Longitudinal Mixed Model Analysis Research Articles

Longitudinal Course of Long Finger Flexor Shortening in Males with Duchenne Muscular Dystrophy: A Retrospective Review1.

Shortening of the long finger flexors (Flexor Digitorum Profundus, FDPs) in Duchenne Muscular Dystrophy (DMD) causes reduced hand function. Until now, longitudinal studies on the natural course of the shortening of the FDPs are lacking, which impedes recommendations on timing and evaluation of preventive measures. To investigate the longitudinal course of the FDP length during different disease stages focusing on symmetry, timing, and decline of the FDP length. A retrospective, longitudinal multicenter study was conducted in the Radboud university medical center and the Leiden university medical center. The FDP outcome was measured using goniometry and gross motor function was assessed using the Brooke score. Longitudinal mixed model analyses were used to describe the course of the FDP outcome, and to investigate symmetry in both hands. Data on 534 visits of 197 males (age ranged 4-48 years) showed that in the ambulatory stages the FDP outcome was within a normal range. The mean decline in FDP outcome is 3.5 degrees per year, the biggest decline was seen in Brooke 5 (>15 degrees per year). In Brooke 4, 41% of the FDP outcome was < 40 degrees. No significant differences were found between right and left. This study supports the consideration of preventive measures to delay shortening of the FDPs in DMD patients transitioning to a Brooke scale of 4 or higher. Besides, natural history of FDP outcome has been established, which provides a base to evaluate (preventive) interventions.

Living cellular constructs for keratinized tissue augmentation: A 13-year follow-up from a split-mouth randomized, controlled, clinical trial.

to evaluate the long term outcomes of living cellular construct (LCC) compared to free gingival graft (FGG) for keratinized tissue width (KTW) augmentation in the natural dentition. Twenty-four subjects out of the original 29 enrolled participants were available at the 13-year follow-up. The primary endpoint was the number of sites demonstrating stable clinical outcomes from 6 months to 13 years (defined as KTW gain, stability or ≤ 0.5 mm of KTW loss, together with reduction, stability or increase of PD and REC ≤ 0.5 mm). Secondary outcomes included the assessment of KTW, attached gingiva width (AGW), recession depth (REC), clinical attachment level (CAL), esthetics and patient-reported outcomes (PROMs) at the 13-year visit, assessing the changes from baseline to 6 months. Nine sites per group (42.9%) were found to have maintained stable (≤ 0.5 mm or improved) clinical outcomes from 6 months to 13 years. No significant differences were observed for the clinical parameters between LCC and FGG from 6 months to 13 years. However, the longitudinal mixed model analysis showed that FGG delivered significantly better clinical outcomes over 13 years (p<0.01). LCC-treated sites exhibited superior esthetic outcomes compared to FGG-treated sites at 6 months and 13 years (p<0.01). Patient-esthetics was significantly higher for LCC over FGG (p<0.01). Patient overall treatment preference was also in favor of LCC (p<0.01). A similar stability of the treatment outcomes from 6 months to 13 years was found for LCC- and FGG-treated sites, with both approaches shown to be effective in augmenting KTW and AGW. However, superior clinical outcomes were found for FGG over 13 years, while LCC was associated with better esthetics and patient-reported outcomes than FGG. This article is protected by copyright. All rights reserved.

Exploring maladaptive cognitions and behaviors as perpetuating factors in patients with persistent somatic symptoms: a longitudinal study

ObjectiveMaladaptive cognitions and behaviors may influence symptoms and impairment in patients with persistent somatic symptoms (PSS). Aims of this study were to examine: (i) whether maladaptive cognitions and behaviors are associated with symptom severity and functional health over time; (ii) if these associations are the result of changes within individuals over time or of differences between individuals; (iii) directions of changes within individuals over time. MethodsLongitudinal data of a heterogeneous sample of patients with PSS were analyzed (n = 322 patients enrolled in the PROSPECTS cohort study). Cognitive and behavioral responses to symptoms (CBRQ), symptom severity (PHQ-15) and physical and mental functioning (RAND-36 PCS and MCS) were assessed seven times over a five-year period (0, 6 months, 1, 2, 3, 4, 5 year). Longitudinal mixed model and hybrid model analysis with and without time-lag were applied. ResultsMaladaptive cognitions and behaviors were associated with more severe symptoms and reduced physical and mental functioning over time. Both changes within individuals over time and differences between individuals were associated with higher symptom severity and reduced physical and mental functioning. The between-subject component was about twice the effect size of the within-subject component. Changes in several specific maladaptive cognitions and behaviors were associated with more severe symptoms and reduced physical and mental functioning later in time and vice versa. ConclusionThis study shows that maladaptive cognitions and behaviors are associated with symptom severity and reduced physical and mental functioning over time in patients with PSS.

Childhood sleep and obesity risk: A prospective cohort study of 10 000 Swedish children.

To identify factors affecting early childhood sleep, and investigate the relationship between sleep and overweight/obesity in childhood. Data were collected using parental-completed questionnaires from N=10.840 one-year-old children in the prospective ABIS-study (All Babies in Southeast Sweden), followed up until 8 years of age. Chi-squared test and Pearson Correlation were used to assess the relationship between covariates affecting the children's sleep. Subsequently, longitudinal mixed model analyses were used to predict the effect of different sleep dimensions (bedtime, sleep duration, sleep quality, and the number of awakenings) on BMI Z-scores. Children to parents born in Sweden, parents with higher education, non-single parents, non-smoking mothers during pregnancy, and children with fewer siblings, were more likely to have appropriate sleep habits at 1 year age. A greater number of awakenings and nocturnal feeds, and particularly later bedtime (β=-0.544, p < 0.0001) were linked to shorter sleep duration. Sleep duration early in life was negatively associated with BMI Z-scores (adjusted effect estimate [95% CI]: β=-0.09, [(-0.15) - (-0.03)], p=0.005) later. In addition, higher birth weight, small size for gestational age, unhealthy food habits, children of mothers who smoked during pregnancy, and higher parental BMI resulted in higher BMI Z-scores. The child's BMI Z-score increases by 0.09 units with every hour shorter sleep duration, indicating that short sleep duration might increase the risk of overweight and obesity in children. Parental educational interventions advising appropriate sleeping patterns should be considered when implementing strategies to combat the development of childhood obesity.

Potentially traumatic events, social support and burden of persistent somatic symptoms: A longitudinal study

ObjectivePsychological trauma is a well-known risk factor for the onset of persistent somatic symptoms (PSS). In contrast, little is known on the relation between potentially traumatic events (PTEs) and the severity of PSS, and on the protective effect of social support. We aimed to: (i) determine whether childhood, adulthood and recent PTEs are associated with burden of PSS over four years of follow-up; (ii) examine associations of multiple and cumulative (in childhood and adulthood) exposure to PTEs with burden of PSS; and (iii) determine whether social support modifies these associations. MethodsLongitudinal data of 322 patients with PSS were analyzed. PTEs (Life Events Questionnaire) and social support (Social Support Scale) were assessed at baseline. Burden of PSS was measured in terms of symptom severity (PHQ-15) and physical functioning (RAND-36 PCS) at six repeated measurements over a four-year interval. Associations were analyzed using longitudinal mixed model analysis. ResultsPatients with multiple childhood PTEs reported higher burden of PSS over four-year time. Adulthood PTEs were associated with burden of PSS in patients with, but not in patients without childhood PTEs. Recent PTEs were not associated with burden over time. Social support did not modify any of the associations. ConclusionsPTEs are associated with higher burden of PSS over time, in addition to the well-known association with the onset of PSS. PTEs in early life and cumulative exposure to PTEs in childhood and adulthood are associated with higher burden over time in patients with PSS. Social support did not attenuate the associations.

Analysing outcome variables with floor effects due to censoring: a simulation study with longitudinal trial data

ackground: Randomised controlled trials (RCTs) are the gold standard to estimate treatment effects. When patients receive effective treatment over time they may reach the limit of a certain measurement scale. This phenomenon is known as censoring and lead to skewed distributions of the outcome variable with an excess of either low (floor effect) or high values (ceiling effect). Applying traditional methods such as linear mixed models to analyse this kind of longitudinal RCT data may result in bias of the regression parameters. To deal with floor effects due to censoring, a tobit mixed model can be used. The objective of this study was to compare the results of longitudinal linear mixed model analyses with longitudinal tobit mixed model analyses.Methods: First, a simulation study was performed in which several situations of RCTs with floor effects were simulated. Second, data from an empirical RCT was analysed with both methods.Results: Although all analyses underestimated the intervention effects, the tobit mixed model performed much better than the linear mixed model in handling floor effects. However, with an increasing number of follow-up measurements in combination with a strong floor effect estimates from the tobit mixed model were also not accurate.Conclusion: tobit mixed model analysis should be used to estimate treatments effects in longitudinal RCTs with floor effects due to censoring.

Low variability of plant protein intake in the CKiD cohort does not demonstrate changes in estimated GFR nor electrolyte balance.

Vegetable or plant-based sources of protein may confer health benefits in children with progressive kidney disease. Our aims were to understand the effect of the proportion of vegetable protein intake on changes in estimated GFR and to understand the effect of the proportion of vegetable protein intake on serum levels of bicarbonate, phosphorus, and potassium. Children with baseline eGFR between 30 and 90 mL/min/1.73 m2 were recruited from 59 centers across North America as part of the chronic kidney disease in children (CKiD) study. The percentage of dietary vegetable protein (VP%) was gathered from annual Food Frequency Questionnaires. We performed longitudinal linear mixed models to determine the effect of VP% on eGFR and longitudinal logistic mixed models to determine the effect of VP% on electrolyte balance (potassium, phosphorus, bicarbonate). Two thousand visits from 631 subjects. Across all dichotomized groups of children (sex, African American race, Hispanic ethnicity, glomerular etiology of CKD, hypertension, anemia, hyperkalemia, hyperphosphatemia, acidosis, BMI < 95th percentile), the median VP% was 32-35%. The longitudinal mixed model analysis did not show any effect of VP% on eGFR electrolyte (bicarbonate, phosphorus, and potassium) abnormalities (p > 0.1). A diverse cohort of children with CKD has a narrow and homogeneous intake of vegetable protein. Due to the low variability of plant-based protein in the cohort, there were no associations between the percentage of plant protein intake and changes in eGFR nor electrolyte balance. A higher resolution version of the Graphical abstract is available as Supplementary information.

Smoothness metric during reach-to-grasp after stroke: part 2. longitudinal association with motor impairment

BackgroundThe cause of smoothness deficits as a proxy for quality of movement post stroke is currently unclear. Previous simulation analyses showed that spectral arc length (SPARC) is a valid metric for investigating smoothness during a multi-joint goal-directed reaching task. The goal of this observational study was to investigate how SPARC values change over time, and whether SPARC is longitudinally associated with the recovery from motor impairments reflected by the Fugl-Meyer motor assessment of the upper extremity (FM-UE) in the first 6 months after stroke.MethodsForty patients who suffered a first-ever unilateral ischemic stroke (22 males, aged 58.6 ± 12.5 years) with upper extremity paresis underwent kinematic and clinical measurements in weeks 1, 2, 3, 4, 5, 8, 12, and 26 post stroke. Clinical measures included amongst others FM-UE. SPARC was obtained by three-dimensional kinematic measurements using an electromagnetic motion tracking system during a reach-to-grasp movement. Kinematic assessments of 12 healthy, age-matched individuals served as reference. Longitudinal linear mixed model analyses were performed to determine SPARC change over time, compare smoothness in patients with reference values of healthy individuals, and establish the longitudinal association between SPARC and FM-UE scores.ResultsSPARC showed a significant positive longitudinal association with FM-UE (B: 31.73, 95%-CI: [27.27 36.20], P < 0.001), which encompassed significant within- and between-subject effects (B: 30.85, 95%-CI: [26.28 35.41], P < 0.001 and B: 50.59, 95%-CI: [29.97 71.21], P < 0.001, respectively). Until 5 weeks post stroke, progress of time contributed significantly to the increase in SPARC and FM-UE scores (P < 0.05), whereafter they levelled off. At group level, smoothness was lower in patients who suffered a stroke compared to healthy subjects at all time points (P < 0.05).ConclusionsThe present findings show that, after stroke, recovery of smoothness in a multi-joint reaching task and recovery from motor impairments are longitudinally associated and follow a similar time course. This suggests that the reduction of smoothness deficits quantified by SPARC is a proper objective reflection of recovery from motor impairment, as reflected by FM-UE, probably driven by a common underlying process of spontaneous neurological recovery early post stroke.

Review of patient-reported outcomes in multiple myeloma registrational trials: highlighting areas for improvement

Over the past 13 years, there have been advances in characterizing the patient experience in oncology trials, primarily using patient-reported outcomes (PROs). This review aims to provide details on the PRO measures and analyses used in multiple myeloma (MM) registrational trials. We identified registrational trials supporting MM indications from 2007 to 2020 from FDA databases. Trial protocols, statistical analysis plans, and clinical study reports were reviewed for PRO measures used, collection methods, statistical analyses, baseline and instrument completion definitions, and thresholds for clinical meaningfulness. Twenty-five trials supporting 20 MM indications were identified; 17 (68%) contained submitted PRO data. Of the 17 trials, 14 were randomized controlled trials and the remainder were single-arm trials. All but one trial were open label trials. Seven trials collected data electronically and five in paper format. The majority of trials evaluated at least two PRO measures (82%) with two trials (12%) utilizing four measures. Nine unique PRO measures were used, most commonly the EORTC QLQ-30 (87%), EQ-5D (65%), and QLQ-MY20 (47%). All 17 (100%) trials provided descriptive summaries, 10 (59%) carried out longitudinal mixed model analysis, 9 (53%) conducted responder analysis, and 2 (12%) did a basic inferential test. We noted substantial heterogeneity in terms of PRO collection methods, measures, definitions, and analyses, which may hinder the ability to effectively capture and interpret patient experience in future MM clinical trials. Further research is needed to determine the most appropriate approaches for statistical and analytical methodologies for PRO data in MM trials.

Incidence and Time Point of Sepsis Detection as Related to Different Sepsis Definitions in Severely Burned Patients and Their Accompanying Time Course of Pro-Inflammatory Biomarkers.

Background: Diagnosis of sepsis in burn patients remains difficult for various reasons. One major problem is the definition of sepsis itself. Therefore, previous and current sepsis definitions are a matter of ongoing validation, but a well-defined consensus on which clinical and laboratory parameters to incorporate in such a definition is lacking. The aim of the present study was to compare the incidence and time-related occurrence of septic events according to different definitions as well as their accompanying time course of pro-inflammatory biomarkers. Methods: Across the first 14 days after admission, the incidence and time point of sepsis according to three different definitions (Sepsis-3, Sepsis American Burns Association [ABA] 2007, Sepsis Zurich Burn Center) were assessed on a daily basis in adult burn patients with total body surface area (TBSA) ≥15% admitted to the Zurich Burn Center between May 2015 and October 2018. In order to investigate how well daily drawn proinflammatory biomarkers (white blood cells (WBCs), C-reactive protein (CRP), procalcitonin (PCT), and novel pancreatic stone protein (PSP)) reflect the progression of sepsis depending on its type of definition, a longitudinal mixed model analysis was performed across the first 14 days for septic and non-septic patients. Additionally, the relative increase of biomarker levels 24, 48, and 72 h prior to a septic event was analyzed for each definition used. Results: In our cohort of 90 severely burned patients, Sepsis-3 identified 46 patients (51.1%) as septic, while ABA 2007 and the Zurich Burn Center definition counted 33 patients (36.7%) and 24 patients (26.6%), respectively. Sepsis-3 detected sepsis about 1 day earlier than Sepsis ABA 2007 (p < 0.001) and about 0.5 days earlier than Sepsis Zurich Burn Center (p = 0.04). The course of pro-inflammatory biomarkers was largely unaffected by the type of sepsis definition. Irrespective of the sepsis definition, PSP was the only marker to demonstrate a highly significant interaction between time and group (sepsis versus no sepsis) (p < 0.001) with a 3.3–5.5-fold increase within 72 h before the event of sepsis, whereas CRP, PCT, and WBC showed only mild undulations. Conclusions: Despite the ongoing dilemma of how to define sepsis in burn patients, a continually calculated SOFA score as used in Sepsis-3 is advantageous to early identify a patient’s detrimental progression to sepsis. Inclusion of biomarkers, such as PSP, may help support the burn specialist’s diagnosis of sepsis and could improve the diagnostic performance of current and future definitions in burn patients.

The pattern of inflammatory markers during electroconvulsive therapy in older depressed patients

Objectives An association is found between changes in cytokine levels and antidepressant treatment outcome. Also, a proinflammatory profile is associated with a favourable electroconvulsive therapy (ECT) outcome. This paper investigates the pattern of inflammatory markers during a course of ECT in older depressed patients and whether this pattern is associated with ECT outcome. We hypothesised that ECT has an anti-inflammatory effect. Methods The pattern of CRP, IL-6, IL-10, and TNF-α during a course of ECT was examined using longitudinal mixed model analyses. Serum samples were collected in 99 older depressed patients (mean age: 72.8 ± 8.3 years, MADRS score 33.8 ± 9.0). Results After Bonferroni correction, there were no statistically significant alterations in levels of inflammatory markers during and after ECT. Effect sizes (Cohen’s d) were −0.29 for CRP, −0.13 for IL-6, −0.06 for IL-10, and −0.07 for TNF-α. Changes in CRP or cytokine levels did not differ between remitters and non-remitters. Median baseline levels of CRP were significantly higher in remitters. Conclusions A small to medium effect size towards decreased CRP and IL-6 levels was observed. An anti-inflammatory effect of ECT could not be confirmed. However, the findings may suggest that patients with an inflammatory profile benefit more from ECT than other patients. Further studies are needed to confirm these findings.

Metformin and N-terminal pro B-type natriuretic peptide in type 2 diabetes patients, a post-hoc analysis of a randomized controlled trial.

BackgroundBeyond antihyperglycemic effects, metformin may improve cardiovascular outcomes. Patients with type 2 diabetes often have an elevated plasma level of N-terminal pro B-type as a marker of (sub) clinical cardiovascular disease. We studied whether metformin was associated with a reduction in the serum level of N-terminal pro B-type natriuretic peptide (NT-proBNP) in these patients.MethodsIn the HOME trial 390 insulin-treated patients with type 2 diabetes were randomized to 850 mg metformin or placebo three times daily. Plasma samples were drawn at baseline, 4, 17, 30, 43 and 52 months. In a post-hoc analysis we analyzed the change in NT-proBNP in both groups. We used a longitudinal mixed model analysis adjusting for age, sex and prior cardiovascular disease. In a secondary analysis we assessed a possible immediate treatment effect post baseline.ResultsMetformin did not affect NT-proBNP levels over time in the primary analysis (-1% [95%CI -4;3, p = 0.62]). In the secondary analysis there was also no sustained time independent immediate treatment effect (initial increase of 17% [95%CI 4;30, p = 0.006] followed by yearly decrease of -4% [95%CI -7;0, p = 0.07]).ConclusionsMetformin as compared to placebo did not affect NT-proBNP plasma levels in this 4.3-year placebo-controlled trial. Potential cardioprotective effects of metformin cannot be explained by changes in cardiac pressures or volumes to the extent reflected by NT-proBNP.

Validation of a three-item Fatigue Severity Scale for patients with substance use disorder: a cohort study from Norway for the period 2016\u20132020

BackgroundLittle attention has been paid to customising fatigue questionnaires for patients with Substance Use Disorders (SUDs). The present study aims to validate and shorten the nine-item Fatigue Severity Scale (FSS-9) and Visual Analogue Fatigue Scale (VAFS) for use with this population.MethodsWe used data from a nested cohort with annual health assessments with responses on the FSS-9 and VAFS. During the period 2016–2020, 917 health assessments were collected from 655 patients with SUD in Bergen and Stavanger, Norway. A total of 225 patients answered the health assessment at least twice. We defined baseline as the first annual health assessment when the health assessments were sorted chronologically per patient. We checked for internal consistency, and we used longitudinal confirmatory factor analysis (CFA) and linear mixed model (LMM) analysis to validate and shorten the FSS-9 and VAFS.ResultsThe internal consistency of the FSS-9 was excellent with a Cronbach’s α of 0.94 at baseline and 0.93 at the second annual health assessment. When shortening the FSS-9 to a three-item FSS (FSS-3, items 5–7), the Cronbach’s α was 0.87 at baseline and 0.84 at the second health assessment. The internal consistency was not affected when the VAFS was added to the FSS-3 and the FSS-9. The longitudinal CFA model showed a well-fitting model for the FSS-3 (χ2 = 13.33, degree of freedom = 8, P = 0.101). The LMM analysis showed equal linear changes at the individual level for the FSS-3 (slope: 0.00, P > 0.05) and FSS-9 (slope: 0.01, P > 0.05) between the health assessments.ConclusionThe FSS-9 could be shortened to the FSS-3 with high validity and reliability for patients with SUDs and the addition of VAFS did not provide much added variability.

The APOE ε4 allele in relation to pre- and postsurgical cognitive functioning of patients with primary brain tumors.

BackgroundRecent studies suggest a relationship between the APOE ε4 allele and cognitive outcome in patients treated for malignant brain tumors. Still, longitudinal investigations that include a pretreatment cognitive assessment are lacking and APOE’s effects in patients with benign tumors are understudied. This study investigated presurgical cognitive performance and postsurgical change in ε4‐carrying and non‐carrying patients with glioma and meningioma.MethodsNeuropsychological test scores (CNS Vital Signs battery [seven measures], Digit Span Forward/Backward, Letter Fluency test) were obtained as part of a prospective study in which patients with meningioma and glioma underwent cognitive assessment 1 day before (T0, n = 505) and 3 (T3, n = 418) and 12 months after (T12, n = 167) surgery. APOE isoforms were identified retrospectively. ε4 carriers and non‐carriers were compared with regard to pretreatment cognitive performance on the group and individual level. Changes in performances over time were compared with longitudinal mixed model analysis in the total sample and the subgroup receiving adjuvant treatment.ResultsCarriers and non‐carriers did not differ with regard to pretreatment performance. No significant main effect of ε4 carrier status or interaction between time (T0–T12) and carrier status was found on any of the tests in the whole sample nor in the sample receiving adjuvant treatment.ConclusionsThis study found no evidence of increased vulnerability for pretreatment cognitive dysfunction or cognitive decline within 1 year after surgery in APOE ε4‐carrying meningioma and glioma patients. Investigations that include larger samples at longer‐term follow‐up are recommended to investigate potential late treatment effects.

Impact of symptom focusing and somatosensory amplification on persistent physical symptoms: A three-year follow-up study

ObjectiveThe somatosensory amplification theory considers symptom focusing and somatosensory amplification as important perpetuating factors of persistent physical symptoms. We investigated whether symptom focusing and somatosensory amplification were associated with symptom severity and mental and physical functioning over a three-year period in patients with persistent physical symptoms (PPS). MethodsBaseline, 6-, 12-, 24- and 36-months follow-up data from the PROSPECTS study, a prospective cohort consisting of 325 patients with PPS, were used. We applied longitudinal mixed model analyses to investigate if symptom focusing (CBRQ Symptom Focusing Subscale) and somatosensory amplification (Somatosensory Amplification Scale) at baseline were associated with symptom severity (PHQ-15), mental and physical functioning (RAND-36 MCS and PCS) over three years, using all measurements. ResultsSymptom focusing was associated with increased symptom severity and lower mental and physical functioning over time. Somatosensory amplification at baseline was associated with increased symptom severity and lower mental and physical functioning over time. Effect sizes were small. Associations with baseline symptom focusing decreased over time, associations with baseline somatosensory amplification were more stable. There was no interaction effect of both constructs, but they partly overlapped. ConclusionThis is the first study to show that over an extended period, symptom focusing and somatosensory amplification are associated with symptom severity and lower mental and physical functioning in patients with PPS. These results support the impact of both symptom focusing and somatosensory amplification on the perpetuation of symptoms and lowered mental and physical functioning in individuals with PPS.

Randomized controlled trials reflected clinical practice when comparing the course of low back pain symptoms in similar populations

ObjectiveThis study compares participants in randomized controlled trials (RCTs) (the Minimal Invasive Treatment [MinT] trials) to participants in a related observational study with regard to their low back pain (LBP) symptom course. Study Design and SettingEligible patients were diagnosed with chronic LBP originating from the facet joints (N = 615) or sacroiliac (SI) joints (N = 533) and were treated with radiofrequency denervation and an exercise program. Randomized patients were compared to patients in the related observational study who fulfilled all RCT eligibility criteria (observational group 1) and to patients who did not fulfill at least one of the RCT eligibility criteria (observational group 2). Outcomes were pain intensity, treatment success, and functional status over a 3-month period. Longitudinal mixed-model analyses and linear regression models were applied to analyze the differences in outcomes between the RCT and observational study groups. ResultsNo differences in symptom course were found between patients in the RCTs and patients in observational group 1. Patients with facet joint pain in observational group 2 had overall less treatment success (odds ratios [OR], 0.67; 95% confidence interval [CI], 0.50–0.90), and less improvement in physical functioning (mean difference [MD], 5.82; 95% CI, 2.54–9.11) compared to the RCT patients. Patients with SI joint pain in observational group 2 had higher pain scores (MD, 0.40; 95% CI, 0.09–0.72), less treatment success (OR, 0.72; 95% CI, 0.54–0.96), and less improvement in physical functioning (MD, 7.16; 95% CI, 3.84–10.47) compared to the RCT patients. ConclusionThis supports the generalizability of results from the MinT RCTs as this study suggests that these RCTs reflect clinical practice when comparing similar populations. To what extent this holds true for all RCTs in LBP should be further explored.

Targeted Muscle Reinnervation Treats Neuroma and Phantom Pain in Major Limb Amputees: A Randomized Clinical Trial.

To compare targeted muscle reinnervation (TMR) to "standard treatment" of neuroma excision and burying into muscle for postamputation pain. To date, no intervention is consistently effective for neuroma-related residual limb or phantom limb pain (PLP). TMR is a nerve transfer procedure developed for prosthesis control, incidentally found to improve postamputation pain. A prospective, randomized clinical trial was conducted. 28 amputees with chronic pain were assigned to standard treatment or TMR. Primary outcome was change between pre- and postoperative numerical rating scale (NRS, 0-10) pain scores for residual limb pain and PLP at 1 year. Secondary outcomes included NRS for all patients at final follow-up, PROMIS pain scales, neuroma size, and patient function. In intention-to-treat analysis, changes in PLP scores at 1 year were 3.2 versus -0.2 (difference 3.4, adjusted confidence interval (aCI) -0.1 to 6.9, adjusted P = 0.06) for TMR and standard treatment, respectively. Changes in residual limb pain scores were 2.9 versus 0.9 (difference 1.9, aCI -0.5 to 4.4, P = 0.15). In longitudinal mixed model analysis, difference in change scores for PLP was significantly greater in the TMR group compared with standard treatment [mean (aCI) = 3.5 (0.6, 6.3), P = 0.03]. Reduction in residual limb pain was favorable for TMR (P = 0.10). At longest follow-up, including 3 crossover patients, results favored TMR over standard treatment. In this first surgical RCT for the treatment of postamputation pain in major limb amputees, TMR improved PLP and trended toward improved residual limb pain compared with conventional neurectomy. NCT02205385 at ClinicalTrials.gov.

Patient-reported quality of life (QoL) of advanced melanoma patients in a Phase 3 study of nivolumab (NIVO) with or without ipilimumab (IPI) versus IPI: CheckMate 067 4-year data.

9551 Background: Early CheckMate 067 data showed maintenance of QoL in patients with advanced melanoma treated with NIVO with or without IPI based on 1-year data; however, the long-term QoL of these patients has not been evaluated previously. The patient-reported outcomes (PRO) analyses presented here for CheckMate 067 is the first time QoL results have been evaluated in this melanoma population over a 4-year period. Methods: In CheckMate 067, 945 patients were randomized 1:1:1 to receive NIVO (3mg/kg Q2W) + placebo (PBO), NIVO+IPI (1mg/kg+3mg/kg Q3W X 4) followed by NIVO (3mg/kg Q2W), or IPI (3mg/kg Q3W X 4) + PBO. PRO data were collected using the EORTC QLQ-C30 (5 functional domains, 9 symptoms, global health status) and EQ-5D-3L (utility index, VAS) at baseline, weeks 1 and 5 of each 6-week tx cycle, and off-tx follow-up (FU) visits. Mean changes in PRO scores from baseline (randomization) were evaluated descriptively for the PRO analysis population, with conclusions drawn from time points with ≥30 patients completing assessments per tx arm. Least square mean changes from baseline were assessed using a longitudinal mixed model analysis adjusting for repeated measures, including all on-tx data for patients. Results: Completion rates at baseline ranged from 89-92% across tx arms. Of 813 patients included in the PRO analysis population (278 NIVO, 274 NIVO+IPI, 261 IPI), &gt; 200 receiving tx remained for the first year, &gt; 100 receiving tx remained after 2 years, and &gt; 50 receiving tx remained after 3 years. QoL, including assessment of functioning and symptom burden, was maintained for the duration of tx and in FU, with no sustained clinically meaningful deterioration in any tx arm. Global health status (EORTC QLQ-C30) and general QoL (EQ-5D-3L VAS) were also maintained during prolonged tx. Overall, results from the mixed model analysis support the long-term maintenance of QoL over the course of tx. Conclusions: Patient-reported QoL and symptoms in patients with advanced melanoma were maintained from baseline during extended tx with NIVO with or without IPI. Clinical trial information: NCT01844505.

Progression of Structural Damage in the Sacroiliac Joints in Patients With Early Axial Spondyloarthritis During Long-Term Anti-Tumor Necrosis Factor Treatment: Six-Year Results of Continuous Treatment With Etanercept.

To evaluate radiographic progression in the sacroiliac (SI) joints and to identify its predictors during long-term treatment (up to 6 years) with the tumor necrosis factor (TNF) inhibitor etanercept in patients with early axial spondyloarthritis (SpA). Patients with early axial SpA who were treated with etanercept for up to 6 years in the Etanercept versus Sulfasalazine in Early Axial Spondyloarthritis (ESTHER) trial were selected based on the availability of radiographs of the SI joints. Two readers who were blinded with regard to clinical data scored the radiographs according to the modified New York criteria (range 0-4 per SI joint). A sacroiliitis sum score (total range 0-8) was calculated as the mean of the scores of the 2 readers. Active and chronic inflammatory changes in the SI joints on magnetic resonance imaging (MRI) performed at baseline, year 2, and year 4 were assessed according to the Berlin MRI scoring system. Of the 76 patients originally included in the study, 42 had radiographs of the SI joints available at baseline and at least 1 follow-up time point (year 2, 4, or 6). The mean ± SD change in the sacroiliitis sum score was 0.13 ± 0.73, -0.27 ± 0.76, and -0.09 ± 0.68, in the time intervals baseline to year 2, year 2 to year 4, and year 4 to year 6, respectively. In the longitudinal mixed model analysis, elevated C-reactive protein level (β = 0.58 [95% confidence interval 0.24, 0.91]) and MRI SI joint osteitis score (β = 0.06 [95% confidence interval 0.03, 0.10]) were independently associated with progression of the sacroiliitis sum score. Our findings indicate that long-term anti-TNF therapy decelerates the progression of structural damage in the SI joints. Elevated CRP level and presence of osteitis on MRI were independently associated with radiographic sacroiliitis progression.

Functional relevance of radiographic spinal progression in axial spondyloarthritis: results from the GErman SPondyloarthritis Inception Cohort.

The aim of the study was to investigate the functional relevance of the development of structural damage in the spine in patients with early axial spondyloarthritis (axSpA). Altogether, 210 patients with early axSpA (symptom duration ⩽10 years) who completed a 2-year clinical and radiographic follow-up in the GErman SPondyloarthritis Inception Cohort were included. An association between structural damage in the spine [modified Stoke AS Spine Score (mSASSS)] and functional status (the BASFI) or spinal mobility (the BASMI) was assessed in a longitudinal linear mixed model analysis; both unstandardized (β) and standardized (βstand) regression coefficients were calculated. There was an association between mSASSS and BASFI: β = 0.05 (95% CI: 0.03, 0.08) and βstand = 0.20 (95% CI: 0.11, 0.59) adjusted for disease activity parameters (the BASDAI and CRP), the presence of definite radiographic sacroiliitis and sex. An association between mSASSS and BASMI was stronger: β = 0.08 (95% CI: 0.05, 0.11) and βstand = 0.41 (95% CI: 0.25, 0.57) adjusted for the same parameters. These data indicate that, over time, an increase of 20 or 12 mSASSS points would be responsible for an increase of one BASFI or one BASMI point, respectively. Disease activity (BASDAI) also showed a significant association with BASFI [β = 0.79 (95% CI: 0.71, 0.86) and βstand = 0.71 (95% CI: 0.63, 0.77)] and BASMI [β = 0.22 (95% CI: 0.15, 0.30) and βstand = 0.28 (95% CI: 0.18, 0.37)]. Structural damage in the spine and disease activity are both determinants of the functional status and spinal mobility in early axSpA.