Mixed Model For Repeated Measures Research Articles

Preliminary Efficacy of a Web-Based Alcohol and Emotion Regulation Intervention on Intimate Partner Aggression Among College Women.

Intimate partner aggression (IPA), encompassing psychological and physical aggression, is a public health concern due to its high rates among young adults. Research and theory connect heavy drinking and emotion regulation (ER) difficulties to IPA and highlight their potential role in reducing IPA. A web-based intervention combining alcohol reduction strategies with ER skills demonstrated initial efficacy at reducing heavy drinking and improving ER abilities among college women with sexual assault victimization histories. The present study represents a secondary analysis of this brief web-based intervention to evaluate its preliminary efficacy on IPA. The sample comprised 200 heavy drinking college women with histories of sexual assault victimization randomized to an assessment only control or the intervention consisting of 14 brief online alcohol reduction and ER skill building modules administered daily over a two-week period. The analytic sample included 103 women who reported their psychological and physical IPA at both the 1- and 6-month follow-up surveys. After controlling for alcohol use, repeated measures mixed models examining changes from baseline to 6-month follow-up by condition revealed a significant time-by-intervention interaction effect on psychological IPA. Women who received the intervention had a significant decrease in psychological IPA from baseline to 6-month follow-up; there was no change in psychological IPA among women in the control condition. There was no significant effect of the intervention on physical IPA. Reducing alcohol use and improving ER skills may be beneficial in helping women cope with relational conflict, thereby decreasing their use of psychological IPA.

The Influence of Protective Headgear on the Peripheral Vision Reaction Time of Recreational-Level Skiers

Alpine skiing is characterized by specific and dynamic conditions and demands constant processing of visual information and fast decision-making. A fast response time is necessary for protective movements which reduce the number and severity of additional head impacts. The apparent detriments to visual performance caused by protective headgear are concerning and should be considered moving forward in recreational alpine skiing. The aim of this study was to examine the effects of wearing the three most common combinations of protective headgear in skiing on the timing of visual stimuli perception and adequate response when simulating on-the-slope situations. The sample consisted of 45 recreational-level skiers (27 M, 18 F; age 30.6 ± 8.19 years) who had finished basic alpine skiing school, had been skiing 6–10 years continuously, and were students of Faculty of Kinesiology, University of Zagreb. They did not report any serious medical conditions regarding vision. The overall testing was conducted in the winter season during January and February of 2022. Reaction time on perceived visual stimuli was observed in a way that a skier was approaching behind a participant’s back from both the left and right side. A 2 × 3 (helmet*condition) mixed-model repeated-measures ANOVA was used to determine differences between helmet users and non-users in each tested condition. When observing the results, it was confirmed that the response time of the participants was the slowest when wearing a ski helmet and goggles combined. Furthermore, one of the most important findings was the determined differences in reaction time between helmet users and non-users, i.e., prior helmet users tended to react faster to the upcoming visual stimuli when wearing combined ski helmet and goggles. In the design and construction of the goggles, it is also necessary to pay attention to reducing the thickness of the frame in order to reduce the distance between the eye and the lens, which consequently reduces interference in the peripheral parts of the field of vision. In future studies, the same testing protocol with all the possible combinations of wearing a ski cap, a helmet, sunglasses, and goggles is necessary to gain a clearer insight into the effect of each item of headgear separately and in various combinations.

The course of insomnia symptoms during the acute treatment of major depressive disorder: A CAN-BIND-1 report

Despite considerable efforts to study the relationship between insomnia and depression, there is minimal research investigating whether insomnia symptoms change over time during a course of antidepressant pharmacotherapy. This study investigated the course of insomnia symptoms during the acute treatment of major depressive disorder (MDD) using a secondary analysis of data from MDD patients (N = 180) who were treated with open-label escitalopram (10–20 mg/day) for 8-weeks. Montgomery-Asberg Depression Rating Scale without sleep item (modified-MADRS) assessed depression and Self-reported Quick Inventory Depressive Scale (QIDS-SR) measured subjective sleep-onset, mid-nocturnal, and early-morning insomnia throughout 8-weeks of treatment. Pittsburgh Sleep Quality Index (PSQI) was used to assess subjective sleep quality, duration, onset latency, and efficiency throughout 8-weeks of treatment. Remission of depression was defined as modified-MADRS ≤10 at week-8. Mixed model repeated measures (MMRMs) were conducted with remission status as an independent variable and each sleep variable as a dependent variable. MMRMs demonstrated that remitters had significantly lower QIDS-SR sleep-onset and mid-nocturnal insomnia scores as well as a significantly lower PSQI sleep quality score than non-remitters throughout 8-weeks of treatment. Monitoring subjective sleep-onset and mid-nocturnal insomnia during the course of treatment with serotonergic antidepressants may be useful for predicting acute remission of depression.

The effectiveness of three mobile-based psychological interventions in reducing psychological distress and preventing stress-related changes in the psycho-neuro-endocrine-immune network in breast cancer survivors: Study protocol for a randomised controlled trial

BackgroundA growing body of literature shows that psychological distress is not only a major threat to psychological well-being but can also have a significant impact on physical health. In cancer patients, it can negatively affect prognosis and posttreatment recovery processes. Since face-to-face psychological interventions are often inaccessible to cancer patients, researchers have recently been focusing on the effectiveness of eHealth adaptations of well-established approaches. In this context, there has been a call for high-quality randomised controlled trials that would allow for a direct comparison of different approaches, potentially addressing different needs and preferences of patients, and also for more systematic research focusing on how psychological interventions affect not only psychological but also biological markers of stress. Both of these questions are addressed in the present study. MethodsA randomised controlled trial will be carried out to test and compare the effectiveness of three eight-week eHealth programmes for the mental health support of cancer patients. All programmes will be delivered through the same application for mobile devices MOU MindCare. N = 440 of breast cancer survivors will be recruited at the end of their adjuvant treatment (chemotherapy, radiotherapy, or both) and randomly assigned to one of the three interventions – Mindfulness-Based Cognitive Therapy for Cancer (MBCT-Ca), Positive Psychology (PP), or Autogenic Training (AT) – or the treatment-as-usual (TAU) control group. Psychological and biological markers of stress and adaptive functioning will be assessed at baseline (T0), post-treatment (T1), three-month follow-up (T2), and nine-month follow-up (T3). Primary outcomes will include heart-rate variability and self-report measures of depression, anxiety, perceived stress, general quality of life, and positive mental health. Secondary outcomes will include the levels of serum cortisol and immunomarkers, sleep quality, fatigue, common health symptoms, and several transdiagnostic psychological variables that are expected to be specifically affected by the MBCT-Ca and PP interventions, including dispositional mindfulness, emotion regulation, self-compassion, perceived hope, and gratitude. The data will be analysed using the mixed model repeated measures (MMRM) approach. DiscussionThis trial is unique in comparing three different eHealth interventions for cancer patients based on three well-established approaches to mental health support delivered on the same platform. The study will allow us to examine whether different types of interventions affect different indicators of mental health. In addition, it will provide valuable data regarding the effects of stress-reducing psychological interventions on the biomarkers of stress playing an essential role in cancer recovery processes and general health.

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<0.001, and 7.6mg/24h, -2.0 (0.57), P<0.001; disorganized thought, 3.8mg/24h, -1.5 (0.38), P<0.001, and 7.6mg/24h, -0.9 (0.38), P=0.03; uncontrolled hostility/excitement: 3.8mg/24h, -1.1 (0.30), P<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.

Zinc, Copper, and Manganese Homeostasis and Potential Trace Metal Accumulation in Dairy Cows: Longitudinal Study from Late Lactation to Subsequent Mid-Lactation

BackgroundTrace metals are supplemented in cattle to prevent nutrient deficiencies. Levels supplemented to mitigate worst-case basal supply and availability scenarios can, however, result in trace metal intakes far above the nutritional requirements of dairy cows with high feed intakes. ObjectivesWe evaluated Zn, Mn, and Cu balance in dairy cows from late lactation through the subsequent mid-lactation, a period of 24 wk characterized by large changes in dry matter intake. MethodsTwelve Holstein dairy cows were housed in a tie-stall from 10 wk before to 16 wk after parturition and fed 1 unique lactation diet when lactating and a dry cow diet otherwise. After 2 wk of adaptation to the facility and diet, Zn, Mn, and Cu balances were determined at weekly intervals, by calculating the difference between total intakes and complete fecal, urinary, and milk outputs, with the latter 3 fluxes quantified over a 48-h period. Repeated measure mixed models were used to evaluate the effects on trace mineral balances over time. ResultsThe Mn and Cu balances of cows were not significantly different from 0 mg/d between 8 wk prepartum and calving (P ≥ 0.54), when dietary intake was the lowest of the period evaluated. However, when dietary intake was highest, between wk 6 and 16 postpartum, positive Mn and Cu balances were observed (80 and 20 mg/d, respectively, P ≤ 0.05). Cows were in positive Zn balance throughout the study except during the first 3 wk after calving during which the Zn balance was negative. ConclusionsLarge adaptations occur in trace metal homeostasis in transition cows in response to changes in dietary intake. High dry matter intakes, associated with high milk production of dairy cows, combined with current Zn, Mn, and Cu supplementation practices may exceed regulatory homeostatic mechanisms resulting in potential body accumulation of Zn, Mn, and Cu.

Sexual function after primary external beam radiation therapy (EBRT) for prostate cancer in a large cohort of men with long-term follow-up.

346 Background: Clinically localized prostate cancer can be treated with prostatectomy, radiation or focal therapy, with known impacts on sexual function. We sought to characterize long term sexual function in a large cohort of men treated with primary EBRT and to differentiate between those who have high vs low sexual function scores at baseline. Methods: Patients enrolled in CaPSURE, a national registry of men diagnosed with prostate cancer, from 1995 - 2017 with clinically localized prostate cancer (cN0M0/X, PSA < = 50) and treated with primary EBRT were included. Sexual function (SF) was self-reported using the UCLA Prostate Cancer Index (PCI). We performed repeated measures mixed models to evaluate SF after EBRT, stratified by baseline SF and adjusted for age, BMI, comorbidities, smoking, clinical risk, receipt of brachytherapy and/or hormonal therapy, and type of clinical site. Results: 1193 patients were included for analysis. Mean age was 70, mean number of comorbidities was 2, and median PSA was 7.5 at diagnosis. Baseline PCI scores were available for 43% of the cohort (data not collected before 1998). The mean PCI score was 38 out of 100 at baseline and after EBRT, declined gradually to 16 by 10 years. When only those men with good SF at baseline were assessed (scores 80 – 100), the initial rate of decline was more severe, but the nadir in this group was higher than those with lower baseline scores. Unadjusted mean PCI scores showed a similar decline amongst both groups, although those with good baseline SF consistently had better scores. 63% of patients were treated for erectile dysfunction (PDE5 inhibitors, intracavernosal injections or both), 13% of whom started therapy before EBRT. In the repeated measures mixed models analysis, we found that SF changed significantly over time and scores differed significantly by age, comorbidities, baseline SF, receipt of brachytherapy boost and concurrent ADT. Conclusions: SF after EBRT declines and persists. The most affected are those who had better PCI scores at baseline, although their overall PCI scores are consistently higher compared to those with baseline scores less than 80. Among both groups however, there was a similar decline that was statistically significant.

Severe obesity and fitness in New York City public school youth, 2010–2018

BackgroundObesity is associated with poorer youth fitness. However, little research has examined the magnitude of this relationship in youth with severe obesity. Therefore, we sought to determine the relationship between increasing weight status and fitness within a sample of children and adolescents from New York City public schools.MethodsThis study utilized longitudinal data from the NYC Fitnessgram dataset years 2010–2018. Height and weight along with fitness were measured annually during physical education classes. Severity of obesity was defined using body mass index relative to the 95th percentile and then categorized into classes. A composite measure of fitness was calculated based on scores for three fitness tests: aerobic capacity, muscular strength, and muscular endurance. To examine the weight status-fitness relationship, repeated measures mixed models with random-intercepts were constructed. Stratified models examined differences by demographic factors.ResultsThe sample included 917,554 youth (51.8% male, 39.3% Hispanic, 29.9% non-Hispanic Black, 14.0%, 4.6%, and 1.6% class I, II and III obesity, respectively). Compared to youth with healthy weight, increasing severity of obesity was associated with decreased fitness: overweight (β = − 0.28, 95% CI:-0.29;-0.28), class I obesity (β = − 0.60, 95% CI:-0.60; − 0.60), class II obesity (β = − 0.94, 95% CI:-0.94; − 0.93), and class III obesity (β = − 1.28; 95% CI:-1.28; − 1.27). Stratified models showed the association was stronger among male and non-Hispanic White youth.ConclusionFindings revealed that more severe obesity was associated with lower fitness. Future research is needed to develop targeted interventions to improve fitness in youth with obesity.

A blended face-to-face and smartphone intervention to improve suicide prevention literacy and help-seeking intentions among construction workers: a randomised controlled trial

PurposeIn Australia and elsewhere, suicide rates among construction workers remain high. Construction workplaces are thus an important setting for targeted suicide prevention programs. This study aimed to compare suicide prevention literacy and help-seeking intentions among participants receiving face-to-face suicide prevention training, with those receiving face-to-face training augmented by a smartphone application.MethodsA two-arm randomised controlled trial of a smartphone suicide prevention intervention was conducted among construction workers in four Australian states (trial registration number: ACTRN12619000625178). All participants received face-to-face training and were randomised to the control condition (face-to-face only, n = 575), or MATESmobile condition (face-to-face + smartphone application,n = 509). Surveys administered at baseline and 3-month follow-up measured suicide prevention literacy and help-seeking intentions for personal/emotional problems and suicidal thoughts. A mixed-model repeated measures (MMRM) analysis included all 1084 randomised participants.ResultsOutcomes did not differ significantly for suicide prevention literacy, nor help-seeking intentions from formal sources, informal sources outside the workplace, or no one (did not intend to seek help from anyone). However, relative to those in the control condition, those in the MATESmobile group showed greater increase in help-seeking intentions for emotional problems from a MATES worker/Connector (mean difference 0.54, 95% CI 0.22–0.87) and help-seeking intentions for suicidal thoughts from a workmate (mean difference 0.47, 95% CI 0.10–0.83) or MATES worker/Connector (mean difference 0.47, 95% CI 0.09–0.85).ConclusionResults indicate that the MATESmobile application, together with face-to-face training, is beneficial in enhancing help-seeking intentions from MATES workers/Connectors and workmates to a greater extent than face-to-face training only. While this research provides some evidence that smartphone applications may support suicide prevention training, further research is needed.

SCORE: A multisite randomised controlled trial evaluating shared care for colorectal cancer survivors.

84 Background: Colorectal cancer (CRC) survivorship is rising. Few studies have considered shared follow up (FU) care (SC) between oncologists and primary care providers (PCPs). SCORE is the first large RCT of SC for CRC survivors. Aim: to compare SC with usual care (UC) for CRC survivors. Primary objective: assess the effect of SC vs UC on the EORTC QLQ-C30 Global Health Status/Quality of Life (GHQ-QoL) scale to 12 months (mo). Secondary objectives: assess the effect of SC vs UC on QoL; pt perceptions of care; costs; clinical care processes (CEA tests, recurrences); and feasibility (recruitment, completion rate). Methods: Pts had stage I-III CRC, completed all treatments within 3 mo, spoke English, had a PCP, and no prior cancer. After pt consent, PCP could opt out. Pts were randomised 1 to 1 to SC or UC. SC replaced 2 routine oncologist visits with PCP visits and included a survivorship care plan, concerns checklist and management guidelines for the PCP. PCPs were asked to request CEA tests at 3 and 9 mo visits. Pts completed measures at baseline (BL) and at 6 and 12 mo FU. An estimate of the difference (diff) between groups on GHQ-QoL to 12 mo was obtained from a mixed model for repeated measures (MMRM). The test of non-inferiority was performed by evaluating the lower limit of the two-sided 95% confidence interval (CI) for the estimated diff (SC–UC) against a pre-specified non-inferiority margin (NIM) of -10 points. All randomised pts with available data were included in the primary analysis. Per-protocol population (PPP) comprised all randomised pts with ≥ 1 post-BL questionnaire (6 +/or 12 mo) and, for SC, ≥ 1 of the PCP visits. Results: 150 pts were randomised to SC (N=74) or UC (N=76); 11 PCPs declined. Median age 63 years, 39% women, 24% had radiotherapy. Primary: colon (59%), rectum (32%), overlapping (9%). 138/150 (92%) had BL and ≥1 post-BL GHQ-QoL score. 65/74 (88%) of SC pts attended 3- and/or 9-mo PCP visit. The mean (SD) GHQ-QoL scores at baseline / 6 mo / 12 mo were: 69 (18.7) / 69 (21.2) / 72 (20.2) for SC versus 68 (20.0) / 73 (15.1) / 73 (17.2) for UC. The MMRM mean estimate of GHQ-QoL across the 6 mo and 12 mo FU was 69 for SC and 73 for UC, mean diff -4.0 (95% CI: -9.0 to 0.9). The lower limit of the 95% CI did not cross the NIM. For the PPP (N=130/150), mean diff was -5.0 (95% CI: -10.1 to 0.2). No clear evidence of between group diffs on other C30 scales (accounting for multiplicity). At 12 mo, most popular preferences for FU were: SC for 40/63 (63%) in the SC group, similar preferences for SC 22/62 (35%) and ‘Hospital-based care with the doctors that treated the cancer’ 22/62 (35%) in UC. CEA completion was 89% at 3 and 83% at 9 mo in SC; 63% and 68% in UC. 5 recurrences in SC and 6 in UC arms. Conclusions: SCORE was highly feasible with high participation and retention, few PCPs declined. Compared to UC, pts having SC had non-inferior QoL. Adherence to CEA testing was higher in SC. Pts exposed to SC prefer this model of FU. Cost and implementation analyses will follow. Clinical trial information: ACTRN12617000004369 .

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<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 >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<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.

Natural cubic splines for the analysis of Alzheimer's clinical trials.

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical-time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.

Examining racial differences in smoking outcomes among smokers enrolled in an intravenous nicotine infusion study

IntroductionLarge racial disparities exist in the prevention and treatment of smoking-related diseases, and minoritized populations carry a heavier burden of smoking-related morbidity and mortality. To date, most studies investigating smoking-related illnesses have been conducted in samples in which the majority, or totality, self-identified as White or Caucasian. While Black individuals who smoke tend to have a lower rate of nicotine clearance, in part due to the use of mentholated cigarettes, less is known about how slower clearance affects their acute subjective and physiologic responses in response to either overnight abstinence or subsequent nicotine administration. This study aimed to investigate differences between the experiences of Black and White individuals who smoke across these outcomes after a period of short-term abstinence and after IV nicotine infusion. MethodsThe study included 206 smokers (N = 103 Black, N = 103 White, by self-report). The study investigated self-report, physiological, and biochemical smoking-related outcomes following confirmed overnight abstinence followed by IV nicotine infusion. The outcome measures were separately analyzed with repeated-measures mixed-models. ResultsBlack individuals had lower rates of nicotine clearance and were more likely to smoke mentholated cigarettes than White individuals. Despite these differences, no differences in withdrawal, cravings, or physiological outcomes were observed between the two groups. There were some trends toward differences in subjective experiences, in that an interaction with trend level significance between race and dose was observed for negative subjective drug effects, with White smokers trending towards endorsing higher levels of negative affect after abstinence and nicotine infusion. We also observed that Black individuals trended towards experiencing more negative drug effects in response to initial nicotine delivery than to saline, whereas White individuals had no differences in negative drug effects across saline or nicotine doses. ConclusionsDespite slower nicotine clearance, Black participants exhibited withdrawal and urges to smoke as severe as White participants, and did not have blunted physiological responses to overnight abstinence or administration of nicotine, which were contrary to our hypotheses. Our findings suggest minimal differences across races in the acute pharmacologic effects of nicotine. We observed trend-level differences in subjective and affective responses to nicotine. Greater insight into these differences may lead to improved prevention and treatment strategies for smoking-related illnesses for Black individuals who smoke.

Assessing chronic stress in wild mammals using claw-derived cortisol: a validation using European badgers (Meles meles).

Measuring stress experienced by wild mammals is increasingly important in the context of human-induced rapid environmental change and initiatives to mitigate human-wildlife conflicts. Glucocorticoids (GC), such as cortisol, mediate responses by promoting physiological adjustments during environmental perturbations. Measuring cortisol is a popular technique; however, this often reveals only recent short-term stress such as that incurred by restraining the animal to sample blood, corrupting the veracity of this approach. Here we present a protocol using claw cortisol, compared with hair cortisol, as a long-term stress bio-indicator, which circumvents this constraint, where claw tissue archives the individual's GC concentration over preceding weeks. We then correlate our findings against detailed knowledge of European badger life history stressors. Based on a solid-phase extraction method, we assessed how claw cortisol concentrations related to season and badger sex, age and body-condition using a combination of generalized linear mixed models (GLMM) (n= 668 samples from 273 unique individuals) followed by finer scale mixed models for repeated measures (MMRM) (n= 152 re-captured individuals). Claw and hair cortisol assays achieved high accuracy, precision and repeatability, with similar sensitivity. The top GLMM model for claw cortisol included age, sex, season and the sex*season interaction. Overall, claw cortisol levels were significantly higher among males than females, but strongly influenced by season, where females had higher levels than males in autumn. The top fine scale MMRM model included sex, age and body condition, with claw cortisol significantly higher in males, older and thinner individuals. Hair cortisol was more variable than claw; nevertheless, there was a positive correlation after removing 34 outliers. We discuss strong support for these stress-related claw cortisol patterns from previous studies of badger biology. Given the potential of this technique, we conclude that it has broad application in conservation biology.

Patient-reported outcomes for the Intergroup Sentinel Mamma study (INSEMA): A randomised trial with persistent impact of axillary surgery on arm and breast symptoms in patients with early breast cancer.

In clinically node-negative breast cancer patients, the INSEMA trial (NCT02466737) assessed the non-inferiority of avoiding sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). Here we present patient-reported outcomes (PROs) as a secondary endpoint. PROs were assessed for patients with no axillary surgery, SLNB alone, and ALND. Quality of life (QoL) questionnaire EORTC QLQ-C30 and its breast cancer module (BR23) were used at baseline (pre-surgery) and 1, 3, 6, 12, and 18 months after surgery. The QoL scores were compared using repeated measures mixed models based on the safety set. Between 2015 and 2019, 5502 patients were recruited for the first randomization, and 5154 were included inthe intent-to-treat set (4124 SLNB versus 1030 no SLNB). In the case of one to three macrometastases after SLNB, 485 patients underwent second randomization (242 SLNB alone versus 243 ALND). Questionnaire completion response remained high throughout the trial: over 70% at all time points for the first randomization. There were significant differences for the BRBS (breast symptoms) and BRAS (arm symptoms) scores favoring the no SLNB group in all post-baseline assessments. Patients in the SLNB group showed significantly and clinically relevant higher scores for BRAS (differences in mean values ≥5.0 points at all times), including pain, arm swelling, and impaired mobility in all postoperative visits, with the highest difference at one month after surgery. Scoring of theQLQ-C30 questionnaire revealed no relevant differences between the treatment groups, although some comparisons were statistically significant. This is one of the first randomized trials investigating the omission of SLNB in clinically node-negative patients and the first to report comprehensive QoL data. Patients with no SLNB benefitted regarding arm symptoms/functioning, while no relevant differences in other scales were seen. Supported by German Cancer Aid (Deutsche Krebshilfe, Bonn, Germany), Grant No. 110580 and Grant No. 70110580 to University Medicine Rostock.

Effects of Combined Exercises and Short Foot Exercise With and Without Isometric Hip Abduction In Women With Flatfoot

Purpose: This study aims to examine the effect of 6 weeks of combined exercises (CE), short foot exercise (SFE), and SFE with isometric hip abduction (IHA) on dynamic balance (DB), joint position sense (JPS), and strength in women with flexible flatfoot (FF). Methods: A total of 40 women with flexible flatfoot (FF) participated in this semi-experimental study and were randomly assigned to three groups as follows: CE (n=14), SFE (n=13), and IHA (n=13). Six weeks of exercise were split into 3 sessions under supervision and 3 sessions at home were completed by the participants. The Y balance test, goniometer, and dynamometer were used to assess DB, JPS, and strength before and after the exercises, respectively. The mixed-model repeated-measures multivariate analysis of variance statistical test was used to analyze the data with a significance level of 0.05. Results: The results revealed that after performing the exercises, there was a significant difference in the DB in the SFE group in two posteromedial and posterolateral directions; meanwhile, in the IHA group this difference was in three directions, while in the CE group, it was in the posterolateral direction (P<0.05). After the exercises, no significant difference was observed in either group’s JPS or plantar flexors and dorsal flexors strength (P>0.05). Between the groups, there was no difference in any of the other variables (P>0.05). Conclusion: Considering that the DB changes in the IHA group were more than in the other two groups, these exercises are suggested to improve the DB in women with FF.

Feasibility and Effectiveness of a Worksite-Weight-Loss Program for Cancer Prevention among School-District Employees with Overweight and Obesity

The effects of Vibrant Lives, a 6-month worksite-weight-loss program, were examined in a cohort of school-district employees with overweight or obesity. The VL Basic (VLB) participants received materials and tailored text messages, the VL Plus (VLP) participants additionally received WIFI-enabled activity monitors and scales and participated in health challenges throughout the school year, and the VL Plus with Support (VLP + S) participants additionally received coaching support. The levels of program satisfaction and retention and changes in weight, physical activity (PA), and diet were compared across groups using Pearson chi-square tests, repeated-measure mixed models, and logistic regression. After the program, the VLB (n = 131), VLP (n = 87), and VLP + S (n = 88) groups had average weight losses of 2.5, 2.5, and 3.4 kg, respectively, and average increases in weekly PA of 40.4, 35.8, and 65.7 min, respectively. The VLP + S participants were more likely than the other participants to have clinically significant weight loss (≥3%; p = 0.026). Compared with the VLB participants, the VLP participants were less likely to meet the recommendations for consuming fast food (p = 0.022) and sugar-sweetened beverages (p = 0.010). The VLP and VLP + S participants reported higher program satisfaction than the VLB participants. The VL program facilitates weight loss among school-district employees with overweight and obesity by increasing their PA and healthy diet.

Persisting neuropsychiatric symptoms, Alzheimer’s disease, and cerebrospinal fluid cortisol and dehydroepiandrosterone sulfate

IntroductionNeuropsychiatric symptoms are important treatment targets in the management of dementia and can be present at very early clinical stages of neurodegenerative diseases. Increased cortisol has been reported in Alzheimer’s disease (AD) and has been associated with faster cognitive decline. Elevated cortisol output has been observed in relation to perceived stress, depression, and anxiety. Dehydroepiandrosterone sulfate (DHEAS) has known anti-glucocorticoid effects and may counter the effects of cortisol.ObjectivesWe aimed to examine whether CSF cortisol and DHEAS levels were associated with (1) neuropsychiatric symptoms at baseline, (2) changes in neuropsychiatric symptoms over 3 years, and (3) whether these associations were related to or independent of AD pathology.MethodsOne hundred and eighteen participants on a prospective study in a memory clinic setting, including patients with cognitive impairment (n = 78), i.e., mild cognitive impairment or mild dementia, and volunteers with normal cognition (n = 40), were included. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). CSF cortisol and DHEAS, as well as CSF AD biomarkers, were obtained at baseline. Neuropsychiatric symptoms were re-assessed at follow-up visits 18 and 36 months from baseline. We constructed linear regression models to examine the links between baseline neuropsychiatric symptoms, the presence of AD pathology as indicated by CSF biomarkers, and CSF cortisol and DHEAS. We used repeated-measures mixed ANCOVA models to examine the associations between the neuropsychiatric symptoms’ changes over time, baseline CSF cortisol and DHEAS, and AD pathology.ResultsHigher CSF cortisol was associated with higher NPI-Q severity scores at baseline after controlling for covariates including AD pathology status (B = 0.085 [0.027; 0.144], p = 0.027; r = 0.277). In particular, higher CSF cortisol was associated with higher baseline scores of depression/dysphoria, anxiety, and apathy/indifference. Elevated CSF cortisol was also associated with more marked increase in NPI-Q scores over time regardless of AD status (p = 0.036, η2 = 0.207), but this association was no longer significant after controlling for BMI and the use of psychotropic medications. CSF DHEAS was associated neither with NPI-Q scores at baseline nor with their change over time. Cortisol did not mediate the association between baseline NPI-Q and changes in clinical dementia rating sum of boxes over 36 months.ConclusionHigher CSF cortisol may reflect or contribute to more severe neuropsychiatric symptoms at baseline, as well as more pronounced worsening over 3 years, independently of the presence of AD pathology. Our findings also suggest that interventions targeting the HPA axis may be helpful to treat neuropsychiatric symptoms in patients with dementia.