Prevention Trial Research Articles

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.

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.

Review of Impact of Risk Reduction Sessions on Sexual Behaviors in HIV Prevention Trials: Insights from Africa.

Over the past two decades, numerous HIV prevention trials have targeted thousands of young African women, aiming not only to reduce transmissions through biomedical interventions but also to promote safe sexual practices through intensive risk reduction sessions. The primary objective of this study was to review the impact of risk reduction sessions in HIV prevention trials conducted in Africa. We assessed changes in sexual behaviors among women enrolled in various biomedical intervention trials across the African region using both visual and quantitative evaluations. Meta-analysis techniques were used to estimate overall odds ratios. In a sub-group analysis, we also used semiparametric regression models to capture important features of the associations between sexual behaviors across the study visits with minimal statistical assumptions. Key time points were identified using the "zero-crossing" technique. Overall summary odds ratio (OR) for condom use in last sex was estimated as 2.21 (95% CI 2.06, 2.36). In our sub-group analysis, women who reported multiple sexual partners declined (adjusted odds ratios (aORs) range: 0.61-0.67) while condom use in last sex improved over time (aORs ranged from 2.22-to-2.60); 347(57%) women HIV seroconverted within the first 6-months which was the most crucial time point with substantial reductions in risky behaviors. This review highlights that the gradual cumulative effect of risk reduction sessions, rather than an immediate substantial impact, may have significant implications in clinical research settings. Effective and sustainable risk reduction programs should include biological components such as pre-exposure prophylaxis (PrEP) to reduce HIV transmission.

L-Arginine and L-Citrulline for Prevention and Treatment of Pre-Eclampsia: A Systematic Review and Meta-Analysis.

Evidence suggests L-arginine may be effective at reducing pre-eclampsia and related outcomes. However, whether L-arginine can prevent or only treat pre-eclampsia, and thus the target population and timing of initiation, remains unknown. To evaluate the effects of L-arginine and L-citrulline (precursor of L-arginine) on the prevention and treatment of pre-eclampsia. MEDLINE, Embase, CINAHL, Global Index Medicus and the Cochrane Library were searched through 7 February 2024. Trials administering L-arginine or L-citrulline to pregnant women, with the comparison group receiving placebo or standard care, were included. Meta-analyses were conducted separately for prevention or treatment trials, using random-effects models. Twenty randomised controlled trials (RCTs) (2028 women) and three non-randomised trials (189 women) were included. The risk of bias was 'high' in eight RCTs and showed 'some concerns' in 12. In prevention trials, L-arginine was associated with a reduced risk of pre-eclampsia (relative risk [RR] 0.52; 95% confidence interval [CI], 0.35, 0.78; low-certainty evidence, four trials) and severe pre-eclampsia (RR 0.23; 95% CI, 0.09, 0.55; low-certainty evidence, three trials). In treatment trials, L-arginine may reduce mean systolic blood pressure (MD -5.64 mmHg; 95% CI, -10.66, -0.62; very low-certainty evidence, three trials) and fetal growth restriction (RR 0.46; 95% CI, 0.26, 0.81; low-certainty evidence, two trials). Only one study (36 women) examined L-citrulline and reported no effect on pre-eclampsia or blood pressure. L-arginine may be promising for pre-eclampsia prevention and treatment, but findings should be interpreted cautiously. More trials are needed to determine the optimal dose and time to commence supplementation and support clinical decision-making.

Dietary Reference Intakes of Selenium for Chinese Residents.

The plasma selenoprotein P (SELENOP) concentration leveling out was thought to represent saturation of the functional selenium body pool and an appropriate supply of selenium to all tissues, indicating that the necessary amount of selenium had been supplied. Based on the selenium intake when SELENOP reaches saturation, the estimated average requirement (EAR) of selenium was set as 50 μg/d, and the recommended nutrient intake (RNI) was 60 μg/d for Chinese general population. According a recent study, "lactating Chinese women with the optimal daily selenium intake" was defined, and the adequate intake (AI) of 0‒6 months old infants was set as 15 μg/d, and 20 μg/d was calculated for 7‒12 months old infants. Considering the negative health effects of intake of excessive nutrient levels of selenium, we recommend reducing the tolerable upper intake level (UL) for adults from 400 μg/d to 255 μg/d based on the results of the Selenium and Vitamin E Cancer Prevention Trial (SELECT). The SELECT trial is a key basis for setting selenium's UL. It has a large sample size and long-term design. Rigorously measures selenium intake and monitors multiple health endpoints precisely. Also, with proper control groups, it effectively determines the threshold of adverse effects, enhancing the reliability of UL determination.

Melatonin Low-Dose for Prevention of Delirium in Critically Ill Patients: A Multi-centre, Randomized, Placebo-controlled Feasibility Trial (MELLOW).

Delirium is a common and serious syndrome of acute brain dysfunction associated with negative outcomes. Melatonin may have a role in delirium prevention for critically ill adults based on data from non-critically ill patient populations. Our objective was to assess the feasibility of a multi-centre, randomized, placebo-controlled trial testing the hypothesis that low-dose melatonin prevents delirium in critically ill adults. We conducted this three-arm feasibility trial in three tertiary academic ICUs. Included participants were ≥18 years old, confirmed free from delirium at enrollment, and anticipated >48 hours intensive care unit (ICU) stay. We randomized participants to nightly melatonin 0.5mg or 2mg or placebo. Feasibility outcomes were protocol adherence and recruitment rates. Our primary feasibility target was ≥85% (±5% margin of error) of drug doses administered as per protocol. Secondary objectives were to explore adverse drug effects, melatonin pharmacokinetics, and clinical outcomes. We screened 2259 patients, excluding 1863 (82.5%), resulting in 396 eligible patients, of whom 71 consented; recruitment rate 0.8 patients/month/site. Median (IQR) age was 60.5 (48,67) years; median admission SOFA score 7 (3,10). Percentage drug administration protocol adherence per patient was median 100% (IQR 92.3%, 100%) or mean 88.7% (SD 24.4). There were 25 protocol violations with no differences between groups. Fourteen (20%) patients developed delirium during the study period; 25 (36%) experienced sub-syndromal delirium; no differences between study groups. No serious adverse effects were detected. Our trial protocol comparing two low doses of melatonin and placebo for delirium prevention in critically ill adults demonstrated feasibility for protocol adherence. However, trial eligibility rates were modest primarily due to delirium being present or the inability to screen. Consent rates were also low. This finding suggests that conducting delirium prevention trials that require delirium to be absent on enrolment is particularly challenging in the ICU.

Recruiting sexual minority youth for a drug abuse prevention trial: Comparing Instagram and Facebook

BackgroundDespite youth's shift from Facebook to Instagram, the literature on how to use Instagram to recruit youth for clinical trials is scant. This paper reports procedures and comparative metrics on the use of Facebook and Instagram to recruit a nationwide sample (N = 1216) of LGBQ youth, aged 15 and 16 years, for an online drug abuse prevention trial. MethodsOur recruitment campaign used ads on Facebook and promoted posts on Instagram. Ads and posts shared common images, headlines, and captions. Ads and posts directed youth to a study recruitment website for informed consent and enrollment procedures. ResultsOur campaign ran for 48 non-consecutive days, yielded N = 1216 participants, had a total cost of $25,400.31, and an average cost per participant of $20.89. Facebook ads and Instagram promoted posts ran for a similar number of days. However, compared to Instagram, Facebook ad costs more twice as much (115 %), 51 % fewer clicks, and had an average cost-per-click that was 338 % higher. Furthermore, despite being shown more than 4 times as often to users and garnering more than twice as many unique views, Facebook ads had a click-through-rate that was 90 % lower than Instagram promoted posts. ConclusionInstagram promoted posts outperformed ads on Facebook by driving more potential participants to the study recruitment website and for less money.

Can an app designed to reduce repetitive negative thinking decrease depression and anxiety in young people? Results from a randomized controlled prevention trial.

Rates of mental health disorders are rising among adolescents and young adults. Therefore, scalable methods for preventing psychopathology in these age groups are needed. As repetitive negative thinking (RNT) is a risk factor for depression and anxiety disorders, targeting RNT via smartphone app promises to be an effective, scalable strategy. The current three-arm, parallel group, randomized controlled trial tested whether a self-help app designed to reduce RNT decreased psychopathological symptoms and RNT in adolescents and young adults at risk for mental disorders. A sample of 16-22-year-olds with elevated levels of RNT (N=365) were randomly allocated to either use a one of two self-help apps designed to reduce RNT for 6 weeks or to a waitlist. The full RNT-focused intervention app encompassed a variety of RNT-reducing strategies, whereas the concreteness training app focused on one of these strategies, namely, concrete thinking. The apps did not decrease depressive symptoms, anxiety symptoms and RNT relative to the waitlist. However, exploratory analyses using a minimum dose criterion showed that participants who used the full-RNT-focused intervention app more often, reported greater baseline to follow-up decreases in depressive symptoms compared to waitlist. Include decreased power due to slightly more dropout than expected and limited generalizability due to the mostly female and highly educated sample. RNT-focused prevention via a self-help app did not decrease depression and anxiety, presumably due to too little engagement with the app content provided.

Posttreatment Blood Pressure as a Key Predictor in a 5-Year Stroke Prediction Model.

Evidence suggests that approximately 63.0%-84.2% of stroke survivors have hypertension, yet there is currently no stroke prediction tool specifically designed for individuals with hypertension. Using data from 20702 hypertensive patients from the China Stroke Primary Prevention Trial (CSPPT), we developed a 5-year stroke risk prediction model. This prospective study collected treated blood pressure every 3 months, resulting in 22 measurements over the study period. The model was internally validated using bootstrap resampling, and its predictive performance was assessed with the C-index and calibration curves. We also developed a random forest model to rank the variable importance. The 5-year stroke risk prediction model for hypertensive individuals includes 10 risk factors, ranked by importance as follows: average systolic blood pressure during treatment, age, average diastolic blood pressure during treatment, baseline systolic blood pressure, history of diabetes, baseline total cholesterol level, baseline folate level, self-reported stress, smoking, and folic acid supplementation or not. The C statistic of the equation was 0.74 and there were no significant differences by gender or treatment group. Calibration plots indicate good internal consistency between observed and predicted 5-year stroke risk. We also developed an online calculator to assist clinicians and patients (https://zhouziyi.shinyapps.io/CSPPT/). Our study indicates that for patients with hypertension, long-term posttreatment blood pressure is the primary predictor of stroke risk. Trial Registration: The CSPPT (clinicaltrials.gov Identifier: NCT00794885).

Development and Validation of a Deep Learning Model Based on MRI and Clinical Characteristics to Predict Risk of Prostate Cancer Progression.

Purpose To validate a deep learning (DL) model for predicting the risk of prostate cancer (PCa) progression based on MRI and clinical parameters and compare it with established models. Materials and Methods This retrospective study included 1607 MRI scans of 1143 male patients (median age, 64 years; IQR, 59-68 years) undergoing MRI for suspicion of clinically significant PCa (csPCa) (International Society of Urological Pathology grade > 1) between January 2012 and May 2022 who were negative for csPCa at baseline MRI. A DL model was developed using baseline MRI and clinical parameters (age, prostate-specific antigen [PSA] level, PSA density, and prostate volume) to predict the time to PCa progression (defined as csPCa diagnosis at follow-up). Internal and external testing was performed. The model's ability to predict progression to csPCa was assessed by Cox regression analyses. Predictive performance of the DL model up to 5 years after baseline MRI in comparison with the European Randomized Study of Screening for Prostate Cancer (ERSPC) future-risk calculator, Prostate Cancer Prevention Trial (PCPT) risk calculator, and Prostate Imaging Reporting and Data System (PI-RADS) was assessed using the Harrell C-index. Optimized follow-up intervals were derived from Kaplan-Meier curves. Results DL scores predicted csPCa progression (internal cohort: hazard ratio [HR], 1.97 [95% CI: 1.61, 2.41; P < .001]; external cohort: HR, 1.32 [95% CI: 1.14, 1.55; P < .001]). The model identified a subgroup of patients (approximately 20%) with risks for csPCa of 3% or less, 8% or less, and 18% or less after 1-, 2-, and 4-year follow-up, respectively. DL scores had a C-index of 0.68 (95% CI: 0.63, 0.74) at internal testing and 0.56 (95% CI: 0.51, 0.61) at external testing, outperforming ERSPC and PCPT (both P < .001) at internal testing. Conclusion The DL model accurately predicted PCa progression and provided improved risk estimations, demonstrating its ability to aid in personalized follow-up for low-risk PCa. Keywords: MRI, Prostate Cancer, Deep Learning Supplemental material is available for this article. ©RSNA, 2025.

Challenges in estimating the counterfactual placebo HIV incidence rate from a registration cohort: The PrEPVacc trial.

There is increasing recognition that the interpretation of active-controlled HIV prevention trials should consider the counterfactual placebo HIV incidence rate, that is, the rate that would have been observed if the trial had included a placebo control arm. The PrEPVacc HIV vaccine and pre-exposure prophylaxis trial (NCT04066881) incorporated a pre-trial registration cohort partly for this purpose. In this article, we describe our attempts to model the counterfactual placebo HIV incidence rate from the registration cohort. PrEPVacc was conducted at four study sites in three African countries. During the set up of the trial, potential participants were invited to join a registration cohort, which included HIV testing every 3 months. The trial included a non-inferiority comparison of two daily, oral pre-exposure prophylaxis regimens (emtricitabine/tenofovir disoproxil fumarate, emtricitabine/tenofovir alafenamide fumarate), administered for a target duration of 26 weeks (until 2 weeks after the third of four vaccinations). We developed a multi-variable Poisson regression model to estimate associations in the registration cohort between HIV incidence and baseline predictors (socio-demographic and behavioural variables) and time-dependent predictors (calendar time, time in follow-up). We then used the estimated regression coefficients together with participant characteristics in the active-controlled pre-exposure prophylaxis trial to predict a counterfactual placebo incidence rate. Sensitivity analyses regarding the effect of calendar period were conducted. A total of 3255 participants were followed up in the registration cohort between July 2018 and October 2022, and 1512 participants were enrolled in the trial between December 2020 and March 2023. In the registration cohort, 106 participants were diagnosed with HIV over 3638 person-years of follow-up (incidence rate = 2.9/100 person-years of follow-up (95% confidence interval: 2.4-3.5)). The final statistical model included terms for study site, gender, age, occupation, sex after using recreational drugs, time in follow-up, and calendar period. The estimated effect of calendar period was very strong, an overall 37% (95% confidence interval: 19-51) decline per year in adjusted analyses, with evidence that this effect varied by study site. In sensitivity analyses investigating different assumptions about the precise effect of calendar period, the predicted counterfactual placebo incidence ranged between 1.2 and 3.7/100 person-years of follow-up. In principle, the use of a registration cohort is one of the most straightforward and reliable methods for estimating the counterfactual placebo HIV incidence. However, the predictions in PrEPVacc are complicated by an implausibly large calendar time effect, with uncertainty as to whether this can be validly extrapolated over the period of trial follow-up. Other limitations are discussed, along with suggestions for mitigating these in future studies.

Contraceptive use, prevalence and incidence of pregnancy and associated factors among women participating in a vaccine preparedness cohort study in Masaka, Uganda, a retrospective secondary analysis

BackgroundHIV prevention trials usually require that women of childbearing potential use an effective method of contraception. This is because the effect of most investigational products on unborn babies is unknown. We assessed contraceptive use, prevalence and incidence of pregnancy and associated factors among women in a HIV vaccine preparedness study in Masaka, Uganda.MethodsHIV sero-negative women (18–45 years) at high risk of HIV infection identified through HIV counselling and testing (HCT) were recruited between July 2018 and October 2022. Study procedures included collection of baseline socio-demographics and contraceptive use data, quarterly HCT, counselling on and provision of contraceptive methods onsite/through referral, and 6-monthly urine pregnancy tests. Multivariable Logistic and Poisson regression analyses were conducted to determine factors associated with contraceptive use, prevalence, and incidence of pregnancy.Results652 (73%) of 891 women reported contraceptive use at baseline. Contraceptive use was higher in women who were in a relationship/married/cohabiting [adjusted odds ratio (aOR) = 1.60; 95% confidence interval (CI) 1.07–2.40] or divorced/separated/widowed [aOR = 1.86; 95% CI 1.24–2.79] versus those that were single, and among women reporting transactional sex [aOR = 2.10; 95% CI 1.16–3.80] versus those who did not. Baseline pregnancy prevalence was 4% (95% CI 3–6%) and lower in women who reported using long-acting contraceptive methods (aOR = 0.17; 95% CI 0.07–0.39) versus women who did not use these methods. A total of 65 pregnancies over 301.3 person-years of observation (PYO), an incidence rate of 21.6/100 (95% CI 16.9–27.5) PYO, higher among younger women (≤ 24 versus 25 + years, adjusted incidence rate ratio = 1.97; 95% CI 1.15–3.40).ConclusionWe observed a high pregnancy incidence in this cohort. Innovative strategies that promote sustained and consistent use of highly effective contraceptive methods especially for young women will be critical to the success of HIV prevention trials in this and similar populations.