Mixed Model Repeated Measures Analysis Research Articles

Associations of alcohol and cannabis use with change in posttraumatic stress disorder and depression symptoms over time in recently trauma-exposed individuals.

Several hypotheses may explain the association between substance use, posttraumatic stress disorder (PTSD), and depression. However, few studies have utilized a large multisite dataset to understand this complex relationship. Our study assessed the relationship between alcohol and cannabis use trajectories and PTSD and depression symptoms across 3 months in recently trauma-exposed civilians. In total, 1618 (1037 female) participants provided self-report data on past 30-day alcohol and cannabis use and PTSD and depression symptoms during their emergency department (baseline) visit. We reassessed participant's substance use and clinical symptoms 2, 8, and 12 weeks posttrauma. Latent class mixture modeling determined alcohol and cannabis use trajectories in the sample. Changes in PTSD and depression symptoms were assessed across alcohol and cannabis use trajectories via a mixed-model repeated-measures analysis of variance. Three trajectory classes (low, high, increasing use) provided the best model fit for alcohol and cannabis use. The low alcohol use class exhibited lower PTSD symptoms at baseline than the high use class; the low cannabis use class exhibited lower PTSD and depression symptoms at baseline than the high and increasing use classes; these symptoms greatly increased at week 8 and declined at week 12. Participants who already use alcohol and cannabis exhibited greater PTSD and depression symptoms at baseline that increased at week 8 with a decrease in symptoms at week 12. Our findings suggest that alcohol and cannabis use trajectories are associated with the intensity of posttrauma psychopathology. These findings could potentially inform the timing of therapeutic strategies.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Zanubrutinib (zanu) is a potent and highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target effects. In the ALPINE study (NCT03734016), zanu demonstrated superiority to ibrutinib (ibr) in both progression-free survival (PFS) and overall response rate and a more favorable safety profile in R/R CLL/SLL. The purpose of this analysis was to assess health-related quality of life (HRQOL) in patients (pts) treated with zanu and ibr. Results from the data cutoff related to recent PFS analysis (8 Aug 2022) are reported here. Methods: HRQOL was measured by EORTC QLQ-C30 and EQ-5D-5L at baseline, cycle 1, and every 3rd 28-day cycle until end of treatment. Key pt-reported outcome (PRO) endpoints included global health status (GHS), physical and role functions, fatigue, pain, diarrhea, and nausea/vomiting. Descriptive analysis was conducted on all the scales; a mixed-model repeated-measure analysis using key PRO endpoints at the key clinical cycles of cycles 7 (6 months) and 13 (12 months) was performed. Adjusted completion rates were defined as the number of pts who completed the questionnaires at each cycle divided by number still on treatment. Clinically meaningful was defined as a ≥5% mean change difference from baseline. Results: A total of 652 pts were randomized to receive zanu (n = 327) or ibr (n = 325); baseline characteristics were generally similar between arms, although the zanu arm had fewer males versus ibr arm (65.1% vs. 71.4%). At baseline, GHS, functional, and symptom scales scores were similar between arms. Although more ibr-treated pts discontinued treatment due to adverse events versus zanu (22.2% vs. 15.4%), adjusted PRO completion rates were high at cycles 7 and 13 in both the zanu (89.6% and 94.3%) and ibr arm (87.7% and 92.3%), respectively. By cycle 7, GHS scores were improved with zanu versus ibr and by cycle 13, the difference in GHS scores from baseline was no longer significant (Table). Pts in the zanu arm experienced clinically meaningful improvements in physical and role functioning as well as pain and fatigue at cycles 7 and 13, but the difference between arms was not significant. Although pts in the zanu arm reported lower diarrhea scores, the difference between treatments was not significant. Nausea/vomiting scores were maintained in both arms with no measurable difference. VAS scores showed greater improvement from baseline at both cycle 7 (7.92 vs. 3.44) and cycle 13 (7.75 vs. 3.92) of treatment with zanu versus ibr, respectively. Conclusions: In ALPINE, pts with R/R CLL/SLL treated with zanu demonstrated improvement versus ibr in the QLQ-C30 GHS/QoL scale at cycle 7. Other endpoints continued to improve, suggesting treatment with zanu positively affected and improved HRQOL over time. As expected, given the generally good HRQOL at baseline in both arms, the differences between the arms were small and not significant. Encore Abstract - previously submitted to EHA 2023 The research was funded by: BeiGene Keyword: Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract. B. Eichhorst Consultant or advisory role: Janssen, AbbVie, Gilead, AstraZeneca, BeiGene, MSD, Lilly Honoraria: Roche, AbbVie, BeiGene, AstraZeneca, MSD Research funding: Janssen, Gilead, Roche, AbbVie, BeiGene, AstraZeneca Educational grants: BeiGene N. Lamanna Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Janssen, Pharmacyclics Research funding: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Octapharma, Oncternal, MingSight, TG Therapeutics S. M. O'Brien Consultant or advisory role: AbbVie, Alexion, Amgen, Aptose Biosciences Inc., Astellas, AstraZeneca, Autolus, BMS, Celgene, DynaMed, Eli Lilly and Company, Gilead, GSK, Janssen Oncology, Johnson and Johnson, Juno Therapeutics, MEI Pharma Inc., Merck, NOVA Research Company, Pfizer, Pharmacyclics, TG Therapeutics, Vaniam Group Inc., Verastem, Vida Ventures Research funding: TG Therapeutics, Pharmacyclics, Pfizer, Nurix Therapeutics, Inc., Mustang, Loxo Oncology Inc., Kite, Gilead, Caribou Biosciences, Inc. BeiGene, Ltd., Alliance, Acerta C. S. Tam Honoraria: BeiGene, AbbVie, Janssen Research funding: Janssen, AbbVie Other remuneration: BeiGene L. Qiu Consultant or advisory role: Janssen, Astra Zeneca, Takeda, Roche, Abbvie, Beigene K. Yang Employment or leadership position: BeiGene Stock ownership: BeiGene Research funding: BeiGene K. Wu Employment or leadership position: BeiGene (Self), Roche/Genentech (Spouse) Stock ownership: BeiGene (Self), Roche/Genentech (Spouse) T. Salmi Employment or leadership position: BeiGene G. Barnes Employment or leadership position: BeiGene Stock ownership: BeiGene J. R. Brown Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Octapharma, Oncternal, MingSight, TG Therapeutics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, SecuraBio, Sun, TG Therapeutics

Treatment with Galcanezumab in Patients with Episodic Migraine: Results from the Open-Label Phase of the PERSIST Study (P10-12.006)

<h3>Objective:</h3> To assess efficacy and safety of galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, in adult patients with episodic migraine. <h3>Background:</h3> Migraine is a neurological disorder with high disease burden and unmet clinical need. <h3>Design/Methods:</h3> This was a phase 3, double-blind (DB), randomized, placebo-controlled, 3-month study with a 3-month open-label extension (OLE). Eligible patients with episodic migraine were randomized to monthly subcutaneous injections of placebo (N=259) or galcanezumab 120mg with a 240mg loading dose (N=261). Patients entering OLE received galcanezumab 120mg/month. Efficacy measures included number of monthly migraine headache days (MHDs), ≥50% reduction in monthly MHDs, and Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive (MSQ-RFR) domain score. Change from baseline in continuous and categorical measures was analyzed using mixed model repeated measures analysis and generalized linear mixed models, respectively. OLE results are reported by prior DB treatment assignment. <h3>Results:</h3> Of the patients who completed DB treatment, 484 (99.4%) entered OLE, with 96.3% completing Month 6. From a baseline of 8.23 monthly MHDs at the beginning of DB, patients at month 6 in the prior placebo and galcanezumab groups had a mean change of −4.56 and −4.62, respectively. At Month 6, the percentage of patients with ≥50% response was 67.2% and 70.9%, respectively. Of the 142 galcanezumab-treated patients with ≥50% response at Month 3, 66.2% maintained that response throughout OLE. At Month 6, patient functioning on the 100-point MSQ-RFR increased from baseline by 24.9 and 23.7 points, respectively. The common (&gt;2%) treatment-emergent adverse events were injection site reaction (3.3%), upper respiratory tract infection (2.7%), and injection site pruritus (2.5%) during the OLE. Three patients (0.6%) discontinued due to an adverse event. There were no clinically meaningful changes in any safety parameters. <h3>Conclusions:</h3> Galcanezumab was effective, safe, and well tolerated during the PERSIST open-label extension in patients with episodic migraine. <b>Disclosure:</b> Prof. Yu has nothing to disclose. Prof. Zhou has nothing to disclose. Dr. Zhuang has received personal compensation for serving as an employee of Eli Lilly. Miss Liu has nothing to disclose. Ms. Qian has received personal compensation for serving as an employee of Eli Lilly.

Factor Analysis Investigating the Efficacy of HP-3070 Transdermal System in Positive and Negative Syndrome Scale Five Adults With Schizophrenia

AbstractIntroductionHP-3070, a once-daily asenapine transdermal system, is FDA-approved for adults with schizophrenia. In a pivotal phase 3 randomized controlled study, patients with schizophrenia who were treated once daily with HP-3070 demonstrated significant improvement in Positive and Negative Syndrome Scale (PANSS) total scores compared with placebo. The PANSS score’s five-factor structure can also assess treatment efficacy across different domains. This post-hoc analysis of the pivotal study evaluated the efficacy of HP-3070 by examining these domains.MethodsIn the pivotal phase 3 study, adults with acute exacerbations of schizophrenia were randomized to 6 weeks of treatment with HP-3070 3.8mg/24h, 7.6mg/24h, or placebo. Factor analysis of PANSS scores was performed using five domains (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression). Mixed-model repeated-measures (MMRM) analysis included change from baseline in PANSS factor score as the repeated dependent variable, with country, treatment, visit, treatment by visit interaction, and baseline PANSS score as covariates.ResultsThe analysis included 607 patients. Least-squares mean estimates (standard error) of the difference from placebo in change from baseline to Week 6 for each factor were as follows: negative symptoms, 3.8mg/24h, -0.9 (0.43), P=0.045, and 7.6mg/24h, -0.4 (0.43), P=0.41; positive symptoms, 3.8mg/24h, -2.3 (0.57), P&lt;0.001, and 7.6mg/24h, -2.0 (0.57), P&lt;0.001; disorganized thought, 3.8mg/24h, -1.5 (0.38), P&lt;0.001, and 7.6mg/24h, -0.9 (0.38), P=0.03; uncontrolled hostility/excitement: 3.8mg/24h, -1.1 (0.30), P&lt;0.001, and 7.6mg/24h -0.9 (0.30), P=0.002; anxiety/depression, 3.8mg/24h, -0.5 (0.31), P=0.14, and 7.6mg/24h, -0.6 (0.31), P=0.07.ConclusionsHP-3070 demonstrated treatment effects on a PANSS five-factor model, with the results indicating impact on negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, and anxiety/depression. These findings suggest that HP-3070 may address a broad range of symptoms in schizophrenia.FundingNoven Pharmaceuticals, Inc., a wholly-owned subsidiary of Hisamitsu Pharmaceutical, Co.

Targeting amyloid β in Alzheimer's disease: Meta-analysis of low-dose solanezumab in Alzheimer's disease with mild dementia studies.

Solanezumab is a monoclonal antibody that binds to the mid-domain of soluble amyloid β peptide. This meta-analysis evaluated the effect of low-dose solanezumab on clinical progression in three phase 3 studies. The population comprised patients aged ≥55 years with Alzheimer's disease (AD) with mild dementia, randomized to 400mg solanezumab or placebo every 4 weeks for 80 weeks. Frequentist mixed-model repeated-measures (MMRM) and Bayesian disease progression model (DPM) longitudinal analyses were conducted. Pooled MMRM analyses showed a statistically significant effect of solanezumab across cognitive and functional outcome measures. DPM results were generally consistent with MMRM results, ranging from 15% to 30% slowing of clinical progression. These analyses suggest low-dose solanezumab slows clinical progression of AD with mild dementia. The ongoing A4 solanezumab study in participants with preclinical AD will ascertain the effect of a higher dose of solanezumab in an earlier disease stage. Individual EXPEDITION studies were negative but suggest low-dose solanezumab had an effect in slowing the clinical progression of Alzheimer's disease (AD) with mild dementia. At 80 weeks, mixed-model repeated-measures analyses showed numeric reductions in measures of clinical decline in solanezumab-treated arms compared with placebo across almost every outcome measure, and statistical significance in multiple outcome measures in each study. Pooled analyses suggest a high probability that low-dose solanezumab has at least some effect on slowing the clinical progression of AD with mild dementia. Across cognitive and functional outcome measures, estimates from disease progression model analyses range from 15% to 30% slowing of decline with low-dose solanezumab in AD with mild dementia.

Effect of low-volume blood withdrawal on hematological biomarkers

Introduction&#x0D; The hematological module of the Athlete Biological Passport (ABP) consists of individual and longitudinal monitoring of hematological parameters biomarkers responsive to erythropoiesis alteration. Based on an adaptive Bayesian model, the ABP seeks to identify non-physiological variations that may correspond to different types of blood doping. In this context, the impact of a standard blood donation (500 ml) was evident on the ABP parameters, hence supporting the robustness of the model. However, there is only scarce evidence of single or multiple withdrawals of smaller volumes of blood, closer to a modern blood doping strategy. This study investigated the impact of low-volume blood withdrawal on hematological variables for anti-doping purposes.&#x0D; Methods&#x0D; Twelve healthy subjects (7 women and 5 men; 26 ±6 yrs, 170 ±7 cm; 65 ±7 kg) were recruited. After baseline measurement, 140 ml whole blood was withdrawn with subsequent measures of hematological parameters by flow cytometry (Sysmex XN-1000, Sysmex Corporation, Japan) for 3 weeks. Blood volumes (BV) and total hemoglobin mass (Hbmass) were determined by means of a validated CO-rebreathing method. Ferritin (FERR) concentration was additionally measured by chemifluminescence immunoassay technique. Individual profiles were generated using the official ABP adaptive model using the official software platform of the World Anti-Doping Agency (WADA). Mixed model repeated measures analyses were run for each parameter to determine whether changes in the dependent (hematological variables) variables differed over time (fixed factor).&#x0D; Results&#x0D; 43.2 ±8 g of hemoglobin was removed during the 140 ml blood withdrawal. A significant decrease in Hbmass (726 ±185 vs. 709 ±189 g; p = 0.007) and Red Blood Cell Volume (RBCV; 2190 ±521 vs. 2129 ±552 L; p = 0.028) was observed at D + 7 with a return to basal value at D + 14. No significant variations were observed for the primary and secondary variables of the ABP. No Atypical Passport Finding (ATPF) were generated in the individual ABP profiles. Conversely, FERR was significantly downregulated at D + 7 (95.8 ±76 vs. 87.1 ±76 μg/l; p = 0.018).&#x0D; Discussion/Conclusion&#x0D; While the ABP has demonstrated substantial advantages for traditional doping scenarios, our results challenge the indirect detection of low-volume blood withdrawals in a contemporary blood doping scenario. The impact of low-volume autologous blood transfusion on time trial performance has recently been demonstrated, supporting the need for novel biomarkers with extended detection windows. Hbmass could hence represent an additional marker to screen blood doping while technical issues for the use of CO-rebreathing remain. FERR as a marker of altered iron metabolism was there against shown to be sensitive and possibly suitable for outlining low-volume blood transfusion. The large inter-subject variability underlines the importance of individual longitudinal monitoring to provide sufficient sensitivity in the interpretation of hematological variations. Our study finally confirms that even low-volume blood withdrawals are associated with significant hematological changes while frequent blood samples and additional biomarkers are certainly required to better tackle blood doping strategies using such low-volume transfusions.

Efficacy of Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder: Effect Size Across the Day.

Objective: To evaluate the treatment effect size throughout the day of amphetamine extended-release oral suspension (AMPH EROS; Tris Pharma, Inc., Monmouth Junction, NJ, USA) in a laboratory classroom study conducted in children aged 6-12 years with attention-deficit/hyperactivity disorder (ADHD). Methods: A post hoc analysis was performed to assess the overall effect size as well as the effect size at each time point from early morning through evening (1, 2, 4, 6, 8, 10, 12, and 13 hours postdose) for each efficacy measure evaluated in a 5-week, randomized, dose-optimized, double-blind, placebo-controlled, laboratory classroom assessment, efficacy, and safety study of AMPH EROS (N = 99). Change from baseline of the primary (Swanson, Kotkin, Agler, M-Flynn, Pelham [SKAMP]-C) and key secondary (secondary efficacy assessments included the SKAMP attention [SKAMP-A], SKAMP-deportment subscale [SKAMP-D], Permanent Product Measure of Performance-number of problems attempted [PERMP-A], PERMP-number of problems correct [PERMP-C]) efficacy measures were analyzed using a linear mixed model repeated-measures analysis model. Comparisons among treatments were adjusted for multiple comparisons using the Bonferroni method. The effect size was estimated using Cohen's d, to determine "small," (0.2), "medium," (0.5), or "large" (0.8) magnitudes of treatment effects. Results: Large overall effect sizes were observed for all primary and key secondary efficacy assessments. Moreover, the SKAMP-C, PERMP-number of problems attempted, and PERMP-C scores showed large effect sizes at each time point evaluated across the day, from 1 to 13 hours postdose. The SKAMP-A and SKAMP-D scores showed a medium to large effect size at each time point. Conclusions: AMPH EROS demonstrated a large and consistent effect size across the day, including early in the morning, in the treatment of symptoms of ADHD in children aged 6-12 years. Trial Registration: clinicaltrials.gov identifier: NCT02083783.

P736 Factors associated with partial Mayo Clinic Score over time in patients with Ulcerative Colitis treated with filgotinib in the phase 2b/3 SELECTION trial

Abstract Background Responses to ulcerative colitis (UC) treatments vary considerably between individuals, and factors associated with a stable response are not well defined. Filgotinib (FIL) is an oral, Janus kinase 1 preferential inhibitor approved in the EU and the UK as a UC therapy. We aimed to identify factors associated with partial Mayo Clinic Score (pMCS) over time in FIL-treated patients with UC in the phase 2b/3 SELECTION trial (NCT02914522). Methods In SELECTION, adults with moderately to severely active UC received FIL 200 mg (FIL200), FIL 100 mg (FIL100) or placebo once daily for 11 weeks in Induction (IND) Study A (biologic-naive) or B (biologic-experienced).1 Patients in clinical remission or with a Mayo Clinic Score (MCS) response at week 10 could enter the 47-week Maintenance (MNT) Study. To evaluate factors associated with pMCS during MNT this post hoc analysis used a mixed model for repeated measures (MMRM), which included fixed effects of time, IND dose (FIL200 or FIL100), the factor of interest and pMCS at IND baseline, and correlated patient residual errors. For categorical factors, the least-squares mean difference with 95% confidence interval (CI) and the overall type III p value were calculated. For continuous factors, the difference in pMCS for a one-unit change in the factor of interest was estimated with 95% CI. Multiplicity adjustment of p values was not performed. Results Data from 371 patients treated with FIL200 (n=199) or FIL100 (n=172) were included. Previous use of at least one biologic therapy or a tumour necrosis factor antagonist/vedolizumab, and week 10 MCS subscores of ≤1 were associated with higher pMCS over time than their respective reference categories (p&amp;lt;0.0001; Table 1). Over time, pMCS was 0.45 units higher in patients assigned to IND Study A versus IND Study B (p=0.0002). Week 10 endoscopic score ≤1, Geboes histologic remission and Inflammatory Bowel Disease Questionnaire total score &amp;gt;170 were associated with lower pMCS over time than their respective reference categories (p≤0.0001). Change from baseline in pMCS at week 10 and faecal calprotectin levels at week 10 were positively associated with pMCS over time (p&amp;lt;0.0001; Table 2). Patient-reported outcome (PRO) measures at week 10 were negatively associated with pMCS over time (p≤0.0001). Conclusion History of previous biologic therapy, and week 10 assessments (endoscopic, clinical, biomarker and PRO) were among the factors influencing pMCS over the course of 1 year of FIL treatment, consistent with previous findings from trajectory modeling.2 Further MMRM analyses may help to identify patients who benefit most from FIL treatment. 1. Feagan BG et al. Lancet 2021;397:2372–84. 2. Schreiber S et al. MP443 [abstract]. UEGJ 2022;10:459.

P375 Izencitinib induction treatment in patients with moderately-to-severely-active Crohn’s Disease: A phase 2 double-blind, randomized, placebo-controlled study

Abstract Background The unmet need in Crohn’s disease (CD) exists for new medications with an optimized risk-benefit ratio with avoidance of systemic side effects. This Phase 2 study evaluated the efficacy and safety of the oral, once-daily, gut-selective pan-Janus kinase inhibitor izencitinib as an induction therapy for CD. Methods This trial was a multicentre, randomized, double-blind, Phase 2 study of adults with moderately-to-severely active CD (≥220 and ≤ 450 CDAI with SES-CD score of ≥6 [or ≥4 if isolated ileal disease]) who were corticosteroid-dependent or had demonstrated failure to aminosalicylates, corticosteroids, immunosuppressive agents, and/or biologic therapies. Patients were randomised 2:3:3 to receive placebo or izencitinib, 80, or 200 mg once daily for 12 weeks. The primary endpoint was change in CDAI score from baseline to week 12 and was analysed using a mixed-model repeated measures analysis. Change from baseline in SES-CD was analysed with an analysis of covariance model and binary endpoints were analyzed using a stratified Cochran-Mantel-Haenszel chi-square test. Results 159 and 145 patients were included in the safety and modified ITT populations, respectively. At week 12, the LS mean change in CDAI was -105.6 (SE: 12.7) and -117.9 (12.4) points for patients randomized to izencitinib 80 and 200 mg, respectively, vs -104.86 (SE: 15.496) for those randomized to placebo. There were no improvements observed in change from baseline in SES-CD. There were non-significant numerical improvements in clinical and endoscopic response between placebo and the highest dose 200mg. No improvements were observed in CDAI-based clinical remission or PRO2 (SF/AP)-based remission at any dose of izencitinib relative to placebo. As expected, plasma izencitinib exposure was low. Serious adverse events (AEs; n = 13) were well balanced among the treatment groups and not considered related to study treatment; no deaths were observed. Exacerbation of Crohn’s Disease, headache, rash, abdominal pain and nausea were the most common treatment-emergent AEs observed with izencitinib treatment. No clinically important changes in laboratory values, electrocardiography parameters, or vital signs were noted in patients treated with izencitinib compared with placebo, and no drug-related AEs of special interest were observed. Conclusion In patients with moderately-to-severely active Crohn’s Disease, izencitinib treatment for 12 weeks did not demonstrate a statistically significant reduction in CDAI or endoscopic severity. Izencitinib at both doses was well tolerated without a new safety signal.

Annual indirect costs savings in patients with episodic or chronic migraine: a post-hoc analysis of phase 3 galcanezumab clinical trials in the United States

BackgroundGalcanezumab (GMB) improved quality-of-life and reduced disability of patients with episodic (EM) and chronic migraine (CM) in Phase 3 trials.AimTo estimate indirect cost savings associated with GMB treatment in patients with migraine in the United States (US).MethodsWe analyzed data of patients from the US from three randomized, Phase 3, double-blind, placebo (PBO)-controlled GMB studies: EVOLVE-1 and EVOLVE-2 (EM patients), REGAIN (CM patients). Annual indirect costs were calculated using items of the Migraine Disability Assessment (MIDAS) questionnaire: lost time/productivity at work/school, household work, and leisure time. All costs were annualized and expressed in 2019 US dollars. While the main analysis considered lost time/productivity at work/school and household work as a full day, a sensitivity analysis was performed by discounting them by half. For EM, annual indirect costs savings were estimated using mixed model repeated measures analysis. For CM, ANCOVA models were used to estimate annual indirect costs savings as change from baseline.ResultsThe analysis included 805 patients with EM (mean age = 41.4 years; PBO = 534; GMB = 271) and 423 patients with CM (mean age = 38.9 years; PBO = 279; GMB = 144). Compared to PBO, GMB significantly reduced annual indirect costs among patients with EM at 3 months (least square mean [95% confidence interval] work/school = $1,883.6 [603.64–3,163.65], p = .0040, household work = $628.9 [352.95–904.88], p <.0001, and leisure activity = $499.17 [42.36–955.98], p = .0323) and 6 months (work/school = $2,382.29 [1,065.48–3,699.10], p = .0004, household work = $559.45 [268.99–849.90], p = .0002, and leisure activity = $753.81 [334.35–1,173.27], p = .0004), whereas a significant difference was not observed among patients with CM. Sensitivity analysis results were similar to primary analysis results.ConclusionsGMB treatment versus PBO resulted in significantly greater indirect cost savings in patients with EM through improved productivity at work/school, household work, and leisure days. Patients with CM receiving GMB versus PBO attained greater cost savings, although not statistically significant, through reduced lost productivity at work/school.

Associations of Molecular-Genetic Bioenergetics and Chemotherapy-Induced Fatigue Symptoms in Patients with Breast Cancer: A proposal development

Introduction: Cancer-related fatigue (CRF) occurs in 82%-96% of cancer patients receiving chemotherapy (CT). CT-induced CRF is a distressing, persistent sense of exhaustion related to the disease or its treatment, and negatively impacts health outcomes. CRF is one of the most prevalent side effects of CT in patients with breast cancer. Despite various attempts to investigate the etiology of CRF, the biochemical mechanisms remain elusive. Objectives: The study aims to explore the molecular-genetic pathway of mitochondrial bioenergetics and its association with CT-induced CRF. We hypothesized that the chemotherapeutic agent containing anthracycline targets cell cycle progression, which triggers genetic and cellular instability, altering expression of mitochondrial genes and proteins, inducing reduced electron transport chain enzymatic activity and impaired oxidative phosphorylation, resulting in adenosine triphosphate (ATP) depletion and excessive reactive oxygen species (ROS) generation, leading to the development and intensification of CRF. Methods: This is a prospective, hypothesis-testing, and longitudinal study design. A total of 60 patients with breast cancer undergoing CT will be enrolled. Validated instruments will be used to measure CRF, depression, sleep disturbance, and physical activity. Whole blood sample will be collected before, during, and at the completion of CT to determine profiles of mitochondrial bioenergetics. A linear mixed model repeated measures analysis will be used to examine associations between changes in study variables. Anticipated Results: Increased scores of CRF will be associated with altered mitochondria-related genes and mitochondrial bioenergetics (e.g., ↓oxidative phosphorylation, ↓electron transport chain complexes activity, ↓ATP content, and ↑ROS production) in patients receiving CT-containing anthracyclines. Conclusion: The results will enable us to discover biomarkers, support the design of nonpharmacological interventions, and initiate precision symptom management to improve CRF.

The biomechanical effects of insoles with different cushioning on the knee joints of people with different body mass index grades.

Background: Enhancing knee protection for individuals who are overweight and obese is crucial. Cushioning insoles may improve knee biomechanics and play a significant protective role. However, the impact of insoles with varying cushioning properties on knee joints in individuals with different body mass index (BMI) categories remains unknown. Our aim was to investigate the biomechanical effects of insoles with different cushioning properties on knee joints across different BMI grades. Methods: Gravity-driven impact tests were used to characterize the cushioning properties of three types of Artificial Cartilage Foam (ACF18, 28, and 38) and ethylene-vinyl acetate (EVA) insoles. Knee joint sagittal, coronal, and vertical axis angles and moments were collected from healthy-weight (BMI 18.5-23.9kg/m2, n = 15), overweight (BMI 24.0-27.9kg/m2, n = 16), and obese (BMI ≥28.0kg/m2, n = 15) individuals randomly assigned four different insoles during a drop jump. The Kruskal-Wallis test and mixed model repeated measures analysis of variance were used to compare differences among cushioning and biomechanical data across various insoles, respectively. Results: ACF showed higher cushioning than EVA, and ACF38 was the highest among the three types of ACF (all p < 0.001). During the drop jump, the knee flexion angles and moments of the ACF insoles were lower than those of the EVA insoles, the knee adduction angles of the ACF18 and ACF28 insoles were lower than those of the EVA insoles, and ACF18 insoles increased the first cushion time (all p < 0.05) for all participants in whom biomechanical variables demonstrated no interactions between insoles and BMI. Regarding the BMI-dependent biomechanical variables, compared with the EVA insoles, ACF28 insoles decreased the knee flexion angle and ACF38 insoles decreased the knee adduction and rotation moment in the healthy-weight group; ACF18 insoles decreased the knee flexion angle and ACF38 insoles decreased the knee moment in the overweight group; ACF28 insoles decreased the knee flexion and adduction moment, and ACF38 insoles decreased the knee flexion angle and rotation moment in the obese group (all p < 0.05). Conclusion: Insoles with higher cushioning properties could improve knee biomechanics and provide better knee joint protection in people across different BMI ranges.

The effectiveness of supportive therapy on psychological capital and post traumatic growth in women with multiple sclerosis

Aim: Multiple sclerosis is a neurological and progressive disease. Living with MS has many negative and positive effects on patients' physical and mental health. This study aimed to investigate the effect of supportive therapy on post-traumatic growth and psychological capital in women with MS. Methods: This study used quasi-experimental method (a pretest-posttest and fallow up plan with a control group). Participants consisted of 30 women with MS who were selected using convenience sampling method and were randomly divided into two groups of experimental and control groups. The measuring tool was psychological capital questionnaire (2007) and post-traumatic growth questionnaire (1996) which was completed by the participants. Then, the participants in the experimental group participated in 10 sessions of 50 min of intervention based on Winston, Rosenthal, &amp; Pinsker (2004) supportive therapy protocol. Repeated-measures mixed-model analysis of variance (ANOVA) was used to analyze data. Results: Data analysis showed that supportive therapy had significantly increased the psychological capital (F=16/50, P≤ 0/001) and post traumatic growth (F=14/40, P≤ 0/001) in the experimental group, compared to the control group and the effects of intervention over time remained constant. Conclusion: Based on the findings of this study, supportive therapy can be an effective intervention to increase psychological capital and post traumatic growth in MS patients and can be used to improve the psychological state and better cope with the disease.

The Impact of Momelotinib on Patient Reported Quality of Life for Symptomatic and Anemic Patients with Myelofibrosis: Results from the Phase 3 Momentum Study

Introduction Disease-related inflammation, anemia and splenomegaly contribute to a host of burdensome symptoms in patients with myelofibrosis (MF), including fatigue, bone pain, night sweats, and others, which can negatively impact health-related quality of life (HRQoL). There are no approved treatments for patients with intermediate- and high-risk MF that specifically target anemia, and approved MF therapies for splenomegaly and symptoms often exacerbate anemia. Momelotinib (MMB) is a Janus kinase (JAK) 1, JAK2, and activin A receptor type 1 (ACVR1) inhibitor with demonstrated symptom, spleen, and anemia benefits in patients with MF. MOMENTUM, a phase 3 study in symptomatic, anemic patients with MF who were previously treated with a JAKi, showed that MMB significantly improved disease-related symptoms compared to danazol (DAN) (24.6% vs 9.2%) as measured by achieving at least a 50% reduction in total symptom score (TSS50) at week 24 compared to baseline. Herein we report the results of patient-reported health status and HRQoL analyses, including impact on fatigue and physical function, for patients treated with MMB compared to DAN in the MOMENTUM study. Methods Patient-reported outcome (PRO) analyses were performed for the following assessments in the intent-to-treat (ITT) population: Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 TSS and individual items, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)-derived scales and items, and Patient-Reported Outcomes Measurement Information System (PROMIS) short form physical function total score 10b and additional PROMIS bank items. Analyses of PRO response were summarized by corresponding meaningful change threshold (MCT) for each PRO. Longitudinal change from baseline scores were analyzed using mixed model for repeated measures (MMRM). Longitudinal responder analyses were performed by generalized estimating equation (GEE) after multiple imputation for missing scores. Odds ratio (OR) for response, 95% confidence interval (CI), and p-value were presented as the treatment effect (MMB vs DAN). Time to first response was analyzed using the Kaplan-Meier method. A stratified log-rank test was performed to compare treatment arms, and hazard ratios (HR) were estimated from a stratified Cox regression model. Results Proportionally greater improvements in MF-related symptoms, physical function, and global quality of life were observed with MMB versus DAN as measured at week 24 by the MFSAF, PROMIS, and EORTC QLQ-C30 questionnaires, respectively. Improvements in all MFSAF individual item scores from baseline at week 24 were greater in the MMB group than in the DAN group based on median scores (Figure 1) and MMRM analysis (Table 1), with the greatest treatment differences noted for night sweats, abdominal discomfort, bone pain, and rib pain, favoring MMB. Longitudinal MFSAF TSS response analysis indicated a higher likelihood of response for patients in the MMB group: an overall OR of 2.50 throughout the 24-week randomized treatment period. HRs for response were greater than 1 (ranging from 1.47 - 3.82) in the time to first response analysis for MFSAF TSS and individual items, excluding itching (0.77), indicating a faster symptom response for more patients in the MMB group for TSS and 6 of 7 individual items. Responder analyses showed that the proportion improved for fatigue was greater in the MMB group based on MFSAF fatigue (18.5% MMB, 9.2% DAN) and EORTC QLQ-C30 fatigue (41.5% MMB, 21.5% DAN), where missing data was considered nonresponse. Consistent with these results, responder analysis using the PROMIS assessments related to physical function also favored MMB (17.7% MMB, 4.6% DAN). This trend was supported by shorter times to first response for physical function in more patients in the MMB group versus the DAN group (HR = 1.93, 95% CI 0.95, 3.91). Improvement in global quality of life as measured by EORTC QLQ-C30 was also greater in the MMB group with a proportion difference of 14.6% between MMB and DAN (95% CI: 1.5-27.7%; p = 0.04). Conclusions Consistent with the positive primary endpoint (TSS50) result of the MOMENTUM study, these responder, longitudinal, and time-to-event analyses demonstrate that MMB provides comprehensive improvements in disease-related symptoms with associated improvement in physical function and overall HRQoL compared with DAN in patients with MF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Health-Related Quality of Life in Patients with Hemophilia A or B with Inhibitors on Concizumab Prophylaxis: Results from the Phase 3 explorer7 Study

Introduction: Concizumab is currently in clinical development as a humanized, monoclonal anti-tissue factor pathway inhibitor antibody that enhances the initiation phase of coagulation. In the phase 3 explorer7 study (NCT04083781), patients with hemophilia A or B with inhibitors received once-daily subcutaneous prophylactic treatment with concizumab for the prevention of bleeding episodes. Patients with hemophilia generally report impaired health-related quality of life (HRQoL), particularly in the areas of pain and physical functioning. Here, we present an analysis of changes in reported HRQoL for patients treated with concizumab for 24 weeks in the explorer7 study. Methods: A total of 133 male patients aged ≥12 years were randomized to no prophylaxis (arm 1) or concizumab prophylaxis (arm 2) or assigned to non-randomized concizumab prophylaxis (arms 3 or 4) depending on the treatment they received before entering the study. All patients were asked to complete the 36-item Short Form Health Survey (SF-36v2; Ware & Sherbourne. Med Care 1992; 30:473-83) and patients aged ≥17 years could complete the Hemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL; von Mackensen & Gringeri, Handbook of Disease Burdens and Quality of Life 2010:1896-920; von Mackensen et al.Haemophilia 2017;23(3):383-391; Wyrwich et al.Haemophilia 2015;(5):578-84). Both questionnaires could be completed at baseline (Week 0), and at Weeks 4, 8, 16 and 24. The SF-36v2 health scales "bodily pain" (BP) and "physical functioning" (PF) were analyzed as key secondary endpoints. Changes in Haem-A-QoL total score and "physical health" score, as well as the remaining SF-36v2 health scales and component summary scores, were analyzed as exploratory endpoints. Unfortunately, due to technical issues, several patient-reported outcomes recordings could not be collected for statistical analysis. As the preplanned statistical analysis could not be implemented, a post-hoc mixed model for repeated measures (MMRM) was applied after the randomization code was broken. The MMRM analysis included patients from arms 1 and 2 who had completed the questionnaire at baseline and had at least one post-baseline visit on the new dosing regimen. Results: The mean estimated change in score from baseline to Week 24 on the SF-36v2 BP scale was 2.2 points (95% CI: -5.1; 9.5) for patients not on prophylaxis (n=9), and 9.2 points (95% CI: 5.1; 13.3) for those on concizumab (n=23), which yielded an estimated treatment difference (ETD) of 7.0 points (95% CI: -1.6; 15.6) (Figure 1). For the SF-36v2 PF scale, the mean change in score from baseline to Week 24 was 1.2 points (95% CI: -4.8; 7.1) in the no prophylaxis arm (n=9) versus 4.5 points (95% CI: 0.8; 8.2) in the concizumab treatment arm (n=23), which yielded an ETD of 3.3 points (95% CI: -3.8; 10.4) (Figure 1). While BP and PF scores were not significantly different between both arms, several other health scales, including "general health", "mental health", "role-emotional" and "vitality", showed statistically significant differences (Figure 1). The total score from the Haem-A-QoL questionnaire showed a significant improvement for patients on concizumab prophylaxis (n=13) compared to no prophylaxis (n=4) (ETD: -22.6 points [95% CI: -42.5; -2.7]; Figure 2). A significant difference was not observed for "physical health", but there were significant improvements in "feeling", "treatment", "view of yourself", and "sport and leisure" (Figure 2). Conclusion: Patients on daily subcutaneous concizumab prophylaxis generally reported better scores on generic (SF-36v2) and disease-specific (Haem-A-QoL) questionnaires when compared with patients treated on-demand. The differences were mostly in favor of concizumab, with the largest ETDs being related to mental and general health. SF-36v2 and Haem-A-QoL are being investigated as part of the explorer8 concizumab phase 3 study in patients with hemophilia A or B without inhibitors. These data reflect the potential benefit of concizumab prophylaxis to improve HRQoL in patients with hemophilia A and B with inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A test of differential susceptibility in behavior trajectories of preterm infants from preschool to adulthood.

Preterm birth predisposes children to internalizing and externalizing behaviors that may persist into adolescence resulting in adult mental health conditions. Social and caregiving contexts, particularly for vulnerable infants born preterm, influence long-term outcomes, but mechanisms are not clearly understood. Healthcare teams caring for those born preterm face difficulty predicting who will be most affected by risk, who will most benefit, and the optimal timing of intervention. Differential susceptibility theory offers an alternative to the traditional risk-only assessments and theories by positing that individuals may be more, or less, susceptible to environmental influences. A sample of preterm- and term-born infants were followed from birth to 23 years of age. Mixed model repeated measures analyses of internalizing and externalizing behaviors were utilized for the comparison groups (N = 214; observations = 1070). Environmental contexts were indexed as proximal protection (low, moderate, high) and medical risk (low, moderate, high). Personal characteristic covariates of sex, race, socioeconomic status, and cognition were modeled. Internalizing behavior trajectories varied significantly over time. Early proximal protective environments conferred a sustained positive influence on behaviors. There is partial support for differential susceptibility theory suggesting that prematurity, as a malleability characteristic enables absorption of both the positive and negative influences of the environment, with greater intensity that those without malleability. The current analyses suggest lasting effects of the preschool age proximal environment on internalizing and externalizing behaviors in young adulthood for those born preterm. Understanding these nuances may aid healthcare professionals in the promotion and timing of interventions to support the child and family.The current manuscript reflects ongoing analyses of longitudinal data. No patient or public contribution to the analyses were required for testing the differential susceptibility theory. The authors would solicit patient or public contribution when implementing practice or policy changes based on the results.

Dosimetric Comparison of Supine vs. Prone Position Utilizing Traditional Linac-Based Stereotactic Body Radiation Therapy for Accelerated Partial Breast Irradiation

<h3>Purpose/Objective(s)</h3> Our institution recently completed a pilot trial using stereotactic body radiation therapy (SBRT) for accelerated partial breast irradiation (APBI) on a traditional Linac delivering 30 Gy in 5 fractions. In this study, we compared dosimetry of patients treated in supine versus prone positions. <h3>Materials/Methods</h3> Patients enrolled on our recent pilot trial and additional post-accrual patients using the same SBRT technique were included. All patients had early-stage breast cancer, met the APBI ASTRO suitability criteria, and were treated on a traditional Linac. Treatment position, breast laterality and volume, BMI, and organs at risk (OAR) dosimetry were recorded. Prone treatments were delivered on a prone breast board using sliding window IMRT, and supine plans used either IMRT or partial arcs. All prone and 15 of 18 supine plans used free breathing technique (3 utilized deep inspiration breath-hold). CTV was 1 cm expansion from GTV. PTV was a 3 mm expansion from CTV and excluded skin surface+3 mm. Laterality was controlled for heart dosimetry. A small subset of patients was simulated in both supine and prone positions with associated radiation plans available for comparison. For unpaired data, unadjusted comparisons of means were performed using two-group t-test, and analysis of covariance was used for adjusted comparisons. For paired data, unadjusted comparisons were performed using the paired t-test, and adjusted comparisons used mixed models repeated measures analysis. Statistical tests were two-sided. <h3>Results</h3> This study included 35 patients with 36 treated plans. One patient had bilateral breast cancer. Of the 36 treated plans, 18 were supine (11 right-sided breast cancer, 7 left-sided) and 18 prone (8 right-sided, 10 left-sided). Eight patients had comparison plans in both positions. For patients with left-sided breast cancer, heart mean dose supine vs prone was 0.49 and 1.14 Gy, respectively (p < 0.001), and continued to be significant when controlling for BMI and treated breast volume. Mean heart dose was not different for right-sided patients supine vs prone, 0.36 vs 0.47 Gy, respectively (p = 0.870). Ipsilateral lung V1.5 Gy was higher for supine vs prone, 39.44 vs 29.89% (p=0.017). Max rib dose was higher for supine compared to prone, 28.29 vs 16.12 Gy (p<0.001). For the subset of patients with plans in both positions, mean heart dose continued to be lower for left-sided patients treated supine vs prone (p = 0.001). Ipsilateral lung V1.5 Gy and max dose to ribs were lower for prone with p values of 0.003 and <0.001, respectively. <h3>Conclusion</h3> Supine treatment provided heart dosimetry benefit for left-sided breast cancer patients compared to prone. Benefit was independent of BMI and breast volume. Prone position offered lower dose to ipsilateral lung and ribs. The results from this study can help determine the best treatment position based on patient-specific OAR concerns.

The association between optimism and future performance: Evidence of impression management from chief executive officer and chairperson letters

Purpose: This article examines the sincerity of two sets of narrative disclosures in the letters of chairpersons (CPs) and chief executive officers (CEOs) to stakeholders. The study sought to compare the level of optimism between the two letters and whether such optimism (as per its link to future performance) was sincere or not and the differences in the level of sincerity between the two letters.Design/methodology/approach: Chairpersons’ and chief executive officers’ letters as contained in annual reports for firms listed on the Johannesburg Stock Exchange over a 4-year period were analysed. Textual analysis software was used to measure optimism in 200 CPs’ and 200 CEOs’ letters. The level of optimism was compared using mixed-model repeated measures analysis of variance. Sincerity was operationalised as the positive association between the level of optimism and future performance and a negative association as evidence of impression management. Two-way linear fixed effect regression models were used.Findings: This study found that CPs’ letters were more optimistic than those of CEOs’. More specifically, the results point to impression management in both CPs’ and CEOs’ letters, with only CPs’ letters indicating a significant negative association.Practical implications: Relative to the CEOs, CPs may use more optimistic writing styles to sway stakeholders who are anticipating worse-than-expected future performance; readers should be aware of the potential consequences of such practices.Originality/value: The results provide support for the obfuscation hypothesis as a theoretical underpinning regarding CPs’ and CEOs’ letters. Overall, the results question the ability of such narratives to lessen agency costs.

Impact of home visiting programs on parenting stress in low-income women: Findings from a community-based trial at an urban health department

Four decades of home visiting research has yet to reveal clear implications regarding the amount and type of services required to produce intended outcomes like reduced parenting stress. This study compared the effects of two home visiting programs on parenting stress and examined whether depressive symptoms and social support were associated with stress levels and differential program effects. Data were collected during an impact study at an urban health department in the Midwest United States from 237 low-income pregnant women who were referred for services between April 2014 and March 2017. Referrals were randomly assigned to a Healthy Families America program or a briefer prenatal care coordination program. A third quasi-experimental study group included women who were referred to but did not receive services. Data on demographics, depressive symptoms, and social support were collected at baseline near the time of program enrollment; 210 participants completed post-baseline parenting stress assessments at up to three time points during the child’s first year. Results from mixed model repeated measures analysis of covariance showed that receiving prenatal care coordination was associated with lower parental distress at 14–60 days postpartum. Neither intervention was linked to reduced stress at 6 or 12 months postpartum. Higher depressive symptoms and lower social support predicted greater stress. Depressive symptoms moderated the effects of prenatal care coordination, with benefits concentrated among participants with higher depression scores. Joining recent calls for greater precision in home visiting, the findings highlight the need to optimize limited resources by effectively tailoring services to address specific outcomes in different populations and contexts.

Clinical effectiveness of care managers in collaborative primary health care for patients with depression: 12- and 24-month follow-up of a pragmatic cluster randomized controlled trial

BackgroundIn previous studies, we investigated the effects of a care manager intervention for patients with depression treated in primary health care. At 6 months, care management improved depressive symptoms, remission, return to work, and adherence to anti-depressive medication more than care as usual. The aim of this study was to compare the long-term effectiveness of care management and usual care for primary care patients with depression on depressive symptoms, remission, quality of life, self-efficacy, confidence in care, and quality of care 12 and 24 months after the start of the intervention.MethodsCluster randomized controlled trial that included 23 primary care centers (11 intervention, 12 control) in the regions of Västra Götaland and Dalarna, Sweden. Patients ≥18 years with newly diagnosed mild to moderate depression (n = 376: 192 intervention, 184 control) were included. Patients at intervention centers co-developed a structured depression care plan with a care manager. Via 6 to 8 telephone contacts over 12 weeks, the care manager followed up symptoms and treatment, encouraged behavioral activation, provided education, and communicated with the patient’s general practitioner as needed. Patients at control centers received usual care. Adjusted mixed model repeated measure analysis was conducted on data gathered at 12 and 24 months on depressive symptoms and remission (MADRS-S); quality of life (EQ5D); and self-efficacy, confidence in care, and quality of care (study-specific questionnaire).ResultsThe intervention group had less severe depressive symptoms than the control group at 12 (P = 0.02) but not 24 months (P = 0.83). They reported higher quality of life at 12 (P = 0.01) but not 24 months (P = 0.88). Differences in remission and self-efficacy were not significant, but patients in the intervention group were more confident that they could get information (53% vs 38%; P = 0.02) and professional emotional support (51% vs 40%; P = 0.05) from the primary care center.ConclusionsPatients with depression who had a care manager maintained their 6-month improvements in symptoms at the 12- and 24-month follow-ups. Without a care manager, recovery could take up to 24 months. Patients with care managers also had significantly more confidence in primary care and belief in future support than controls.Trial registrationClinicalTrials.gov identifier: NCT02378272. Submitted 2/2/2015. Posted 4/3/2015.