults are available, as are effective evidence-based treatments for ADHD and its negative outcomes. More research is needed on gender differences, and in older adults with ADHD.

The effect of bariatric surgery on serum 25-OH vitamin D levels: a systematic review and meta-analysis.

BACKGROUND: Concerns have emerged about post-operative decreases in calcium and vitamin D following bariatric surgery. This review explores changes in metabolic bone health in persons with obesity undergoing gastric bypass surgery compared to non-surgical controls, providing an updated and comprehensive perspective on the literature. METHODS: An electronic search was conducted in MEDLINE, Pubmed, EMBASE and Cochrane databases to 8 November 2016. Eligible trials included randomized controlled trials or controlled observational studies of patients who have undergone laparoscopic gastric bypass surgery. Statistical analysis was carried out using the Cochrane Collaboration Review Manager (RevMan 5.0), and a random effects model was implemented. Outcomes were expressed as weighted mean difference (WMD). The primary outcome examined was change in 25-OH-D levels at 12 months post surgery, and secondary outcomes included change in bone mineral density (BMD) measurements at 12 months post surgery at the lumbar spine (LS) and total hip (TH). RESULTS: At 12 months, there was no significant difference in 25-OH vitamin D in the surgical group compared to controls (WMD = 6.79%; 95% CI: -9.01, 22.59; p = 0.40; I2 = 68%). There was no statistically significant difference between fracture risk in the surgical population compared to controls (RR = 1.24; 95% CI: 0.99, 1.56; p = 0.06; I2 = 0%). A significant BMD reduction was however shown at the TH (WMD, -7.33%, 95% CI = -8.70 to -5.97, p < .001, I2 = 0%), and a trend towards decline was observed at the LS (WMD, -1.73%, 95% CI = -3.56 to 0.11, p = 0.06, I2 = 0%). Changes at 24 months for applicable outcomes were similar to the results at 12 months. CONCLUSIONS: Bariatric surgery may compromise metabolic bone health, but the paucity of high-quality literature limits conclusions.

Approaches to interpreting and choosing the best treatments in network meta-analyses.

When randomized trials have addressed multiple interventions for the same health problem, network meta-analyses (NMAs) permit researchers to statistically pool data from individual studies including evidence from both direct and indirect comparisons. Grasping the significance of the results of NMAs may be very challenging. Authors may present the findings from such analyses in several numerical and graphical ways. In this paper, we discuss ranking strategies and visual depictions of rank, including the surface under the cumulative ranking (SUCRA) curve method. We present ranking approaches' merits and limitations and provide an example of how to apply the results of a NMA to clinical practice.

Relationships between obesity, bipolar spectrum features, and personality traits: a case-control study.

OBJECTIVE: Recently there has been widening stream of research on the relationships between obesity and mental disorders. Patients with obesity seem to be prone to developing bipolar spectrum disorders and they present with specific personality traits. The aim of this study was to analyze the associations between obesity, bipolarity features, and personality traits. PATIENTS AND METHODS: A nested case-control study was performed. Patients with obesity constituted the sample of cases (N = 90), and healthy individuals were ascribed to the control group (N = 70). The lifetime presence of bipolarity features was analyzed with the Mood Disorder Questionnaire (MDQ), while personality traits were assessed with the NEO-Five Factor Inventory (NEO-FFI). RESULTS: Bipolarity features were more prevalent in the patients with obesity, as compared to healthy individuals. Patients with obesity had both higher mean value of MDQ score (p = 0.01) and a higher proportion of subjects with MDQ score ≥ 7 points (p = 0.012) as well as lower score on the NEO-FFI openness to experience (p > 0.001), compared to control subjects. Using multivariate model, in patients with obesity, a significant positive correlation between bipolarity and neuroticism, and negative with agreeableness and conscientiousness was established. Such relationship was not observed in control subjects. CONCLUSIONS: In the population of patients with obesity, there is a specific combination between bipolarity and personality traits (high-trait neuroticism, low-trait conscientiousness, and low-trait agreeableness). This may have some consequences for both pharmacological and psychological management of such patients.

Fluid type and the use of renal replacement therapy in sepsis: a systematic review and network meta-analysis.

Fluid resuscitation, along with the early administration of antibiotics, is the cornerstone of treatment for patients with sepsis. However, whether differences in resuscitation fluids impact on the requirements for renal replacement therapy (RRT) remains unclear. To examine this issue, we performed a network meta-analysis (NMA), including direct and indirect comparisons, that addressed the effect of different resuscitation fluids on the use of RRT in patients with sepsis. The data sources MEDLINE, EMBASE, ACPJC, CINAHL and Cochrane Central Register were searched up to March 2014. Eligible studies included randomized trials reported in any language that enrolled adult patients with sepsis or septic shock and addressed the use of RRT associated with alternative resuscitation fluids. The risk of bias for individual studies and the overall certainty of the evidence were assessed. Ten studies (6664 patients) that included a total of nine direct comparisons were assessed. NMA at the four-node level showed that an increased risk of receiving RRT was associated with fluid resuscitation with starch versus crystalloid [odds ratio (OR) 1.39, 95% credibility interval (CrI) 1.17-1.66, high certainty]. The data suggested no difference between fluid resuscitation with albumin and crystalloid (OR 1.04, 95% CrI 0.78-1.38, moderate certainty) or starch (OR 0.74, 95% CrI 0.53-1.04, low certainty). NMA at the six-node level showed a decreased risk of receiving RRT with balanced crystalloid compared to heavy starch (OR 0.50, 95% CrI 0.34-0.74, moderate certainty) or light starch (OR 0.70, 95% CrI 0.49-0.99, high certainty). There was no significant difference between balanced crystalloid and saline (OR 0.85, 95% CrI 0.56-1.30, low certainty) or albumin (OR 0.82, 95% CrI 0.49-1.37, low certainty). Of note, these trials vary in terms of case mix, fluids evaluated, duration of fluid exposure and risk of bias. Imprecise estimates contributed to low confidence in most estimates of effect. Among the patients with sepsis, fluid resuscitation with crystalloids compared to starch resulted in reduced use of RRT; the same may be true for albumin versus starch.

To what extent do congestive heart failure patients in sinus rhythm benefit from digoxin therapy? A systematic overview and meta-analysis.

PURPOSE: To reappraise the effectiveness of digoxin for the treatment of congestive heart failure (CHF) in patients with sinus rhythm in light of data from recently published randomized controlled trials and to quantitatively assess its usefulness. STUDY IDENTIFICATION: Computerized searches of the MEDLINE database were performed, and the reference list of each retrieved article was reviewed. STUDY SELECTION: Review of more than 360 citations and the reference lists of 19 review articles and 61 potentially relevant articles revealed seven double-blind randomized controlled trials that were included in this overview. DATA EXTRACTION: Study quality was assessed and descriptive information concerning the study populations, the specific interventions, and clinically relevant outcome measurements was extracted. RESULTS OF DATA SYNTHESIS: The common odds ratio for CHF deterioration while receiving digoxin versus placebo was 0.28, with a 95% confidence interval of 0.16 to 0.49. Predictors of digoxin benefit included presence of a third heart sound and the severity and duration of CHF. CONCLUSION: Data from seven trials of high methodologic quality suggest that, on average, one out of nine patients with CHF and sinus rhythm derive a clinically important benefit from digoxin (with a 95% confidence interval of 1/33 to 1/5).

Measuring health status: what are the necessary measurement properties?

The different measurement properties necessary for instruments whose goal is to detect differences between subjects at a single point in time (discriminative instruments) and those whose goal is to detect longitudinal change within subjects (evaluative instruments) is becoming increasingly recognized. Up to now, requirements for evaluative instruments have been presented as reproducibility, validity, and responsiveness (i.e. the ability to detect change over time). An alternative conceptualization would characterize any instrument as requiring two crucial measurement properties. One is validity, the other a high ratio of signal to noise. For discriminative instruments, the signal to noise ratio can be summarized in a reliability coefficient; for evaluative instruments, in a responsiveness index or coefficient. This formulation can simplify and clarify the understanding and teaching of issues in health status measurement.

An index of scientific quality for health reports in the lay press.

Although the quality of health reporting has been criticized for being unscientific, evaluations of health care reporting have been limited by the lack of a reliable and credible measure of scientific quality. We developed an index of scientific quality (ISQ) for health-related news reports and tested its reliability and sensibility. Items were generated from a survey of the literature and experts in research methodology. Items that were unclear, confusing or discriminated poorly between articles of high and low scientific quality were revised or deleted in an iterative process wherein potential criteria were independently applied to samples of 5 to 15 articles by 6 raters. To test the reliability of the final criteria 60 articles were drawn from three sampling frames: newspapers, magazines, and professional journals. Articles were intentionally selected to obtain a wide range of quality and topics. Two categories of raters were used: research assistants and physicians with research training. All 6 raters assessed all 60 articles. The sensibility of the index was tested by a questionnaire with 13 items related to face validity and content validity as well as other aspects of sensibility. The questionnaire was completed by 20 researchers and 13 health and science writers. The final ISQ includes 7 items that address the extent to which a report allows readers to draw conclusions about the applicability, validity and practical importance of the information that is reported. Chance corrected agreement (kappa) among all 6 raters for overall scientific quality was 0.62 (SE 0.02). The index was found to be sensible with only one major problem, the need for judgment in making ratings. While some degree of subjectivity appears to be inevitable in rating the scientific quality of health reports, the ISQ is acceptable reliable and credible and should be useful for evaluating and improving the scientific quality of health reporting.

Interviewer versus self-administered questionnaires in developing a disease-specific, health-related quality of life instrument for asthma.

We wished to determine the extent to which respondents provided the same answers to a health-related quality of life (HRQL) questionnaire in self- and interviewer-administered forms. One hundred and fifty patients with asthma who were symptomatic or required treatment at least once a week, and had airway hyperresponsiveness to methacholine aerosol (PC20 < 8.0 mg/ml) participated. Patients completed a 152-item HRQL questionnaire in both interviewer and self-administered forms, separated by a 2-week interval, the order determined by random allocation. The percentage of items endorsed by the self-administered approach was significantly higher than that of the interviewer-administered approach overall (46.9 vs 35.8%) (p < 0.0001). The difference was consistent across all six domains; the absolute difference in the proportion of items endorsed varied from 8.9 to 12.3%. The intraclass correlations for the proportion of subjects endorsing an item was 0.84. Self- and interviewer-administered questionnaires yield very similar results in discriminating between subjects, but the self-administered version shows systematically greater HRQL impairment.

Grades of recommendation for antithrombotic agents.

The strength of any recommendation depends on two factors: the trade-off between benefits and risks, and the strength of the methodology that leads us to estimates of the treatment effect. The framework that we used for this conference captures these factors. We grade the trade-off between benefits and risks in two categories: (1) the trade-off is clear enough that most patients, despite differences in values, would make the same choice; and (2) the trade-off is less clear, and each patient's values will likely lead to different choices. We grade methodologic strength in three categories: (1) randomized trials, ideally summarized in a meta-analysis, that show consistent results; (2) randomized trials with inconsistent results; and (3)observational studies. The framework summarized in Table 1 therefore generates recommendations from the very strong (1A: benefit/risk clear, methods strong) to the very weak (2C: benefit/risk questionable, methods weak). Whatever the grade of recommendation, clinicians must bring their judgment considering local and individual patient circumstances, and patient values, to bear in making individual decisions. In general, however, they should place progressively greater weight on expert recommendations as they move from 2C to 1A.

The clinical utility of invasive diagnostic techniques in the setting of ventilator-associated pneumonia. Canadian Critical Care Trials Group.

OBJECTIVE: To evaluate the clinical utility of bronchoscopy with protected brush catheter (PBC) and BAL for patients with ventilator-associated pneumonia (VAP). DESIGN: Prospective cohort study. SETTING: Ten tertiary care ICUs in Canada. PATIENTS: Ninety-two mechanically ventilated patients with a clinical suspicion of VAP who underwent bronchoscopy were compared with 49 patients with a clinical suspicion of pneumonia who did not. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: We compared antibiotic use, duration of mechanical ventilation, ICU stay, and mortality. In addition, for patients who received bronchoscopy, we administered a questionnaire (before and after bronchoscopy) to evaluate the effect of PBC or BAL on (1) physician perception of the probability of VAP, (2) physician confidence in the diagnosis of VAP, and (3) changes to antibiotic management. After bronchoscopy results became available, from the physician's perspective, the diagnosis of VAP was deemed much less likely (p < 0.001), confidence in the diagnosis increased (p = 0.03), and level of comfort with the management plan increased (p = 0.02). Following the results of invasive diagnostic tests, in the group that underwent bronchoscopy, patients were receiving fewer antibiotics (31/92 vs 9/49, p = 0.05) and more patients had treatment with all their antibiotics discontinued (18/92 vs 3/49, p = 0.04) compared with the group that did not undergo bronchoscopy. Duration of mechanical ventilation and ICU stay were similar between the two groups, but mortality was lower in the group that underwent bronchoscopy with PBC or BAL (18.5% vs 34.7%, p = 0.03). CONCLUSIONS: Invasive diagnostic testing may increase physician confidence in the diagnosis and management of VAP and allows for greater ability to limit or discontinue antibiotic treatment. Whether performing PBC or BAL affects clinically important outcomes requires further study.

Randomized trials in the study of antihypertensive drugs.

Heterogeneity in response to antihypertensive drugs can be addressed by randomized trials in individual subjects. In such a trial a patient receives pairs of treatment periods (one period of each pair active drug, one matched placebo, in random order); patient and clinician are blinded to allocation, and treatment targets are monitored. These trials can optimize antihypertensive therapy in clinical practice and facilitate the investigation of new drugs and the study of pathophysiology. Such trials also have potential in helping decide whether common, nonspecific symptoms reported by patients are really drug related.

The effect of increasing doses of beta-agonists on airflow in patients with chronic airflow limitation.

OBJECTIVE: To determine the increase in FEV1 associated with increasing doses of inhaled terbutaline and salbutamol, the reproducibility of the increase in FEV1, and the reproducibility of the associated optimal bronchodilator dose, in patients with chronic airflow limitation (CAL). DESIGN: Double-blind, randomized, controlled trial examining spirometric response to cumulative doses of bronchodilators. PATIENTS AND SETTING: Patients with clinical diagnosis of CAL, FEV1 below 70% predicted, and FEV1 to FVC ratio less than 0.7 after administration of bronchodilator recruited from secondary care respirology practices. MEASURES OF OUTCOME: The estimates of maximum and optimal bronchodilation, as well as the associated drug dosages, were established in each patient on three occasions (twice on terbutaline and once on salbutamol). The 'optimal' drug dose was defined as the lowest dose associated with an FEV1 not exceeded by 50 ml on any other dose. MAIN RESULTS: Thirty-five patients completed the trial. FEV1 improved from 0.93 to a maximum of 1.191 with terbutaline (average of the two administrations) and from 0.951 to 1.141 with inhaled salbutamol (difference in increase in FEV1 between terbutaline and salbutamol P = 0.006). In less than 50% of cases administration of more than four puffs of bronchodilator resulted in FEV1 increase by more than 50 ml. The average dose of salbutamol and terbutaline associated with optimal bronchodilation were 430 micrograms and 1160 micrograms respectively. Patients varied widely in the optimal dose. Estimates of optimal dose were not reproducible (intraclass correlation coefficient < 0.5). CONCLUSION: Substantial incremental increase in FEV1 in response to increasing doses of beta-agonists beyond those commonly used in clinical practice is restricted to a minority of patients. Lack of reproducibility limits the clinical usefulness of establishing the optimal dose of beta-agonist for a given patient.

Reassessing quality-of-life instruments in the evaluation of new drugs.

Investigators use 2 fundamental approaches to the measurement of health-related quality of life (HR-QOL). Generic instruments include health profiles that tap into the full range of HR-QOL issues and are widely applicable, but may lack responsiveness to small but important changes in HR-QOL. Utility measures summarise HR-QOL in a single number between 0 (death) and 1 (full health) and are useful for economic analysis, but may lack responsiveness. Accumulating data suggest the alternatives to generic measures, instruments that are specific to a function or a health problem, are more responsive than generic measures. While direct comparison of the validity and responsiveness of alternative approaches remains limited and should be extended, it is already clear that comprehensive assessment of HR-QOL requires more than 1 type of instrument. To be useful, HR-QOL instruments must be interpretable. Investigators are beginning to elucidate what constitutes trivial, small but important, or large changes in HR-QOL. Approaches include both within- and between-patient global ratings, observing HR-QOL scores in different patient populations, and observing the magnitude of change in HR-QOL with established interventions.