Unveiling the Therapeutic Potential of Folate-Dependent One-Carbon Metabolism in Cancer and Neurodegeneration.

Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate's impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate's impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments.

Evaluation of Antitumor Activity of Xanthones Conjugated with Amino Acids.

Cancer is a complex disease characterized by several alterations, which confer, to the cells, the capacity to proliferate uncontrollably and to resist cellular death. Multiresistance to conventional chemotherapy drugs is often the cause of treatment failure; thus, the search for natural products or their derivatives with therapeutic action is essential. Chiral derivatives of xanthones (CDXs) have shown potential inhibitory activity against the growth of some human tumor cell lines. This work reports the screening of a library of CDXs, through viability assays, in different cancer cell lines: A375-C5, MCF-7, NCI-H460, and HCT-15. CDXs' effect was analyzed based on several parameters of cancer cells, and it was also verified if these compounds were substrates of glycoprotein-P (Pgp), one of the main mechanisms of resistance in cancer therapy. Pgp expression was evaluated in all cell lines, but no expression was observed, except for HCT-15. Also, when a humanized yeast expressing the human gene MDR1 was used, no conclusions could be drawn about CDXs as Pgp substrates. The selected CDXs did not induce significant differences in the metabolic parameters analyzed. These results show that some CDXs present promising antitumor activity, but other mechanisms should be triggered by these compounds.

Effectiveness and Users' Perceptions of Upper Extremity Exoskeletons and Robot-Assisted Devices in Children with Physical Disabilities: Systematic Review.

AIM: Systematically determine the effectiveness and users' perceptions of upper extremity (UE) exoskeletons and robot-assisted devices for pediatric rehabilitation. METHODS: PubMed/Medline, Web of Science, Scopus, and Cochrane Library were searched for studies with "exoskeletons"/"robot-assisted devices", children with disabilities, effectiveness data, and English publication. Intervention effectiveness outcomes were classified within components of the International Classification of Functioning, Disability, and Health, Children and Youth Version (ICF-CY). Secondary data (users' perceptions; implementation setting) were extracted. Risk of bias and methodological quality were assessed. Descriptive analyses were performed. RESULTS: Seventy-two articles were included. Most evaluated body structure and function and activity outcomes with less emphasis on participation. Most effects across all ICF-CY levels were positive. Devices were primarily evaluated in clinical or laboratory rather than natural environments. Perceptions about device effectiveness were mostly positive, while those about expression, accessibility, and esthetics were mostly negative. A need for increased rigor in research study design was detected. CONCLUSIONS: Across populations, devices, settings, interventions, and dosing schedules, UE exoskeletons and robot-assisted devices may improve function, activity, and perhaps participation for children with physical disabilities. Future work should transition devices into natural environments, design devices and implementation strategies to address users' negative perceptions, and increase research rigor.

Depth and Quality of Recommendations in Popular Sources About How to Play with Infants: Content Analysis.

AIM: Systematically evaluate the depth and quality of play recommendations provided in popular sources for parents of infants in the first year of life. METHODS: This represents the second stage of a larger analysis of educational content available to parents. Two coders (>90% agreement) extracted and coded play activities from popular websites, applications, and books screened from a systematic online search. Depth of instruction variables were extracted. Activity quality was rated based on opportunities for child-initiated movement, problem-solving with objects, and responsive communication. RESULTS: 4370 play activities from 214 sources were analyzed. Activities were likely to suggest specific ages for infants and that a caregiver be present. Less than half of the activities incorporated toys or provided guidance about how to position or physically support infants. Activity quality was low; most activities did not explicitly encourage parents to provide opportunities for child-initiated movement, problem-solving with objects, or quality communication. CONCLUSIONS: Parents may encounter a large number of play activities in popular sources, but the depth of instruction and quality of those activities could be improved. Provision of higher-quality education to parents may enhance parent-child play interactions to positively impact parent and child outcomes, especially for children at risk for delays.

Trends in the morbidity and mortality of coronavirus disease 2019 in different ethnic groups and gender in a large Brazilian city.

As the coronavirus disease 2019 (COVID-19) outbreak spread, evidence has emerged that gender and race would bear a disproportionate impact on the morbimortality of COVID-19. Here, we conducted a retrospective observational study using the TabNet/Departamento de informática do sistema único de saúde platform of the city of São Paulo. COVID-19 records from March 2020 through December 2021 were included, and we evaluated the temporal trends of confirmed cases and case fatality rate by gender and ethnicity. Statistical analysis was performed using the R-software and BioEstat-software, considering p < 0.05 significant. From March/2020 to December/2021, 1 315 160 COVID-19 confirmed cases were recorded (57.1% females), and 2973 deaths were due to COVID-19. Males presented higher median mortality (0.44% vs. 0.23%; p < 0.05) and intensive care unit (ICU) admission rates (0.34% vs. 0.20%; p < 0.05). Men were also associated with a higher risk of death (risk ratio [RR] = 1.28; p < 0.05) and a higher chance of requiring ICU care (RR = 1.29; p < 0.05). Black ethnicity was associated with a higher risk of death (RR = 1.19; p < 0.05). White patients were more likely to require ICU admission (RR = 1.13; p < 0.05), whereas Browns were associated with a protective effect (RR = 0.86; p < 0.05). Furthermore, men presented a higher chance of death than women across the three major ethnic groups: Whites (RR = 1.33; p < 0.05), Blacks (RR = 1.24; p < 0.05), and Browns (RR = 1.35; p < 0.05). In this study of COVID-19 in São Paulo, men were associated with worse outcomes, including in the three major ethnicities in the population. Blacks exhibited a higher risk of death, Whites were more likely to require intensive care, and Browns were at protection from ICU hospitalization.

The Effect of START-Play Intervention on Reaching-Related Exploratory Behaviors in Children with Neuromotor Delays: A Secondary Analysis of a Randomized Controlled Trial.

AIMS: Children with neuromotor delays are at risk for reaching and object exploration impairments, which may negatively affect their cognitive development and daily activity performance. This study evaluated the effectiveness of the Sitting Together And Reaching To Play (START-Play) intervention on reaching-related exploratory behaviors in children with neuromotor delays. METHODS: In this randomized controlled clinical trial, 112 children (Mean = 10.80, SD = 2.59 months old at baseline) with motor delays were randomly assigned to receive START-Play intervention or usual care-early intervention. Performance for ten reaching-related exploratory behaviors was assessed at baseline and 1.5, 3, 6, 12 months post-baseline. Piecewise linear mixed-effects modeling was used to evaluate short- and long-term effects of the intervention. RESULTS: Benefits of START-Play were observed for children with significant motor delays, but not for those with mild delays. START-Play was especially beneficial for children with significant motor delays who demonstrated early mastery in the reaching assessment (i.e., object contact ≥65% of the time within 3 months after baseline); these children showed greater improvements in manual, visual, and multimodal exploration, as well as intensity of exploration across time. CONCLUSIONS: START-Play advanced the performance of reaching-related exploratory behaviors in children with significant motor delays.

Development and Initial Evaluation of a Soft Ankle Support for Children With Ankle Impairments.

PURPOSE: Develop and initially evaluate a soft ankle support (SAS) garment for children with ankle impairments. DESCRIPTION OF CASES: Two participants were evaluated at baseline and interviews with their parent(s) to identify wants and needs for the SAS. The SAS was developed and evaluated via participant report and functional measures in barefoot, ankle-foot orthosis (AFO), and SAS conditions. OUTCOMES: Children and parents expressed dissatisfaction with AFOs' dimensions, weight, adjustability, comfort, and ease of use. Gait and gross motor function were similar for SAS and AFOs' conditions; however, participants rated the SAS better for weight and bulk, integration with shoes, adjustability, comfort, cost, and washability. DISCUSSION: The SAS and AFOs performed similarly in this initial testing, yet the SAS also met participants' needs across key metrics not well addressed by AFOs. Ankle support devices that meet users' broad needs may support improved adherence and user satisfaction.

START-Play Physical Therapy Intervention Indirectly Impacts Cognition Through Changes in Early Motor-Based Problem-Solving Skills.

PURPOSE: This study tested whether the Sitting Together and Reaching to Play (START-Play) physical therapy intervention indirectly impacts cognition through changes in perceptual-motor skills in infants with motor delays. METHODS: Participants were 50 infants with motor delays randomly assigned to START-Play plus Usual Care Early Intervention (UC-EI) or UC-EI only. Infants' perceptual-motor and cognitive skills were assessed at baseline and 1.5, 3, 6, and 12 months post-baseline. RESULTS: Short-term changes in sitting, fine motor skills, and motor-based problem-solving, but not reaching, predicted long-term changes in cognition. START-Play indirectly impacted cognition through motor-based problem-solving but not sitting, reaching, or fine motor skills. CONCLUSIONS: This study provided preliminary evidence that early physical therapy interventions that blend activities across developmental domains and are supported by an enriched social context can place infants on more optimal developmental trajectories.

The Effect of Early-Life Seizures on Cognitive and Motor Development: A Case Series.

PURPOSE: This case series documents developmental changes over time and in response to a novel intervention, Sitting Together and Reaching to Play (START-Play), in children with early-life seizures. METHODS: Thirteen children with early-life seizures were included from a subset of participants in the START-Play multisite, randomized controlled trial. Seven received 3 months of twice weekly START-Play intervention; 6 continued with usual care early intervention. Bayley Scales of Infant Development-III (Cognitive Composite), Gross Motor Function Measure-66 Item Set, Assessment of Problem-Solving in Play, and reaching assessments were administered at baseline, 3, 6, and 12 months postbaseline. Change scores are reported at 3 and 12 months postbaseline. RESULTS: Over time, plateau or decline was noted in standardized cognition measures; motor development improved or was stable. Children receiving START-Play showed positive trends in problem-solving (71.4%) and reaching behaviors (57.2%). CONCLUSIONS: Interventions such as START-Play that combine motor and cognitive constructs may benefit children with early-life seizures.

Assistive and Rehabilitative Effects of the Playskin LiftTM Exoskeletal Garment on Reaching and Object Exploration in Children With Arthrogryposis.

IMPORTANCE: Children with arthrogryposis multiplex congenita are often delayed in their development of reaching and object exploration, which can place them at risk for associated delays in motor and cognitive development. OBJECTIVE: To evaluate the longitudinal assistive and rehabilitative effects of the Playskin Lift™ (hereinafter Playskin), a novel exoskeletal garment, on reaching and object exploration abilities in children with arthrogryposis. DESIGN: Single-case ABA design with a 1-mo baseline, 4-mo intervention, and 1-mo postintervention. SETTING: Home environment. PARTICIPANTS: Seventeen children with arthrogryposis (ages 6-35 mo at first visit; 5 boys). INTERVENTION: Participants used the Playskin daily for 30 to 45 min while participating in structured intervention activities to encourage reaching for objects across play spaces larger than they were typically able to. OUTCOMES AND MEASURES: Participants were tested biweekly throughout the study with and without the Playskin using a systematic reaching assessment. Coding of reaching and object exploration behavior was performed using OpenSHAPA software; statistical analyses were conducted using Hierarchical Linear and Nonlinear Modeling software. Feasibility of the Playskin for daily home intervention was evaluated with a parent perception questionnaire. RESULTS: Positive assistive effects (improved performance when wearing the Playskin within sessions) and rehabilitative effects (improved independent performance after the Playskin intervention) were observed with increased active range of motion, expanded reaching space, improved grasping with the ventral side of the open hand, and greater complexity and multimodality and intensity of object exploration. CONCLUSIONS AND RELEVANCE: The Playskin may be a feasible, effective assistive and rehabilitative device to advance object interaction and learning in young children with arthrogryposis. WHAT THIS ARTICLE ADDS: The novel exoskeletal Playskin garment improves reaching and object exploration in young children with arthrogryposis.

A Novel Means-End Problem-Solving Assessment Tool for Early Intervention: Evaluation of Validity, Reliability, and Sensitivity.

PURPOSE: To evaluate validity, reliability, and sensitivity of the novel Means-End Problem-Solving Assessment Tool (MEPSAT). METHODS: Children with typical development and those with motor delay were assessed throughout the first 2 years of life using the MEPSAT. MEPSAT scores were validated against the cognitive and motor subscales of the Bayley Scales of Development. Intra- and interrater reliability, developmental trends, and differences among groups were evaluated. RESULTS: Changes in MEPSAT scores positively related to changes in Bayley scores across time for both groups of children. Strong intra- and interrater reliability was observed for MEPSAT scoring across all children. The MEPSAT was sensitive to identify change across time and differences in problem-solving among children with varying levels of motor delay. CONCLUSIONS: The MEPSAT is supported by validity and reliability evidence and is a simple tool for screening early problem-solving delays and evaluating change across time in children with a range of developmental abilities. What this adds to the evidence: The novel MEPSAT is supported by validity and reliability evidence. It is sensitive to detect problem-solving differences among young children with varying motor ability and to capture changes in problem-solving across time. It requires minimal equipment and time to administer and score and, thus, is a promising tool for clinicians to screen for early problem-solving delays or to track intervention progress in young children with or at risk for problem-solving delays.

Assessing the Validity and Reliability of a New Video Goniometer App for Measuring Joint Angles in Adults and Children.

OBJECTIVE: To assess the convergent validity and reliability of joint angle measurements from a new video goniometer iPhone/iPad application separately in adults, older and young children. DESIGN: Cross-sectional. SETTING: Child care and university environments. PARTICIPANTS: Fifty-four adults (mean ± SD=22.5±4.5y), 20 older children (mean ± SD=10.9±2.2y), 20 younger children (mean ± SD=1.6±0.8y) (N=94). INTERVENTIONS: Adults and older children performed both standardized static positions and functional activities. Younger children performed only a functional activity protocol. MAIN OUTCOME MEASURES: Joint angle measurements using the app were validated against a commercially validated two-dimensional goniometric software program. In addition, validity of the app was compared to a standard mechanical goniometer for the measurement of angles drawn on a white board. Intra- and interrater reliability were assessed through independent rescoring of videos. RESULTS: Correlations between joint angle estimates obtained from the app and goniometer software or a mechanical goniometer were positive and very strong (r>.900; P<.0001). The intraclass correlation coefficient (ICC) for repeated scoring from the app indicated excellent intra- and interrater reliability (ICC>.900). CONCLUSIONS: High correlations for repeated measures and comparison to gold standard angle measurement instruments suggest that the new app is a valid and reliable tool for assessing joint angles during functional activity. This tool may provide clinicians an inexpensive yet accurate method for quantification of movements and immediate feedback on range of motion during tasks in a natural environment.

Play with objects in children with arthrogryposis: Effects of intervention with the Playskin Lift™ exoskeletal garment.

Children with arthrogryposis multiplex congenita (AMC) often exhibit arm movement impairments that can negatively impact activities of daily living, such as reaching, object exploration, object play, and self-care. This study evaluated the effects of intervention involving the Playskin Lift™ (Playskin) exoskeletal garment on arm function during object play for children with AMC. Seventeen children with AMC (5 males; 6-35 months at the beginning of the study) were tested in their homes biweekly with and without the Playskin throughout a 1-month Baseline, 4-month Intervention, and 1-month Post-Intervention. Within sessions (assistive effects), children contacted and manipulated objects more while wearing the Playskin; they also showed greater intensity, complexity, and variability of behaviors performed during free play, as well as increased play space and reduced number of compensatory arm and trunk flings to facilitate reaching. Across time (rehabilitative effects), children significantly improved their visual-manual coupling as well as their ability to lift objects from a surface and to manipulate objects using one hand; in addition, children exhibited greater multimodality, variability, and intensity of their play behaviors. Current results suggest the Playskin Lift™ may serve as an effective assistive and rehabilitative device to improve play for children with arm movement impairments.

Development of self-feeding behavior in children with typical development and those with arm movement impairments.

Self-feeding is a critical self-care skill that unites motor abilities (e.g., grasping and transporting utensils/food to the mouth) and cognitive abilities (e.g., using a spoon as a tool). This cross-sectional study assessed self-feeding behavior in a sample of 38 children with typical development (TD) and compared it between 18 of those children and 18 age- and sex-matched peers with arm movement impairments (MI). Children were assessed with a bowl of cereal and two spoons presented in four different orientations. Results suggested that children with MI were less successful than their TD peers in both motor aspects (e.g., grasp and transport of food and utensils) and cognitive aspects (correct grasp across spoon orientations) of self-feeding. Novel findings highlight: (a) interesting differences in visual attention between children with TD or MI; (b) the role of hand-preference in the correct grasping of the spoon(s) and effective self-feeding; (c) the positive relation between motor and cognitive aspects of self-feeding; and (d) that greater variability of self-feeding behavior relates to improved performance of cognitive aspects of the task. These results identify challenging components of self-feeding for children with MI that should be targeted by early interventions and assistive technologies aimed at increasing self-feeding independence.

Means-end problem solving in infancy: Development, emergence of intentionality, and transfer of knowledge.

Behaviors and performance of 23 typically developing infants were assessed longitudinally at 6, 9, 12, 18, and 24 months in two means-end tasks: pulling a towel or rotating a turntable to obtain a supported object. With age, infants performed more goal-directed behaviors, leading to increased problem-solving success. Intentionality emerged earlier in the towel task than in the turntable task (6.9 vs. 10.8 months). Potential knowledge transfer between the tasks was first observed at 9 months. This study provides insight into the development of means-end learning, the emergence of intentionality, and potential transfer of knowledge in tasks involving a similar concept (support) but requiring different modes of action for success (pulling vs. rotating).

Single-Case Design, Analysis, and Quality Assessment for Intervention Research.

BACKGROUND AND PURPOSE: The purpose of this article is to describe single-case studies and contrast them with case studies and randomized clinical trials. We highlight current research designs, analysis techniques, and quality appraisal tools relevant for single-case rehabilitation research. SUMMARY OF KEY POINTS: Single-case studies can provide a viable alternative to large group studies such as randomized clinical trials. Single-case studies involve repeated measures and manipulation of an independent variable. They can be designed to have strong internal validity for assessing causal relationships between interventions and outcomes, as well as external validity for generalizability of results, particularly when the study designs incorporate replication, randomization, and multiple participants. Single-case studies should not be confused with case studies/series (ie, case reports), which are reports of clinical management of a patient or a small series of patients. RECOMMENDATIONS FOR CLINICAL PRACTICE: When rigorously designed, single-case studies can be particularly useful experimental designs in a variety of situations, such as when research resources are limited, studied conditions have low incidences, or when examining effects of novel or expensive interventions. Readers will be directed to examples from the published literature in which these techniques have been discussed, evaluated for quality, and implemented.

Feasibility and Effectiveness of a Novel Exoskeleton for an Infant With Arm Movement Impairments.

PURPOSE: To determine whether a novel exoskeletal device (Pediatric-Wilmington Robotic Exoskeleton [P-WREX]) is feasible and effective for intervention to improve reaching and object interaction for an infant with arm movement impairments. METHODS: An 8-month old infant with arthrogryposis was followed up every 2 weeks during a 1-month baseline, 3-month intervention, and 1-month postintervention. At each visit, reaching and looking behaviors were assessed. RESULTS: Within sessions, the infant spent more time contacting objects across a larger space, contacting objects with both hands, and looking at objects when wearing the P-WREX. Throughout intervention, the infant increased time contacting objects both with and without the device and increased bilateral active shoulder flexion. CONCLUSIONS: (1) It may be feasible for families to use exoskeletons for daily intervention, (2) exoskeletons facilitate immediate improvements in function for infants with impaired upper extremity mobility, and (3) interventions using exoskeletons can improve independent upper extremity function across time.

Feasibility of At-Home Hand Arm Bimanual Intensive Training in Virtual Reality: Case Study.

This single-participant case study examines the feasibility of using custom virtual reality (VR) gaming software in the home environment for low-dose Hand Arm Bimanual Intensive Training (HABIT). A 10-year-old with right unilateral cerebral palsy participated in this trial. Fine and gross motor skills as well as personal goals for motor outcomes were assessed before and after the intervention using the Box and Blocks Test, Nine-Hole Peg Test, and Canadian Occupational Performance Measure. Movement intensities collected via the VR hardware accelerometers, VR game scores, and task accuracy were recorded via the HABIT-VR software as indices of motor performance. The child and family were instructed to use the HABIT-VR games twice daily for 30 minutes over a 14-day period and asked to record when they used the system. The child used the system and completed the 14-hour, low-dose HABIT-VR intervention across 22 days. There was no change in Box and Blocks Test and Nine-Hole Peg Test scores before and after the intervention. Canadian Occupational Performance Measure scores increased but did not reach the clinically relevant threshold, due to high scores at baseline. Changes in motor task intensities during the use of VR and mastery of the VR bimanual tasks suggested improved motor efficiency. This case study provides preliminary evidence that HABIT-VR is useful for promoting adherence to HABIT activities and for the maintenance of upper extremity motor skills in the home setting.

The impact of severity of motor delay, timing of task mastery, and START-play intervention on the development of means-end problem solving in young children.

BACKGROUND: Children with motor delays are at increased risk for delayed means-end problem-solving (MEPS) performance. OBJECTIVES: To evaluate children with motor delays: 1) the impact of motor delay severity and MEPS mastery timing on developmental trajectories of MEPS; and 2) the effectiveness of Sitting Together And Reaching To Play (START-Play) intervention for improving MEPS. METHODS: This represents a secondary analysis from a multi-site randomized controlled trial, with blinded assessors and prospective registration. Children with mild or significant motor delays (n = 112, mean age=10.80, SD=2.59 months at baseline) were randomly assigned to START-Play or usual care early intervention (UC-EI) and assessed at five visits across one year using the Means-End Problem-Solving Assessment Tool that included three 30-second MEPS trials per visit. Task mastery occurred at the first visit the child achieved the highest level of performance in at least two of the three trials. Multilevel analyses evaluated trajectories of MEPS outcomes dependent upon the timing of MEPS mastery, motor delay severity, and intervention group. RESULTS: At baseline, children with mild motor delays demonstrated better MEPS than children with significant delays, but this difference was only observed for children who achieved mastery late. Children with significant delays demonstrated greater improvements in MEPS in the post-intervention phase compared to children with mild delays. No MEPS differences were found between START-Play and UC-EI. CONCLUSION: Motor delay severity and timing of task mastery impacted MEPS trajectories, whereas START-Play intervention did not impact MEPS for children with motor delays. CLINICAL TRIALS REGISTRY IDENTIFIER: NCT02593825 (https://clinicaltrials.gov/ct2/show/NCT02593825).