Mixed Model Repeated Measures Analysis Research Articles

P-575. Evaluation of Weight Gain on Incident Hypertension among People Living with HIV-1 Receiving Dolutegravir (DTG)-Based Regimens or Comparator Antiretroviral Therapy (cART) in Randomized Clinical Trials through 96 Weeks

Abstract Background Weight gain has been observed with integrase strand transfer inhibitor (INSTI)-based treatment with an association between INSTI use and hypertension (HTN) in some studies. We observed no difference in odds of incident HTN and minimal weight increase in participants receiving DTG-based or comparator antiretroviral therapy (cART) through Week (W)96. Here, we evaluated the relationship between ART use, weight gain, and HTN risk among participants without baseline (BL) HTN receiving DTG or cART in pooled phase 2/3 studies. Methods Data from ART-naive participants randomized to either DTG-based ART (+ ABC/3TC or TDF/FTC), or cART (EFV/TDF/FTC, RAL + 2 NRTIs, or DRV/r + 2 NRTIs), were pooled from the SPRING-1 and -2, SINGLE, and FLAMINGO trials. HTN at BL, W24, W48, and W96 was defined as a single systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg, HTN history or HTN adverse event, and/or antihypertensive use. Mixed-models repeated-measures (MMRM) analyses evaluated adjusted change from BL in weight. Bayesian Joint Models (JM) evaluated the associations between treatment, weight change, and treatment and weight change interaction with HTN risk. Models were adjusted for key BL variables and pooled treatment. Results Among 2345 participants, 23% (n=530) were excluded for BL HTN; of the remaining, 927 received DTG-based ART and 888 received cART. At W96, adjusted mean (SE) change in weight was 1.98 (0.242) kg for DTG-based ART vs 1.59 (0.212) kg for cART (treatment difference: 0.39 kg; 95% CI: −0.25, 1.04; P=0.230). From JM, treatment (DTG-based ART vs cART) was not independently associated with HTN risk through W96 (mean, M [hazard ratio, HR]: 1.099; 95% credible interval [CrI]: 0.876, 1.370). On average, a 1-kg increase in weight was estimated to increase HTN risk (HR) by 1.012 (CrI: 1.004, 1.020). No evidence of treatment separation was observed through the treatment-weight interaction (DTG-based ART HR: 1.013 [1.003, 1.022]; cART HR: 1.009 [0.998, 1.020]). Conclusion Weight gain was moderately associated with HTN risk through W96. ART was not an independent risk factor for HTN. Weight gain attributed to treatment effect impacted HTN risk similarly. Disclosures Clifford B. Jones, BSc MSc MB ChB, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee Sofia Pozsonyiova, MS, GSK: Employee|GSK: Stocks/Bonds (Public Company) Richard Grove, MSc, GSK: Employee|GSK: Stocks/Bonds (Public Company) Michael McKenna, MBChB, GSK: Employee|GSK: Stocks/Bonds (Public Company) Parul Patel, MSW, GSK: Stocks/Bonds (Public Company)|ViiV Healthcare: Employee

Effects on impulsivity and delay discounting of intermittent theta burst stimulation add-on to dialectical behavioral therapy in borderline personality disorder: a randomized, sham-controlled pilot trial

BackgroundDialectical behavioral therapy (DBT) and repetitive transcranial magnetic stimulation (rTMS) are both effective in treating borderline personality disorder (BPD). Impulsivity and impaired decision-making are prominent features of BPD, and therapeutic interventions targeting these symptoms could lead to significant improvements.Objective/HypothesisWe hypothesized that intermittent theta burst stimulation (iTBS), a modified rTMS protocol that targets the left dorsolateral prefrontal cortex, would enhance the therapeutic effects of DBT, leading to greater improvements in impulsivity and decision-making compared with sham stimulation.MethodsWe performed a single-blind, randomized, sham-controlled pilot study to evaluate the efficacy of iTBS as an add-on to an 8-week DBT program for BPD in a routine inpatient setting. A total of 53 BPD patients were randomly assigned to receive either iTBS (n = 25) or sham stimulation (n = 28) during weeks 4 to 8 of DBT, and 36 patients met the inclusion criteria for the present analysis (≥ 16 of 20 iTBS/sham sessions and assessment of delay discounting). The study endpoints were the Barratt Impulsiveness Scale-15 for impulsivity and the Monetary Choice Questionnaire for decision-making/delay discounting.ResultsA mixed model repeated measures analysis with a 2 × 2 factorial between-subjects design showed a significant overall improvement over time in impulsivity but not in decision-making/delay discounting. No significant differences were found between iTBS and sham, although post hoc tests revealed significant changes in impulsivity in the iTBS group (meandiff = -4.7, p = .001, Cohen’s d = 0.68) but not in the sham group (meandiff = -2.1, p = .077, d = 0.31).ConclusionsiTBS may offer long-term benefits as an add-on treatment to DBT for impulsivity in BPD, suggesting the need for further investigation in larger-scale studies.Trial registrationRegistered at drks.de (no. DRKS00020413) on January 13, 2020.

Complex intervention including pain science education and patient-led goal setting-based self-management strategies for management of aromatase inhibitor-induced musculoskeletal symptoms: a single-arm feasibility and pilot study.

Up to 74% of breast cancer survivors (BCS) treated with aromatase inhibitor (AI) experience AI-induced musculoskeletal symptoms (AIMSS). AIMSS is the predominant cause of poor adherence to AI therapy, yet no definitive treatment exists. The primary research objectives of this study were (1) to develop a novel BCS-specific complex intervention to alleviate AIMSS, and to assess its feasibility. The secondary research objective was (2) to assess the preliminary efficacy of this intervention. A single-arm, longitudinal pilot study was conducted involving 15 BCS with AIMSS. The complex intervention, which included pain science education, patient-led goal setting, and self-management strategies, was administered over 3months. Feasibility was assessed by measuring overall participation, treatment completion rates, and satisfaction after 3months of intervention. Additionally, the preliminary efficacy of the intervention was evaluated using a mixed model repeated measures analysis, with the change in pain intensity (brief pain inventory [BPI] worst pain/stiffness intensity) at 3months as the primary endpoint. The feasibility assessment showed promising results, with a 70.7% participation rate, an 83.3% intervention completion rate, and a satisfaction score of 8.2 ± 1.5. The intervention significantly reduced BPI worst pain/stiffness intensity by 2.78 points after 3months (95% CI, - 4.5 to - 0.87, p < 0.01). Secondary outcomes demonstrated significant improvements in disability, quality of life, and pain catastrophizing (p < 0.05). The novel complex intervention appears valuable for management AIMSS in BCS. Future large-scale studies, including randomized controlled trials, are warranted. The study was registered in the Clinical Trials Registry of the University Hospital Medical Information Network (UMIN-CTR: UMIN 000049035) in October 2022. The novel BCS-specific complex intervention program holds the potential to aid in managing AIMSS, improving adherence to AI therapy, and enhancing their quality of life.

Measuring Residents' Competence in Chest Tube Insertion on Thiel-Embalmed Bodies: A Validity Study.

Chest tube insertions (CTIs) have a high complication rate, prompting the training of technical skills in simulated settings. However, assessment tools require validity evidence prior to their implementation. This study aimed to collect validity evidence for assessment of technical skills in CTI on Thiel-embalmed human bodies. Invitations were sent to residents and staff from the departments of surgery, pulmonology, and emergency medicine. Participants were familiarized with the Thiel body and the supplied equipment. Standardized clinical context and instructions were provided. All participants performed 2 CTIs and were assessed with the Assessment for Competence in Chest Tube InsertiON (ACTION) tool, consisting of a 17-item rating scale and a 16-item error checklist. Live and post hoc video-based assessments by 2 raters were performed. Generalizability analysis was performed to evaluate reliability. Mean scores and errors were compared using a mixed-model repeated measures analysis of variance (ANOVA). A pass/fail score was determined using the contrasting groups' method. Ten novices and 8 experienced participants completed the study. The Generalizability coefficients were moderate for the rating scale (0.75), and low for the error checklist (0.4). Novices scored lower on the rating scale?? (44±6.7/68 vs 50.8 ± 5.7/68, P = 0.024), but did not commit significantly more errors (1.6 ± 1.1/16 vs 1.0 ± 0.6/16, P = 0.066). A pass/fail score of 47/68 was established. The rating scale in the Assessment for Competence in Chest Tube InsertiON tool has a robust validity argument for use on Thiel-embalmed bodies, allowing it to be used in simulation-based mastery learning curricula. In contrast, its error checklist has insufficient reliability and validity to be used for summative assessment.

Structural alterations as a predictor of depression - a 7-Tesla MRI-based multidimensional approach.

Major depressive disorder (MDD) is a debilitating condition that is associated with changes in the default-mode network (DMN). Commonly reported features include alterations in gray matter volume (GMV), cortical thickness (CoT), and gyrification. A comprehensive examination of these variables using ultra-high field strength MRI and machine learning methods may lead to novel insights into the pathophysiology of depression and help develop a more personalized therapy. Cerebral images were obtained from 41 patients with confirmed MDD and 41 healthy controls, matched for age and gender, using a 7-T-MRI. DMN parcellation followed the Schaefer 600 Atlas. Based on the results of a mixed-model repeated measures analysis, a support vector machine (SVM) calculation followed by leave-one-out cross-validation determined the predictive ability of structural features for the presence of MDD. A consecutive permutation procedure identified which areas contributed to the classification results. Correlating changes in those areas with BDI-II and AMDP scores added an explanatory aspect to this study. CoT did not delineate relevant changes in the mixed model and was excluded from further analysis. The SVM achieved a good prediction accuracy of 0.76 using gyrification data. GMV was not a viable predictor for disease presence, however, it correlated in the left parahippocampal gyrus with disease severity as measured by the BDI-II. Structural data of the DMN may therefore contain the necessary information to predict the presence of MDD. However, there may be inherent challenges with predicting disease course or treatment response due to high GMV variance and the static character of gyrification. Further improvements in data acquisition and analysis may help to overcome these difficulties.

Efficacy and safety of Neurocognitive Adaptive Training for Depression combined with SSRIs for treating cognitive impairment among patients with late-life depression: a 12-week, randomized controlled study

BackgroundThis randomized, open-label study examined the therapeutic effects of Neurocognitive Adaptive Training for Depression (NCAT-D) combined with selective serotonin reuptake inhibitors (SSRIs) on cognitive impairment among patients with late-life depression (LLD).MethodStudy data were collected from May 5, 2021, to April 21, 2023. Outpatients who met the diagnostic criteria for major depressive disorder according to the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (i.e., a total score on the 17-item Hamilton Depression Rating Scale (HAMD-17) ≥ 18 and a total score on the Montreal Cognitive Assessment scale (MOCA) < 26) were recruited at Beijing Anding Hospital. These participants were randomly assigned to receive up to 12 weeks of NCAT-D and SSRIs treatment (n = 57) or SSRIs with a control treatment (n = 61). Primary outcomes included changes in Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores from baseline to week 12 between the two groups. Assessments were conducted at baseline, after 2 weeks, 4 weeks, 8 weeks, and at 12 weeks. Mixed model repeated measures (MMRM) analysis was performed on modified intention-to-treat (mITT) and completer populations.ResultsThe full analysis set (FAS) included 118 patients (NCAT-D and SSRIs group, n = 57; SSRIs and Control group, n = 61). During the 12-week study period, MMRM analysis revealed a significantly greater reduction in cognitive function (as indicated by ADAS-cog total scores) from baseline to post-treatment in the NCAT-D and SSRIs group compared to the SSRIs and Control groups [(F (1,115) = 13.65, least-squares mean difference [95% CI]: −2.77 [− 3.73, − 1.81], p < 0.001)]. The intervention group showed a significantly greater reduction in HAMD-17 scores compared to the control group [MMRM, estimated mean difference (SE) between groups: −3.59 [− 5.02, − 2.15], p < 0.001]. There was no significant difference in the incidence of adverse events between the two groups.ConclusionsNCAT-D combined with SSRIs was efficacious and well tolerated in LLD patients with cognitive impairment.Trial registrationRegistered on October 18, 2022, at ClinicalTrials.gov Identifier: (#NCT05588102).

Small sample adjustment for inference without assuming orthogonality in a mixed model for repeated measures analysis

ABSTRACT The mixed model for repeated measures (MMRM) analysis is sometimes used as a primary statistical analysis for a longitudinal randomized clinical trial. When the MMRM analysis is implemented in ordinary statistical software, the standard error of the treatment effect is estimated by assuming orthogonality between the fixed effects and covariance parameters, based on the characteristics of the normal distribution. However, orthogonality does not hold unless the normality assumption of the error distribution holds, and/or the missing data are derived from the missing completely at random structure. Therefore, assuming orthogonality in the MMRM analysis is not preferable. However, without the assumption of orthogonality, the small-sample bias in the standard error of the treatment effect is significant. Nonetheless, there is no method to improve small-sample performance. Furthermore, there is no software that can easily implement inferences on treatment effects without assuming orthogonality. Hence, we propose two small-sample adjustment methods inflating standard errors that are reasonable in ideal situations and achieve empirical conservatism even in general situations. We also provide an R package to implement these inference processes. The simulation results show that one of the proposed small-sample adjustment methods performs particularly well in terms of underestimation bias of standard errors; consequently, the proposed method is recommended. When using the MMRM analysis, our proposed method is recommended if the sample size is not large and between-group heteroscedasticity is expected.

Efficacy and safety profile of oral creatine monohydrate in add-on to cognitive-behavioural therapy in depression: An 8-week pilot, double-blind, randomised, placebo-controlled feasibility and exploratory trial in an under-resourced area

Pre-clinical and clinical evidence proposes that creatine monohydrate, an affordable nutraceutical, could be a useful adjunct to conventional antidepressant treatments. In this pilot feasibility and exploratory study, we investigate the 8-week effects of creatine in addition to cognitive-behavioural therapy (CBT) versus placebo plus CBT in depression. For the primary efficacy outcome of change in Patient Health Questionnaire-9 depression score at study endpoint, we used mixed-model repeated measures analysis of covariance. Logistic regressions were employed to assess acceptability (any-cause dropouts), tolerability (dropouts for adverse events), and safety (patients experiencing one or more adverse events). We calculated effect sizes adjusted for age, sex, and baseline depression score. One-hundred participants (50 females, mean age= 30.4 ± 7.4 years) with depression (mean PHQ-9 = 17.6 ± 6.3) were randomised to either creatine+CBT (N = 50) or placebo+CBT (N = 50). At 8 weeks, PHQ-9 scores were lower in both study arms, but significantly more so in participants taking creatine (mean difference= -5.12). Treatment discontinuations due to any cause and to adverse events, and proportion of participants with at least one adverse event were comparable between study arms. This hypothesis-generating trial suggests that creatine could be a useful and safe supplement to CBT for depression. Longer and larger clinical trials are warranted.

Patient-reported outcomes in patients with relapsed or refractory follicular lymphoma treated with zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy: results from the ROSEWOOD trial

Objective We report patient-reported outcomes (PROs) measuring health-related quality of life (HRQoL) from the ROSEWOOD trial (NCT03332017), which demonstrated superior efficacy and a manageable safety profile with zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) in patients with heavily pretreated relapsed/refractory follicular lymphoma (R/R FL). Methods PROs were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30) and EQ-5D-5L questionnaires at baseline and subsequently every 12 weeks. All QLQ-C30 domains and EQ-5D-5L visual analog scale (VAS) scores were analyzed descriptively. At the key clinical timepoints (weeks 12 and 24), a mixed model for repeated measures (MMRM) analysis was used to evaluate the key PRO endpoints, including global health status, physical and role functioning, and symptoms of fatigue, pain, diarrhea, and nausea/vomiting. Clinically meaningful change was defined as a ≥ 5-point mean difference from baseline and between the ZO and O arms. Results Patients were randomized to ZO (n = 145) or O (n = 72). By week 48, descriptive analysis results indicated that patients in the ZO arm demonstrated improved outcomes in role functioning and fatigue and nausea/vomiting symptoms, compared with those in the O arm. Both groups experienced improvements in pain symptoms. EQ-5D-5L VAS scores showed no observable differences between treatment arms through week 48. MMRM analysis revealed that the global health status/quality of life of patients treated with ZO improved, as did fatigue, at week 12. At week 24, patients in the ZO arm experienced a clinically meaningful improvement in role functioning, pain, and fatigue. Conclusions In patients with R/R FL, ZO was associated with improved PROs compared with O. These findings suggest that zanubrutinib contributed clinically meaningful benefits to patient HRQoL when added to obinutuzumab. Trial registration The ROSEWOOD trial is registered on ClinicalTrials.gov (BGB-3111-212; ClinicalTrials.gov identifier: NCT03332017).

Effects of intermittent theta burst stimulation add-on to dialectical behavioral therapy in borderline personality disorder: results of a randomized, sham-controlled pilot trial

AbstractDialectical behavioral therapy (DBT) and repetitive transcranial magnetic stimulation (rTMS) are both effective in borderline personality disorder (BPD). We hypothesized that intermittent theta burst stimulation (iTBS), a modified rTMS protocol that provides unilateral stimulation to the left dorsolateral prefrontal cortex, would enhance the effects of DBT and reduce BPD-specific symptoms more than sham stimulation. We performed a single-blind, randomized, sham-controlled pilot study to evaluate iTBS as an add-on to 8-week DBT for BPD in routine inpatient treatment. A total of 53 BPD patients were randomly assigned to either iTBS (n = 25) or sham stimulation (n = 28) in weeks 4–8 of DBT; 40 patients were eligible for inclusion in the analyses according to pre-specified criteria (≥ 16 of 20 iTBS sessions). The primary endpoint was change on the 23-item Borderline Symptom List; secondary endpoints were changes in depressive symptoms and general level of functioning. A mixed model repeated measures analysis with a 2 × 2 factorial between-subjects design showed no significant effect of add-on iTBS treatment, but a distinct trend was observed in favor of iTBS (Cohen’s d = 0.23 for group difference). We found a main effect of DBT with and without iTBS over time, indicating efficacy of 8 weeks’ DBT (d = 0.89–1.12). iTBS may be beneficial as an add-on to DBT in the long term and warrants further evaluation in larger studies. Trial registration Registered at drks.de (no. DRKS00020413) on January 13, 2020.

Improvement Across Dimensions of Disease with Lebrikizumab Use in Atopic Dermatitis: Two Phase 3, Randomized, Double-Blind, Placebo-Controlled Monotherapy Trials (ADvocate1 and ADvocate2).

Atopic dermatitis is a complex, chronic, inflammatory skin disease thatrequires long-term control of symptoms like itch and sleep loss and improvement in quality of life, in addition to reduction of clinical signs. Lebrikizumab is a selective interleukin-13 inhibitor approved in the European Union, United Kingdom, United Arab Emirates, Canada, and Japan for treatment of moderate-to-severe atopic dermatitis in adults and adolescents. Here, we assess the magnitude of changes across signs and symptoms of atopic dermatitis with lebrikizumab monotherapy over the 16-week induction period in two phase 3 studies, ADvocate1 and ADvocate2. Eligible adults (aged≥18years) and adolescents (aged 12 to<18years and weighing≥40kg) with moderate-to-severe atopic dermatitis were randomized to receive either 250mg of lebrikizumab or placebo subcutaneously every two weeks. Least squares mean percentage change from baseline through week 16 was compared between lebrikizumab and placebo using mixed model repeated measure analysis for the following endpoints: Eczema Area and Severity Index (EASI), Pruritus Numeric Rating Scale (NRS), Sleep-Loss Scale, Patient-Oriented Eczema Measure (POEM), and Dermatology Life Quality Index (DLQI). In both trials, significant (P<0.05) improvements were observed for lebrikizumab treatment compared with placebo at each 2-week timepoint for EASI, Pruritus NRS, Sleep-Loss Scale, and POEM, and at each 4-week timepoint for DLQI, through week 16. Statistically significant (P<0.001) improvements were observed at 16weeks for lebrikizumab treatment versus placebo in ADvocate1/ADvocate2 for EASI (71.9%/75.0% vs. 35.6%/43.3%), Pruritus NRS (53.3%/46.3% vs. 21.4%/18.0%), Sleep-Loss Scale (57.7%/55.6% vs. 23.9%/25.5%), POEM (54.4%/45.8% vs. 18.8%/16.9%), and DLQI (64.2%/60.5% vs. 28.5%/32.2%). Patient photos show improvements in skin appearance when disease measures improve. Lebrikizumab monotherapy resulted in significant and fast improvements in multiple dimensions of disease (clinical signs, symptoms, and quality of life) over 16weeks in patients with moderate-to-severe atopic dermatitis. ClinicalTrials.gov identifiers, NCT04146363; NCT04178967.

The Chronic Progressive Repeated Measures (CPRM) Model for Clinical Trials Comparing Change Over Time in Quantitative Trait Outcomes

Repeated measures analysis is a common analysis plan for clinical trials comparing change over time in quantitative trait outcomes in treatment versus control. Mixed model for repeated measures (MMRM) assuming an unstructured covariance of repeated measures is the default statistical analysis plan, with alternative covariance structures specified in the event that the MMRM model with unstructured covariance does not converge. We here describe a parsimonious covariance structure for repeated measures analysis that is specifically appropriate for longitudinal repeated measures of chronic progressive conditions. This model has the parsimonious features of the mixed effects model with random slopes and intercepts, but without restricting the repeated measure means to be linear with time. We demonstrate with data from completed trials that this pattern of longitudinal trajectories spreading apart over time is typical of Alzheimer’s disease. We further demonstrate that alternative covariance structures typically specified in statistical analysis plans using MMRM perform poorly for chronic progressive conditions, with the compound symmetry model being anticonservative, and the autoregressive model being poorly powered. Finally, we derive power calculation formulas for the chronic progressive repeated measures model that have the advantage of being independent of the design of the pilot studies informing the power calculations. When data follow the pattern of a chronic progressive condition. These power formulas are also appropriate for sizing clinical trials using MMRM analysis with unstructured covariance of repeated measures.

A phase 3, randomized, double-blind, sham-controlled trial of SI-6603 (condoliase) in patients with radicular leg pain associated with lumbar disc herniation

BACKGROUND CONTEXTSI-6603 (condoliase) is a chemonucleolytic agent approved in Japan in 2018 for the treatment of lumbar disc herniation (LDH) associated with radicular leg pain. Condoliase, a mucopolysaccharidase with high substrate specificity for glycosaminoglycans (GAGs), offers a unique mechanism of action through the degradation of GAGs in the nucleus pulposus. As LDH management is currently limited to conservative approaches and surgical intervention, condoliase could offer a less invasive treatment option than surgery for patients with LDH. PURPOSEThe Discovery 6603 study (NCT03607838) evaluated the efficacy and safety of a single-dose injection of SI-6603 (condoliase) vs sham for the treatment of radicular leg pain associated with LDH. STUDY DESIGN/SETTINGA randomized, double-blind, sham-controlled, phase 3 study conducted across 41 sites in the United States. PATIENT SAMPLEMale and female participants (N=352; aged 30–70 years) with contained posterolateral LDH and unilateral radiculopathy/radicular leg pain for greater than 6 weeks. OUTCOME MEASURESThe primary endpoint was the change from baseline (CFB) in average worst leg pain score at 13 weeks, assessed using the 100-mm visual analogue scale. Key secondary endpoints were CFB in average worst leg pain score at 52 weeks, herniation volume at 13 weeks, and Oswestry Disability Index (ODI) score at 13 weeks. Safety evaluations included adverse events (AEs) and imaging findings. METHODSParticipants were randomized 1:1 to receive a single intradiscal injection of condoliase (1.25 units) or sham injection followed by 52 weeks of observation. The primary and key secondary endpoints were assessed using a mixed model for repeated measures (MMRM) analysis and a protocol-specified multiple imputation (MI) sensitivity analysis on the modified intention-to-treat (mITT) population. A prespecified serial gatekeeping algorithm was used for multiple comparisons. Safety endpoints included AEs, laboratory tests, vital signs, imaging (by X-ray and magnetic resonance imaging [MRI]), and occurrence of posttreatment lumbar surgery. RESULTSOf the 352 randomized participants, 341 constituted the mITT population (condoliase n=169; sham n=172) and the safety population (condoliase n=167; sham n=174). For the primary endpoint, the condoliase group showed significantly greater improvement in CFB in worst leg pain at Week 13 (least squares mean [LSM] CFB: −41.7) compared with sham injection (−34.2; LSM difference: −7.5; 95% confidence interval [CI]: −14.1, −0.9; p=.0263) based on the MMRM analysis. CFB in worst leg pain at Week 52 favored condoliase vs sham, but the difference was not statistically significant (p=.0558), which halted the serial gatekeeping testing algorithm and dictated that the CFB in herniation volume and ODI scores at Week 13 would be considered nonsignificant, regardless of their p-values. Treatment group differences in CFB in herniation volume and ODI score favored the condoliase group vs sham at all timepoints. The MI sensitivity analysis showed differences in CFB in worst leg pain at Week 13 (p=.0223) and Week 52 (p=.0433) in favor of the condoliase group. Treatment-emergent AEs (TEAEs) were more common in the condoliase group (≥1 TEAE: 71.9%; ≥1 treatment-related TEAE: 28.1%) compared with the sham group (≥1 TEAE: 60.3%; ≥1 treatment-related TEAE: 10.3%). Of the TEAEs, spinal MRI abnormalities and back pain occurred most frequently. No treatment-related serious AEs occurred. CONCLUSIONSCondoliase met its primary endpoint of significantly improving radicular leg pain at Week 13 and was generally well tolerated in patients with LDH. Chemonucleolysis with condoliase has the potential to provide a less invasive treatment option than surgery for those unresponsive to conservative treatment strategies.

Mental health training for physicians supervising resident physicians: a cluster randomised controlled trial.

To evaluate an online training program for physician supervisors with the aim of promoting a mentally healthy workplace by improving their use of both responsive and preventive mental health support strategies. Cluster randomised, waitlist-controlled trial. Royal Australasian College of Physicians fellows who were supervising at least one resident physician in any of the 31 primary health networks in Australia and 20 district health boards in New Zealand (health network clusters). A brief online skills-based mental health training program, comprising twelve modules grouped into three topics: common mental illnesses; helping trainees you are concerned about (responsive strategies); and minimising mental health risks at work (preventive strategies). Change between baseline and the 3-month assessment in self-reported recommended supervisor behaviours; differences between intervention and control groups in recommended behaviour scores three weeks, three months, and six months after the program. Ninety physicians from 20 health network clusters were allocated to the intervention group, 88 physicians from 22 clusters to the control group. Intervention group participants reported greater positive change in behaviour across the study period than those in the control group (mixed model repeated measures analysis, group × time interaction: P < 0.001). The mean change in self-reported supervisory behaviour score was higher for the intervention than the control group at the 3-week (mean difference in score, 1.6; 95% confidence interval [CI], 0.8-2.4), 3-month (0.9; 95% CI, 0.2-1.6), and 6-month assessments (1.9; 95% CI, 1.1-2.7). The mean change in self-reported responsive behaviour score was also greater for the intervention group at the 3-week (mean difference, 2.3; 95% CI, 1.5-3.1), 3-month (1.0; 95% CI, 0.2-1.9), and 6-month assessments (2.0; 95% CI, 1.1-2.9); differences in the mean change in preventive behaviour scores were statistically significant at the 3-week (mean difference, 1.1; 95% CI, 0.1-2.2) and 6-month assessments (1.8; 95% CI, 0.8-2.8), but not the 3-month assessment (0.8; 95% CI, -0.1 to 1.7). Brief online mental health training for senior physicians can lead to changes in their self-reported behaviour for supporting the mental health needs of resident physicians. Whether this leads to better mental health for resident physicians should be investigated. Australian New Zealand Clinical Trials Registry, ACTRN12619001496101 (prospective).

Neurocognitive profiles of 22q11.2 and 16p11.2 deletions and duplications

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function.

Mental health literacy in Australian schools: evaluation of the Australian adapted youth education and support program

ABSTRACT Objective The prevalence of youth mental illness is increasing, and accessible preventative approaches, such as school-based mental health literacy programs, are needed. Mental health literacy is the ability to understand how to obtain and maintain good mental health. Schools are an ideal and accessible setting to base programs targeting mental health literacy. Method This study used a non-randomised waitlist control design to evaluate the effects of the Youth Education and Support (YES) program on mental health literacy, help seeking, and resilience for 38 Australian youth (12 male, 26 female) aged 12–16 years (M = 14.05, SD = 1.01). Data was analysed using t-tests, frequency analyses, mixed-model repeated measures analysis of variance, and directed content analysis. Results No significant interaction effect on mental health literacy from pre to post intervention was found between participants in the YES condition and control condition. Participants (n = 26) were significantly more likely to seek help from a helpline for suicidal ideation than control (n = 12) postintervention. Participants within the YES condition demonstrated significantly improved mental health literacy from pre to postintervention. Conclusions This study provides initial evidence supporting the inclusion of mental health literacy programs in Australian school environments.

Effects of a physical exercise programme on bodyweight, body condition score and chest, abdominal and thigh circumferences in dogs

BackgroundResearch on the effects of physical exercise on canine body composition is limited. The aim of this study was to investigate the effects of a physical exercise programme on bodyweight, body condition score (BCS) and chest, abdominal and thigh circumferences in dogs. Twenty-one healthy dogs of different breeds exercised together with their owners during an eight-week programme consisting of jogging and strength exercises. Standardised measurements were performed in triplicates with a measuring tape on standing dogs. Chest circumference was measured at three anatomical locations, abdomen at two and thigh at one. Data on bodyweight, BCS (9-point scale) and circumferences were analysed with mixed model repeated measures analyses to evaluate changes after the programme and effects of target distance.ResultsSeven dog owners choose a target distance of 2 km and 14 owners choose 5–10 km. Mean BCS decreased (P = 0.007) after the programme (5.1 ± 0.9 vs. 4.7 ± 0.6) but there was no effect of target distance. Almost all chest and abdominal circumference measurements decreased (P ≤ 0.007) with the 2 km group driving the reduction in chest circumference and the 5–10 km group driving the reduction in abdominal circumference. In contrast, thigh circumference (28.8 ± 0.4 vs. 30.2 ± 0.4) increased (P = 0.007) while bodyweight was maintained. There were positive correlations between BCS and abdominal/chest ratios before and after the programme (Pearson correlation; R square ≤ 0.43, P ≤ 0.0012) but the mean ratio remained constant.ConclusionsResults indicated a redistribution between total body fat and muscle mass in body composition of normal weight to slightly overweight dogs after the physical exercise programme. The use of bodyweight alone was not a reliable evaluation method to complement the BCS assessment. However, repeated measurements of chest, abdominal and thigh circumference might aid in the assessment of body composition in dogs performing physical exercise. Further research should include a control group and objective evaluations of total body fat and lean mass, in order to investigate the effectiveness of physical exercise as a freestanding method for decreasing BCS and increasing muscle mass in overweight dogs.

Efficacy and Safety of LX9211 for Relief of Diabetic Peripheral Neuropathic Pain (RELIEF-DPN 1): Results of a Double-Blind, Randomized, Placebo-Controlled, Proof-of-Concept Study.

To evaluate the efficacy of LX9211 in reducing pain related to diabetic peripheral neuropathy. In this double-blind, multicenter, proof-of-concept trial, 319 individuals with diabetic peripheral neuropathic pain (DPNP) were randomized (1:1:1) to LX9211 10 mg (n = 106), LX9211 20 mg (n = 106), or matching placebo (n = 107), administered once daily for 6 weeks. DPNP was rated daily with an 11-point numerical rating scale. The primary end point was change from baseline to week 6 in the average daily pain score. The difference between each LX9211 group and placebo was evaluated with mixed-model repeated-measures analysis. For those on low-dose LX9211 the primary efficacy end point was achieved: -1.39 vs. -0.72 points for placebo, least squares mean (SE) difference -0.67 (0.249), 95% CI -1.16 to -0.18, P = 0.007; results for high-dose LX9211 demonstrated improvement in pain severity versus placebo (-1.27 vs. -0.72 points, respectively), but the between-group LS mean difference did not reach the prespecified statistical significance (-0.55 [0.254], 95% CI -1.06 to -0.05, P = 0.030). Treatment benefit was observed beginning at week 1 and maintained thereafter. Results for LX9211 also demonstrated improvement in several patient-reported secondary outcomes. Most common adverse events (AEs) were dizziness, nausea, and headache. More participants treated with LX9211 (20 mg, n = 28 [26.4%]; 10 mg, 17 [16.0%]) than placebo (3 [2.8%]) discontinued study drug prematurely due to AEs; serious AEs were uncommon (2 [1.9%], 0, and 1 [0.9%], respectively). These preliminary findings of improvement in DPNP with LX9211 support further investigation in larger trials.

Efficacy of Faricimab versus Aflibercept in Diabetic Macular Edema in the 20/50 or Worse Vision Subgroup in Phase III YOSEMITE and RHINE Trials

PurposeDRCR.net Protocol T data suggest the response to treatment among patients with diabetic macular edema (DME) may vary depending on baseline best-corrected visual acuity (BCVA). We evaluated the efficacy of faricimab 6 mg versus aflibercept 2 mg over 2 years in patients with DME enrolled in faricimab phase 3 trials with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA ≤20/50. DesignYOSEMITE/RHINE were identically designed, multicenter, randomized, double-masked, active comparator–controlled, noninferiority trials. ParticipantsAdults aged ≥18 years with center-involving macular edema secondary to type 1 or 2 diabetes. MethodsPatients were randomized to faricimab every 8 weeks (Q8W), faricimab per a personalized treat-and-extend–based regimen (T&E), or aflibercept Q8W. Post hoc subgroup analyses were conducted using the intent-to-treat population with baseline BCVA ≤20/50 (ETDRS letters <69). Main Outcome MeasuresChanges in ETDRS BCVA and central subfield thickness (CST) from baseline to years 1 and 2 were compared between treatment arms using mixed-model repeated measures analyses. ResultsIn YOSEMITE/RHINE, 220/217 patients in the faricimab Q8W; 220/219, faricimab T&E; and 219/214, aflibercept Q8W arms had baseline BCVA ≤20/50. In both trials, mean change in ETDRS BCVA was comparable between treatments at years 1 and 2. In YOSEMITE, adjusted mean (95% CI) change from baseline in CST (μm) at year 1 was greater with faricimab Q8W (–232.8 [–243.5, –222.1]) and faricimab T&E (–217.4 [–227.9, –206.9]) versus aflibercept Q8W (–190.4 [–200.9, –179.8]; P<0.0001 and P=0.0004, respectively). The pattern was similar in RHINE: faricimab Q8W, –214.2 (–225.3, –203.1); faricimab T&E, –206.6 (–217.4, –195.7); aflibercept Q8W, –186.6 (–197.7, –175.5); P=0.0006 and P=0.0116 for faricimab arms versus aflibercept, respectively. In both trials, change from baseline in CST at year 2 was greater with faricimab Q8W versus aflibercept. Median time to first CST <325 μm and first absence of intraretinal fluid was shorter in the faricimab arms versus aflibercept, with fewer injections on average. ConclusionsIn patients with DME and baseline ETDRS BCVA ≤20/50, faricimab treatment resulted in comparable visual acuity, greater reduction in retinal thickness, and fewer injections compared with aflibercept over 2 years of treatment.

#723 The impact of kidney function on arterial stiffness in COVID-19 survivors: an analysis from CARTESIAN Study

Abstract Background and Aims SARS-CoV-2 pandemic has been linked to an increased incidence of cardiovascular events, potentially due to accelerated vascular aging [1]. Conversely, impaired kidney function is known to contribute to the pathogenesis of heightened arterial stiffness, independent of traditional cardiovascular risk factors [2]. This study aimed to assess the impact of COVID-19 on arterial stiffness among a cohort of survivors of the first pandemic wave, with varying degrees of infection severity. The assessment was conducted at 6 ± 3 (T1) and 12 ± 3 months (T2) post-infection, with the population stratified based on kidney function. Method the CARTESIAN study, a large international multicenter cohort study, was designed to assess the long-term effects of COVID-19 on vascular aging. A total of 938 subjects were stratified into three groups based on their estimated glomerular filtration rate (eGFR) percentiles using the CKD-EPI_2021 equation: 1) &amp;gt;75th percentile, 2) 75th-25th percentile, and 3) &amp;lt;25th percentile, respectively. The same population was further categorized based on the severity of COVID-19 into three groups: 1) patients who were not hospitalized (No-Hosp), 2) subjects requiring hospitalization in a medical unit (Hosp), or 3) those in an intensive care unit (ICU). Arterial stiffness was evaluated using carotid-femoral pulse wave velocity (cf-PWV). A hierarchical repeated measures mixed model analysis was conducted to compare cf-PWV across these groups (&amp;gt;75th, 75th-25th, and &amp;lt;25th groups, respectively). Results in the cross-section analysis (T1) &amp;lt;25th group exhibited higher age, increased cardiovascular risk factors, and higher prevalence of severe COVID-19 compared to the &amp;gt;75th group. Using hierarchical linear modeling, the &amp;lt;25th exhibited higher cf-PWV than the &amp;gt;75th group, even after adjusting for both all the random and fixed variables, included the three COVID-19 group (+0.51 m/s, p = 0.013). In longitudinal analysis, globally, no substantial changes were found in the cf-PWV between T1 and T2, remained significantly higher in the &amp;lt;25th group compared to the &amp;gt;75th group (p = 0.003), in a linear mixed model adjusted for all the random and fixed variables. Interestingly, a significant interaction between eGFR groups* COVID-19 groups was found in repeated measures analysis (p = 0.039). In particular, within ICU group, we found a significant increase of cf-PWV between 6- and 12-months in &amp;lt;25th group, from 8.64 [7.59-9.31] to 9.41 [8.89-10.41] m/s, p = 0.021) (Fig. 1). Conclusion the findings suggest that individuals with both lower eGFR and a history of severe COVID-19 may be at a heightened risk of accelerated arterial aging. Understanding these dynamics is crucial for targeted interventions to mitigate long-term cardiovascular consequences in COVID-19 survivors with kidney disease.