Mixed-effects Model For Repeated Measures Research Articles

A Blinded Crossover Study Design to Evaluate Midazolam as an Adjunct for Equine Standing Sedation for Routine Oral Examinations

This study aimed to evaluate the effects of including midazolam to a common equine standing sedation protocol for routine oral examination. Twelve horses underwent two examinations at least seven days apart. Horses were randomly assigned to receive midazolam intravenously (IV) (0.02mg/kg) or a placebo injection of saline (2-2.5mL IV). Five minutes later, detomidine (0.01mg/kg) and butorphanol (0.01mg/kg) were administered IV and horses were placed in standing stocks. A veterinarian blinded to the treatment protocol used a descriptive scoring system to assess degree of ataxia, acceptance of speculum, chewing on the speculum, headshaking, tongue movement, resistance to palpation, and eye appearance as related to the grimace score. During each examination, additional sedation of IV detomidine (0.006mg/kg) and butorphanol (0.006mg/kg) was administered at the discretion of the blinded practitioner to facilitate safe examination. At the second examination horses received the opposite treatment protocol and, following examination, a routine occlusal adjustment. Scores were compared using JMP software with a repeated measures mixed effects model, treatment as a fixed effect and horse and horse/treatment interaction as random effects. Significance was set at P<0.05. There were no significant differences in any of the single or overall sedation scores between treatment groups or within individual horses (P=0.3). Trends towards improvement of some assessed characteristics of sedation, including decreased tongue movement and less resistance to acceptance of speculum were observed. The use of midazolam may prove beneficial for routine oral examination, as well as other standing procedures, with no obvious undesired side effects.

Comprehensive assessment of corneal microstructural changes following V4c implantable collamer lens surgery using in vivo confocal microscopy

BackgroundImplantable Collamer Lense (ICL) presents a viable alternative to conventional refractive surgeries, but their impact on corneal microstructure remains unclear. By employing in vivo confocal microscopy (IVCM), we examined changes in stromal and endothelial cells following the insertion of V4c ICLs, with the goal of enhancing post-surgical care and outcomes.MethodsIn this longitudinal investigation, we conducted detailed preoperative assessments on 103 eyes from 53 participants. Follow-up evaluations were carried out after surgery at set intervals: one day, one week, one month, three months, six months, and twelve months. We used IVCM to analyze changes in stromal and endothelial cells. To assess differences between pre- and post-surgery variables and to investigate correlations with age, axial length (AL), and spherical equivalent refraction (SER), we applied a repeated measures mixed-effects model, with statistical significance set at P < 0.05.ResultsNo vision-threatening complications were reported post-surgery. Significant reductions in stromal cell density (SCD) were observed postoperatively, with anterior and mid- SCD reaching their lowest values at 3 months and posterior SCD at 1 month, remaining below baseline at 12 months. endothelial cell density (ECD) and percentage of hexagonal cells (PHC) decreased initially, recovering by 12 months. Conversely, endothelial cellular area (ECA) and coefficient of variation of cell size (CoV) increased postoperatively, with the most significant change at 1 week. Endothelial deposits were detected in 49 of 101 eyes on postoperative day 1, half of them were absorbed within 3 months post-surgery. Changes in posterior SCD were negatively related to AL, while AL, SER, lens thickness showed associated with endothelium changes.ConclusionOur findings elucidate the corneal microstructural changes following V4c ICL implantation, particularly the significant early reductions in stromal and endothelial cell densities. We recommend careful management of viscoelastics during surgery to minimize endothelial deposits that may harm the endothelium. Enhanced early postoperative monitoring and these surgical adjustments can lead to improved surgical and post-surgical care, ultimately supporting better patient recovery.

Purpose development in the context of higher education

The aim of this study was to examine the development of purpose among college students, especially in relation to experiences typical of a liberal arts education. We surveyed 1,019 students in 11 U.S. colleges and universities at two-time points over three years. At Time 1, 546 of the students were in their first year of college and 473 were in their second year or above. The survey assessed three dimensions of purpose, as well as learning experiences, advising experiences, and course types. Repeated measures mixed-effects model analyses were conducted to investigate the associations between purpose and college experiences and changes in purpose from Time 1 to Time 2. Results indicate some college experiences predict modest changes in purpose during college. However, these limited effects suggest that colleges could do more to promote students’ purpose development during college and to sustain students’ purpose after graduation.

The effects of treatment, clinical and demographic factors on recovery of orientation after ECT: A care network study

BackgroundTime to reorientation after electroconvulsive therapy (ECT) has been shown to predict retrograde amnesia and is a useful measure for monitoring patients over the acute treatment course. This study investigated the effects of treatment, clinical and demographic factors on the recovery of orientation after ECT. MethodsData from 555 ECT patients across two different clinical CARE Network sites were analysed. The main outcome variable was recovery of orientation on the 10-Item Orientation Questionnaire assessed after every ECT treatment. A linear mixed-effects repeated measures model was used to predict the recovery of orientation across the ECT course based on multiple factors, including age, gender, electrode montage, ECT number and frequency, diagnosis, and baseline cognitive impairment. ResultsType of ECT demonstrated a significant effect (F(2, 2341) = 48.414, p = 0.000): individuals who received right unilateral (RUL) ultrabrief ECT or bifrontal ECT had higher orientation scores compared to those who received RUL brief pulse ECT. Older age groups and female patients had lower orientation scores. Baseline global cognitive functioning significantly influenced orientation scores (F(3, 2339) = 43.597, p = 0.000), with individuals with no or mild cognitive impairment exhibiting higher scores. LimitationsThe study involved a retrospective analysis of de-identified data, which may have introduced inherent biases with missing data. ConclusionsThis large-scale retrospective, real-world study showed that recovery of orientation after ECT was most affected by ECT type, though age, gender, and baseline level cognitive impairment also affected outcomes. These findings can inform the interpretation of post ECT orientation scores, facilitating its monitoring and optimisation of patient outcomes.

Relationship Between Cardiac Structure and Function With Renal Function Trajectory and Outcomes in Patients With Heart Failure: Insights From the PARAGON-HF Trial.

Renal dysfunction is common and associated with a poor prognosis in patients with heart failure. However, the association of cardiac structure and function with decline in kidney function in this population is unknown. We aimed to assess the association between individual measures of cardiac structure and function with changes in renal function and renal outcomes in patients with heart failure with preserved ejection fraction. Patients enrolled in the PARAGON-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin-Receptor Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction) echocardiographic substudy were included. The association between each echocardiographic parameter (expressed in standardized units) and changes over time in estimated glomerular filtration rate was calculated with repeated-measures mixed-effect models. Multivariable Cox proportional hazards models were used to identify individual cardiac parameters associated with the composite renal outcome (≥50% decline in estimated glomerular filtration rate relative to baseline, development of end-stage renal disease, or death attributable to renal causes), after adjusting for covariates. Among 1097 patients (mean age 74±8 years and 53% women), over a median follow-up of 2.9 years, 28 composite renal events (0.9 per 100 person-years) occurred. Higher left ventricular (LV) mass index and higher E/average e' ratio were associated with significantly more profound annual decline in estimated glomerular filtration rate (for both, -0.4 [95% CI, -0.7 to -0.1] mL/min/1.73 m2/y per 1 higher SD). Higher LV mass index, LV end-diastolic volume index, right ventricular end-diastolic area, and a lower right ventricular fractional area change were each associated with a significantly higher risk for the composite renal outcome. In the PARAGON-HF echocardiographic substudy, higher LV mass and filling pressures were independently associated with more profound kidney function decline, and higher LV mass and volume, as well as impaired right ventricular structure and function, were each associated with renal events. Assessing these parameters may help identify patients with heart failure with preserved ejection fraction at higher risk for adverse renal events and indicate potential therapeutic targets. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Less inflammatory response in the direct anterior than in the direct lateral approach in patients with femoral neck fractures receiving a total hip arthroplasty: exploratory results from a randomized controlled trial.

It is still debatable which is the least invasive approach to the hip joint in arthroplasty for a femoral neck fracture (FNF). We compared the traditional direct lateral approach (DLA) with the direct anterior approach (DAA) regarding creatine kinase (CK), C-reactive protein (CRP), and hemoglobin (Hb). In a randomized controlled trial, 130 elderly patients with dislocated FNFs treated with total hip arthroplasty (THA) were included. CK, CRP, and Hb were measured preoperatively and on postoperative days 1 to 4 and were compared between the DAA and DLA groups using repeated measures mixed-effect models. The CK level was significantly higher on the 1st postoperative day in the DLA group, 597 U/L (95% confidence interval [CI] 529-666) vs 461 U/L (CI 389-532), estimated mean difference (MD) 136 U/L (CI 38-235). The CRP levels were significantly higher on postoperative days 3 and 4 in the DLA group, 207 mg/L (CI 189-226) vs 161 mg/L (CI 143-180), estimated MD 46 mg/L (CI 19-72) and 162 mg/L (CI 144-181) vs 121 (CI 102-140), estimated MD 41 mg/L (CI 15-68). Blood loss, expressed as difference in Hb, did not differ between the groups. In an elderly population with FNFs, we found that the DAA, compared with the DLA, results in less CK and CRP increase, but no change in Hb.

Quality of life in cemiplimab-treated patients with locally advanced basal cell carcinoma in a Phase IIclinical trial.

Aim: To evaluate health-related quality of life (HRQoL) in cemiplimab-treated patients with locally advanced basal cell carcinoma (laBCC). Materials & methods: Eighty-four patients withlaBCC received cemiplimab 350mg every 3weeks (up to 9 cycles). HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 (QLQ-C30) and Skindex-16 questionnaires at baseline and each cycle. Mixed-effects repeated-measures models evaluated change from baseline across cycles. Results: Clinically meaningful improvement or maintenance was reported by 62-90% of patients on QLQ-C30 scales and by approximately80% on Skindex-16 scales at Cycle 2, with consistent results at Cycle 9 except fatigue. Conclusion: Most cemiplimab-treated patients with laBCC reported improvement or maintenance of HRQoL with low symptom burden except fatigue.Clinical Trial Registration: ClinicalTrials.gov identifier NCT03132636, registered 28April 2017.

Ketamine vs Electroconvulsive Therapy for Treatment-Resistant Depression

The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD. To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT. This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians. Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks. Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses. Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment. In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.

Prolonged intermittent theta burst stimulation targeting the left prefrontal cortex and cerebellum does not affect executive functions in healthy individuals

Repetitive transcranial magnetic stimulation (rTMS) for alleviating negative symptoms and cognitive dysfunction in schizophrenia commonly targets the left dorsolateral prefrontal cortex (LDLPFC). However, the therapeutic effectiveness of rTMS at this site remains inconclusive and increasingly, studies are focusing on cerebellar rTMS. Recently, prolonged intermittent theta-burst stimulation (iTBS) has emerged as a rapid-acting form of rTMS with promising clinical benefits. This study explored the cognitive and neurophysiological effects of prolonged iTBS administered to the LDLPFC and cerebellum in a healthy cohort. 50 healthy participants took part in a cross-over study and received prolonged (1800 pulses) iTBS targeting the LDLPFC, cerebellar vermis, and sham iTBS. Mixed effects repeated measures models examined cognitive and event-related potentials (ERPs) from 2-back (P300, N200) and Stroop (N200, N450) tasks after stimulation. Exploratory non-parametric cluster-based permutation tests compared ERPs between conditions. There were no significant differences between conditions for behavioural and ERP outcomes on the 2-back and Stroop tasks. Exploratory cluster-based permutation tests of ERPs did not identify any significant differences between conditions. We did not find evidence that a single session of prolonged iTBS administered to either the LDLPFC or cerebellum could cause any cognitive or ERP changes compared to sham in a healthy sample.

#653 Changes in iron markers and D-dimer levels during enarodustat treatment depends on different iron prescription patterns in hemodialysis patients

Abstract Background and Aims Iron preparations are commonly administered with erythropoiesis-stimulating agents or hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PH inhibitors) in hemodialysis patients to promote hematopoiesis and prevent iron deficiency. A recent study highlighted the causal relationship between thrombosis and upregulated serum transferrin levels due to iron deficiency. Additionally, rapid increase of hemoglobin (Hb) during HIF-PH inhibitor use is also considered a risk factor for the development of thromboembolism. Therefore, monitoring iron parameters and Hb is essential for managing anemia and thrombosis risk. We investigated the impact of practice patterns of iron supplementation on iron metabolism in patients receiving a HIF-PH inhibitor enarodustat. Changes in D-dimer levels, a thrombosis-related factor, were also assessed. Method We performed a post-hoc analysis using pooled data from two phase 3 clinical studies of enarodustat in Japanese maintenance hemodialysis patients, SYMPHONY HD and SYMPHONY HD-Long studies. We divided the subjects into three groups according to practice patterns of iron administration: subjects who did not receive iron at all during the enarodustat administration period (Non-Iron Group), subjects who received intravenous iron at least once (IV Iron Group), and subjects who continuously received oral iron-containing preparations including ferric citrate (Oral Iron Group). The time courses of transferrin saturation (TSAT), serum ferritin, and D-dimer levels were compared across these three groups using mixed effects models for repeated measures (MMRM) (with an unstructured covariance structure for the dependent variables). Results The Non-Iron Group, IV Iron Group, and Oral Iron Group consisted of 60, 69, and 73 cases, respectively. Figures show the time courses of TSAT, serum ferritin levels, and changes in D-dimer levels for each practice pattern. MMRM analysis revealed that TSAT levels in the Non-Iron Group and IV Iron Group during the enarodustat administration period were significantly lower than those in the Oral Iron Group (p &amp;lt; 0.01 and p &amp;lt; 0.01, respectively). Similar results were observed for serum ferritin levels (p &amp;lt; 0.01 and p &amp;lt; 0.01, respectively). Moreover, the rate of D-dimer increase in the Non-Iron Group was significantly higher than in the Oral Iron Group (p = 0.029). There was a trend toward a higher rate of D-dimer increase in IV Iron Groups compared to the Oral Iron Group (p = 0.11). Conclusion These findings suggest the superiority of continuous oral iron supplementation over intermittent IV iron supplementation or no iron supplementation during HIF-PH inhibitor administration in terms of preventing thrombosis through maintaining TSAT levels. The association between iron-related parameters and the occurrence of thrombosis needs to be analyzed.

A mobile app providing individually-tailored psychoeducation about sleep for older adults with chronic health conditions and low health literacy.

This paper reports on a study of a mobile app that provides tailored information about sleep to individuals aged 40 and older who have chronic health conditions and low health literacy. The sleep module was a part of a multitopic app focused on chronic disease self-management. Participants were randomly assigned to receive sleep psychoeducation at reading levels equivalent to 3rd, 6th or 8th grade. The primary outcome measure was the Pittsburgh Sleep Quality Index (PSQI), which was completed at baseline, after the intervention, and again three months later. Outcomes were assessed using repeated measures mixed effects models. Most participants were Black, Indigenous, or Other Persons of Color (BIPOC; 87%); they had average reading level at the 7th grade. Health literacy, socioeconomic status, and number of health conditions were related to the PSQI. The PSQI score decreased over the course of the three study visits for all groups, consistent with a small to medium effect size (d = 0.40). No effect of treatment group was observed. Participants were positive about the usefulness and helpfulness of the app. Results suggest that a brief tailored information intervention may be beneficial for individuals aged 40 and older who have low health literacy and chronic health conditions. Further development of the intervention may enhance its clinical effectiveness.

Association between cooking fuel exposure and respiratory health: Longitudinal evidence from the China Health and Retirement Longitudinal Study (CHARLS)

The epidemiological evidences for the association between cooking fuel exposure and respiratory health were inconsistent, and repeated-measures prospective evaluation of cooking fuel exposure was still lacking. We assessed the longitudinal association of chronic lung disease (CLD) and lung function with cooking fuel types among Chinese adults aged ≥ 40 years. In this prospective, nationwide representative cohort of the China Health and Retirement Longitudinal Study from 2011 to 2018, 9004 participants from 28 provinces in China were included. CLD was identified based on self-reported physician diagnosis in 2018. Lung function was assessed by peak expiratory flow (PEF) in 2011, 2013 and 2015. Multivariable logistic and linear mixed-effects repeated-measures models were conducted to measure the associations of CLD and PEF with cooking fuel types. Three-level mixed-effects model was performed as sensitivity analysis. Among the participants, 3508 and 3548 participants used persistent solid and clean cooking fuels throughout the survey, and 1948 participants who used solid cooking fuels at baseline switched to clean cooking fuels. Use of persistent clean cooking fuels (adjusted odds ratio [aOR] = 0.73, 95 % confidence interval [CI]: 0.61, 0.88) and switch of solid fuels to clean fuels (aOR = 0.81, 95 % CI: 0.67, 0.98) were associated with lower risk of CLD. The use of clean cooking fuels throughout the survey and switch of solid fuels to clean fuels in 2013 were also significantly associated with higher PEF level. Similar results were observed in stratified analyses and different statistical models. The evidence from CHARLS cohort suggested that reducing solid cooking fuel exposure was associated with lower risk of CLD and better lung function. Given the recent evidence, improving household air quality will reduce the burden of chronic lung diseases.

Abstract P193: Sex Moderates Diet Quality Differences in Integrated Collaborative Care for Comorbid Obesity and Depression: Post-Hoc Analysis of the Research Aimed at Improving Both Mood and Weight Randomized Clinical Trial

Background: High-quality diets, such as the Dietary Approaches to Stop Hypertension (DASH), are associated with lower risk for obesity and obesity-related chronic diseases. It is unclear whether diet quality improves aside from reduced calories in evidence-based behavioral weight loss interventions. Objective: Leveraging data from the Research Aimed at Improving Both Mood and Weight (RAINBOW) randomized trial, the objective of this post hoc analysis is to investigate (1) whether the study intervention was associated with improved diet quality in adults with comorbid obesity and depression, compared to usual care; and (2) whether the associations were modified by sex. Methods: Participants completed 24-hour dietary recalls at baseline, 6, 12, 18, and 24 months. Dietary outcomes included the DASH score as the composite measure of diet quality and its components. Between-group differences in dietary outcomes were examined among 409 participants and by sex, using repeated-measures mixed-effects linear models. Results: Changes in DASH scores did not differ between the intervention and usual care control groups through 24 months in both women and men. Compared with controls, men in the intervention group had significantly decreased nut, seed, and legume intake at 6 (mean difference, -1.1; 95% CI, -1.9, -0.3 servings/day; P=0.01) and 12 months (-1.0; -2.0, -0.0 servings/day; P=0.048). Compared with controls, women in the intervention group had significantly decreased fruit and vegetable intake at 18 (-1.8; -2.9, -0.6 servings/day; P=0.002) and 24 months (-1.1; -2.2, -0.1 servings/day; P=0.03), and whole grain intake at 24 months (-0.5; -0.9, -0.1 servings/day; P=0.03), but increased percent calories from fat at 24 months (3.6; 0.6, 6.5; P=0.02). Conclusions: Diet quality not only did not improve in an effective behavioral weight loss intervention but deteriorated in women, in particular. These post-hoc findings warrant confirmation and may suggest that behavior change techniques targeting diet quality that are tailored to women and men need to be an explicit focus of behavioral weight loss interventions aside from caloric reductions.

Urinary acid-base excretion deciphers high acid load from colonic bicarbonate loss in intestinal failure patients with ileocolonic anastomosis – Guidance for composition of parenteral support

Background & AimsAcid-base disturbances are common in short bowel (SB) patients due to increased intestinal bicarbonate loss. However, the resulting systemic acid load has not been quantified. Base excess is used to monitor metabolic acid-base disturbances but inadequately reflects the acid load. Our aim was to investigate the systemic acid/base load in SB-patients to obtain quantitative estimates to guide the composition of parenteral support. MethodsWe calculated total acid load in SB patients by summing 24-hour urinary net acid excretion (NAE) and the provision of base equivalents in parenteral support. We then compared differences among anatomical SB-types: jejunostomy (SB-J), jejunocolostomy (SB-JC), and jejunoileostomy (SB-JIC). 47 urine samples from 34 SB patients were analyzed for bicarbonate (HCO3-), ammonium (NH4+), and titratable acidity (TA) concentrations. NAE was calculated as (TA + NH4+) - HCO3-. Mixed-effects repeated-measures models were used to statistically examine differences between SB-types and associations with parenteral nutrition and NAE. A healthy cohort served as control. ResultsIn comparison to SB-J, SB-JC patients had a 4.1 mmol/l lower base excess (95% CI: -6.3 to -1.8) and an 84.5 mmol/day higher total acid load (CI: 41.3 to 127.7). There were no significant differences between SB-JIC and SB-J regarding base excess, NAE, or total acid load. Higher amounts of infused acetate, sodium, and chloride, but not the acetate/chloride ratio, were associated with lower NAE and higher base excess. ConclusionsDue to increased colonic bicarbonate loss, patients with SB-JC have a ∼4.4-fold higher acid load than healthy controls. The ion transport mechanisms mediating this bicarbonate loss from the remaining colon need further experimental investigation. NAE could be a useful tool to adjust base infusion in SB.

Design and Rationale of Prolonged Nightly Fasting for Multiple Myeloma Prevention (PROFAST): Protocol for a Randomized Controlled Pilot Trial.

Obesity is an established, modifiable risk factor of multiple myeloma (MM); yet, no lifestyle interventions are routinely recommended for patients with overweight or obesity with MM precursor conditions. Prolonged nightly fasting is a simple, practical dietary regimen supported by research, suggesting that the synchronization of feeding-fasting timing with sleep-wake cycles favorably affects metabolic pathways implicated in MM. We describe the design and rationale of a randomized controlled pilot trial evaluating the efficacy of a regular, prolonged nighttime fasting schedule among individuals with overweight or obesity at high risk for developing MM or a related lymphoid malignancy. We aim to investigate the effects of 4-month prolonged nightly fasting on body composition and tumor biomarkers among individuals with overweight or obesity with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or smoldering Waldenström macroglobulinemia (SWM). Individuals with MGUS, SMM, or SWM aged ≥18 years and a BMI of ≥25 kg/m2 are randomized to either a 14-hour nighttime fasting intervention or a healthy lifestyle education control group. Participants' baseline diet and lifestyle patterns are characterized through two 24-hour dietary recalls: questionnaires querying demographic, comorbidity, lifestyle, and quality-of-life information; and wrist actigraphy measurements for 7 days. Fasting intervention participants are supported through one-on-one telephone counseling by a health coach and automated SMS text messaging to support fasting goals. Primary end points of body composition, including visceral and subcutaneous fat (by dual-energy x-ray absorptiometry); bone marrow adiposity (by bone marrow histology); and tumor biomarkers, specifically M-proteins and serum free light-chain concentrations (by gel-based and serum free light-chain assays), are assessed at baseline and after the 4-month study period; changes therein from baseline are evaluated using a repeated measures mixed-effects model that accounts for the correlation between baseline and follow-up measures and is generally robust to missing data. Feasibilityis assessed as participant retention (percent dropout in each arm) and percentage of days participants achieved a ≥14-hour fast. The PROlonged nightly FASTing (PROFAST) study was funded in June 2022. Participant recruitment commenced in April 2023. As of July 2023, six participants consented to the study. The study is expected to be completed by April 2024, and data analysis and results are expected to be published in the first quarter of 2025. PROFAST serves as an important first step in exploring the premise that prolonged nightly fasting is a strategy to control obesity and obesity-related mechanisms of myelomagenesis. In evaluating the feasibility and impact of prolonged nightly fasting on body composition, bone marrow adipose tissue, and biomarkers of tumor burden, this pilot study may generate hypotheses regarding metabolic mechanisms underlying MM development and ultimately inform clinical and public health strategies for MM prevention. ClinicalTrials.gov NCT05565638; http://clinicaltrials.gov/ct2/show/NCT05565638. DERR1-10.2196/51368.

Guselkumab provides durable improvement across psoriatic arthritis disease domains: post hoc analysis of a phase 3, randomised, double-blind, placebo-controlled study

ObjectiveEvaluate long-term guselkumab effectiveness across Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)-recognised domains/related conditions of psoriatic arthritis (PsA).MethodsPost hoc analyses used data from DISCOVER-2 (NCT03158285) biologic/Janus-kinase...

Patient-reported outcomes (PROs) with talazoparib (TALA) plus enzalutamide (ENZA) vs. placebo (PBO) plus ENZA in men with metastatic castration-resistant prostate cancer (mCRPC): Subgroup analysis of patients with novel hormonal therapy (NHT) pretreatment in the TALAPRO-2 study.

116 Background: In TALAPRO-2 (NCT03395197), TALA +ENZA vs PBO + ENZA demonstrated significant improvement in radiographic progression-free survival, a manageable adverse event (AE) profile, and a delay in time to definitive clinical meaningful deterioration in global health status (GHS)/quality of life (QoL) overall and across all pre-specified subgroups. This post hoc analysis evaluated PROs in patients with prior NHT treatment. Methods: PROs were assessed on day 1 and scheduled visits (every 4 weeks until week 53 then every 8 weeks) until radiographic progression using the EORTC QLQ-C30 and its prostate cancer module, QLQ-PR25. PRO analyses, performed in NHT-pretreated/ patients for GHS/QoL functional and symptom scales, included on treatment comparison of overall change from baseline (per longitudinal repeated measures mixed-effects model). Results: Of the 805 men randomized and treated, 49 patients were included in this subgroup analysis (TALA + ENZA n= 22, PBO + ENZA n= 27). A statistically significant and clinically meaningful estimated overall change from baseline favored TALA + ENZA in physical functioning (20.5 [95% confidence interval {CI}: 8.8, 32.2]; P=0.0007), role functioning (20.4 [95% CI 4.8, 35.9]; P=0.0103), pain (32.9 [95% CI 50.3, 15.5]; P=0.0002), and constipation (12.5 [24.4, 0.6]; P=0.0399). No significant differences disfavoring TALA + ENZA were observed. Conclusions: In these subgroup analyses of NHT pretreated patients, significant differences in PROs favoring TALA + ENZA were observed. Results should be interpreted with caution given the small sample sizes and exploratory nature of this analysis. Clinical trial information: NCT03395197 .

Long-term patient-reported outcomes from monarchE: Abemaciclib plus endocrine therapy as adjuvant therapy for HR+, HER2-, node-positive, high-risk, early breast cancer

BackgroundIn monarchE, abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile at 42-months median follow-up. With no expected disease-related symptoms, therapies in the adjuvant setting should preserve quality of life (QoL). With all patients off abemaciclib, we report updated patient-reported outcomes (PROs) for the full 2-year treatment period and follow-up. MethodsPatients completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, and 24 months during treatment, and 1, 6, and 12 months after treatment discontinuation. Mixed effects repeated measures model estimated changes from baseline within and between arms for QoL scales and individual items. Meaningful changes were prespecified and no statistical testing was performed. Frequencies of responses to items associated with relevant adverse events and treatment bother were summarized. ResultsAt baseline, completion rates for PRO instruments were >96 %. Mean changes from baseline for all QoL scales were numerically similar within and between arms (ie, less than prespecified thresholds). The same was observed for all individual items, except diarrhea. Within abemaciclib arm, meaningful differences for diarrhea were observed at 3 and 6 months (mean increases of 1.19 and 1.03 points on 5-point scale, respectively). During treatment, most patients in both arms (69–78 %) reported being bothered “a little bit” or “not at all” by side effects. Overall, patterns for fatigue were similar between arms. During post-treatment follow-up, PROs in both arms were similar to baseline. ConclusionPRO findings confirm a tolerable and reversible toxicity profile for abemaciclib. QoL was preserved with the addition of adjuvant abemaciclib to endocrine therapy, supporting its use in patients with HR+, HER2-, high-risk early breast cancer.

The effects of treatment with pimavanserin on activities of daily living in patients with Parkinson's disease psychosis: a 16-week, single-arm, open-label study.

More than half of patients with Parkinson's disease will experience psychosis symptoms in the form of hallucinations or delusions at some point over the course of their disease. These symptoms can significantly impact patients' health-related quality of life, cognitive abilities, and activities of daily living (ADLs) and function. Clinical assessment of how psychosis impacts these measures is crucial; however, few studies have assessed this sufficiently, in part due to a lack of appropriate scales for comprehensively assessing function. The objective was to assess how symptoms of Parkinson's disease psychosis (PDP) impact ADLs and function, cognitive function, and health-related quality of life. To address this unmet need, we utilized a modified version of the Functional Status Questionnaire (mFSQ) to measure the impact of psychosis on ADLs and function in patients with PDP treated with pimavanserin, a US Food and Drug Administration-approved medication to treat hallucinations and delusions associated with PDP. Eligible patients entered a 16-week, single-arm, open-label study of oral pimavanserin (34 mg) taken once daily. The primary endpoint was change from baseline to Week 16 on the mFSQ. Secondary endpoints included the Movement Disorders Society-modified Unified Parkinson's Disease Rating Scale (MDS-UPDRS) I and II; Schwab and England ADL; Clinical Global Impression-Severity of Illness (CGI-S), Clinical Global Impression-Improvement (CGI-I), and Patient Global Impression-Improvement (PGI-I), and were also measured as change from baseline to Week 16 using mixed-effects model for repeated measures (MMRM) and least-squares mean (LSM). Our results in a proof-of-concept, 16-week, open-label clinical study in 29 patients demonstrated that an improvement in psychosis symptoms following treatment with pimavanserin was associated with improvements in multiple measures of ADLs and function. Notably, a significant improvement was found on the primary endpoint, change from baseline to Week 16 in mFSQ score [LSM [SE] 14.0 [2.50], n = 17; 95% CI (8.8, 19.3); p < 0.0001]. These findings highlight the potential for improvement in function with improvement of psychosis symptoms in patients with PDP and suggest that the mFSQ may be a measurement tool to evaluate the level of improvement in function. ClinicalTrials.gov Identifier: NCT04292223.

Left atrial strain is reduced following trastuzumab in breast cancer patients.

The effect of trastuzumab therapy on left atrial (LA) function remains largely unknown. Our aim was to assess the changes in LA strain parameters longitudinally in patients treated with trastuzumab. We retrospectively studied 170 patients with stage I-IV HER2+ breast cancer. All patients had baseline echocardiograms and repeat echocardiograms at 3months and after 1year. We measured LA strain at all three time points. Changes in LA strain and strain rate (sr) parameters were evaluated using repeated-measures mixed-effects models. The cohort was stratified according to development of cancer therapeutics-related cardiac dysfunction (CTRCD) during follow-up. The mean age was 52.7±13.8years, 25.3% had hypertension and 16.0% had metastatic disease. Multiple LA strain parameters (predicted delta value, [95%CI]) showed statistically significant declines in patients who developed CTRCD from baseline to the 3-month follow-up after multivariable adjustment; LA reservoir strain (LAεres ): -4.7%; [-8.1% to -1.3%], p=.007; LA conduit strain (LAεcon ): -2.8%; [-5.3% to -.4%], p=.021); and LAεres sr: -.2/s; [-.3/s to -.09/s], p<.001). In patients who did not develop CTRCD, LA strain parameters declined significantly but to a smaller degree than in the CTRCD group (LAεres : -1.7%; [-3.1% to -.3%], p=.020, LAεcon : -2.2%; [-3.3% to -1.1%], p<.001, and LA booster pump strain : -2.4%; [-3.5% to -1.4%], p<.001). LA strain rates did not decline significantly in the non-CTRCD group. Trastuzumab treatment was associated with declines in LA strain parameters in patients with breast cancer. The largest declines were observed in patients who developed CTRCD during treatment.