Mixed Model Repeated Measures Analysis Research Articles

POS1030 EFFICACY OF UPADACITINIB IN PATIENTS WITH PSORIATIC ARTHRITIS STRATIFIED BY BASELINE SKIN SEVERITY: A SUBGROUP ANALYSIS OF TWO PHASE III TRIALS

Background:In the SELECT-PsA 1 and 2 clinical trials, upadacitinib (UPA) demonstrated efficacy and safety in patients (pts) with active psoriatic arthritis (PsA).1,2 PsA is associated with varying degrees of psoriatic symptoms; however, the impact of skin severity on treatment outcomes is not well understood.Objectives:This post-hoc analysis assessed the effects of baseline skin severity on UPA efficacy.Methods:SELECT-PsA 1 and SELECT-PsA 2 enrolled pts with PsA and prior inadequate response (IR) or intolerance to ≥1 non-biologic disease-modifying antirheumatic drug (DMARD)1 or ≥1 biologic DMARD2, respectively. In both trials, pts received once daily UPA 15 mg or UPA 30 mg or placebo (switched at Wk 24 to either UPA 15 mg or 30 mg); SELECT-PsA 1 also included the active comparator adalimumab (ADA). Only continuous UPA 15 mg and ADA are presented here. In this analysis, pts were divided into subgroups based on the extent of psoriasis at baseline (body surface area [BSA] of ≥3%-<10% or BSA ≥10%); efficacy endpoints were analyzed at Wk 56. Results for binary endpoints are based on non-responder imputation; continuous endpoints are based on mixed model repeated measures analysis with as-observed data.Results:In the UPA 15 mg and ADA groups, respectively, 32% (138/429) and 31% (132/429) of pts had a BSA ≥3-<10% at baseline in SELECT-PsA 1; 18% (76/429) in each treatment group had a BSA ≥10%. In SELECT-PsA 2, 38% (80/211) had a BSA ≥3-<10% and 24% (50/211) had a BSA ≥10% at baseline in the UPA 15 mg group. Across pt populations (non-biologic DMARD-IR and biologic DMARD-IR), generally consistent results were observed between patients in both skin severity subgroups (Figure 1). In non-biologic DMARD-IR pts, a numerically greater proportion of UPA 15 mg pts with lower skin involvement compared with higher skin involvement achieved PASI100 and PASI≤1, two more stringent skin endpoints. The achievement of MDA was generally consistent across skin severity subgroups; when pts were required to achieve the skin component of MDA, results were numerically better in the ≥3-<10% skin severity group (Table 1). In non-biologic DMARD-IR pts, results were similar between UPA 15 mg and ADA.Conclusion:UPA is a viable treatment option for pts with active PsA regardless of the extent of psoriasis at baseline. Although these results are of interest and hypothesis-generating, they should be interpreted with caution due to low sample size.

Characterisation of depressive symptoms in rheumatoid arthritis patients treated with tocilizumab during routine daily care.

To assess whether tocilizumab treatment is associated with changes in depression symptoms in patients with rheumatoid arthritis (RA) during routine daily care. We retrospectively analysed data from a German non-interventional study (ARATA) of adult, tocilizumab-naïve RA patients who initiated subcutaneous tocilizumab and were followed for 52 weeks. The Beck Depression Inventory II (BDI-II) was used to assess symptoms of depression and create baseline subgroups of no (BDI-II<14), mild (14-19), moderate (20-28), and severe (≥29) depression. Other key outcomes included Disease Activity Score-28 joints (DAS28), patient-reported outcomes (PROs), and adverse events. Mixed model repeated measures (MMRM) assessed the impact of DAS28 on BDI-II over time, and Pearson correlation analyses evaluated associations between changes from baseline. Of 474/1155 ARATA patients who completed the BDI-II at baseline, 47.7% had evidence of depression: 18.4% mild, 17.7% moderate, and 11.6% severe. 229 patients (48.3%) completed the BDI-II at both baseline and week 52. Two-thirds of patients with moderate or severe depression at baseline improved to a milder or no depression subgroup at week 52 (44/65 [67.7%]). Improvements in disease activity and PROs were observed in all subgroups, but patients with depression had lower response and higher adverse events rates. We observed an association between DAS28 and BDI-II over time in MMRM analyses, but the Pearson correlation for change from baseline was weak (r=0.10). Depression is common in patients receiving routine care for RA. Improvements in depressive symptoms in RA during tocilizumab therapy appear to be distinct from changes in disease activity.

Thumb to spinous process is a false metric for glenohumeral internal rotation

The measurement of internal rotation by noting the maximal vertebral level reached by the patient's thumb behind their back is an established physical examination technique, as outlined in the American Shoulder and Elbow Surgeons Shoulder Assessment Form.7 The purpose of the present study is to correlate real-time glenohumeral internal rotation with thumb to spinous process movement to determine the accuracy of the technique. Healthy volunteers with no previous history of shoulder injury or symptoms were recruited from the local medical school population. Ultrasound probe was placed over the anterolateral shoulder, and relevant anatomy was identified. Internal rotation was evaluated by measuring displacement of the peak of the medial aspect of the bicipital groove relative to the anterior glenoid rim with the arm held in defined positions of progressively increasing internal rotation. The difference in displacement between arm positions was calculated and recorded. A total of 20 participants (11 women/9 men, aged 22-42 years) were recruited for measurement. A mixed-model repeated-measures analysis of variance was used. The most significant differences in displacement, and therefore internal rotation, were observed between the neutral and anterior superior iliac spine (0.21 ± 0.39 mm, P= .0269) and between the anterior superior iliac spine and peak iliac crest (0.26 ± 0.44 mm, P= .0163). After the peak iliac crest, there was no further statistically significant change in rotation. The present study suggests that most glenohumeral internal rotation occurs before reaching the arm behind the back. Although not directly studied, this supports the notion that the maximal vertebral level reached involves an interplay of various joint motions. While the thumb to spinous process maneuver remains a functional evaluation, our results suggest a different examination technique be used to more accurately test glenohumeral internal rotation.

Foot Posture and Plantar Loading With Ankle Bracing.

Arch height is one important aspect of foot posture. An estimated 20% of the population has pes planus and 20% has pes cavus. These abnormal foot postures can alter lower extremity kinematics and plantar loading and contribute to injury risk. Ankle bracing is commonly used in sport to prevent these injuries, but no researchers have examined the effects of ankle bracing on plantar loading. To evaluate the effects of ankle braces on plantar loading during athletic tasks. Cross-sectional study. Laboratory. A total of 36 participants (11 men, 25 women; age = 23.1 ± 2.5 years, height = 1.72 ± 0.09 m, mass = 66.3 ± 14.7 kg) were recruited for this study. Participants completed walking, running, and cutting tasks in 3 bracing conditions: no brace, lace-up ankle-support brace, and semirigid brace. We analyzed the plantar-loading variables of contact area, maximum force, and force-time integral for 2 midfoot and 3 forefoot regions and assessed the displacement of the center of pressure. A 3 × 3 mixed-model repeated-measures analysis of variance was used to determine the effects of brace and foot type (α = .05). Foot type affected force measures in the middle (P range = .003-.047) and the medial side of the foot (P range = .004-.04) in all tasks. Brace type affected contact area in the medial midfoot during walking (P = .005) and cutting (P = .01) tasks, maximum force in the medial and lateral midfoot during all tasks (P < .001), and force-time integral in the medial midfoot during all tasks (P < .001). Portions of the center-of-pressure displacement were affected by brace wear in both the medial-lateral and anterior-posterior directions (P range = .001-.049). Ankle braces can be worn to redistribute plantar loading. Additional research should be done to evaluate their effectiveness in injury prevention.

Aerobic and resistance exercise improve patient-reported sleep quality and is associated with cardiometabolic biomarkers in Hispanic and non-Hispanic breast cancer survivors who are overweight or obese: results from a secondary analysis.

Poor sleep quality affects nearly one-third of breast cancer survivors and is associated with insulin resistance. The purpose of this secondary analysis was to examine the effects of a 16-week exercise intervention on patient-reported sleep quality among breast cancer survivors and assess whether changes in patient-reported sleep quality were associated with cardiometabolic biomarkers. We explored Hispanic ethnicity as a moderator of the effects of exercise on patient-reported sleep quality. Breast cancer survivors who were overweight or obese were randomized to exercise (n = 50) or usual care (n = 50). The 16-week intervention included aerobic and resistance exercise. Patient-reported sleep quality (Pittsburgh Sleep Quality Index [PSQI]) and biomarkers of cardiometabolic health were assessed at baseline and post-intervention. Within- and between-group differences were assessed using general linear models repeated-measures analyses of variance and mixed-model repeated-measure analysis, respectively. Associations between changes in PSQI and cardiometabolic biomarkers were computed using Pearson correlations. Linear mixed-models were used to evaluate effect modification by ethnicity. Participants were 52 ± 10.4 years old, and over half were of Hispanic ethnicity. As compared to usual care, PSQI global scores improved significantly in the exercise group (mean between-group difference -2.2; 95% CI -3.2 to -0.6). Change in PSQI was inversely associated with changes in all cardiometabolic biomarkers (p < 0.01) among the exercise group. Ethnicity was found to moderate the effects of exercise training on global sleep quality (p < 0.001). An aerobic and resistance exercise intervention effectively improved patient-reported sleep quality in breast cancer survivors. Hispanic ethnicity as a moderator showed greater improvement in patient-reported sleep indicating Hispanic versus non-Hispanic breast cancer survivors may derive larger sleep benefits. NCT01140282.

Itch and Sleep Improvements with Baricitinib in Patients with Atopic Dermatitis: A Post Hoc Analysis of 3 Phase 3 Studies.

IntroductionBurdensome symptoms of atopic dermatitis include itch and sleep disturbance. This post hoc analysis reports the effect of baricitinib on itch and sleep disturbance during the first week of treatment in 3 phase 3 studies.MethodsPatients were randomized 2:1:1:1 to once-daily placebo or baricitinib 1 mg, 2 mg, or 4 mg in the BREEZE-AD1 and -AD2 studies and 1:1:1 to once-daily placebo or baricitinib 2 mg or 4 mg in the BREEZE-AD7 study. Topical corticosteroids were only allowed in BREEZE-AD7. Patients completed the itch numerical rating scale and atopic dermatitis sleep scale (ADSS) items 1–3 using an electronic daily diary. Data were analyzed by study as least squares mean percent change from baseline in daily scores for the randomized patients. Mixed model repeated measures analysis was used to analyze change from baseline values.ResultsA total of 624, 615, and 329 patients were randomized in BREEZE-AD1, -AD2, and -AD7, respectively. Itch severity significantly improved with baricitinib 2 mg and 4 mg versus placebo starting at day 2 (1 day after first dose) in BREEZE-AD1 and -AD7 and at day 1 in BREEZE-AD2. Patients’ ability to fall asleep (ADSS item 1) significantly improved with baricitinib 2 mg and 4 mg versus placebo starting at day 2 in all three studies. There were significant improvements in patients waking due to itch (ADSS item 2) with baricitinib 4 mg versus placebo starting at day 2 in all three studies. Patients’ ability to return to sleep after being woken by itch (ADSS item 3) was significantly improved with baricitinib 4 mg versus placebo starting at day 2 in BREEZE-AD1 and -AD2 and at day 4 in BREEZE-AD7.ConclusionRapid onset of action, typically 1 day after taking the first dose of baricitinib, was observed consistently for the burdensome symptoms of itch and sleep disturbance.ClinicalTrials.gov identifiersBREEZE-AD1, NCT03334396; BREEZE-AD2, NCT03334422; BREEZE-AD7, NCT03733301.

Comparison of phytoplankton control measures in reducing cyanobacteria assemblage of reservoirs found in the arid region of Southern Africa.

Ecological restorations of reservoirs are implemented worldwide; however, minimal successes are reported and understood for warmer African lakes like Swakoppoort Dam, Namibia. The objectives of the study were (a) to establish the effectiveness of the two control measures in reducing cyanobacteria growths in comparison with untreated control areas and (b) to compare the results generated before and after control measures with the reference Von Bach Dam. During Phoslock® treatment, the average cyanobacteria cells and total phosphate (TP) were 90,521cells/ml and 0.3mg/L in the treated area and 55,338cells/ml and 0.1mg/L in the control area. During Solar Powered Circulation (SPC) treatment, the average cyanobacteria cells were on average 906,420cells/ml in the treated areas and 121,891cells/ml in the control area. The TP on average was 0.3mg/L during SPC treatment, while during the combined treatment, the average cyanobacteria cells, TP, and total nitrogen (TN) were 18,387,226cells/ml, 0.27mg/L, and 2.41mg/L before and 22,836,511cells/ml, 0.42mg/L, and 1.50mg/L after treatment. This was higher compared to the reference site. PCA triplot indicates no grouping pattern, and the repeated-measures mixed model analyses indicate that treatment had no significant effect on cyanobacteria cells. It was evident that the two control measures were ineffective in reducing cyanobacterial cells. PRACTITIONER POINTS: Key findings of the article: Two phytoplankton control measures were found ineffective to reduce the cyanobacterial cell numbers. High cell numbers of cyanobacteria were recorded at the treatment areas compared to untreated control areas during both treatments. The combined effect of the two control measures was ineffective as more cyanobacterial cells were recorded during the treatment. During control measure treatment, the Swakoppoort Dam was hypertrophic, which could be due to a malfunctioned WWTP upstream. The inefficiency of the control measures could be due to small treatment area, higher nutrients, or treatment period. The implications of the results to water/wastewater practice: The selection of appropriate mitigation measures considering treatment area for dams with high nutrient situated in warmer arid environments. There is a need to understand the trophic relationships, climatic conditions, and the sources of the internal and external nutrients to manage water quality. Focus on point and non-point sources of nutrients as the root causes of the degradation of Swakoppoort Dam water.

Sex-Specific Difference in Dynamic Balance Following Total Hip Replacement

Background and ObjectivesTotal hip arthroplasty (THA) is a common surgical procedure in older adults (65 years or older). THA has high patient satisfaction, but little is known about balance and mobility limitations after surgery and if outcomes are sex-specific. This study was aimed to evaluate post-THA asymmetry during unilateral standing and a dynamic balance and reach test and test the hypotheses that balance performance would be decreased on the surgical limb and that balance deficits would be greater in women than in men.Research Design and MethodsPrimary, unilateral THA (70 male, 57 female) patients completed a bilateral 10-s single-leg stance test. Sixty male but only 34 female participants could maintain unilateral balance for 10 s or greater. The cohort who successfully completed the 10-s single-limb stance test then completed a Lower Quarter Y-Balance Test in which the maximum anterior (ANT), posteromedial (PM), and posterolateral reach distances were obtained bilaterally and used to calculate the asymmetry score. All variables were compared using a mixed-model repeated-measures analysis of variance (sex by limb), while independent samples t tests were used to assess sex-specific asymmetry.ResultsWomen failed single-leg stance at a higher rate than men (85.7% vs 59.6%; p = .001). Reach distance was different between limbs for all reach directions (p < .004) with greater reach distance on the nonoperative limb for all patients. Men had a greater reach distance in the ANT (p = .004) and PM (p = .006) directions.Discussion and ImplicationsThese results indicate that post-THA, the operative limb and female patients have greater balance limitations. These results are novel and reveal sex-specific patterns that emphasize the need for sex-specific postoperative rehabilitation programs to improve long-term outcomes, especially in older adults with muscle weakness and balance deficits.

Amantadine ER (Gocovri®) Significantly Increases ON Time Without Any Dyskinesia: Pooled Analyses From Pivotal Trials in Parkinson's Disease.

Background: Clinical trials for antiparkinsonian drugs aimed at managing motor complications typically use patient diaries to divide levodopa-induced dyskinesias (LID) into “troublesome” and “non-troublesome” categories. Yet, given the choice, most patients would prefer to live without experiencing any dyskinesia. However, the concept of evaluating time spent ON without any dyskinesia as an outcome has never been tested. We conducted analyses of pooled Gocovri pivotal trial data in order to evaluate the extent to which Gocovri increased the time PD patients spent ON without dyskinesia (troublesome or non-troublesome), beyond its already identified improvement in reducing troublesome dyskinesia.Methods: Patients enrolled in phase 3 trials (EASE LID [NCT02136914] or EASE LID 3 [NCT02274766]) recorded time spent in the following PD diary states at baseline and Week 12 (endpoint): asleep, OFF, ON with troublesome dyskinesia, ON with non-troublesome dyskinesia, and ON without dyskinesia. Mixed model repeated measures analyses with estimated Cohen D effect sizes were performed on the modified intent to treat population to evaluate changes in time spent in these states.Results: Patients randomized to receive Gocovri showed an increase in ON time without dyskinesia and corresponding decreases in ON time with dyskinesia and OFF time vs. placebo. Treatment effects were statistically significant for Gocovri vs. placebo starting at Week 2 and were sustained until Week 12. On MMRM analysis at Week 12, patients in the Gocovri group showed an adjusted mean ± SE increase over placebo of 2.9 ± 0.6 h in ON time without dyskinesia (Cohen D effect size 0.79) and an adjusted mean ± SE decrease of −1.9 ± 0.6 h in ON time with dyskinesia (troublesome + non-troublesome) (Cohen D effect size 0.49), that included a −1.5 ± 0.4 h placebo-adjusted reduction in ON time with troublesome dyskinesia and a −0.6 ± 0.4 h reduction in ON time with non-troublesome dyskinesia. OFF time was reduced by −1.0 ± 0.3 h compared to placebo.Conclusions: Gocovri treatment more than doubled the daily time patients spent ON without dyskinesia. These results suggest that the Gocovri treatment effect was driven by a reduction in overall motor complications including ON time with both troublesome and non-troublesome dyskinesia as well as time spent OFF.

Randomized trial of exercise on depressive symptomatology and brain derived neurotrophic factor (BDNF) in ovarian cancer survivors: The Women's Activity and Lifestyle Study in Connecticut (WALC)

ObjectivesDepression is one of the most prevalent mental disorders, and rates are higher among cancer survivors than the general population, and higher in ovarian cancer patients compared to cohorts of other cancer survivors. Physical activity has been associated with lower depressive symptoms in cancer survivors, yet no trial has examined this association in women with ovarian cancer. We examined the effect of exercise on depression symptomatology and serum brain derived neurotrophin factor (BDNF) which has been associated with depression, in women with ovarian cancer. MethodsWe conducted a 6-month home-based randomized trial of exercise vs. attention-control (AC) in 144 ovarian cancer survivors. Depressive symptomatology was measured via the Center for Epidemiologic Studies Depression Scale (CES-D). Serum total and free BDNF was measured at baseline and 6-months. Student's t-statistic and mixed-model repeated measures analysis was used to evaluate six-month change between arms in CES-D scores and BDNF. ResultsWomen were 57.3 ± 8.6 (mean ± SD) years old, 1.7 ± 1.0 years post-diagnosis with a baseline CES-D score of 11.79 ± 10.21. The majority (55%) were diagnosed with stage III/IV ovarian cancer. CES-D scores decreased in the exercise arm by 2.7 points (95% CI: −4.4, −0.9) or a 21% decrease compared to a 0.3 point decrease (−2.2, 1.5) (3% decrease) in the AC arm (P = 0.05). There was no difference in change in total or free BDNF between the exercise and AC arms. ConclusionsOvarian cancer survivors are able to exercise at recommended levels, and exercise was associated with a significant reduction in depressive symptomatology.

One-year outcomes following physical therapist-led intervention for chronic hip-related groin pain: Ancillary analysis of a pilot multicenter randomized clinical trial.

Evidence related to physical therapist-led intervention for patients with chronic hip-related groin pain (HRGP) is limited. The purpose was to assess sustainability of treatment effects for people with HRGP undergoing two physical therapist-led interventions. We completed an ancillary analysis of a pilot multicenter, randomized clinical trial. Forty-six patients with chronic HRGP, 15-40 years, were enrolled. Patients were randomized to participate in 10 sessions over 12 weeks of either movement pattern training (MoveTrain) or traditional strength/flexibility (Standard). Participants completed self-report questionnaires before treatment and 6 and 12 months after treatment completion. Outcome measures included Hip disability and Osteoarthritis and Outcome Score (HOOS), Patient Specific Functional Scaleand Numeric Pain Rating Scalefor average and worst pain. Continuous data were analyzed with mixed model repeated measures analysis of variance (RM-ANOVA) within each group. Numeric pain rating scale (NPRS) was analyzed using multinomial generalized estimating equations (GEE) with a cumulative logit. Reported p values are from statistical contrasts within the RM-ANOVAs and GEEs testing a priori hypotheses regarding change from pretest to month 6, and pretest to month 12. A total of 43/46 (93.5%) participants completed treatment, 40 (87.0%) completed 6 and 38 (82.6%) completed 12 month questionnaires. At 6 and 12 months, both groups demonstrated clinically significant improvements, compared to pretest, in all subscales of HOOS (p < 0.01), Patient Specific Functional Scale (p < 0.001), and NPRS (p < 0.0001). Among patients with chronic HRGP, both MoveTrain and Standard resulted in improved outcomes that were sustained 12 months after treatment. Further investigation in a larger sample is needed to confirm our findings.

Mindset Moderates Healthcare Providers' Longitudinal Performance in a Digital Neonatal Resuscitation Simulator.

Background: Simulation education can benefit healthcare providers (HCPs) by providing opportunities to practice complex neonatal-resuscitation tasks in low-stake environments. To our knowledge, no study investigated the role of growth mindset on longitudinal performance on neonatal resuscitation before and after simulation-based training.Objectives: This study examines whether 1) the RETAIN digital/table-top simulators facilitate HCPs' neonatal resuscitation knowledge gain, retention, and transfer and 2) growth mindset moderates HCPs' longitudinal performance in neonatal resuscitation.Methods: Participants were n = 50 HCPs in a tertiary perinatal center in Edmonton, Canada. This longitudinal study was conducted in three stages including 1) a pretest and a mindset survey, immediately followed by a posttest using the RETAIN digital simulator from April to August 2019; 2) a 2-month delayed posttest using the same RETAIN neonatal resuscitation digital simulator from June to October 2019; and 3) a 5-month delayed posttest using the low-fidelity table-top neonatal resuscitation digital simulator from September 2019 to January 2020. Three General Linear Mixed Model (GLMM) repeated-measure analyses investigated HCPs' performance on neonatal resuscitation over time and the moderating effect of growth mindset on the association between test time points and task performance.Results: Compared with their pretest performance, HCPs effectively improved their neonatal resuscitation knowledge after the RETAIN digital simulation-based training on the immediate posttest (Est = 1.88, p < 0.05), retained their knowledge on the 2-month delayed posttest (Est = 1.36, p < 0.05), and transferred their knowledge to the table-top simulator after 5 months (Est = 2.01, p < 0.05). Although growth mindset did not moderate the performance gain from the pretest to the immediate posttest, it moderated the relationship between HCPs' pretest and long-term knowledge retention (i.e., the interaction effect of mindset and the 2-month posttest was significant: Est = 0.97, p < 0.05). The more they endorsed a growth mindset, the better the HCPs performed on the posttest, but only when they were tested after 2 months.Conclusions: Digital simulators for neonatal resuscitation training can effectively facilitate HCPs' knowledge gain, maintenance, and transfer. Besides, growth mindset shows a positive moderating effect on the longitudinal performance improvement in simulation-based training. Future research can be conducted to implement growth-mindset interventions promoting more effective delivery of technology-enhanced, simulation-based training and assessment.

Abstract PS9-11: Health-related quality of life for margetuximab + chemotherapy vs. trastuzumab + chemotherapy in the phase 3 SOPHIA trial of patients with pretreated HER2+ metastatic breast cancer

Abstract Background: Margetuximab (M), an investigational Fc-engineered, immune-activating, HER2-targeted monoclonal antibody, shares specificity with trastuzumab (T) and is being studied in HER2 overexpressing tumors including MBC. The randomized phase 3 SOPHIA trial (NCT02492711) in pretreated HER2+ MBC demonstrated PFS superiority by blinded analysis of M + chemotherapy over T + chemotherapy. M demonstrated a tolerable safety profile. Here, patient-reported health-related quality of life (HRQOL) is reported. Methods: In SOPHIA, 536 patients with HER2+ MBC and ≥ 2 prior HER2+ directed therapies, including pertuzumab, were randomized 1:1 to M (15mg/kg IV q3w) or T (6 [8 for loading dose] mg/kg IV q 3wk). Each antibody was given with physician’s choice chemotherapy (standard dose capecitabine, eribulin, gemcitabine, or vinorelbine). HRQOL was measured at baseline and on D1 of each odd cycle using the Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI) - 16 and EuroQol 5-Dimension 5 level (EQ-5D-5L) questionnaires. Descriptive statistics were performed on NFBSI-16 total score (possible score range: 0 [most symptomatic] - 64 [least symptomatic]), EQ-5D-5L overall score (possible score range: 0 [most symptomatic] - 100 [least symptomatic]), and subscales of each measures. Lower scores reflect a higher impact on HRQOL domains. Changes from baseline in NFBSI-16 total score and in EQ-5D-5L utility score were assessed using mixed model repeated measures analysis (MMRM) with treatment group, stratification factors, time, and treatment group by time interaction as covariates. Each analysis used an unstructured covariance matrix, and least square mean estimates were calculated at each time point. A Cox proportional hazard model was used to assess time to symptom progression, defined as a ≥ 5-point decrease from baseline in NFBSI-16, using the same covariates as in MMRM analyses.Results: HRQOL questionnaire completion rates were comparable between M and T treatment groups. Mean NFBSI-16 total scores and EQ-5D-5L overall scores were similar between treatment arms at baseline and at end of treatment. During cycles 11-17, a greater proportion of patients in the M group reported being bothered by side effects and fatigue “quite a bit” or “very much” on the NFBSI-16. However, adverse event assessments at corresponding time points were largely attributed to concomitant chemotherapy. Also, a smaller proportion of patients on T completed these measures at these times. Overall, least mean square estimates (95% CIs) of change from baseline NFBSI-16 total scores were -1.99 (-3.395, -0.594) in the M group, and -2.13 (-3.794, -0.469) in the T group. A slightly higher proportion of patients in the M group had ≥ 5-point decrease from baseline NFBSI-16 total score compared to those in the T group (M: 105 [39.5%]; T: 100 [37%]). However, this difference was neither prespecified nor statistically significant (Cox model HR: 0.88, 95% CI: 0.672, 1.164; p=0.382). Overall least square mean estimates (95% CIs) of change from baseline in EQ-5D-5L total scores were -0.93 (-4.493, 2.637) in the M group, and -3.93 (-8.253, 0.387) in the T group, suggesting that patients on M had less signs of deterioration compared to the T group; statistical significance testing was not prespecified. Conclusions: Overall, HRQOL domains, including symptoms and functioning, were maintained. Changes from baseline were similar between the 2 treatment groups. Treatment-specific symptoms were consistent with side effects associated with chemotherapy, not antibody study therapy. Findings support similar, acceptable safety profiles demonstrated previously for margetuximab and trastuzumab. Citation Format: Fatima Cardoso, Javier Cortes, William Gradishar, Seock-Ah Im, Mark D. Pegram, Hope S. Rugo, Gail S. Wright, Michelino De Laurentiis, Christelle Levy, Jean-Marc Ferrero, Janine Mansi, Raul Oyola, Francesco Ricci, Erik H. Jakobsen, Beatriz Uziely, Daniel Egle, Aristoteles Giagounidis, Kirstin Williams, Shengyan Hong, Edwin Rock, Giuseppe Curigliano. Health-related quality of life for margetuximab + chemotherapy vs. trastuzumab + chemotherapy in the phase 3 SOPHIA trial of patients with pretreated HER2+ metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-11.

Efficacy of Vortioxetine Monotherapy for Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial.

There are few efficacious pharmacological treatments for posttraumatic stress disorder (PTSD) and many patients fail to benefit from existing treatments. Vortioxetine, a recently developed antidepressant, acts as a serotonin modulator through inhibition of the serotonin transporter and actions at multiple types of serotonin receptors. Its unique pharmacodynamic profile suggests it may have efficacy for the treatment of PTSD. We conducted a 12-week placebo-controlled, randomized clinical trial of vortioxetine (flexibly dosed from 10 to 20 mg/d) versus placebo in adults with PTSD. The primary outcome was change from baseline in the past-month version of the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), analyzed using a mixed-model repeated-measures analysis of variance. Forty-one patients were randomized, and 32 (78%) completed the 12 weeks of treatment. The mean reduction in CAPS-5 scores at week 12 did not significantly differ between the 2 arms; the effect size for the difference in changes between vortioxetine and placebo on CAPS-5 total scores at week 12 was Cohen d = 0.29. However, at week 8, the drug-placebo difference was d = 0.78, which met the multivariate criteria for statistical significance, P = 0.014. In this study of 41 patients, vortioxetine did not demonstrate superiority over placebo for adults with PTSD. Future PTSD trials may benefit from stratifying the randomization based on number of years since the index traumatic event and a history of failure to respond to treatment.

A Japanese Study Assessing Glycemic Control with Use of IDegAsp Co-formulation in Patients with Type2 Diabetes in Clinical Practice: The JAGUAR Study.

IntroductionThe aim of this study was to evaluate the glycemic control and safety of insulin degludec/insulin aspart (IDegAsp) co-formulation in Japanese patients with type 2 diabetes (T2D) in a real-world clinical setting, including elderly patients (aged > 75 years).MethodsPatients (≥ 18 years) diagnosed with T2D, previously treated with insulin were included from the Japanese Medical Data Vision database. Baseline data were taken at the index date, defined as the first IDegAsp prescription claim. Change in glycated hemoglobin (HbA1c) at 12 months was estimated using a mixed model repeated measures analysis. The proportion of patients achieving target HbA1c < 8.0% without experiencing hypoglycemia (identified by International Classification of Disease codes) was calculated at 12 months (365 ± 90 days) after baseline.ResultsOverall, 10,798 patients were included, 3940 were aged > 75 years, and 913 had baseline HbA1c values available. Switching to IDegAsp was associated with significantly improved HbA1c values at 12 months (− 1.23% [− 1.43, − 1.02]95%CI, p < 0.001) versus baseline. Moreover, relative to baseline, a significantly greater proportion of patients achieved HbA1c < 8.0% without hypoglycemia at 12 months, relative rate (RR) 1.30 [1.15, 1.45]95%CI, p < 0.001. Results were similar for patients aged ≤ 75 years and aged > 75 years; 66% and 64% of patients, respectively, achieved HbA1c < 8.0% without hypoglycemia at 12 months.ConclusionSwitching from insulin to IDegAsp co-formulation was associated with significantly improved glycemic control and a reduction in hypoglycemia rate during 12 months of follow-up in Japanese patients with T2D, including those aged > 75 years.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01623-y.

Heart rate response to alarm tones in firefighters.

To examine cardiovascular responses to medical (MED) and fire (FIRE) alarm tones in firefighters. Heart rate was collected throughout 24-h shifts (N = 41). Call logs were utilized post hoc to identify heart rate at the time the alarm sounded (TIMETONE), peak heart rate following the alarm (TIMEPEAK), and heart rate at the time of station departure (TIMEDEPART) for MED and FIRE calls. A 2X3 (TONE x TIME) split-plot mixed-model repeated-measures analysis of variance (ANOVA) and least significant differences tests examined the influence of tone type on heart rate, expressed as a percent of age estimated maximum. Bivariate Pearson correlations examined the relationship between body mass index (BMI) and TIMEPEAK and TIMEDEPART. An alpha of 0.05 determined statistical significance and Bonferroni Corrections were applied to post hoc comparisons (p < 0.017). Follow-up analyses for the significant 2 × 3 repeated-measures ANOVA (p = 0.035) indicated differences in heart rate for MED (p < 0.001) and FIRE (p < 0.001) where TIMETONE < TIMEPEAK, TIMETONE < TIMEDEPART, and TIMEPEAK > TIMEDEPART. There was a non-significant simple effect of time for MED and FIRE at TIMETONE (p = 0.259), but significant effects of tone type where FIRE > MED at TIMEPEAK (p < 0.001) and TIMEDEPART (p = 0.002). There was a significant small positive relationship between BMI and TIMEPEAK (p = 0.002) and TIMEDEPART (p < 0.001) for MED only. Alarms increased heart rates to a greater extent in FIRE than MED calls. Higher BMI was related to greater heart rate responses in MED but was unrelated to FIRE response.

Back Dominant Pain Has Equal Outcomes to Radicular Dominant Pain Following Posterior Lumbar Fusion in Adult Isthmic Spondylolisthesis: A CSORN Study.

Study Design:Retrospective Cohort Study.Objectives:This study aimed to determine how the surgeon-determined and patient-rated location of predominant pain influences patient-rated outcomes at 1-year after posterior lumbar fusion in adult isthmic spondylolisthesis.Methods:We retrospectively reviewed consecutive patients prospectively enrolled in the Canadian Spine Outcomes and Research Network national registry between 2009 and 2017 that underwent posterior lumbar fusion for isthmic spondylolisthesis. Using longitudinal mixed-model repeated-measures analysis the change from baseline in patient-reported outcome measures (PROMs) at 1 year after surgery was compared between surgeon-determined groups (back vs. radicular) and between patient-rated pain groups (back, leg, and equal) derived from preoperative pain scores on the numerical rating scale (NRS).Results:83/252 (33%) patients had a surgeon-determined chief complaint of back pain, while 103 (41%) patients rated their back pain as the predominant pain location, and 78 (31%) rated their back and leg pain to be equal. At baseline patients in the surgeon-determined radicular group had worse NRS-leg pain than those in the back-pain group but equal NRS-back pain. At baseline patients in the patient-rated equal pain group had similar back pain compared to the patient-rated back pain group and similar leg pain compared to the patient-rated leg pain group. All PROMs improved post-operatively and were not different between the 2 groups at 1 year.Conclusions:Our study found no difference in outcome, irrespective of whether a surgeon determines the patient’s primary pain complaint back or radicular dominant, or the patient rates pain in one location greater than another.

Evaluation of Intraocular Pressure Changes with Topical Dexamethasone 0.1%, Prednisolone 1% and Difluprednate 0.05% Postcataract Surgery- A Randomised Clinical Trial

Introduction: Topical corticosteroids are most commonly used for the control of postoperative inflammation after cataract surgery. Topical steroids may cause increase in Intraocular Pressure (IOP) which, if left untreated may lead to progressive optic nerve damage and glaucomatous field defects. Aim: To compare the ocular hypertensive response of three commonly used corticosteroids in an effort to generate evidence for managing postcataract surgery inflammation more effectively. Materials and Methods: This randomised clinical trial was carried out for a period of one year from November 2018 to October 2019, among 150 patients undergoing cataract surgery. Patients were divided into three groups. Group A-50 patients received topical dexamethasone 0.1%, Group B-50 patients received topical prednisolone 1% and Group C-50 patients received topical difluprednate 0.05% four times a day for six weeks after cataract surgery. Postoperative IOP was recorded preoperatively, on first postoperative day and at the end of first week, third week and sixth week with non contact tonometer and statistical significance was assessed with the help of repeated measures mixed model Analysis of Variance (ANOVA). Results: The mean age of the patients was 64.4±9.39 years, 48% were males and 52% patients were females. Mean IOP in the three drug groups was not statistically significant at 1st week, 3rd week and at 6th week after cataract surgery. Two patients belonging to difluprednate group at the end of 1st week and one patient at the end of 3rd week after cataract surgery developed significant rise in IOP (&gt;31 mmHg). Conclusion: It can be concluded that all three steroids were equally safe and did not cause any statistically significant rise in IOP over six-week postoperative period. However, higher values were noted in difluprednate group at the end of first and third week after cataract surgery.

A Non-Controlled Study of a Multi-Factorial Exercise and Nutritional Intervention to Improve Functional Performance and Prevent Frailty Progression in Community-Dwelling Pre-Frail Older Adults.

Preventing frailty is important to avoid adverse health outcomes. Intervention studies have largely focused on frail elderly, although the intermediate pre-frail state may be more amenable to improvement. This study aims to assess how physical performance may change among pre-frail elderly enrolled in a pragmatic non-controlled exercise and nutritional intervention programme. This is a non-controlled study involving a 4-month exercise and nutritional intervention for community dwelling pre-frail older adults. Pre-frailty was defined as the presence of 1 or 2 positive responses on the FRAIL questionnaire, or evidence of weak grip strength (<26kg for males; <18kg for females) or slow gait speed (<0.8m/s) amongst participants who were asymptomatic on FRAIL. Physical performance in flexibility, grip and lower limb strength, endurance, balance, and Short Physical Performance Battery were measured at 3 time-points: baseline, 3-month from recruitment (without intervention), and immediate post-intervention. Repeated measures mixed model analysis was performed to compare physical performance measures across the 3 time-points. 94 pre-frail participants were eligible for intervention, of whom 59 (mean age = 70.9±7.2 years) were ready for the post-intervention review. 21 (35.6%) transitioned to robust phenotype while 32 (54.2%) remained as pre-frail. Significant improvement post-intervention was observed in lower limb strength and power, evident on reduction in time taken for 5 sit-to-stand repetitions (0.46±0.20s, p=0.03). There was no significant change to the other physical performance measures examined. We observed reversibility of pre-frailty, and the benefit of multi-component intervention in improving physical performance of pre-frail older adults. The findings in this non-controlled study will need to be corroborated with future controlled trials.

Ageing-Related Gait Adaptations to Knee Joint Kinetics: Implications for the Development of Knee Osteoarthritis

The prevalence of knee osteoarthritis (OA) increases with ageing and this research aimed to identify gait adaptations that could reduce OA by investigating ageing effects on knee joint biomechanics. Participants were 24 healthy young males (18–35 yrs) and 14 healthy older males (60–75 yrs). Three-dimensional motion capture (Optotrak) and walkway-embedded force plates (AMTI) recorded their natural preferred-speed walking and the following parameters were computed: knee adduction moment, knee joint vertical force, foot contact angle, toe-out angle, foot centre of pressure displacement, time to foot flat, step length, step width and double support time. A 2 × 2 (age × limb) repeated measures mixed model analysis of variance design determined main effects and interactions. Pearson’s correlations between knee kinetic parameters and stride phase variables were also calculated. Both knee adduction moment and vertical joint force were larger in the older group. Relative to the young controls, older individuals showed a longer time to foot flat, less toe-out angle and wider steps. Correlation analysis suggested that reduced toe-out angle and increased step width were associated with lower knee adduction moment; furthermore, knee joint vertical force reduced with greater step length. Future research could focus on intervention strategies for managing excessive knee joint stresses to prevent the ageing-related development of knee OA.