A service-oriented approach to clinical trial recruitment for dementia and brain health: Methods and case examples of MyAlliance for Brain Health.

INTRODUCTION: Recruitment of sufficient and diverse participants into clinical research for Alzheimer's disease and related dementias remains a formidable challenge. The primary goal of this manuscript is to provide an overview of an approach to diversifying research recruitment and to provide case examples of several methods for achieving greater diversity in clinical research enrollment. METHODS: The University of Kansas Alzheimer's Disease Research Center (KU ADRC) developed MyAlliance for Brain Health (MyAlliance), a service-oriented recruitment model. MyAlliance comprises a Primary Care Provider Network, a Patient and Family Network, and a Community Organization Network, each delivering tailored value to relevant parties while facilitating research referrals. RESULTS: We review three methods for encouraging increased diversity in clinical research participation. Initial outcomes reveal an increase in underrepresented participants from 17% to 27% in a research registry. Enrollments into studies supported by the research registry experienced a 51% increase in proportion of participants from underrepresented communities. DISCUSSION: MyAlliance shifts power, resources, and knowledge to community advocates, promoting brain health awareness and research participation, and demands substantial financial investment and administrative commitment. MyAlliance offers valuable lessons for building sustainable, community-centered research recruitment infrastructure, emphasizing the importance of localized engagement and cultural understanding. Highlights: MyAlliance led to a significant increase in the representation of underrepresented racial and ethnic groups and individuals from rural areas.The service-oriented approach facilitated long-term community engagement and trust-building, extending partnerships between an academic medical center and community organizations.While effective, MyAlliance required substantial financial investment, with costs including infrastructure development, staff support, partner organization compensation, and promotional activities, underscoring the resource-intensive nature of inclusive research recruitment efforts.

Effect of Montelukast vs Placebo on Time to Sustained Recovery in Outpatients with COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain. Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19. Design Setting and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate the effectiveness of repurposed medications in treating mild to moderate COVID-19. Between January 27, 2023, and June 23, 2023, 1250 participants ≥30 years of age with confirmed SARS-CoV-2 infection and ≥2 acute COVID-19 symptoms for ≤7 days, were included across 104 US sites to evaluate the use of montelukast. Interventions: Participants were randomized to receive montelukast 10 mg once daily or matched placebo for 14 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID clinical progression scale; and difference in mean time unwell. Results: Among participants who were randomized and received study drug, the median age was 53 years (IQR 42-62), 60.2% were female, 64.6% identified as Hispanic/Latino, and 56.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR] 1.02; 95% credible interval [CrI] 0.92-1.12; P(efficacy) = 0.63]). Unadjusted median time to sustained recovery was 10 days (95% confidence interval 10-11) in both groups. No deaths were reported and 2 hospitalizations were reported in each group; 36 participants reported healthcare utilization events (a priori defined as death, hospitalization, emergency department/urgent care visit); 18 in the montelukast group compared with 18 in the placebo group (HR 1.01; 95% CrI 0.45-1.84; P(efficacy)=0.48). Five participants experienced serious adverse events (3 with montelukast and 2 with placebo). Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with montelukast does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov ( NCT04885530 ).

Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain. Objective: To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19. Design, Setting, and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less. Interventions: Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607). Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28. Results: Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Prevalence of elevated alkaline phosphatase levels among post-bariatric surgery patients.

INTRODUCTION: Little is known about the prevalence of elevated alkaline phosphatase in post-bariatric surgery patients due to under-utilization of this test after surgery. Elevated alkaline phosphatase levels are caused by hepatobiliary disease or bone resorption, which can lead to gallstones and osteoporosis. Early, post-operative measurement of alkaline phosphatase can prevent complications, thus reducing morbidity and overall healthcare costs. The purpose of this study was to determine the prevalence of elevated alkaline phosphatase levels among post-operative bariatric surgery patients. METHODS: This was a retrospective study of patients 18 years or older, who underwent laparoscopic sleeve gastrectomy (LSG) at a Midwestern Weight Management Clinic between January 1, 2002 and December 31, 2020. Alkaline phosphatase levels, weight, body mass index (BMI), gamma-glutamyl transferase (GGT), parathyroid hormone (PTH), calcitriol, and calcitonin, vitamin D and multivitamin supplementation were measured at baseline, 3, 6, and 12 months post-surgery. RESULTS: Two hundred thirty patients with mean age of 47 years and BMI of 44.6 were included with 80.9% (n = 186) female. Alkaline phosphatase was elevated relative to baseline for 36.1% of patients (n = 52) at 3 months post-surgery, 42.4% of patients (n = 56) at 6 months, and 43.3% of patients (n = 45) at 12 months (p < 0.001). There were six cases of documented cholelithiasis post-surgery. CONCLUSION: A significant proportion of participants experienced elevations in alkaline phosphatase following surgery, indicating that the prevalence of gallbladder pathology and bone resorption may be higher than previously thought. This merits additional investigation into these complications post-operatively to determine prevalence and avoid excess morbidity.

Discovery of New Transmitter Systems and Hence New Drug Targets.

The development of medications used to treat psychiatric conditions has largely proceeded through serendipity, where a potential drug to treat mental illness is identified by chance. This approach is based on a limited understanding of the underlying pathophysiology of mental illness and brain disorders. Identification of novel neurotransmitter systems has allowed for new molecular-based approaches for drug development that identify specific receptor targets to treat a specific symptom. An example of this approach includes the development of suvorexant, which is a dual orexin receptor antagonist FDA approved in 2014 for the treatment of insomnia. This chapter will discuss challenges in psychiatric drug development; the importance of identifying discrete neurotransmitter systems that target a specific symptom, not a syndrome; the orexin pathway and targets within this pathway that can be used to modulate sleep; and a high-throughput approach to streamlining drug development.

Reverse Engineering Drugs: Lorcaserin as an Example.

Novel central nervous system (CNS)-based therapies have been difficult to produce due to the complexity of the brain, limited knowledge of CNS-based disease development and associated pathways, difficulty in penetrating the blood brain barrier, and a lack of reliable biomarkers of disease. Reverse engineering in drug development allows the utilization of new knowledge of disease pathways and the use of innovative technology to develop medications with enhanced efficacy and reduced toxicities. Lorcaserin was developed as a specific 5HT2C serotonin receptor agonist for the treatment of obesity with limited off-target effects at the 5HT2A and 5HT2B receptors. This receptor specificity limited the hallucinogenic and cardiovascular side effects noted with other serotonin receptor agonists. Reverse engineering approaches to drug development reduce the cost of producing new medications, identify specific populations of patients that will derive the most benefit from therapy, and produce novel therapies with greater efficacy and limited toxicity.

Acceptability and Preliminary Effectiveness of a Remote Dementia Educational Training Among Primary Care Providers and Health Navigators.

BACKGROUND: Optimal care can improve lives of families with dementia but remains under-implemented. Most healthcare professional training is in person, time-intensive, and does not focus on key aspects such as early detection, and cultural competency. OBJECTIVE: We explored the acceptability and preliminary effectiveness of a training, The Dementia Update Course, which addressed these issues. We hypothesized that the training would lead to increased levels of perceived dementia care competency among key healthcare workers, namely primary care providers (PCPs) and health navigators (HNs). METHODS: We conducted pre-post training assessments among 22 PCPs and 32 HNs. The 6.5-h training was remote, and included didactic lectures, case discussion techniques, and materials on dementia detection and care. Outcomes included two 5-point Likert scales on acceptability, eleven on perceived dementia care competency, and the three subscales of the General Practitioners Confidence and Attitude Scale for Dementia. We used paired samples t-tests to assess the mean differences in all preliminary effectiveness outcomes. RESULTS: The training included 28.6% of PCPs and 15.6% of HNs that self-identified as non-White or Latino and 45.5% of PCPs and 21.9% of HNs who served in rural areas. PCPs (84.2%) and HNs (91.7%) reported a high likelihood to recommend the training and high satisfaction. Most preliminary effectiveness outcomes analyzed among PCPs (11/14) and all among HNs (8/8) experienced an improvement from pre- to post-training (p < 0.05). CONCLUSION: A relatively brief, remote, and inclusive dementia training was associated with high levels of acceptability and improvements in perceived dementia care competency among PCPs and HNs.

Bariatric Surgery Improves Renal Function in Patients With Obesity.

Background Obesity affects 93.3 million adults in the United States and is a predisposing factor for the development and progression of chronic kidney disease (CKD). The objective of this study is to examine the association between weight loss and renal function in participants undergoing bariatric surgery following a 12-week multidisciplinary, community-based weight loss program. Methodology This is a retrospective chart review of participants who voluntarily enrolled in a 12-week multidisciplinary weight loss program prior to bariatric surgery from 2009 to 2018. The primary outcome was to assess the association between weight loss and renal function in participants undergoing bariatric surgery. Secondary outcomes included changes in hemoglobin A1c, lipids, fasting glucose, and blood pressure. Results Among the 55 participants, baseline glomerular filtration rate (GFR) was 49 mL/min/m2, 80% were female, and the average baseline weight was 131 kg. At one-year post-intervention, 69% of patients improved in the CKD stage, with 45% of the participants improving from stage 3A to stage 2. GFR improved to 15 mL/min/1.73m2 (p = 0.025), and there was a negative correlation (rs = -0.3556) between weight and GFR (p = 0.013). Participants with hyperlipidemia had a 12 mL/min/1.73m2 rise in GFR, while participants without the diagnosis at one year had a 24 mL/min/1.73m2 rise in GFR (p = 0.007). Conclusions This study demonstrated improved renal function and reduced progression of CKD following a combined lifestyle and surgical intervention, indicating the importance of a comprehensive approach for the management of the chronic disease.

Bariatric Metabolic Surgery Reduced Liver Enzyme Levels in Patients with Non-Alcohol Fatty Liver Disease.

INTRODUCTION: Approximately 93.3 million Americans are obese (BMI > 30 kg/m2) and 51% have non-alcoholic fatty liver disease (NAFLD). Progression of NAFLD can lead to non-alcoholic steatohepatitis (NASH), which is the leading cause of liver transplant in the United States. This study analyzed liver enzyme levels following bariatric metabolic surgery in NAFLD patients up to one-year post-surgical intervention. METHODS: A retrospective analysis of adults with NAFLD who underwent bariatric metabolic surgery from 2009 to 2016 was conducted. The primary outcomes were transaminase levels following surgery. Secondary outcomes included levels of blood glucose and lipids. RESULTS: A total of 130 participants consisting of 80% Caucasian females with an average BMI of 47.5 kg/m2 participated in the study. Reductions were noted in ALT (57.6% decrease) and AST (47.7% decrease) at one-year post-surgical intervention. Significant reductions also were noted in levels of blood glucose (22.34%; p < 0.0001), HbA1c (1.11% change; p < 0.0001), LDL (19.75%; p = 0.0046), total cholesterol (10.12%; p = 0.0153), and triglycerides (37.21%; p < 0.0001) with an increase in HDL levels (17.22%; p = 0.0007). Significant correlations were noted at six months between levels of alkaline phosphatase and both ALT (p = 0.0101) and AST (p = 0.0009), as well as an additional correlation trending toward significance between ALT and alkaline phosphatase at one year (p = 0.0547). When separated by obesity class, participants with class II obesity experienced improved outcomes compared to participants with class III obesity. CONCLUSIONS: Bariatric metabolic surgery was associated with a reduction in liver enzyme levels in NAFLD. These findings suggested that bariatric metabolic surgery is a viable treatment option for participants with NAFLD.

Impact of a Community-Based Weight Loss Program on Renal Function.

Introduction Obesity is associated with increased morbidity and mortality and is an independent risk factor for the development and progression of chronic kidney disease (CKD). This study investigated the effect of a community-based, lifestyle-focused, weight-loss intervention on renal function among participants at baseline following 12 weeks of therapy.  Methods A retrospective analysis of adults enrolled in a weight management program from 2009 to 2014 was conducted. Participants consumed at least 800 kilocalories per day in meal replacements, attended weekly behavioral education classes, and expended approximately 300 kilocalories per day in physical activity. The primary outcome was the association of weight loss and changes in glomerular filtration rate (GFR). Secondary outcomes included changes in blood sugar levels, lipid parameters, blood pressure, and the use of medication for hypertension and diabetes mellitus.  Results Of the 71 participants, 63.4% were female, the average weight was 289 pounds, the average body mass index (BMI) of 53, and baseline GFR 47 ml/min/1.73m2. Following 12 weeks of the intervention, 76.1% of participants improved in CKD stage, 22.4% remained within the same stage, and 1.5% progressed to a higher stage (3A to 3B). Analysis revealed a correlation between weight loss and improved GFR (p=0.0006). Improvements were noted in blood sugar levels, blood pressure, and lipids (p<0.05). Medications were reduced in 61.8% of participants for hypertension and 83.3% for diabetes. Conclusions A significant correlation was observed between weight loss and improved renal function, with most participants improving in CKD stage. Participants also improved in markers of chronic disease and required fewer medications. When controlling for both diabetes and hypertension, the effect of improved renal function persisted.

Long-term liraglutide treatment is associated with increased insulin content and secretion in ß-cells, and a loss of α-cells in ZDF rats.

The ultimate treatment goal of diabetes is to preserve and restore islet cell function. Treatment of certain diabetic animal models with incretins has been reported to preserve and possibly enhance islet function and promote islet cell growth. The studies reported here detail islet cell anatomy in animals chronically treated with the incretin analog, liraglutide. Our aim was to quantitatively and qualitatively analyze islet cells from diabetic animals treated with vehicle (control) or liraglutide to determine whether normal islet cell anatomy is maintained or enhanced with pharmaceutical treatment. We harvested pancreata from liraglutide and vehicle-treated Zucker Diabetic Fatty (ZDF) rats to examine islet structure and function and obtain isolated islets. Twelve-week-old male rats were assigned to 3 groups: (1) liraglutide-treated diabetic, (2) vehicle-treated diabetic, and (3) lean non-diabetic. Liraglutide was given SC twice daily for 9 weeks. As expected, liraglutide treatment reduced body weight by 15% compared to the vehicle-treated animals, eventually to levels that were not different from lean controls. At the termination of the study, blood glucose was significantly less in the liraglutide-treated rats compared to vehicle treated controls (485.8±22.5 and 547.2±33.1mg/dl, respectively). Insulin content/islet (measured by immunohistochemistry) was 34.2±0.7 pixel units in vehicle-treated rats, and 54.9±0.6 in the liraglutide-treated animals. Glucose-stimulated insulin secretion from isolated islets (measured as the stimulation index) was maintained in the liraglutide-treated rats, but not in the vehicle-treated. However, liraglutide did not preserve normal islet architecture. There was a decrease in the glucagon-positive area/islet and in the α-cell numbers/area with liraglutide treatment (6.5 cells/field), compared to vehicle (17.9 cells/field). There was an increase in ß-cell numbers, the ß- to α-cell ratio that was statistically higher in the liraglutide-treated rats (24.3±4.4) compared to vehicle (9.1±2.8). Disrupted mitochondria were more commonly observed in the α-cells (51.9±10.3% of cells) than in the ß-cells (27.2±4.4%) in the liraglutide-treated group. While liraglutide enhanced or maintained growth and function of certain islet cells, the overall ratio of α- to ß-cells was decreased and there was an absolute reduction in islet α-cell content. There was selective disruption of intracellular α-cell organelles, representing an uncoupling of the bihormonal islet signaling that is required for normal metabolic regulation. The relevance of the findings to long-term liraglutide treatment in people with diabetes is unknown and should be investigated in appropriately designed clinical studies.