Effect modification in network meta-analyses for relapsed/refractory multiple myeloma: systematic review and meta-analysis.

OBJECTIVES: To systematically review and meta-analyse the evidence for effect modification by refractory status and number of treatment lines in relapsed/refractory multiple myeloma (RRMM); and to assess whether effect modification is likely to invalidate network meta-analyses (NMA) that assume negligible modification. DESIGN: Systematic review, meta-analysis and simulation. DATA SOURCES: We systematically searched the literature (e.g., OVID Medline) to identify eligible publications in February 2020 and regularly updated the search until January 2022. We also contacted project stakeholders (including industry) ELIGIBILITY CRITERIA: Phase 2 and 3 randomised controlled trials reporting stratified estimates for comparisons with at least one of a prespecified set of treatments relevant for use in Norwegian RRMM patients. OUTCOMES: We used meta-analysis to estimate relative HRs (RHRs) for overall survival (OS) and progression-free survival (PFS) with respect to refractory status and number of treatment lines. We used the estimated RHRs in simulations to estimate the percentage of NMA results expected to differ significantly in the presence versus absence of effect modification. RESULTS: Among the 42 included publications, stratified estimates were published by and extracted from up to 18 (43%) publications and on as many as 8364 patients. Within-study evidence for effect modification is very weak (p>0.05 for 47 of 49 sets of stratified estimates). The largest RHR estimated was 1.32 (95% CI 1.18 to 1.49) for the modifying effect of refractory status on HR for PFS. Simulations suggest that, in the worst case, this would result in only 4.48% (95% CI 4.42% to 4.54%) of NMA estimates differing statistically significantly in the presence versus absence of effect modification. CONCLUSIONS: Based on the available evidence, effect modification appears to be sufficiently small that it can be neglected in adequately performed NMAs. NMAs can probably be relied on to provide estimates of HRs for OS and PFS in RRMM, subject to caveats discussed herein.

Pulmonary function, working capacity and strength in young adults with Marfan syndrome.

OBJECTIVE: To investigate pulmonary function, working capacity and isokinetic muscle strength in subjects with Marfan syndrome. MATERIALS AND METHODS: Seventeen subjects, mean age 23 years, performed spirometry, maximal ergometer cycle tests and knee extension and flexion isokinetic torque tests. RESULTS: The subjects with Marfan syndrome had increased total and residual lung volume values compared with predicted values in healthy subjects and reduced peak oxygen uptake compared with healthy subjects of the same age. The isokinetic peak torque was reduced only at the highest velocity in the women. CONCLUSION: Thirteen subjects were able to perform the bicycle test until exhaustion without cardiovascular complications or pulmonary restrictions. However, their aerobic capacity was considerably decreased, which we suggest is caused by deconditioning. Further investigations are needed to reveal how pulmonary and cardiovascular limitations change with ageing and to give guidelines for exercise.

Comparison of daily and weekly retrospectively reported pain intensity in patients with localized and generalized musculoskeletal pain.

The purpose of the study was to compare daily and weekly recalled pain intensity over time and their correspondence with real-time pain intensity in patients with localized (LP) and generalized (GP) musculoskeletal pain. Daily recalled pain, averaged over seven consecutive days, and weekly recalled pain at day 8 were recorded on 100 mm visual analogue scales monthly over 4 months for 40 LP and 50 GP patients. Multiple real-time pain ratings on numerical rating scales (0-10) were averaged over the week for 23 LP and 33 GP patients in Month 4. Reliability was assessed using the intraclass correlation coefficients (ICC) and the standard deviations of the repeated measurements. Daily pain ratings were lower than weekly ratings across the 4-month period. Reliability was lower for weekly than for daily recalled pain in the GP group, and lower than in the LP group. These results were independent of the magnitude of pain intensity. No difference was found between daily recalled and real-time ratings. The ICC was higher between daily and real-time ratings than between weekly and real-time ratings in Month 4. Weekly ratings were higher than real-time ratings in the GP group, and the overestimation increased with increasing pain intensity. The results of the present study indicated that reliability was improved by using ratings of daily recalled pain averaged over a week rather than single ratings of weekly recalled pain in subjects with localized or generalized pain. Weekly recalled pain was overestimated in subjects exhibiting generalized pain and high pain intensity.

Attenuated adrenergic responses to exercise in women with fibromyalgia--a controlled study.

The pathogenesis of widespread pain and fibromyalgia (FM) is unknown. Altered responses from the hypothalamus-pituitary-adrenal axis, sympathetic nervous system and muscular system have been suggested as being of importance. The present study was undertaken to determine: (i) whether the sympathoadrenal response to repetitive isometric contractions until exhaustion is altered in patients with FM, and (ii) whether sympathoadrenal responses are associated with muscle fatigue and pain during exercise. Nineteen women with FM, and 19 healthy women matched for age, smoking and self-reported physical activity, participated. Maximal voluntary contraction (MVC), repetitive isometric contractions (6s contraction and 4s resting phases) were performed with both quadriceps muscles at 30% of MVC until exhaustion. Muscle activity was recorded from the quadriceps muscles by surface electromyography (EMG). Plasma adrenalin (Adr), noradrenalin (NAdr) and cortisol were measured and perceived exertion and pain reported during exercise. Attenuated Adr responses (p<0.001) with normal plasma NAdr and cortisol (p>0.19) responses were found during exercise in the FM group compared with the control group. Significantly higher EMG amplitude (%EMG(max)) during the contraction phases (p=0.001) was found in the FM than in the control group. Perceived exertion and pain responses to exercise were higher in the FM group than in the controls (p<0.001), without relationship to the sympathoadrenal responses. In conclusion; the exercise was perceived as being more painful and strenuous in the FM group. Muscle performance was altered with increased muscle activity during the exercise. Women with FM showed an attenuated Adr response to repetitive isometric exercise.