Prevention Trial Research Articles

How I approach pharmacological thromboprophylaxis in children.

The incidence of venous thromboembolism in children continues to rise, with the most recent analysis from the Pediatric Hospital Information Systems database in the United States reporting a 200-fold increase in pediatric hospitalization-related venous thromboembolism diagnoses over the past two decades. In the past decade, several pediatric venous thromboembolism risk prediction models have been published, in some cases derived from multi-institutional data and multicenter randomized clinical trials of thromboembolism prevention in specific pediatric subpopulations have been conducted. Yet, apart from children hospitalized for COVID-19, guidelines for thromboprophylaxis (TP) in children that address several distinct at-risk subpopulations and settings for venous thromboembolism are presently lacking. It is becoming increasingly apparent that approaches to pharmacological TP for hospitalized children should be risk-stratified regarding a priori risks of both venous thromboembolism and clinically-relevant bleeding. In this manuscript, we present model cases of common inpatient clinical scenarios and review the evidence related to venous thromboembolism risk models and pharmacological TP clinical trials in children, describing a pragmatic approach to pharmacological TP for each scenario. We then conclude by describing our evidence-informed, subpopulation- and setting-specific approach to pharmacological TP for the clinical scenarios and reviewing critical knowledge gaps well-suited for future pediatric trials to inform thromboprophylaxis in children.

Introducing the suicide prevention trials database: A publicly available data repository of suicide prevention studies.

Healthcare, research, policy, and legislative stakeholders need timely, accurate, and detailed information on the effectiveness and potential harms of suicide prevention approaches. We created the Suicide Prevention Trials Database (SPTD) to provide a centralized, publicly accessible, detailed database of harmonized study-level suicide prevention clinical trial data. We searched for randomized controlled trials (RCTs) of suicide prevention published from 1980 to 2023. Over 300 data variables were extracted from each RCT. We identified a total of 140 unique RCTs in 180 articles. Most of the included RCTs compared two treatment arms (92%), and the remainder compared three arms (88%). Nearly half of the RCTs reported on Behavioral Interventions (49%), followed by Care Management, Follow-up, or Monitoring (16%). Typically, the comparator condition was Treatment as Usual (53%). Interventions were most often delivered in person (61%) in an individual format (79%). The SPTD provides efficient, accurate, up-to-date access to a comprehensive suicide prevention trials database, which can be utilized by a range of stakeholders. It can reduce the time required for high-quality systematic reviews and provides researchers, administrators, and funders with current data on the state of the literature.

Abstract WP333: Population-based Study of Stroke Recurrence in Overweight or Obese Patients: Considerations for Future Prevention Trials

Abstract WP333: Population-based Study of Stroke Recurrence in Overweight or Obese Patients: Considerations for Future Prevention Trials

Sensitivity Analysis for Binary Outcome Misclassification in Randomization Tests via Integer Programming

Conducting a randomization test is a common method for testing causal null hypotheses in randomized experiments. The popularity of randomization tests is largely because their statistical validity only depends on the randomization design, and no distributional or modeling assumption on the outcome variable is needed. However, randomization tests may still suffer from other sources of bias, among which outcome misclassification is a significant one. We propose a model-free and finite-population sensitivity analysis approach for binary outcome misclassification in randomization tests. A central quantity in our framework is “warning accuracy,” defined as the threshold such that a randomization test result based on the measured outcomes may differ from that based on the true outcomes if the outcome measurement accuracy did not surpass that threshold. We show how learning the warning accuracy and related concepts can amplify analyses of randomization tests subject to outcome misclassification without adding additional assumptions. We show that the warning accuracy can be computed efficiently for large data sets by adaptively reformulating a large-scale integer program with respect to the randomization design. We apply the proposed approach to the Prostate Cancer Prevention Trial (PCPT). We also developed an open-source R package for implementation of our approach.

2860 Can clinical assessments be administered in a remotely delivered clinical trial targeting older adults at risk for dementia?

Abstract Introduction Research suggests that physical and cognitive exercise can have a positive effective on those with dementia, but less is known about such interventions in those at risk for dementia. Understanding the feasibility of administering clinical assessments remotely using Zoom for HealthcareTM in the context of a dementia prevention trial for at risk older adults is not well understood. Methods SYNERGIC@Home/SYNERGIE~Chez soi (NCT04997681) is a home-based, remotely delivered clinical trial targeting older adults at risk for dementia. Participants underwent a screening/baseline assessment and were randomised to one of four physical and cognitive exercise intervention arms for 16 weeks (3 times per week). They were reassessed immediately post-intervention and 6-months later. The standardised assessments of cognition, physical activity, mobility, mental health, nutrition, sleep, and quality of life were done at all three points. A research coordinator completed the assessments on a one-on-one basis via Zoom for HealthcareTM. The quality-of-life questionnaire was mailed to the participant. Results Forty-eight of 60 participants (80%) (mean age 68.7 ± 5.7 years, 81.3% female) completed the study. Most participants (75.0%) were cognitively intact with at least 2 dementia risk factors. No participants withdrew from the trial because of difficulty with the remote delivery of the assessments. There were no statistically significant changes in any of the assessments of cognition, physical activity, mobility, mental health, nutrition, sleep, or quality of life throughout the study. Conclusion This study demonstrates it is possible to administer standardised clinical assessments of cognition, physical activity, mobility, mental health, nutrition, sleep, and quality of life remotely in the context of a clinical trial. The study was not powered to detect meaningful differences in these assessments. Nevertheless, this confirms the feasibility of remotely administering clinical assessments to older adults at risk for dementia.

P-1967. Characteristics of the first immunocompromised patients to receive Sipavibart as an early access treatment for COVID-19 pre-exposure prophylaxis in France

Abstract Background Immunocompromised patients account for a large proportion of COVID-19 hospitalizations and deaths, even in the most recent periods, despite having received several COVID-19 vaccine doses. Monoclonal antibodies effectively prevented COVID-19 in the general population in randomized control trials and the immunocompromised population in real-world studies. Unfortunately, the emergence of new variants precluded their use. Sipavibart (AZD3152) is an investigational long-acting monoclonal antibody designed to provide broad coverage across Omicron and ancestral viral variants currently being studied in the SUPERNOVA prevention trial. France was the first country to grant Sipavibart as a COVID-19 pre-exposure prophylaxis treatment in immunocompromised individuals with an early access authorization in December 2023. Methods We performed a retrospective multicentric study in France, including the first consecutive patients to receive one intramuscular dose of Sipavibart in January and February 2024, to collect their characteristics and COVID-19-related medical history. Results Overall, we included 47 patients with a median age of 61 years (IQR:64—69) and 64% male. The three main immunosuppressive conditions were Stem cell transplants (38%), solid organ transplants (32%), and immune-based therapies (mostly Rituximab) (19%) for chronic inflammatory diseases or haematologic malignancies. Nearly half had hypogammaglobulinemia and 71% had at least another key comorbidity (Table 1). 15% and 11% had a history of severe and persistent COVID-19, respectively. The median number of COVID-19 doses was 4 (IQR 3-6), and nearly one-third had previously received previous generation of monoclonal antibodies for COVID-19 prophylaxis (Casirivimab/imdevimab or Tixagevimab/Cilgavimab). SARS-CoV-2 serology results before Sipavibart administration were available in 11 patients (without Immunoglobulins substitution). The median anti-Spike IgG titers was 30 UI/L (IQR 0-179). Conclusion The first patients to receive Sipavibart in France had different profiles, but they were all highly immunocompromised with frequently associated hypogammaglobulinemia and other chronic conditions. Disclosures Paul LOUBET, MD, PhD, Astrazeneca: Advisor/Consultant|Gilead: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant Iliès Benotmane, n/a, Astrazeneca: Advisor/Consultant|Astrazeneca: Board Member

Mediation of modifiable risk factors in two multidomain dementia prevention trials.

We explored which dementia risk factors in two multidomain prevention trials mediate beneficial, neutral, or counteracting effects on dementia incidence. We pooled data from the multidomain MAPT (Multidomain Alzheimer Preventive Trial; n=1679, up to 5-year follow-up) and preDIVA trials (Prevention of Dementia by Intensive Vascular Care; n=3526, up to 12-year follow-up) in adults aged 70+. We used multiple mediation analysis to quantify the role of 2-year changes in body mass index, systolic blood pressure, total cholesterol, and physical activity in the intervention effects on dementia incidence. Mixed linear and Cox proportional hazard models were used to explore pathways. We observed no mediation of individual risk factors in the effect of the interventions on dementia incidence. The interventions slightly lowered only blood pressure, but this did not translate into an effect on dementia incidence. In older populations, multidomain interventions may not sufficiently affect dementia risk factors to lower dementia incidence, particularly in settings where cardiovascular risk factor management is well implemented. There is no mediating role of risk factor change in the effects of multidomain interventions on dementia incidence in two large dementia prevention randomized controlled trials. The lack of effect of the interventions on risk factors explains the absence of impact on dementia. Counteracting mediators do not explain the lack of effect of the interventions on dementia. A small effect of the interventionson blood pressure did not translate into a lower dementia incidence.

Cognivue Clarity® characterizes amyloid status and preclinical Alzheimer's disease in biomarker confirmed cohorts in the Bio-Hermes Study.

Cognivue Clarity® is an FDA-cleared computerized cognitive test to screen for cognitive impairment included in the Bio-Hermes Study to test blood-based and digital biomarkers' ability to screen for mild cognitive impairment (MCI) and Alzheimer's disease (AD). A subset of cognitively normal individuals have amyloid deposition (Preclinical AD) but no current assessment can identify these individuals in the absence of expensive biomarkers. We examined differences in Cognivue Clarity performance between amyloid positive and amyloid negative individuals and whether Cognivue Clarity could differentiate True Controls (cognitively normal/amyloid negative), Preclinical AD (cognitively normal/amyloid positive), and MCI due to AD (MCI-AD, cognitively impaired/amyloid positive). Cognivue Clarity was administered to all participants in the Bio-Hermes Study who also had amyloid PET and blood-based biomarkers. Performance was compared between biomarker-defined groups: True Controls (n = 297), Preclinical AD (n = 95), and MCI-AD (n = 113). Cognivue Clarity global scores distinguished amyloid positive individuals from amyloid negative individuals (p < 0.001) and differentiated True Controls versus Preclinical AD (p = 0.014) and Preclinical AD versus MCI-AD (p < 0.001). Three subtests [Shape Discrimination (p = 0.004), Visual Salience (p = 0.008), Adaptive Motor Control (p = 0.004)] and the 3-test mean (p < 0.001) differentiated True Controls from Preclinical AD. The 3-test composite correlated with Amyloid PET (r = -0.433) and pTau217 (r = -0.400). The 3-test mean identified Preclinical AD in both White and Black participants. Cognivue Clarity, a 10-min computerized battery, screens for individuals with cognitive impairment, characterizes amyloid positive individuals, and identifies Preclinical AD. This has great potential as a cost- and time-effective strategy to screen and enroll in AD prevention trials.

Adolescents’ and young women’s perspectives on participation in biomedical clinical trials for HIV prevention in Tanzania and India: a qualitative inquiry

ABSTRACT Adolescent girls and young women are disproportionately affected by HIV in many lower-resource settings. These individuals are often excluded from early clinical trials for new HIV prevention products, thus delaying potential access. We explored adolescent girls’ and young women’s (AGYW) perceptions of HIV risk, perspectives on trial participation, and understanding of research concepts. Individual or repeated in-depth interviews were conducted with a total of 43 AGYW. Interviews were conducted in participants’ language of choice, audio-recorded, transcribed, and translated into English. Thematic analysis was applied. A total of 21 participants were enrolled from Dar es Salaam, Tanzania, and 22 from Pune, India. HIV risk perception varied by country, with Tanzanian participants often describing risk as behaviors tied to economic factors, and Indian participants describing risk as behaviors associated with limited HIV knowledge, inequitable gender norms, and pervasive sexual violence. Trial participation was largely viewed as acceptable; however, concerns were raised regarding standard recommendations for using condoms and contraception during trial participation, and the potential for side effects. Research concepts were notably challenging for participants to understand, particularly the concept of placebo. Although adult involvement was perceived as useful support in Tanzania, it was deemed essential for trial participation in India. Participants in our study described a need for and potential benefits of new HIV prevention products. Taking into consideration the local context, clinical trials with adolescent girls and young women should ensure understanding of research requirements and concepts, minimize preventive misconceptions, and consider involvement of a trusted adult.

Usefulness of urinary biomarker-based risk score and multiparametric MRI for clinically significant prostate cancer detection in biopsy-naïve patients.

This study aimed to investigate the accuracy of multiparametric magnetic resonance imaging (mpMRI), genetic urinary test (GUT), and prostate cancer prevention trial risk calculator version 2.0 (PCPTRC2) for the clinically significant prostate cancer (csPCa) diagnostic in biopsy-naïve patients. In a single center study between 2021 and 2024 participants underwent prostate mpMRI, GUT, and ultrasound (US) guided biopsy. The csPCa risk was calculated using PCPTRC2. After conducting a digital rectal examination (DRE), a GUT was performed. It incorporated the RNA levels of prostate cancer antigen 3 (PCA3) and transmembrane serine protease 2 (TMPRSS2) gene and ETS-related gene (ERG) fusion genes (T: E), along with the patient's age and PSA density. The McNemar test compared detection rates between modalities. 208 (mean age 62.9 years +/- 8.2) men were included prospectively. A positive GUT score was found in 67.8% and PIRADS ≥3 in 81.7% of all cases. The combination of GUT with mpMRI showed significantly higher sensitivity (99.1%) than GUT and mpMRI alone, 84.4% and 93.8%, respectively (p ≤ 0.05). Similarly, very high sensitivity (99.0%) was achieved by combining mpMRI with PCPTCR2. Nevertheless, mpMRI plus GUT combination exceeded mpMRI plus PCPTCR2 by allowing to save a higher fraction of unnecessary biopsies, 25% and 2.4%, respectively. GUT and mpMRI combination would allow saving a substantial fraction of unnecessary biopsies with minimal risk of missing csPCa cases.

P0558 An Integrative Blood-Based Risk Score Predicts Development of Crohn's Disease

Abstract Background Individual blood markers have been associated with future risk of Crohn's disease (CD). However, there is a need to understand which combination of biomarkers will be most predictive to facilitate CD prevention trial recruitment. We aimed to develop and validate a blood-based integrative risk score for CD development. Methods We analyzed data from 200 patients with CD and 100 age, sex, and race-matched healthy controls (HC) from PREDICTS, a nested case-control study of US active-component service members (ACSM). Longitudinal serum samples were collected at four time points up to 6+ years prior to diagnosis. Anti-microbial antibodies (Prometheus), proteomic markers (Olink inflammation panel), and anti-granulocyte macrophage-colony stimulating factor autoantibodies (anti-GM-CSF) were assayed in each sample. Participants were randomly divided into equal sized training and testing sets. Time-varying trajectories of marker abundance were estimated for each biomarker. Logistic regression modeled disease status as a function of each marker for different time points and multivariate modeling was performed via logistic lasso regression. A risk score to predict CD onset within 2 years was developed using penalized mixed-effects logistic regression. Prediction models were fit on the testing set and predictive performance evaluated via receiver operating characteristic (ROC) curves and area under the curve (AUC). Results The AUCs of individual markers were dynamic over time, with some having stable predictive capacity and others increasing or decreasing closer to time of diagnosis (Figure 1A). The AUCs for a model combining antibodies (Prometheus and anti-GM-CSF) and proteins were consistently above 0.8 starting 4 years prior to diagnosis, primarily driven by proteomic markers (Figure 1B). An integrative model predicting CD onset within 2 years incorporated 10 biomarkers and significantly associated with CD onset (Figure 1C). The model resulted in an AUC of 0.87 with a specificity of 99% and positive predictive value of 84% at a classification threshold of 0.7 (Figure 1D). Stratifying the integrative model scores into quartiles revealed a clear gradient in CD incidence within 2 years, increasing from 2% in the first quartile to 57.7% in the fourth quartile (Figure 1E). The relative risk (RR) for developing CD among ACSM in the top quartile, compared to the lower quartiles, was 10.4 (95% CI 6.9, 15.6). Conclusion An integrative blood-based model combining anti-microbial antibodies and proteins predicts onset of CD. Serologic and proteomic markers have dynamic changes years before diagnosis, highlighting the varying preclinical phases of CD and how leveraging biomarker dynamics can predict time to diagnosis. Figure 1

Standard of prevention for infectious diseases' prevention clinical trials during pandemics: learning lessons for global policies from biomedical HIV prevention clinical trials and a case study of COVID-19.

Lessons from biomedical HIV prevention research indicate that standard of prevention packages evolve over time, and require active engagement of stakeholders and community advocates to define packages accept to community members and trial participants. Using COVID-19 prevention research as an example, this paper discusses the reasons why a standard of prevention package must be defined for infectious diseases prevention research, what the minimum content of this package may be, the importance of stakeholder engagement in defining the package, the role of the government, and ethical considerations. As the experience from the HIV pandemic had shown, multiple ethics guidelines argue for a comprehensive standard of prevention package for biomedical HIV prevention trials that does not preclude the inclusion of newly developed HIV prevention tools including those experimental products listed for emergency use during health crisis. In the case of COVID-19, the standard of prevention package should include at a minimum, risk reduction counseling on physical distancing, provision of hand sanitizers, education on how to use available prevention tools, and provision for the possibility of vaccine-induced seropositivity. When pre-exposure prophylaxis studies are conducted for healthcare workers and home carers, personal protective equipment should be provided. Regional and country level regulatory provisions on these issues can provide critical guidance for research design and implementation.

Stage-based analysis of an adaptive worksite intervention trial for diabetes prevention.

Stage-based models of change posit stage specific factors to promote motivation and intention formation for those not ready to change and volitional action strategies for others. The impact of two interventions on energy restriction and weight change among adults with prediabetes (n = 190) was examined by baseline stage. Stage classification included: Pre-intenders had no intention to change; Intenders set an intention but were not acting; and Actors reported eating a low-fat diet at baseline. Intervention impact on intention formation, planning, self-efficacy, energy intake, and weight change was evaluated. Structural equation modeling identified mechanisms of change. At baseline, Pre-intenders (28.3 %) and Actors (41.7 %) significantly differed in action self-efficacy, planning, and energy intake. Post-intervention, 91.7 % of the sample remained Actors or progressed in stage placement; intention to consume a low-fat diet increased for Pre-intenders. An increase in action self-efficacy strengthened intention formation for Intenders/Actors. Model fit for post-intentional factors was unsatisfactory, but dietary planning may promote energy restriction. The lifestyle interventions promoted stage progression. Whether post-intentional mechanisms of change differ for Pre-intenders compared to Intenders/Actors requires further research. Classifying participants by intention and tailoring interventions to stage may promote greater intention formation and reduction in energy intake.

Understanding the experiences of young, urban, Indigenous mothers-to-be in British Columbia, Canada

BackgroundIndigenous Peoples comprise the youngest and fastest growing demographic in Canada, with many living in urban-suburban areas. Given higher fertility rates, younger overall ages and higher adolescent pregnancy rates, perinatal research is needed—to inform policymaking and programming throughout pregnancy and childhood. Yet such data remain scarce in British Columbia (BC), Canada. This study therefore aimed to describe the experiences of young, urban, Indigenous mothers-to-be who enrolled in a larger BC early prevention trial designed to reach families experiencing socioeconomic disadvantage.MethodsThis descriptive study utilized baseline data from a trial that enrolled first-time mothers-to-be who met indicators of socioeconomic disadvantage and who were residing in select urban-suburban areas. These indicators included being young (19 years or younger) or having limited income, low access to education, and being single (aged 20−24 years). We described and compared survey data on girls (n = 109; aged 14−19 years) and young women (n = 91; aged 20−24 years) using Chi-square or Student’s t-tests.ResultsOf the 739 trial participants, 200 or 27% identified as Indigenous and met trial eligibility criteria: limited income (92.9%), limited access to education (67.0%), and/or being single (90.9%). Beyond this, participants reported associated adversities including: unstable housing (63.3%), psychological distress (29.3%), severe anxiety or depression (48.5%), experiences of childhood maltreatment (59.4%) and intimate partner violence (39.5%). Compared to girls, young women reported higher income and educational attainment (p < 0.001), more unstable housing (p = 0.02) and more childhood maltreatment (p = 0.014). Many had recently received primary healthcare (75%), but few had received income assistance (34%). Most (80.5%) reported experiencing four or more adversities.ConclusionsWe present data illustrating that a high proportion of pregnant Indigenous girls and young women engaged with public health and consented to long-term research participation—despite experiencing cumulative adversities. The trial socioeconomic screening criteria were successful in reaching this population. Girls and young women reported relatively similar experiences—beyond expected developmental differences in income and education—suggesting that adolescent maternal age may not necessarily infer risk. Our findings underscore the need for Indigenous community-led services that address avoidable adversities starting in early pregnancy.

Association between herpes simplex virus infection and Alzheimer’s disease biomarkers: analysis within the MAPT trial

In vitro and animal studies have suggested that inoculation with herpes simplex virus 1 (HSV-1) can lead to amyloid deposits, hyperphosphorylation of tau, and/or neuronal loss. Here, we studied the association between HSV-1 and Alzheimer’s disease biomarkers in humans. Our sample included 182 participants at risk of cognitive decline from the Multidomain Alzheimer Preventive Trial who had HSV-1 plasma serology and an amyloid PET scan. Plasma Aβ42/40 ratio, neurofilament light chain and p-tau181 were also available for a sub-sample of participants. Multivariate linear regressions were performed and stratified by APOE4 genotype. The median age was 74.0 years, 85.2% were infected with HSV-1. Infected participants tended to have a lower cortical amyloid load than uninfected participants (β = -0.08, p = 0.06), especially those suspected of reactivating HSV-1 most frequently (i.e. with a high anti-HSV-1 IgG level; n = 58, β = -0.09 p = 0.04). After stratification, the association was only significant in APOE4 carriers (n = 43, β = -0.21 p = 0.01). No association was found with the plasma biomarkers. The trend toward lower cortical amyloid load in HSV-1-infected participants was unexpected given the pre-existing literature and may be explained either by a modified immune response in HSV-1 infected subjects which could favour the clearance of amyloid deposits or by a selection bias.

Association between inflammatory biomarkers and the cognitive response to a multidomain intervention: secondary longitudinal analyses from the MAPT study.

The aim of this study is to evaluate the association of systemic inflammation measured by plasma biomarkers with the change in cognitive function among participants from the Multidomain Alzheimer Preventive Trial (MAPT) exposed to the multidomain intervention (MI). Secondary analysis of the MAPT longitudinal data. MAPT is a randomized, placebo-controlled trial with 3 interventional groups (omega-3 only, MI only, omega-3 plus MI) and a control group. We tested the association of the change in cognitive function with inflammatory biomarkers (tumoral necrosis factor receptor-1 (TNFR1), monocyte chemoattractant protein-1 (MCP1), Growth Differentiation Factor-15 (GDF15), Interleukin-6 (IL6) and C reactive protein (CRP)) using mixed-effects models. A subgroup analysis was performed in those exposed to the MI. The response to the MI was defined as the change in the composite cognitive score over the 2-year clinical follow-up period. by modeling the response to the intervention and identifying "good responders", i.e., those in the 5th quintile of response at the end of the intervention period (2years after the measurement of inflammatory markers). We included 1,527 participants (mean age 75.3, SD = 4.4; 64% female). Higher levels of GDF15 and TNFR1 were associated with a worse trajectory in the cognitive composite score in adjusted models. "Good responders" had an estimated mean change in the composite score of 0.051 (SD 0.062) over two years of intervention, compared to -0.136 (SD = 0.111) for the "not-good responders". Higher IL6 levels were associated with a decreased likelihood of being a "good responder" (OR = 0.22, p = 0.018, 95% CI 0.06; 0.78), with similar results for CRP (OR = 0.48, p = 0.009, 95% CI 0.28; 0.84). Higher inflammation was associated with a worse cognitive trajectory among nondemented participants and a lower likelihood of being classified as a "good responder" in those receiving a MI. Further confirmation of these findings could lead to the use of systemic inflammation as inclusion or stratification criteria in prevention trials.

Searching for responders to multidomain dementia prevention in late life: A pooled analysis of individual participant data from the MAPT and preDIVA trials.

It is unknown in which, if any, subgroups of older adults multidomain interventions are effective at reducing long-term dementia incidence. We pooled up to 12 years of follow-up data from 5205 participants aged > 70 from the Multidomain Alzheimer Preventive Trial (MAPT) and Prevention of Dementia by Intensive Vascular Care (preDIVA) studies. The primary outcome was incident all-cause dementia. Pre-specified subgroups were defined by dementia risk factors (age, sex, education, apolipoprotein E [APOE] genotype, cognitive status, and cardiovascular risk factors). Four hundred eighty-six participants developed dementia during 37,782 person-years of follow-up. Higher incidence was associated with baseline age, APOE ε4 genotype, physical inactivity, Mini-Mental State Examination, and blood pressure. Multidomain intervention had no effect on incident dementia overall (hazard ratio =0.98, 95% confidence interval 0.80-1.21), or in any pre-specified subgroup. A recursive partitioning algorithm also did not detect any subgroups, defined by single or multiple risk factors, showing a differential intervention effect. We did not identify any subgroups of older adults in whom multidomain interventions significantly reduced incident dementia. MAPT: NCT00672685 (clinicaltrials.gov); PreDIVA: ISRCTN29711771 (ISRCTN registry) HIGHLIGHTS: We pooled up to 12 years of follow-up data from two multidomain prevention trials. Five thousand two hundred five participants aged ≥ 70 were included. Subgroups were pre-defined by modifiable and non-modifiable dementia risk factors. A data-driven recursive partitioning algorithm was also used. Multidomain intervention did not lower incident dementia overall or in any subgroup.

Somatic CAG repeat expansion in blood associates with biomarkers of neurodegeneration in Huntington's disease decades before clinical motor diagnosis.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with the age at which characteristic symptoms manifest strongly influenced by inherited HTT CAG length. Somatic CAG expansion occurs throughout life and understanding the impact of somatic expansion on neurodegeneration is key to developing therapeutic targets. In 57 HD gene expanded (HDGE) individuals, ~23 years before their predicted clinical motor diagnosis, no significant decline in clinical, cognitive or neuropsychiatric function was observed over 4.5 years compared with 46 controls (false discovery rate (FDR) > 0.3). However, cerebrospinal fluid (CSF) markers showed very early signs of neurodegeneration in HDGE with elevated neurofilament light (NfL) protein, an indicator of neuroaxonal damage (FDR = 3.2 × 10-12), and reduced proenkephalin (PENK), a surrogate marker for the state of striatal medium spiny neurons (FDR = 2.6 × 10-3), accompanied by brain atrophy, predominantly in the caudate (FDR = 5.5 × 10-10) and putamen (FDR = 1.2 × 10-9). Longitudinal increase in somatic CAG repeat expansion ratio (SER) in blood was a significant predictor of subsequent caudate (FDR = 0.072) and putamen (FDR = 0.148) atrophy. Atypical loss of interruption HTT repeat structures, known to predict earlier age at clinical motor diagnosis, was associated with substantially faster caudate and putamen atrophy. We provide evidence in living humans that the influence of CAG length on HD neuropathology is mediated by somatic CAG repeat expansion. These critical mechanistic insights into the earliest neurodegenerative changes will inform the design of preventative clinical trials aimed at modulating somatic expansion. ClinicalTrials.gov registration: NCT06391619 .

Performance of the pooled cohort equations and D:A:D risk scores among individuals with HIV in a global cardiovascular disease prevention trial: a cohort study leveraging data from REPRIEVE.

Risk estimation is an essential component of cardiovascular disease prevention among people with HIV. We aimed to characterise how well atherosclerotic cardiovascular disease (ASCVD) risk scores used in clinical guidelines perform among people with HIV globally. In this prospective cohort study leveraging REPRIEVE data, we included participants aged 40-75 years, with low-to-moderate traditional cardiovascular risk, not taking statin therapy. REPRIEVE participants were enrolled from sites in 12 countries across Global Burden of Disease Study (GBD) regions. We assessed the performance of the pooled cohort equations (PCE) risk score for ASCVD and the data-collection on adverse effects of anti-HIV drugs (D:A:D) risk score. We calculated C statistics, observed-to-expected (OE) event ratios, and Greenwood-Nam-D'Agostino goodness-of-fit (GND) statistics, overall and in subgroups by race, sex, and GBD regions (clustering low-income and middle-income countries and high-income countries). We did a recalibration for PCE risk score among people with HIV in high-income countries. REPRIEVE was registered with ClinicalTrials.gov, NCT02344290. We included 3893 participants, recruited between March 26, 2015, and July 31, 2019. The median age was 50 years (IQR 45-55), with 2684 (69%) male and 1209 (31%) female participants. 1643 (42%) were Black or African American, 1346 (35%) participants were White, 566 (15%) were Asian, and 338 (9%) were recorded as other race. Overall, discrimination of the PCE risk score was moderate (C statistic 0·72 [95% CI 0·68-0·76]) and calibration was good (OE event ratio 1·11; GND p=0·87). However, calibration suggested overprediction of risk in low-income and middle-income countries and corresponding underprediction in high-income countries. When restricted to high-income countries, we found underprediction (OE event ratio >1·0) among women (2·39) and Black or African American participants (1·64). Findings were similar for the D:A:D risk score (C statistic 0·71 [0·65-0·77]; OE event ratio 0·89; p=0·68). Improved calibration of the PCE risk score in high-income countries was achieved by multiplying the original score by 2·8 in Black or African American women, 2·6 in women who were not Black or African American, and 1·25 in Black or African American men. Among the global cohort of people with HIV in REPRIEVE, the PCE risk score underpredicted cardiovascular events in women and Black or African American men in high-income countries and overpredicted cardiovascular events in low-income and middle-income countries. Underprediction in subgroups should be considered when using the PCE risk score to guide statin prescribing for cardiovascular prevention among people with HIV in high-income countries. Additional research is needed to develop risk scores accurate in predicting ASCVD among people with HIV in low-income and middle-income countries. US National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare.

The place of school-based strategies for universal, selective, and indicated prevention for depression

Abstract In response to the question ‘what is the place of universal, selective and indicated prevention strategies for depression and other mood disorders’ posed by Hickie et al. (2024) we examine the role of school-based strategies for universal and targeted (including selective and indicated) prevention of depression. Schools represent a unique opportunity for systematic evidence-based depression prevention, targeting key developmental risk periods before peak depression onset. However, the realisation of this potential has been challenging particularly for universal approaches. We summarise the evidence for each of these tiers of prevention, including recent large-scale trials of universal prevention in high-income countries. Targeted approaches show more consistent preventive effects on depression however hold significant implementation challenges in the school context. We provide recommendations about next steps for the field including a continuum of support across all levels of prevention outlined above and broadening current strategies to focus on the school contexts and structural factors in which prevention programs are delivered, as well as teacher mental health.