Early Intervention Trials Research Articles

Risk factors for development of hyper-reflective foci overlying drusen in eyes with intermediate age-related macular degeneration

AimsThe aim of this study is to assess baseline characteristics of drusen preceding the development of intraretinal hyper-reflective foci (IHRF) in eyes with intermediate age-related macular degeneration (AMD).MethodsIn this retrospective...

Impact of the Korea Early Childhood Home-visiting Intervention (KECHI) on child health and development and maternal health: a randomised controlled trial protocol

IntroductionRandomised controlled trials (RCTs) of early childhood home-visiting interventions led by nurses have been conducted mainly in Western countries, whereas such trials have been limited in non-Western cultures, including Asia....

Scenarios for the long-term efficacy of amyloid-targeting therapies in the context of the natural history of Alzheimer's disease.

Recent clinical trials of amyloid beta (Aβ)-targeting therapies in Alzheimer's disease (AD) have demonstrated a clinical benefit over 18 months, but their long-term impact on disease trajectory is not yet understood. We propose a framework for evaluating realistic long-term scenarios. Results from recent phase 3 trials of Aβ-targeting antibodies were integrated with an estimate of the long-term patient-level natural history trajectory of the Clinical Dementia Rating-Sum of Boxes (CDR-SB) score to explore realistic long-term efficacy scenarios. Three distinct long-term efficacy scenarios were examined, ranging from conservative to optimistic. These extrapolations of positive phase 3 trials suggested treatments delayed onset of severe dementia by 0.3 to 0.6 years (conservative), 1.1 to 1.9 years (intermediate), and 2.0 to 4.2 years (optimistic). Our study provides a common language for long-term impact of disease-modifying treatments. Our work calls for studies with longer follow-up and results from early intervention trials to provide a comprehensive assessment of these therapies' true long-term impact. We present long-term scenarios of the efficacy of AD therapies. In this framework, scenarios are defined relative to the natural history of AD. Long-term projections with different levels of optimism can be compared. It provides a common language for expressing beliefs about long-term efficacy.

The Difficulty in Defining the True High-Risk Smoldering Myeloma.

Early intervention trials have been initiated for the precursor disease smoldering myeloma (SMM). A recent study showed that genomic complexity varies widely among patients treated for high-risk SMM and is associated with response to triplet therapy, suggesting that established clinical risk scores often fail to discriminate between stable and aggressive disease. See related article by Kazandjian et al., p. 4482.

Identifying early language predictors: A replication of Gasparini et al. (2023) confirming applicability in a general population cohort

AbstractBackgroundIdentifying language disorders earlier can help children receive the support needed to improve developmental outcomes and quality of life. Despite the prevalence and impacts of persistent language disorder, there are surprisingly no robust predictor tools available. This makes it difficult for researchers to recruit young children into early intervention trials, which in turn impedes advances in providing effective early interventions to children who need it.AimsTo validate externally a predictor set of six variables previously identified to be predictive of language at 11 years of age, using data from the Longitudinal Study of Australian Children (LSAC) birth cohort. Also, to examine whether additional LSAC variables arose as predictive of language outcome.Methods & ProceduresA total of 5107 children were recruited to LSAC with developmental measures collected from 0 to 3 years. At 11–12 years, children completed the Clinical Evaluation of Language Fundamentals, 4th Edition, Recalling Sentences subtest. We used SuperLearner to estimate the accuracy of six previously identified parent‐reported variables from ages 2–3 years in predicting low language (sentence recall score ≥ 1.5 SD below the mean) at 11–12 years. Random forests were used to identify any additional variables predictive of language outcome.Outcomes & ResultsComplete data were available for 523 participants (52.20% girls), 27 (5.16%) of whom had a low language score. The six predictors yielded fair accuracy: 78% sensitivity (95% confidence interval (CI) = [58, 91]) and 71% specificity (95% CI = [67, 75]). These predictors relate to sentence complexity, vocabulary and behaviour. The random forests analysis identified similar predictors.Conclusions & ImplicationsWe identified an ultra‐short set of variables that predicts 11–12‐year language outcome with ‘fair’ accuracy. In one of few replication studies of this scale in the field, these methods have now been conducted across two population‐based cohorts, with consistent results. An imminent practical implication of these findings is using these predictors to aid recruitment into early language intervention studies. Future research can continue to refine the accuracy of early predictors to work towards earlier identification in a clinical context.WHAT THIS PAPER ADDSWhat is already known on the subject There are no robust predictor sets of child language disorder despite its prevalence and far‐reaching impacts. A previous study identified six variables collected at age 2–3 years that predicted 11–12‐year language with 75% sensitivity and 81% specificity, which warranted replication in a separate cohort.What this study adds to the existing knowledge We used machine learning methods to identify a set of six questions asked at age 2–3 years with ≥ 71% sensitivity and specificity for predicting low language outcome at 11–12 years, now showing consistent results across two large‐scale population‐based cohort studies.What are the potential or clinical implications of this work? This predictor set is more accurate than existing feasible methods and can be translated into a low‐resource and time‐efficient recruitment tool for early language intervention studies, leading to improved clinical service provision for young children likely to have persisting language difficulties.

The impact of malnutrition on secondary diabetes and calcific pancreatitis: A comprehensive review

Introduction: Malnutrition in low- and middle-income countries significantly impacts the development of secondary diabetes and calcific pancreatitis. Aim and Methods: This review summarizes the prevalence, characteristics, and findings from key studies over the past decade on the link between malnutrition and secondary diabetes, focusing on protein-deficient pancreatic diabetes (PDPD) and fibro-calculous pancreatic diabetes (FCPD). A comprehensive literature search was conducted in PubMed, Scopus, and Google Scholar for articles published between 1995 and 2023. Studies included were peer-reviewed articles focusing on the link between malnutrition and secondary diabetes, conducted in LMICs, and discussing the prevalence, clinical characteristics, and outcomes of PDPD and FCPD. Both observational and interventional studies were considered. Results: The review of studies revealed several key findings: · PDPD is characterized by lower C-peptide levels and varied responses to glibenclamide post-nutritional rehabilitation. · FCPD patients show rapid calcification, diminished exocrine and beta-cell function, and more severe exocrine deficiency compared to PDPD. · Both PDPD and FCPD patients often present with lower BMI and significant renal involvement. · Recent studies indicate improved nutritional status and prognosis of FCPD patients with enhanced medical care. · Insulin-requiring diabetes in Ethiopia is strongly linked with poor education, poverty markers, and childhood malnutrition. · Lean diabetes, linked to childhood malnutrition, is characterized by low-normal BMI, early onset, and rapid beta-cell failure. Discussion: The development of diabetes following early malnutrition can be attributed to several interconnected mechanisms involving metabolic, endocrine, and epigenetic factors. Early nutritional intervention trials are crucial to prevent glucose abnormalities and diabetes later in life. Studies highlight that improving early-life nutrition can enhance beta-cell function, reduce insulin resistance, and mitigate long-term metabolic dysfunction. Lean diabetes, linked to childhood malnutrition, presents unique challenges but can be addressed through targeted nutritional support. Conclusion: The review underscores the significant impact of malnutrition on the development of secondary diabetes and calcific pancreatitis in LMICs. Addressing malnutrition through early nutritional interventions is crucial to mitigate the risk of chronic conditions and improve metabolic health outcomes. Continued research and targeted public health strategies are essential to break the cycle of malnutrition and disease in vulnerable populations.

'ThinkCancer!': randomised feasibility trial of a novel practice-based early cancer diagnosis intervention.

UK cancer deaths remain high; primary care is key for earlier cancer diagnosis as half of avoidable delays occur here. Improvement is possible through lower referral thresholds, better guideline adherence, and better safety-netting systems. Few interventions target whole practice teams. We developed a novel whole-practice team intervention to address this. To test the feasibility and acceptability of a novel, complex behavioural intervention, 'ThinkCancer!', for assessment in a subsequent Phase III trial. Pragmatic, superiority pilot randomised controlled trial (RCT) with an embedded process evaluation and feasibility economic analysis in Welsh general practices. Clinical outcome data were collected from practices (the unit of randomisation). Practice characteristics and cancer safety-netting systems were assessed. Individual practice staff completed evaluation and feedback forms and qualitative interviews. The intervention was adapted and refined. Trial recruitment and workshop deliveries took place between March 2020 and May 2021. Trial progression criteria for recruitment, intervention fidelity, and routine data collection were met. Staff-level fidelity, retention, and individual level data collection processes were reviewed and amended. Interviews highlighted positive participant views on all aspects of the intervention. All practices set out to liberalise referral thresholds appropriately, implement guidelines, and address safety-netting plans in detail. 'ThinkCancer!' appears feasible and acceptable. The new iteration of the workshops was completed and the Phase III trial has been funded to assess the effectiveness and cost-effectiveness of this novel professional behaviour change intervention. Delivery at scale to multiple practices will likely improve fidelity and reach.

Predictive Factors Influencing the Evolution of Acquired Vitelliform Lesions in Intermediate Age-Related Macular Degeneration Eyes

PurposeIn this study, we identify risk factors that predict the progression of AVL lesions over time. DesignRetrospective cohort study Subjects163 eyes of 132 patients with a diagnosis of iAMD with AVL MethodsThis retrospective study evaluated consecutive eyes with AMD from a retina clinic population and included 1181 patients and 2362 eyes. After excluding cases with associated geographic atrophy, macular neovascularization (MNV), vitreomacular traction, and those with less than two years of follow-up data, the final analysis cohort consisted of 163 eyes (132 patients) with at least one AVL lesion. The first available visit in which an AVL lesion was evident was considered the baseline visit, and follow-up data was collected from a visit 2years (+/- 3 months) later. Progression outcomes at the follow visit were classified into six categories: Resorbed, Collapsed, MNV, Stable, Increasing, and Decreasing. Subsequently, we analyzed the baseline characteristics for each category and calculated odds ratios to predict these various outcomes. Main Outcome MeasuresThe study focused on identifying predictive factors influencing the evolution of AVL in iAMD eyes. ResultsIn total, 163 eyes with AVL had follow-up data at 2 years. The collapsed group demonstrated a significantly greater baseline AVL height and width compared to other groups (P < 0.001). With regards to qualitative parameters, subretinal drusenoid deposits (SDD) and intra-retinal hyper-reflective foci (IHRF) at the eye level, AVL located over drusen, and IHRF and ELM disruption over AVL were significantly more prevalent in the collapsed group compared to other groups (P< 0.05 for all comparisons). Odds Ratio for progressing to atrophy after 2 years of follow-up, compared to the resorbed group, were significant for SDD (OR = 2.82, P = 0.048) and AVL height (OR = 1.016, P = 0.006). ConclusionsThe presence of SDD and greater AVL height significantly increases the risk of developing atrophy at the location of AVL after 2 years of follow-up. These findings may be of value in risk prognostication and defining patient populations for inclusion in future early intervention trials aimed at preventing progression to atrophy.

Effect of Hormone Therapy on Lipoprotein Subfractions in Early and Late Postmenopausal Women.

The Early vs Late Intervention Trial with Estradiol (ELITE) showed that hormone therapy (HT) reduced atherosclerosis progression among early but not late postmenopausal women (PMW). Determined by time-since-menopause (1) HT effects on lipids and lipoprotein particle subfractions (LPs), (2) associations of estradiol (E2) level with lipids and LPs, (3) associations of lipids and LPs with atherosclerosis progression. Randomized controlled trial stratified by time-since-menopause. Academic institution. Healthy postmenopausal women. Oral E2 with/without sequential vaginal progesterone. Standard lipids and 21 LPs quantitated by ion mobility every 6 months. Among 562 PMW (240 early, 322 late), HT significantly increased total triglycerides (TG), high-density lipoprotein (HDL) cholesterol, small low-density lipoproteins (LDL), large HDL, and TG/C ratio in LDL and HDL and decreased LDL-cholesterol, total very low density lipoproteins (VLDL), small VLDL, intermediate-density lipoproteins, large LDL, and LDL peak diameter. HT showed no lipid or LP differences between time-since-menopause. Associations of E2 level with lipids and LPs explained the HT effects. Despite the nonsignificant P interaction by time-since-menopause, we observed that very small LDL and total HDL LPs were associated with atherosclerosis progression in late PMW. HT effects on standard lipids and LPs are consistent with the literature. HT has similar effect on lipids and LPs in early and late PMW. Novel findings include discordant effects of HT on TG and VLDL particles, which can be explained by increased catabolism of atherogenic remnants of TG-rich lipoproteins. Our findings extend the well-known HT effects on standard lipids and LPs that may contribute to the beneficial effects on atherosclerosis progression in PMW.

Comparison of Goal Achievement during an Early, Intensive Nutrition Intervention Delivered to People with Upper Gastrointestinal Cancer by Telephone Compared with Mobile Application.

This study is aimed at exploring whether the mode of nutrition intervention delivery affected participant goal achievement in a three-arm randomised controlled trial of early and intensive nutrition intervention delivered to upper gastrointestinal cancer patients. Newly diagnosed upper gastrointestinal cancer patients were recruited from four tertiary hospitals in Melbourne, Australia. Participants in the intervention groups received a regular nutrition intervention for 18 weeks from an experienced dietitian via telephone or mobile application (app) using behaviour change techniques to assist in goal achievement. Univariate and multiple regression models using STATA determined goal achievement, dose, and frequency of contact between groups. A p value <0.05 was considered statistically significant. The telephone group (n = 38) had 1.99 times greater frequency of contact with the research dietitian (95% CI: 1.67 to 2.36, p < 0.001) and 2.37 times higher frequency of goal achievement (95% CI: 1.1 to 5.11, p = 0.03) compared with the mobile app group (n = 36). The higher dose (RR 0.03) of intervention and more behaviour change techniques employed in the telephone group compared with the mobile app group increased participant goal achievement (95% CI: 0.01 to 0.04, p < 0.001). Discussion. Telephone nutrition intervention delivery led to a higher frequency of goal achievement compared to the mobile app intervention. There was also a higher number of behaviour change techniques employed which may have facilitated the greater goal achievement. Mobile app-based delivery may have poorer acceptance in this population with high levels of withdrawal. Practice Implications. We need to ensure that specifically designed technologies for our target populations are fit for purpose, efficacious, and acceptable to both patients and healthcare providers. This trial is registered with ACTRN12617000152325.

COMPLETE RETINAL PIGMENT EPITHELIAL AND OUTER RETINAL ATROPHY IN AGE-RELATED MACULAR DEGENERATION: A Longitudinal Evaluation.

There is a need for robust earlier biomarkers of atrophic age-related macular degeneration that could act as surrogate endpoints for geographic atrophy (GA) in early interventional trials. This study sought to examine the risk of progression of complete retinal pigment epithelium and outer retinal atrophy (cRORA) to the traditional atrophic endpoint of GA on color fundus photography. This study also compared the risk of progression for cRORA to that associated with the specific optical coherence tomography features that define nascent GA (nGA), a strong predictor of GA development. One hundred forty participants with bilateral large drusen at baseline underwent optical coherence tomography imaging and color fundus photography at 6-month intervals for up to 36 months. Optical coherence tomography volume scans were graded for the presence of cRORA and nGA, and color fundus photographs were graded for the presence of GA. The association and rate of progression to GA for cRORA and nGA were examined. Both cRORA and nGA were significantly associated with GA development (adjusted hazard ratio, 65.7 and 76.8 respectively; both P < 0.001). The probability of progression of cRORA to GA over 24 months (26%) was significantly lower than the probability of progression of nGA (38%; P = 0.039). This study confirmed that cRORA was a significant risk factor for developing GA, although its rate of progression was slightly lower compared with nGA. While requiring replication in future studies, these findings suggest that the specific features of photoreceptor degeneration used to define nGA appear important when assessing the risk of progression.

The Specialist Treatment of Inpatients: Caring for Diabetes in Surgery (STOIC-D Surgery) Trial: A Randomized Controlled Trial of Early Intervention With an Electronic Specialist-Led Model of Diabetes Care.

To investigate the effect of early intervention with an electronic specialist-led "proactive" model of care on glycemic and clinical outcomes. The Specialist Treatment of Inpatients: Caring for Diabetes in Surgery (STOIC-D Surgery) randomized controlled trial was performed at the Royal Melbourne Hospital. Eligible participants were adults admitted to a surgical ward during the study with either known diabetes or newly detected hyperglycemia (at least one random blood glucose result ≥11.1 mmol/L). Participants were randomized 1:1 to standard diabetes care or the intervention consisting of an early consult by a specialist inpatient diabetes team using electronic tools for patient identification, communication of recommendations, and therapy intensification. The primary outcome was median patient-day mean glucose (PDMG). The key secondary outcome was incidence of health care-associated infection (HAI). Between 12 February 2021 and 17 December 2021, 1,371 admissions met inclusion criteria, with 680 assigned to early intervention and 691 to standard diabetes care. Baseline characteristics were similar between groups. The early intervention group achieved a lower median PDMG of 8.2 mmol/L (interquartile range [IQR] 6.9-10.0 mmol/L) compared with 8.6 mmol/L (IQR 7.2-10.3 mmol/L) in the control group for an estimated difference of -0.3 mmol/L (95% CI -0.4 to -0.2 mmol/L, P < 0.0001). The incidence of HAI was lower in the intervention group (77 [11%] vs. 110 [16%]), for an absolute risk difference of -4.6% (95% CI -8.2 to -1.0, P = 0.016). In surgical inpatients, early diabetes management intervention with an electronic specialist-led diabetes model of care reduces glucose and HAI.

N-Acetylcysteine and a Specialized Preventive Intervention for Individuals at High Risk for Psychosis: A Randomized Double-Blind Multicenter Trial.

Clinical high risk for psychosis (CHR-P) offers a window of opportunity for early intervention and recent trials have shown promising results for the use of N-acetylcysteine (NAC) in schizophrenia. Moreover, integrated preventive psychological intervention (IPPI), applies social-cognitive remediation to aid in preventing the transition to the psychosis of CHR-P patients. In this double-blind, randomized, controlled multicenter trial, a 2 × 2 factorial design was applied to investigate the effects of NAC compared to placebo (PLC) and IPPI compared to psychological stress management (PSM). The primary endpoint was the transition to psychosis or deterioration of CHR-P symptoms after 18 months. While insufficient recruitment led to early trial termination, a total of 48 participants were included in the study. Patients receiving NAC showed numerically higher estimates of event-free survival probability (IPPI + NAC: 72.7 ± 13.4%, PSM + NAC: 72.7 ± 13.4%) as compared to patients receiving PLC (IPPI + PLC: 56.1 ± 15.3%, PSM + PLC: 39.0 ± 17.4%). However, a log-rank chi-square test in Kaplan-Meier analysis revealed no significant difference of survival probability for NAC vs control (point hazard ratio: 0.879, 95% CI 0.281-2.756) or IPPI vs control (point hazard ratio: 0.827, 95% CI 0.295-2.314). The number of adverse events (AE) did not differ significantly between the four groups. The superiority of NAC or IPPI in preventing psychosis in patients with CHR-P compared to controls could not be statistically validated in this trial. However, results indicate a consistent pattern that warrants further testing of NAC as a promising and well-tolerated intervention for CHR patients in future trials with adequate statistical power.

Protocol for a randomised controlled feasibility trial of parent-delivered early language intervention for children with Down syndrome (PACT-DS)

BackgroundDown syndrome is the most common genetic cause of intellectual disability, affecting 700–800 babies annually in the UK (Wu J, Morris J, Eur J Hum Genet 21:1016–9, 2013). Children with Down syndrome have difficulties developing language skills. These difficulties can have long-term negative consequences for all aspects of their lives including social development, education and employment opportunities, and emotional wellbeing and mental health (Irwin LG et. al 2007). These aspects all have the potential to be improved through targeted early language intervention. Parents and Children Together (PACT) is a parent-delivered early language teaching programme for typically developing pre-school children at risk of language delays. A previous project (Burgoyne K, J Child Psychol Psychiatry 59(5):545–55, 2018) showed that PACT leads to improvements in children’s language and early literacy skills. Our team has worked closely with six families to adapt PACT for children with Down syndrome. The aim of the current study is to conduct a feasibility randomised controlled trial (RCT) to evaluate the feasibility of a definitive RCT and explore initial evidence of the adapted programme’s potential to support children’s language and literacy development.MethodThis is a two-arm feasibility randomised controlled trial in which children will be randomly allocated to either a PACT-DS group or to a waiting control group (who will receive intervention at the end of the project). We aim to recruit 28–30 children with Down syndrome (aged 3–6 years) and their parents/caregivers to take part. The PACT-DS group will be trained to deliver PACT-DS every day (20 min a day; 5 days a week) to their child over 30 weeks. We will collect data using assessments of child language and early literacy, measures of parent wellbeing, qualitative surveys and interviews, and monitoring data to explore trial feasibility (including recruitment and retention of families and adherence and acceptability of intervention) and cost and benefits. Data will be collected before intervention, immediately after the 30-week intervention programme, and 6 months after intervention ends. Clear progression criteria will be used to assess suitability for a definitive trial.DiscussionThis study represents initial steps in developing a definitive trial of the PACT-DS programme and will add to the limited evidence base on early language intervention for children with Down syndrome. This programme of research has the potential to make significant advancements in early language intervention research and practice for this group.Trial registrationThe trial is registered with the ISRCTN registry: study ID ISRCTN63251282. Registered on 14 July 2023.

Molecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years

We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC.

Association Between Symptom Burden and Early Lymphatic Abnormalities After Regional Nodal Irradiation for Breast Cancer

Background: Dermal backflow visualized on near-infrared fluorescence lymphatic imaging (NIRFLI) signals preclinical lymphedema that precedes the development of volumetrically-defined lymphedema. We sought to evaluate whether dermal backflow correlates with patient-reported lymphedema outcomes (PRLO) surveys in breast cancer patients treated with regional nodal irradiation (RNI). Methods and Materials: Breast cancer patients planned for axillary dissection and RNI prospectively underwent perometry, NIRFLI, and PRLOs (the Lymphedema Symptom Intensity and Distress Survey (LSIDS) and QuickDash) at baseline, after surgery, and at 6, 12, and 18 months following radiation. Clinical lymphedema was defined as an arm volume increase ≥ 5% over baseline. Trends over time were assessed using ANOVA testing. The association between survey responses and both dermal backflow and lymphedema was assessed using a linear mixed-effects model. Results: Sixty participants completed at least two sets of measurements and surveys and were eligible for analysis. Fifty-four percent of patients had cT3-T4 disease, 53% cN3 disease, and 75% had a BMI >25. Dermal backflow and clinical lymphedema increased from 10% to 85% and from 0% to 40%, respectively, from baseline to 18mo. In the adjusted model, soft tissue sensation, neurologic sensation, and functional LSIDS subscale scores were associated with presence of dermal backflow (all p<0.05). Both dermal backflow and lymphedema were associated with Quickdash score (p<0.05). Conclusion: In this high-risk cohort, we found highly prevalent early signs of lymphedema, with increased symptom burden from baseline. Presence of dermal backflow correlated with PRLO measures, highlighting a potential NIRFLI use to identify patients for early intervention trials following RNI.

Protocol for a randomized controlled trial to evaluate a year-long (NICU-to-home) evidence-based, high dose physical therapy intervention in infants at risk of neuromotor delay.

Developmental disabilities and neuromotor delay adversely affect long-term neuromuscular function and quality of life. Current evidence suggests that early therapeutic intervention reduces the severity of motor delay by harnessing neuroplastic potential during infancy. To date, most early therapeutic intervention trials are of limited duration and do not begin soon after birth and thus do not take full advantage of early neuroplasticity. The Corbett Ryan-Northwestern-Shirley Ryan AbilityLab-Lurie Children's Infant Early Detection, Intervention and Prevention Project (Project Corbett Ryan) is a multi-site longitudinal randomized controlled trial to evaluate the efficacy of an evidence-based physical therapy intervention initiated in the neonatal intensive care unit (NICU) and continuing to 12 months of age (corrected when applicable). The study integrates five key principles: active learning, environmental enrichment, caregiver engagement, a strengths-based approach, and high dosage (ClinicalTrials.gov identifier NCT05568264). We will recruit 192 infants at risk for neuromotor delay who were admitted to the NICU. Infants will be randomized to either a standard-of-care group or an intervention group; infants in both groups will have access to standard-of-care services. The intervention is initiated in the NICU and continues in the infant's home until 12 months of age. Participants will receive twice-weekly physical therapy sessions and caregiver-guided daily activities, assigned by the therapist, targeting collaboratively identified goals. We will use various standardized clinical assessments (General Movement Assessment; Bayley Scales of Infant and Toddler Development, 4th Edition (Bayley-4); Test of Infant Motor Performance; Pediatric Quality of Life Inventory Family Impact Module; Alberta Infant Motor Scale; Neurological, Sensory, Motor, Developmental Assessment; Hammersmith Infant Neurological Examination) as well as novel technology-based tools (wearable sensors, video-based pose estimation) to evaluate neuromotor status and development throughout the course of the study. The primary outcome is the Bayley-4 motor score at 12 months; we will compare scores in infants receiving the intervention vs. standard-of-care therapy.

Charting infants’ motor development at home using a wearable system: validation and comparison to physical growth charts

Early neurodevelopmental care and research are in urgent need of practical methods for quantitative assessment of early motor development. Here, performance of a wearable system in early motor assessment was validated and compared to developmental tracking of physical growth charts. Altogether 1358h of spontaneous movement during 226 recording sessions in 116 infants (age 4-19 months) were analysed using a multisensor wearable system. A deep learning-based automatic pipeline quantified categories of infants' postures and movements at a time scale of seconds. Results from an archived cohort (dataset 1, N=55 infants) recorded under partial supervision were compared to a validation cohort (dataset 2, N=61) recorded at infants' homes by the parents. Aggregated recording-level measures including developmental age prediction (DAP) were used for comparison between cohorts. The motor growth was also compared with respective DAP estimates based on physical growth data (length, weight, and head circumference) obtained from a large cohort (N=17,838 infants; age 4-18 months). Age-specific distributions of posture and movement categories were highly similar between infant cohorts. The DAP scores correlated tightly with age, explaining 97-99% (94-99% CI 95) of the variance at the group average level, and 80-82% (72-88%) of the variance in the individual recordings. Both the average motor and the physical growth measures showed a very strong fit to their respective developmental models (R2=0.99). However, single measurements showed more modality-dependent variation that was lowest for motor (σ=1.4 [1.3-1.5 CI 95] months), length (σ=1.5 months), and combined physical (σ=1.5 months) measurements, and it was clearly higher for the weight (σ=1.9 months) and head circumference (σ=1.9 months) measurements. Longitudinal tracking showed clear individual trajectories, and its accuracy was comparable between motor and physical measures with longer measurement intervals. A quantified, transparent and explainable assessment of infants' motor performance is possible with a fully automated analysis pipeline, and the results replicate across independent cohorts from out-of-hospital recordings. A holistic assessment of motor development provides an accuracy that is comparable with the conventional physical growth measures. A quantitative measure of infants' motor development may directly support individual diagnostics and care, as well as facilitate clinical research as an outcome measure in early intervention trials. This work was supported by the Finnish Academy (314602, 335788, 335872, 332017, 343498), Finnish Pediatric Foundation (Lastentautiensäätiö), Aivosäätiö, Sigrid Jusélius Foundation, and HUS Children's Hospital/HUS diagnostic center research funds.

APOE Peripheral and Brain Impact: APOE4 Carriers Accelerate Their Alzheimer Continuum and Have a High Risk of Suicide in PM2.5 Polluted Cities

This Review emphasizes the impact of APOE4—the most significant genetic risk factor for Alzheimer’s disease (AD)—on peripheral and neural effects starting in childhood. We discuss major mechanistic players associated with the APOE alleles’ effects in humans to understand their impact from conception through all life stages and the importance of detrimental, synergistic environmental exposures. APOE4 influences AD pathogenesis, and exposure to fine particulate matter (PM2.5), manufactured nanoparticles (NPs), and ultrafine particles (UFPs) associated with combustion and friction processes appear to be major contributors to cerebrovascular dysfunction, neuroinflammation, and oxidative stress. In the context of outdoor and indoor PM pollution burden—as well as Fe, Ti, and Al alloys; Hg, Cu, Ca, Sn, and Si UFPs/NPs—in placenta and fetal brain tissues, urban APOE3 and APOE4 carriers are developing AD biological disease hallmarks (hyperphosphorylated-tau (P-tau) and amyloid beta 42 plaques (Aβ42)). Strikingly, for Metropolitan Mexico City (MMC) young residents ≤ 40 y, APOE4 carriers have 4.92 times higher suicide odds and 23.6 times higher odds of reaching Braak NFT V stage versus APOE4 non-carriers. The National Institute on Aging and Alzheimer’s Association (NIA-AA) framework could serve to test the hypothesis that UFPs and NPs are key players for oxidative stress, neuroinflammation, protein aggregation and misfolding, faulty complex protein quality control, and early damage to cell membranes and organelles of neural and vascular cells. Noninvasive biomarkers indicative of the P-tau and Aβ42 abnormal protein deposits are needed across the disease continuum starting in childhood. Among the 21.8 million MMC residents, we have potentially 4 million APOE4 carriers at accelerated AD progression. These APOE4 individuals are prime candidates for early neuroprotective interventional trials. APOE4 is key in the development of AD evolving from childhood in highly polluted urban centers dominated by anthropogenic and industrial sources of pollution. APOE4 subjects are at higher early risk of AD development, and neuroprotection ought to be implemented. Effective reductions of PM2.5, UFP, and NP emissions from all sources are urgently needed. Alzheimer’s Disease prevention ought to be at the core of the public health response and physicians-scientist minority research be supported.

Omega-3 Fatty Acids in Arterial Hypertension: Is There Any Good News?

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including alpha-linolenic acid (ALA) and its derivatives eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are "essential" fatty acids mainly obtained from diet sources comprising plant oils, marine blue fish, and commercially available fish oil supplements. Many epidemiological and retrospective studies suggested that ω-3 PUFA consumption decreases the risk of cardiovascular disease, but results of early intervention trials have not consistently confirmed this effect. In recent years, some large-scale randomized controlled trials have shed new light on the potential role of ω-3 PUFAs, particularly high-dose EPA-only formulations, in cardiovascular prevention, making them an attractive tool for the treatment of "residual" cardiovascular risk. ω-3 PUFAs' beneficial effects on cardiovascular outcomes go far beyond the reduction in triglyceride levels and are thought to be mediated by their broadly documented "pleiotropic" actions, most of which are directed to vascular protection. A considerable number of clinical studies and meta-analyses suggest the beneficial effects of ω-3 PUFAs in the regulation of blood pressure in hypertensive and normotensive subjects. These effects occur mostly through regulation of the vascular tone that could be mediated by both endothelium-dependent and independent mechanisms. In this narrative review, we summarize the results of both experimental and clinical studies that evaluated the effect of ω-3 PUFAs on blood pressure, highlighting the mechanisms of their action on the vascular system and their possible impact on hypertension, hypertension-related vascular damage, and, ultimately, cardiovascular outcomes.