Prevention Clinical Trials Research Articles

Associations between sex and lifestyle activities with cognitive reserve in mid-life adults with genetic risk for Alzheimer’s disease

BackgroundFemales have a higher age-adjusted incidence of Alzheimer’s Disease (AD) than males, even when accounting for longer lifespan and, therefore, stand to benefit the most from dementia prevention efforts. As exposure to many modifiable risk factors for dementia begins in mid-life, interventions must be implemented from middle-age. Building cognitive reserve, particularly through stimulating avocational activities and occupational attainment presents a crucial, underexplored, dementia prevention approach for mid-life. It is currently unknown, however, whether modifiable lifestyle factors can protect against AD processes, from mid-life, differentially for females and males who carry inherited risk for late-life dementia. To address this gap, this study investigated the impact of biological sex and APOE4 carrier status on the relationship between stimulating activities, occupational attainment, and cognition in mid-life.MethodsWe leveraged the PREVENT–Dementia program, the world’s largest study investigating the origins and early diagnosis of dementia in mid-life at-risk individuals (N = 700; 40–59 years). Cognitive performance was measured using the Cognito Battery and the Visual Short Term Memory Binding task. Mid-life specific reserve contributors were assessed via the Lifetime of Experiences Questionnaire.ResultsFemales had significantly better episodic and relational memory (p < 0.001), and lower occupational attainment than males (p < 0.001). Engagement in stimulating activities was positively associated with episodic and relational memory, regardless of sex and APOE4 status (β = 0.05, CI 0.03–0.07, p < 0.001). APOE4 carriers showed significant sex differences in the association between occupational attainment and episodic and relational memory (β = 0.38, CI 0.12–0.63, p = 0.003). APOE4 carrier females with higher occupational attainment showed better cognition (β = 0.16, CI -0.002–0.32, p = 0.053), whereas APOE4 carrier males showed the opposite effect (β = -0.20, CI -0.40 – -0.001, p = 0.049).ConclusionOur findings suggest that occupational attainment in mid-life contributes to cognitive reserve against inherited risk of dementia in females, but not males. They highlight the need for high precision approaches that consider biological sex and APOE4 carrier status to inform Alzheimer’s disease prevention strategies and clinical trials.

Exploring multimodal biomarker candidates of post-traumatic epilepsy following moderate to severe traumatic brain injury: A systematic review and meta-analysis.

This review systematically analyzes potential biomarker candidates for post-traumatic epilepsy (PTE) in humans who have experienced moderate to severe traumatic brain injury (TBI). Focusing on biomarkers across biofluid-based protein, genetic, neuroimaging, and neurophysiological categories, this review distinguishes between TBI patients who develop PTE and those who do not. The review adheres to established methodologies outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Data presentation follows the Meta-analyses of Observational Studies (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medline, Embase, and Web of Science were systematically searched and yielded 7538 records, of which 18 met inclusion criteria (moderate-severe TBI in humans, follow-up of at least 6 months, and no prior history of epilepsy). The review aggregates data from 15 cohort and 3 case-control studies (risk of bias was assessed using the Newcastle-Ottawa Scale). Statistically significant biomarkers were identified, with neurophysiological biomarkers showing the strongest effect size in a two-study meta-analysis. PTE, a severe long-term outcome of TBI affecting 2% to 53% of individuals with TBI, lacks validated biomarkers for forecasting development, crucial for designing preventive clinical trials. A multimodal approach, integrating biofluid-based protein, genetic, neuroimaging, and neurophysiological data, offers a promising strategy to enhance the predictability of PTE development and, potentially, its treatment. The study's protocol is registered in the International Prospective Register of Systematic Reviews PROSPERO (Registration ID: CRD42023470245).

Long-Term Adverse Effects and Complications After Prostate Cancer Treatment

Due to the often indolent nature of prostate cancer (PCA), treatment decisions must weigh the risks and benefits of cancer control with those of treatment-associated morbidities. To characterize long-term treatment-related adverse effects and complications in patients treated for PCA compared to a general population of older males. This cohort study used a novel approach linking data from 2 large PCA prevention clinical trials (the Prostate Cancer Prevention Trial and the Selenium and Vitamin-E Cancer Prevention Trial) with Medicare claims records. This analysis included patients with PCA who had been treated with prostatectomy or radiotherapy compared with an untreated control group. Multivariable Cox regression was used, with a time-varying covariate for the occurrence of PCA treatment, adjusted for age, race, and year of time-at-risk initiation, and stratified by study and intervention arm. Data analyses were performed from September 21, 2022, to March 18, 2024. Prostatectomy and radiotherapy occurring after a PCA diagnosis, identified from trial data or Medicare claims records. Ten potential PCA treatment-related complications identified from Medicare claims data. The study sample comprised 29 196 participants (mean [SD] age at time-at-risk initiation, 68.7 [4.8] years). Of these, 3946 participants had PCA, among whom 655 were treated with prostatectomy and 1056 with radiotherapy. The 12-year hazard risk of urinary or sexual complications was 7.23 times greater for those with prostatectomy (95% CI, 5.96-8.78; P < .001) and 2.76 times greater for radiotherapy (95% CI, 2.26-3.37; P < .001) compared to untreated participants. Moreover, among participants treated with radiotherapy, there was a nearly 3-fold greater hazard risk of bladder cancer than in the untreated (hazard ratio [HR], 2.78; 95% CI, 1.92-4.02; P < .001), as well as an approximately 100-fold increased hazard risk of radiation-specific outcomes including radiation cystitis (HR, 131.47; 95% CI, 52.48-329.35; P < .001) and radiation proctitis (HR, 87.91; 95% CI, 48.12-160.61; P < .001). The incidence per 1000 person-years of any 1 of the 10 treatment-related complications was 124.26 for prostatectomy, 62.15 for radiotherapy, and 23.61 for untreated participants. This cohort study found that, even after accounting for age-related symptoms and disease, PCA treatment was associated with higher rates of complications in the 12 years after treatment. Given the uncertain benefit of PCA treatment for most patients, these findings highlight the importance of patient counseling before PCA screening and treatment and provide a rationale for pursuing opportunities for cancer prevention.

Sex differences in outcomes of percutaneous left atrial appendage closure

Abstract Background Atrial fibrillation (AF) is the most common arrhythmia in adults and is associated with an increased risk of embolic stroke. In a previous survey, 91% of nonrheumatic AF-related left atrial thrombi was originated in the left atrial appendage (LAA). Percutaneous left atrial appendage closure (LAAC) with the Watchman device has been shown to be noninferior to anticoagulation therapy in clinical trials for stroke prevention in nonrheumatic AF. It has been used in Japan since September 2019 only for patients who are at the high risk of bleeding events. The WATCHMAN family is the only left atrial appendage closure (LAAC) device in Japan. Since long time ago, sex differences have been attracting attention in the cardiology. Due to the cardiovascular protective effects of endogenous estrogens, premenopausal women are thought to be less likely to develop cardiovascular disease. Whereas, in area of AF, Female with AF have higher stroke risk and female with AF have severe after effect. However, there are few studies on sex differences in LAAC implantation outcomes. Purpose We aimed to identify the sex differences of outcomes of LAAC in Japanese patients. Methods A total of 118 consecutive patients who underwent LAAC at our hospital from January 2020 to August 2023 were prospectively analyzed. Various patient characteristics, comorbidities, and outcomes were identified and compared between male and female. Results Results are shown in Table. Female were older (79 vs. 73 years, p = 0.0009), thinner (Body mass index 22 vs. 24 kg/m2, p = 0.0326), and less likely to have had diabetes (19 vs. 40%, p = 0.0340). Pulmonary embolism was significantly more common in female after LAAC. If anticoagulants are discontinued after LAAC, women’s susceptibility to coagulation may become apparent. Conclusions LAAC was feasible and safe for Japanese patients of both genders. However, these results could have a relevant impact on the antithrombotic management of patients who are at the high risk of embolic considering sex difference. Especially, we should pay great attention when discontinuing anticoagulants after LAAC in female.

Typologies of Psychiatric Diagnoses Among Inpatients with Recent Suicide Attempts

Objective Psychiatric multimorbidity is a well-documented risk factor for suicide. However, diagnostic heterogeneity and patterns of comorbidity likely exists within the population of those who attempt suicide. Person-centered statistical approaches, such as latent class analysis (LCA), extract distinguishable groups differentiated by prevalence and comorbidity of psychiatric disorders. Method The present study used LCA to identify typologies of psychiatric heterogeneity in a sample of 213 inpatients (M age = 33.04 [SD = 12.67]; 57.3% female; 62.4% White; 23.9% Hispanic/Latino) with a history of suicide attempt who were recruited for a suicide prevention clinical trial. Class differences in suicide history characteristics; demographic characteristics; and cognitive-affective and behavioral risk factors, obtained from an initial evaluation involving the administration of a semi-structured diagnostic interview, suicide risk assessment, and battery of self-report measures, were explored. Results LCA identified three classes in the best-fitting solution: Depressive-High Comorbidity (n = 68), Depressive-Low Comorbidity (n = 86), and Bipolar (n = 59). The Depressive-Low Comorbidity class reported less severe suicidal ideation (p < .001), anxiety (p < .001), stress (p < .001), unlovability beliefs (p = .006), and impulsivity (p < .001). The Depressive-Low Comorbidity class also reported fewer actual attempts than the Bipolar class (p = .001) and fewer interrupted attempts than the Depressive-High Comorbidity class (p = .004). Conclusions The Depressive-High Comorbidity and Bipolar classes consistently endorsed higher levels of suicide risk factors. These findings may help to illuminate typologies of suicide attempters with unique clinical needs, which is an essential step toward personalized medicine.

The pathway to delivering injectable CAB for HIV prevention: strategies from global PrEP leaders leveraging an adapted version of the Intervention Scalability Assessment Tool (ISAT)

BackgroundLonger-acting cabotegravir (CAB) is a novel, safe, and efficacious pre-exposure prophylaxis (PrEP) for HIV prevention. As we near a time for CAB scale-up, the experience of global leaders in PrEP research and implementation can be leveraged to identify optimal strategies for scaling and integrating CAB into existing PrEP infrastructure worldwide.MethodsWe recruited leaders of HIV prevention clinical trials and large PrEP programs through a combination of purposive and snowball sampling for participation in individual interviews. We conducted interviews using a semi-structured guide that compared CAB to oral PrEP and sought perspectives on barriers and strategies for CAB scale-up. Interviews were conducted virtually, audio recorded, and transcribed. We used thematic analysis, grounded in an adapted version of the Intervention Scalability Assessment Tool (ISAT), to identify critical elements for optimizing delivery of CAB.ResultsFrom October 2021 to April 2022, we interviewed 30 participants with extensive experience in PrEP research, care, and programming. Participants worked in all seven WHO regions and reported a median of 20 years working in HIV and 10 years in PrEP. Participants agreed that CAB was efficacious and discrete, therefore having the potential to address current concerns about oral PrEP adherence and stigma. Participants indicated direct and indirect costs for provider training, expansion of existing medical infrastructure, and the current medication cost of CAB as major concerns for roll out. The true cost to the end-user and health system were unknown. There were some conflicting strategies on how to best address product targeting, presentation of efficacy, and timing of product availability with scale-up. Some thought that targeting CAB for the general population could normalize PrEP and decrease stigma, while others thought that prioritizing key populations could optimize impact by targeting those with highest risk. Overall, participants emphasized that to ensure successful CAB scale-up, communities and stakeholders must be involved at every stage of planning and implementation.ConclusionsOur evaluation found that although there is a clear and urgent need for additional HIV PrEP options beyond daily oral PrEP, CAB scale-up must be thoughtful, flexible, and based in lessons learned from oral PrEP rollout.

Cardiac stasis imaging, stroke, and silent brain infarcts in patients with nonischemic dilated cardiomyopathy.

Cardioembolic stroke is one of the most devastating complications of nonischemic dilated cardiomyopathy (NIDCM). However, in clinical trials of primary prevention, the benefits of anticoagulation are hampered by the risk of bleeding. Indices of cardiac blood stasis may account for the risk of stroke and be useful to individualize primary prevention treatments. We performed a cross-sectional study in patients with NIDCM and no history of atrial fibrillation (AF) from two sources: 1) a prospective enrollment of unselected patients with left ventricular (LV) ejection fraction <45% and 2) a retrospective identification of patients with a history of previous cardioembolic neurological event. The primary end point integrated a history of ischemic stroke or the presence intraventricular thrombus, or a silent brain infarction (SBI) by imaging. From echocardiography, we calculated blood flow inside the LV, its residence time (TR) maps, and its derived stasis indices. Of the 89 recruited patients, 18 showed a positive end point, 9 had a history of stroke or transient ischemic attack (TIA) and 9 were diagnosed with SBIs in the brain imaging. Averaged TR, [Formula: see text] performed well to identify the primary end point [AUC (95% CI) = 0.75 (0.61-0.89), P = 0.001]. When accounting only for identifying a history of stroke or TIA, AUC for [Formula: see text] was 0.92 (0.85-1.00) with odds ratio = 7.2 (2.3-22.3) per cycle, P < 0.001. These results suggest that in patients with NIDCM in sinus rhythm, stasis imaging derived from echocardiography may account for the burden of stroke.NEW & NOTEWORTHY Patients with nonischemic dilated cardiomyopathy (NIDCM) are at higher risk of stroke than their age-matched population. However, the risk of bleeding neutralizes the benefit of preventive oral anticoagulation. In this work, we show that in patients in sinus rhythm, the burden of stroke is related to intraventricular stasis metrics derived from echocardiography. Therefore, stasis metrics may be useful to personalize primary prevention anticoagulation in these patients.

Systems biology and novel biomarkers for the early detection of diabetic kidney disease.

Diabetic kidney disease is the most common driver of chronic kidney disease (CKD)-associated mortality and kidney replacement therapy. Despite recent therapeutic advances (SGLT2 inhibitors, finerenone), the residual kidney and mortality risk remains high for patients already diagnosed of having CKD (i.e., estimated glomerular filtration rate &lt;60 ml/min/1.73 m2 or urinary albumin:creatinine ratio &gt;30 mg/g). The challenge for the near future is to identify patients at higher risk of developing CKD to initiate therapy before CKD develops (primary prevention of CKD) and to identify patients with CKD and high risk of progression or death, in order to intensify therapy. We now discuss recent advances in biomarkers that may contribute to identify such high-risk individuals for clinical trials of novel primary prevention or treatment approaches for CKD. The most advanced biomarker from a clinical development point of view is the urinary peptidomics classifier CKD273, that integrates prognostic information from 273 urinary peptides and identifies high risk individuals before CKD develops.

Plasma Phosphorylated Tau 217 and Aβ42/40 to Predict Early Brain Aβ Accumulation in People Without Cognitive Impairment

Phase 3 trials of successful antiamyloid therapies in Alzheimer disease (AD) have demonstrated improved clinical efficacy in people with less severe disease. Plasma biomarkers will be essential for efficient screening of participants in future primary prevention clinical trials testing antiamyloid therapies in cognitively unimpaired (CU) individuals with initially low brain β-amyloid (Aβ) levels who are at high risk of accumulating Aβ. To investigate if combining plasma biomarkers could be useful in predicting subsequent development of Aβ pathology in CU individuals with subthreshold brain Aβ levels (defined as Aβ levels <40 Centiloids) at baseline. This was a longitudinal study including Swedish BioFINDER-2 (enrollment 2017-2022) and replication in 2 independent cohorts, the Knight Alzheimer Disease Research Center (Knight ADRC; enrollment 1988 and 2019) and Swedish BioFINDER-1 (enrollment 2009-2015). Included for analysis was a convenience sample of CU individuals with baseline plasma phosphorylated tau 217 (p-tau217) and Aβ42/40 assessments and Aβ assessments with positron emission tomography (Aβ-PET) or cerebrospinal fluid (CSF) Aβ42/40. Data were analyzed between April 2023 and May 2024. Baseline plasma levels of Aβ42/40, p-tau217, the ratio of p-tau217 to nonphosphorylated tau (%p-tau217), p-tau231, and glial fibrillary acidic protein (GFAP). Cross-sectional and longitudinal PET and CSF measures of brain Aβ pathology. This study included 495 (BioFINDER-2), 283 (Knight ADRC), and 205 (BioFINDER-1) CU participants. In BioFINDER-2, the mean (SD) age was 65.7 (14.4) with 261 females (52.7%). When detecting abnormal CSF Aβ-status, a combination of plasma %p-tau217 and Aβ42/40 showed better performance (area under the curve = 0.949; 95% CI, 0.929-0.970; P <.02) than individual biomarkers. In CU participants with subthreshold baseline Aβ-PET, baseline plasma %p-tau217 and Aβ42/40 levels were significantly associated with baseline Aβ-PET (n = 384) and increases in Aβ-PET over time (n = 224). Associations of plasma %p-tau217 and Aβ42/40 and their interaction with baseline Aβ-PET (%p-tau217: β = 2.77; 95% CI, 1.84-3.70; Aβ42/40: β = -1.64; 95% CI, -2.53 to -0.75; %p-tau217 × Aβ42/40: β = -2.14; 95% CI, -2.79 to -1.49; P < .001) and longitudinal Aβ-PET (%p-tau217: β = 0.67; 95% CI, 0.48-0.87; Aβ42/40: β = -0.33; 95% CI, -0.51 to -0.15; %p-tau217 × Aβ42/40: β = -0.31; 95% CI, -0.44 to -0.18; P < .001) were also significant in the models combining the 2 baseline biomarkers as predictors. Similarly, baseline plasma p-tau217 and Aβ42/40 were independently associated with longitudinal Aβ-PET in Knight ADRC (%p-tau217: β = 0.71; 95% CI, 0.26-1.16; P = .002; Aβ42/40: β = -0.74; 95% CI, -1.26 to -0.22; P = .006) and longitudinal CSF Aβ42/40 in BioFINDER-1 (p-tau217: β = -0.0003; 95% CI, -0.0004 to -0.0001; P = .01; Aβ42/40: β = 0.0004; 95% CI, 0.0002-0.0006; P < .001) in CU participants with subthreshold Aβ levels at baseline. Plasma p-tau231 and GFAP did not provide any clear independent value. Results of this cohort study suggest that combining plasma p-tau217and Aβ42/40 levels could be useful for predicting development of Aβ pathology in people with early stages of subthreshold Aβ accumulation. These biomarkers might thus facilitate screening of participants for future primary prevention trials.

Precision medicine and patient-centered outcomes: Learning from APOE for prevention clinical trials in older adults.

This editorial comments on the article by Clocchiatti‐Tuozzo et al.

Movement and Pressure Injury Prevention Care for Nursing Home Residents: Addressing the Nescience.

To compare movement associated with position changes among nursing home residents who remain in lying versus upright positions for more than 2 hours and among residents living with obesity, dementia, or neither condition. The authors conducted a descriptive exploratory study using secondary data (N = 934) from the Turn Everyone And Move for Ulcer Prevention (TEAM-UP) clinical trial to examine transient movements (<60 seconds) within prolonged periods of 2 to 5 hours without repositioning. Nursing home residents exhibit significantly more episodic transient movements when upright than lying. Residents with obesity or dementia exhibited similar frequencies of episodic transient movements compared with residents with neither obesity nor dementia. Upright or lying movements were more frequent among residents with obesity than among those with neither obesity nor dementia selectively when prolonged events ranged from 2 to 4 hours. Pairwise comparisons of movement rates among resident subgroups (living with obesity, living with dementia, or neither group) across repositioning intervals showed episodic transient movements were significantly higher across all subgroups for repositioning intervals up to 3 hours when compared with repositioning intervals of greater than 3 hours. Findings challenge assumptions that nursing home residents are inactive and at risk for prolonged sitting. These preliminary findings, along with TEAM-UP findings where no pressure injuries occurred in up to 5 hours in prolonged positions, support establishing a standard 3-hour repositioning interval with use of high-density mattresses without a negative impact on pressure injury occurrence. There should be caution when considering repositioning intervals greater than 3 hours. Further research is indicated to explore protective effect of episodic transient movements of other subgroups.

Disability and Recurrent Stroke Among Participants in Stroke Prevention Trials

Stroke secondary prevention trials have disproportionately enrolled participants with mild or no disability. The impact of this bias remains unclear. To investigate the association between poststroke disability and the rate of recurrent stroke during long-term follow up. This cohort study is a post hoc analysis of the Prevention Regimen For Effectively Avoiding Second Strokes (PRoFESS) and Insulin Resistance Intervention After Stroke (IRIS) secondary prevention clinical trial datasets. PRoFESS enrolled patients from 2003 to 2008, and IRIS enrolled patients from 2005 to 2015. Data were analyzed from September 23, 2023, to May 16, 2024. The exposure was poststroke functional status at study baseline, defined as modified Rankin Scale (mRS; range, 0-5; higher score indicates more disability) score of 0 vs 1 to 2 vs 3 or greater. The primary outcome was recurrent stroke. The secondary outcome was major cardiovascular events (MACE), defined as recurrent stroke, myocardial infarction, new or worsening heart failure, or vascular death. A total of 20 183 PRoFESS participants (mean [SD] age, 66.1 [8.5] years; 12 931 [64.1%] male) and 3265 IRIS participants (mean [SD] age, 62.7 [10.6] years; 2151 [65.9%] male) were included. The median (IQR) follow-up was 2.4 (1.9-3.0) years in PRoFESS and 4.7 (3.2-5.0) years in IRIS. In PRoFESS, the recurrent stroke rate was 7.2%, among patients with an mRS of 0, 8.7% among patients with an mRS of 1 or 2, and 10.6% among patients with an mRS of 3 or greater (χ22 = 27.1; P < .001); in IRIS the recurrent stroke rate was 6.4% among patients with an mRS of 0, 9.0% among patients with an mRS of 1 or 2, and 11.7% among patients with an mRS of 3 or greater (χ22 = 11.1; P < .001). The MACE rate was 10.1% among patients with an mRS of 0, 12.2% among patients with an mRS of 1 or 2, and 17.2% among patients with an mRS of 3 or greater (χ22 = 103.4; P < .001) in PRoFESS and 10.9% among patients with an mRS of 0, 13.3% among patients with an mRS of 1 or 2, and 15.3% among patients with an mRS of 3 or greater (χ22 = 5.8; P = .06) in IRIS. Compared with patients with an mRS of 0, patients with an mRS of 3 or greater had increased hazard for recurrent stroke in PRoFESS (hazard ratio [HR], 1.63; 95% CI, 1.38-1.92; P < .001) and in IRIS (HR, 1.91; 95% CI, 1.28-2.86; P = .002). There was also increased hazard for MACE in PRoFESS (HR, 1.90; 95% CI, 1.66-2.18; P < .001) and in IRIS (HR, 1.45; 95% CI, 1.03-2.03; P = .03). This cohort study found that higher baseline poststroke disability was associated with increased rates of recurrent stroke and MACE. Including more patients with greater baseline disability in stroke prevention trials may improve the statistical power and generalizability of these studies.

Incidence of acute kidney injury and attributive mortality in acute respiratory distress syndrome randomized trials.

The development of acute kidney injury (AKI) after the acute respiratory distress syndrome (ARDS) reduces the chance of organ recovery and survival. The purpose of this study was to examine the AKI rate and attributable mortality in ARDS patients. We performed an individual patient-data analysis including 10 multicenter randomized controlled trials conducted over 20years. We employed a Super Learner ensemble technique, including a time-dependent analysis, to estimate the adjusted risk of AKI. We calculated the mortality attributable to AKI using an inverse probability of treatment weighting estimator integrated with the Super Learner. There were 5148 patients included in this study. The overall incidence of AKI was 43.7% (n = 2251). The adjusted risk of AKI ranged from 38.8% (95% confidence interval [CI], 35.7 to 41.9%) in ARMA, to 55.8% in ROSE (95% CI, 51.9 to 59.6%). 37.1% recovered rapidly from AKI, with a significantly lower recovery rate in recent trials (P < 0.001). The 90-day excess in mortality attributable to AKI was 15.4% (95% CI, 12.8 to 17.9%). It decreased from 25.4% in ARMA (95% CI, 18.7 to 32%), to 11.8% in FACTT (95% CI, 5.5 to 18%) and then remained rather stable over time. The 90-dayoverall excess in mortality attributable to acute kidney disease was 28.4% (95% CI, 25.3 to 31.5%). The incidence of AKI appears to be stable over time in patients with ARDS enrolled in randomized trials. The development of AKI remains a significant contributing factor to mortality. These estimates are essential for designing future clinical trials for AKI prevention or treatment.

Decentralized clinical trials for medications to reduce the risk of dementia: Consensus report and guidance.

Recent growth in the functionality and use of technology has prompted an increased interest in the potential for remote or decentralized clinical trials in dementia. There are many potential benefits associated with decentralized medication trials, but we currently lack specific recommendations for their delivery in the dementia field. A modified Delphi method engaged an expert panel to develop recommendations for the conduct of decentralized medication trials in dementia prevention. A working group of researchers and clinicians with expertise in dementia trials further refined the recommendations. Overall, the recommendations support the delivery of decentralized trials in dementia prevention provided adequate safety checks and balances are included. A total of 40 recommendations are presented, spanning aspects of decentralized clinical trials, including safety, dispensing, outcome assessment, and data collection. These recommendations provide an accessible, pragmatic guide for the design and conduct of remote medication trials for dementia prevention. Clinical trials of medication have begun adopting decentralized approaches. Researchers in the field lack guidance on what would be appropriate circumstances and frameworks for what would be appropriate circumstances and frameworks for the use of decentralized trial methods in dementia prevention. The present report provides consensus-based expert recommendations for decentralized clinical trials for dementia prevention.

Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome.

Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS. CD19-directed CAR (CAR19) T cell transfer in B cell lymphoma-bearing mice caused microglia activation and neurocognitive deficits. The TGFβ-activated kinase-1 (TAK1)-NF-κB-p38 MAPK pathway was activated in microglia after CAR19 T cell transfer. Pharmacological TAK1 inhibition or genetic Tak1 deletion in microglia using Cx3cr1CreER:Tak1fl/fl mice resulted in reduced microglia activation and improved neurocognitive activity. TAK1 inhibition allowed for potent CAR19-induced antilymphoma effects. Individuals with ICANS exhibited microglia activation in vivo when studied by translocator protein positron emission tomography, and imaging mass cytometry revealed a shift from resting to activated microglia. In summary, we prove a role for microglia in ICANS pathophysiology, identify the TAK1-NF-κB-p38 MAPK axis as a pathogenic signaling pathway and provide a rationale to test TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy.

APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease.

This study aimed to evaluate the impact of APOE4 homozygosity on Alzheimer's disease (AD) by examining its clinical, pathological and biomarker changes to see whether APOE4 homozygotes constitute a distinct, genetically determined form of AD. Data from the National Alzheimer's Coordinating Center and five large cohorts with AD biomarkers were analyzed. The analysis included 3,297 individuals for the pathological study and 10,039 for the clinical study. Findings revealed that almost all APOE4 homozygotes exhibited AD pathology and had significantly higher levels of AD biomarkers from age 55 compared to APOE3 homozygotes. By age 65, nearly all had abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, with the prevalence of these markers increasing with age, indicating near-full penetrance of AD biology in APOE4 homozygotes. The age of symptom onset was earlier in APOE4 homozygotes at 65.1, with a narrower 95% prediction interval than APOE3 homozygotes. The predictability of symptom onset and the sequence of biomarker changes in APOE4 homozygotes mirrored those in autosomal dominant AD and Down syndrome. However, in the dementia stage, there were no differences in amyloid or tau positron emission tomography across haplotypes, despite earlier clinical and biomarker changes. The study concludes that APOE4 homozygotes represent a genetic form of AD, suggesting the need for individualized prevention strategies, clinical trials and treatments.

0977 A Non-Pharmacological Insomnia Treatment for Suicidal Behavior in High-Risk Civilians: An Open-Label Clinical Trial

Abstract Introduction Suicide has emerged as a public health crisis, where interventions remain scarce, unacceptable, and inaccessible to those high in need. By comparison, poor sleep is non-stigmatizing, visible, and highly treatable as a risk factor and transdiagnostic intervention target in suicide prevention. Aim 1: To develop, manualize, and test feasibility of a sleep-oriented treatment for suicidal behaviors within an open label clinical trial. Aim 2: To test antisuicidal response and indications of efficacy posttreatment across primary (suicidal ideation), secondary (sleep indices), and exploratory (mood indices) outcomes. Methods A multicomponent selective treatment was developed integrating: CBT for Insomnia (CBTi), Imagery Rehearsal Treatment (IRT), and Social Rythyms Treatment (SRT) (to address insomnia, nightmares, sleep variability) within an abbreviated (5-session) format (iSleep: Insomnia Treatment for Improved Well-Being). Treatment was manualized across session-by-session materials (powerpoints, homework, therapist guidesheets). Participants were enrolled based on screening and inclusion criteria: (a) age &amp;gt;18, (b) clinically-significant sleep disturbance (Insomnia Severity Index (ISI&amp;gt;10)); Pittsburgh Sleep Quality Index (PSQI&amp;gt;5)), (c) DSM-V-Defined Major Depressive Disorder, (d) current suicidal ideation (Columbia Suicidal Severity Rating Scale (CSSRS&amp;gt;1)). Comprehensive data and safety monitoring procedures were used to support risk assessment, triage, and outpatient safety planning. Outcomes were assessed at Baseline, Treatment, and Posttreatment (1,3 mos) timepoints. Results Of n=590 new contacts, n=310 participants were screened for high suicide risk. Fifty-nine participants were interviewed by full-battery eligibility assessment, resulting in n=35 participants enrolled for treatment allocation. Feasibility analyses demonstrated high rates of acceptance, tolerability, and safety. Paired t-tests revealed large posttreatment reductions in suicidal ideation (CSSRS, p&amp;lt;.001), in addition to secondary outcomes of sleep disturbance (ISI, p&amp;lt;.001; DDNSI, p&amp;lt;.001) and depression (QIDS-SR, p&amp;lt;.001). Effects were large and sustained through study follow up. Conclusion A non-pharmacological insomnia intervention (iSleep Treatment) resulted in antisuicidal symptom response and posttreatment improvements in sleep and overall well-being. Effects were large and observed across primary, secondary, and exploratory outcomes. This is the first known report testing use of a newly-developed, multicomponent insomnia treatment within an open label suicide prevention clinical trial, demonstrating excellent feasibility, safety, and therapeutic impact to suicidal risk. Support (if any) Work was supported by NIH (K23MH093490) and DOD/MOMRP/MSRC funding (W81XWH-10-2-0178)

Accrual Quality Improvement Program for clinical trials.

The Early Phase Cancer Prevention Clinical Trials Program (Consortia), led by the Division of Cancer Prevention, National Cancer Institute, supports and conducts trials assessing safety, tolerability, and cancer preventive potential of a variety of interventions. Accrual to cancer prevention trials includes the recruitment of unaffected populations, posing unique challenges related to minimizing participant burden and risk, given the less evident or measurable benefits to individual participants. The Accrual Quality Improvement Program was developed to address these challenges and better understand the multiple determinants of accrual activity throughout the life of the trial. Through continuous monitoring of accrual data, Accrual Quality Improvement Program identifies positive and negative factors in real-time to optimize enrollment rates for ongoing and future trials. The Accrual Quality Improvement Program provides a web-based centralized infrastructure for collecting, analyzing, visualizing, and storing qualitative and quantitative participant-, site-, and study-level data. The Accrual Quality Improvement Program approaches cancer prevention clinical trial accrual as multi-factorial, recognizing protocol design, potential participants' characteristics, and individual site as well as study-wide implementation issues. The Accrual Quality Improvement Program was used across 39 Consortia trials from 2014 to 2022 to collect comprehensive trial information. The Accrual Quality Improvement Program captures data at the participant level, including number of charts reviewed, potential participants contacted and reasons why participants were not eligible for contact or did not consent to the trial or start intervention. The Accrual Quality Improvement Program also captures site-level (e.g. staffing issues) and study-level (e.g. when protocol amendments are made) data at each step of the recruitment/enrollment process, from potential participant identification to contact, consent, intervention, and study completion using a Recruitment Journal. Accrual Quality Improvement Program's functionality also includes tracking and visualization of a trial's cumulative accrual rate compared to the projected accrual rate, including a zone-based performance rating with corresponding quality improvement intervention recommendations. The challenges associated with recruitment and timely completion of early phase cancer prevention clinical trials necessitate a data collection program capable of continuous collection and quality improvement. The Accrual Quality Improvement Program collects cumulative data across National Cancer Institute, Division of Cancer Prevention early phase clinical trials, providing the opportunity for real-time review of participant-, site-, and study-level data and thereby enables responsive recruitment strategy and protocol modifications for improved recruitment rates to ongoing trials. Of note, Accrual Quality Improvement Program data collected from ongoing trials will inform future trials to optimize protocol design and maximize accrual efficiency.

Abstract LB139: Disparities in oral precancerous lesion surveillance in the United States upper Midwest

Abstract Objective: To determine whether geographic representation and race of patients in a regional oral cancer surveillance program (University of Minnesota Cancer Active Surveillance Population (UMN CASP)) mirror characteristics in the corresponding National Cancer Institute (NCI) designated comprehensive cancer center catchment. Introduction: Oral cancer poses a significant public health concern that may be mitigated through lesion surveillance. Representation of patients for clinical trials throughout an NCI cancer center catchment area is a crucial goal to promote improved health outcomes. This study investigates the demographic landscape of patients with preneoplastic oral lesions seen at the CASP. Methods: Through the UMN Clinical and Translational Sciences Institute, we queried 30 International Classification of Disease (ICD) 9 and 10 codes corresponding to 120 unique mucosal oral precancerous lesion descriptors of CASP patients. Automated extraction of electronic medical record (EMR) data for 4,496 patients treated by the senior author between 2011 and 2023 identified 1,375 patients with preneoplastic lesions. The proportion of patients residing in three-digit zip code regions of Minnesota were compared to 2021 American Community Survey state population data. Additionally, race data were compared between CASP patients and the UMN Masonic Cancer Center (MCC) patient catchment data. Results: CASP patients were over-represented relative to state population distributions within the Minneapolis-St. Paul metropolitan area and surrounding suburbs (region 554 p&amp;lt;0.0001 and region 551 p&amp;lt;0.0001). Under-representation of CASP patients was observed in all western and southern border regions (regions 559 p&amp;lt;0.0001, 560 p&amp;lt;0.0001, 561 p&amp;lt;0.0001, 562 p=0.0037, 565 p&amp;lt;0.0001, and 567 p=0.0006) as well as portions of central (563 p&amp;lt;0.0001), northern (566 p=0.0015), and north-eastern (558 p&amp;lt;0.0001) Minnesota. Proportional representation was observed in several regions of central (553 and 564), eastern (550), and north-eastern (557 and 556) Minnesota. Comparisons of CASP race data revealed a higher proportion of black patients (CASP 8.59% [95% CI 7.17-10.27%] vs. MCC 7.16% [95% CI 7.14-7.17%]) and a lower proportion of Asian/Pacific Islander patients (CASP 3.74% [95% CI 2.82-4.94%] vs. MCC 5.32% [95% CI 5.30-5.34%]) relative to MCC catchment patients. White, American Indian/Alaskan Native, and mixed-race groups were proportionally represented in both data sets. Conclusions: These data show that system wide EMR searches can be implemented to identify patients in an NCI cancer center catchment area with precancerous or other at-risk conditions for cancer. Importantly, Native patients were proportionally represented in the screening program while several rural locations were under-represented. This information can instruct the expenditure of additional resources for under-represented groups and permit streamlined enrollment of patients for cancer prevention clinical trials. Citation Format: Alexander J. Dwyer, Lindsey Mortensen, Beverly R. Wuertz, Frank G. Ondrey. Disparities in oral precancerous lesion surveillance in the United States upper Midwest [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB139.

Abstract P171: Patient and Interdisciplinary HIV Care Experts Illness Representations on HIV Comorbidities and Usability of a Virtual Environment as Heart Disease Prevention Education in Ethnic and Racial Sexual Minority Men With HIV

Background: Black and Latinx sexual minority men with HIV are at increased risk of CVD and have been underrepresented in clinical trials. The American Heart Association has called for an increase in interventions that focus on enhancing cardiovascular health in underserved communities by addressing social determinants and modifiable risk factors of CVD. Objective: To explore patient and HIV care experts’ perceptions about HIV comorbidities and assess usability of a virtual environment as CVD prevention education in Black and Latinx sexual minority men with HIV. Methods: This two-phase study is part of a pilot behavioral clinical trial informed by the American Heart Association’s metrics for cardiovascular health. Qualitative Phase 1 data were collected June 2021 to May 2022. Phase 2 data were collected August 2022 to October 2022. Using convenience sampling, we recruited a) Black and Latinx sexual minority men with HIV, and b) interdisciplinary HIV care experts. Eligibility criteria for non-HIV care experts were: 1) self-identify as gay or bisexual; 2) HIV serostatus positive; 3) ages 30 to 65; 4) access to a laptop or desktop. We explored HIV comorbidities of concern and conducted usability testing of the virtual environment. Eighty-four pages of interview data were analyzed using NVivo 12. Results: Phase 1 themes included: Mixed Perceptions about Health, High Risk for Comorbidities, and Virtual Environment Features. CVD risk factors were consistently expressed in relation to HIV, including hypertension, heart attack, stroke, and diabetes. Additionally, kidney, and liver disease were identified as important. Cancer was a common concern and so were the development of mental health conditions. All participants in Phase 2 completed the usability checklist with favorable feedback. Conclusions: We identified hypertension, diabetes, asthma, and cancer were comorbidities of concern. These findings carry significant implications for mitigating barriers to preventative health screenings in Black and Latinx sexual minority men with HIV, given shared risk factors between HIV, CVD, and cancer. We also found that usability of a virtual environment as CVD prevention education was promising as it offered anonymity and access to reliable health information that traverses geography. A virtual environment may serve as a novel modality for extending the reach of prevention education and clinical trials into the hands of ethnic and racial, sexual minoritized individuals that have been underrepresented in advancements in health equity.