Conducting clinical trials in persons with Down syndrome : summary from the NIH INCLUDE Down syndrome clinical trials readiness working group

The recent National Institute of Health (NIH) INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) initiative has bolstered capacity for the current increase in clinical trials involving individuals with Down syndrome (DS). This new NIH funding mechanism offers new opportunities to expand and develop novel approaches in engaging and effectively enrolling a broader representation of clinical trials participants addressing current medical issues faced by individuals with DS. To address this opportunity, the NIH assembled leading clinicians, scientists, and representatives of advocacy groups to review existing methods and to identify those areas where new approaches are needed to engage and prepare DS populations for participation in clinical trial research. This paper summarizes the results of the Clinical Trial Readiness Working Group that was part of the INCLUDE Project Workshop: Planning a Virtual Down Syndrome Cohort Across the Lifespan Workshop held virtually September 23 and 24, 2019

COVID-19 Vaccination of Individuals with Down Syndrome—Data from the Trisomy 21 Research Society Survey on Safety, Efficacy, and Factors Associated with the Decision to Be Vaccinated

Individuals with Down syndrome (DS) are among the groups with the highest risk for severe COVID-19. Better understanding of the efficacy and risks of COVID-19 vaccines for individuals with DS may help improve uptake of vaccination. The T21RS COVID-19 Initiative launched an international survey to obtain information on safety and efficacy of COVID-19 vaccines for individuals with DS. De-identified survey data collected between March and December 2021 were analyzed. Of 2172 individuals with DS, 1973 (91%) had received at least one vaccine dose (57% BNT162b2), 107 (5%) were unvaccinated by choice, and 92 (4%) were unvaccinated for other reasons. Most participants had either no side effects (54%) or mild ones such as pain at the injection site (29%), fatigue (12%), and fever (7%). Severe side effects occurred in <0.5% of participants. About 1% of the vaccinated individuals with DS contracted COVID-19 after vaccination, and all recovered. Individuals with DS who were unvaccinated by choice were more likely to be younger, previously recovered from COVID-19, and also unvaccinated against other recommended vaccines. COVID-19 vaccines have been shown to be safe for individuals with DS and effective in terms of resulting in minimal breakthrough infections and milder disease outcomes among fully vaccinated individuals with DS

COVID-19 Vaccination of Individuals with Down Syndrome—Data from the Trisomy 21 Research Society Survey on Safety, Efficacy, and Factors Associated with the Decision to Be Vaccinated

Individuals with Down syndrome (DS) are among the groups with the highest risk for severe COVID-19. Better understanding of the efficacy and risks of COVID-19 vaccines for individuals with DS may help improve uptake of vaccination. The T21RS COVID-19 Initiative launched an international survey to obtain information on safety and efficacy of COVID-19 vaccines for individuals with DS. De-identified survey data collected between March and December 2021 were analyzed. Of 2172 individuals with DS, 1973 (91%) had received at least one vaccine dose (57% BNT162b2), 107 (5%) were unvaccinated by choice, and 92 (4%) were unvaccinated for other reasons. Most participants had either no side effects (54%) or mild ones such as pain at the injection site (29%), fatigue (12%), and fever (7%). Severe side effects occurred in <0.5% of participants. About 1% of the vaccinated individuals with DS contracted COVID-19 after vaccination, and all recovered. Individuals with DS who were unvaccinated by choice were more likely to be younger, previously recovered from COVID-19, and also unvaccinated against other recommended vaccines. COVID-19 vaccines have been shown to be safe for individuals with DS and effective in terms of resulting in minimal breakthrough infections and milder disease outcomes among fully vaccinated individuals with DS

Excitability of the Motor Cortex Ipsilateral to the Moving Body Side Depends on Spatio-Temporal Task Complexity and Hemispheric Specialization

Unilateral movements are mainly controlled by the contralateral hemisphere, even though the primary motor cortex ipsilateral (M1ipsi) to the moving body side can undergo task-related changes of activity as well. Here we used transcranial magnetic stimulation (TMS) to investigate whether representations of the wrist flexor (FCR) and extensor (ECR) in M1ipsi would be modulated when unilateral rhythmical wrist movements were executed in isolation or in the context of a simple or difficult hand-foot coordination pattern, and whether this modulation would differ for the left versus right hemisphere. We found that M1ipsi facilitation of the resting ECR and FCR mirrored the activation of the moving wrist such that facilitation was higher when the homologous muscle was activated during the cyclical movement. We showed that this ipsilateral facilitation increased significantly when the wrist movements were performed in the context of demanding hand-foot coordination tasks whereas foot movements alone influenced the hand representation of M1ipsi only slightly. Our data revealed a clear hemispheric asymmetry such that MEP responses were significantly larger when elicited in the left M1ipsi than in the right. In experiment 2, we tested whether the modulations of M1ipsi facilitation, caused by performing different coordination tasks with the left versus right body sides, could be explained by changes in short intracortical inhibition (SICI). We found that SICI was increasingly reduced for a complex coordination pattern as compared to rest, but only in the right M1ipsi. We argue that our results might reflect the stronger involvement of the left versus right hemisphere in performing demanding motor tasks

DataSheet_1_Validation of factor structure of the neurodevelopmental parent report for outcome monitoring in down syndrome: confirmatory factor analysis.docx

IntroductionThe Neurodevelopmental Parent Report for Outcome Monitoring (ND-PROM), initially developed to monitor developmental and behavioral functions in children with autism spectrum disorder (ASD), assesses symptoms across a wide range of domains relevant in Down syndrome (DS).MethodsPsychometric properties of ND-PROM were assessed in 385 individuals with DS and 52 with a combined diagnosis of DS and ASD (DS+ASD), whose caregivers completed the ND-PROM questionnaire for a clinical visit in a specialized Down syndrome program at a tertiary pediatric hospital. Confirmatory factor analysis was conducted to evaluate the internal structure validity of the ND-PROM. Measurement invariance was assessed, with a comparison group of 246 individuals with ASD, and latent mean differences between the DS and ASD-only groups, as well as the combined DS+ASD groups, were assessed.ResultsFindings support the existence of the 12 clinically-derived factors in the DS population: Expressive Language, Receptive Language, Adaptive skills/Toileting, Social Emotional Understanding, Social Interaction, Independent Play, Sensory Processes, Challenging Behaviors, Impulse/ADHD, and Mental Health. Differences in response patterns of development and behaviors were observed between those with DS and those with ASD, including those with DS having higher abilities in nonverbal communication, social emotional understanding, and social interaction, and fewer restricted and repetitive behaviors and interests, impulsivity or ADHD symptoms, and mental health concerns compared to those with ASD. Individuals in the DS+ASD group had more difficulties with expressive and receptive language, nonverbal and social communication, social interaction, independent play, and adaptive skills than either the DS-only group or the ASD-only groups.DiscussionThe ND-PROM has a desirable factor structure and is a valid and clinically useful tool that captures a range of distinct and independent areas of developmental and behavioral functioning in DS, for individuals with and without an ASD diagnosis.</p

Differences in clinical presentation, severity, and treatment of COVID-19 among individuals with Down syndrome from India and high-income countries: Data from the Trisomy 21 Research Society survey

Background: People with Down syndrome (DS) are one of the highest risk groups for mortality associated with COVID-19, but outcomes may differ across countries due to different co-morbidity profiles, exposures, and societal practices, which could have implications for disease management. This study is designed to identify differences in clinical presentation, severity, and treatment of COVID-19 between India and several high-income countries (HICs). Methods: We used data from an international survey to examine the differences in disease manifestation and management for COVID-19 patients with DS from India vs HIC. De-identified survey data collected from April 2020 to August 2021 were analysed. Results: COVID-19 patients with DS from India were on average nine years younger than those from HICs. Comorbidities associated with a higher risk for severe COVID-19 were more frequent among the patients from India than from HICs. Hospitalizations were more frequent among patients from India as were COVID-19-related medical complications. Treatment strategies differed between India and HICs, with more frequent use of antibiotics in India. The average severity score of 3.31 was recorded for Indian DS in contrast to 2.3 for European and 2.04 for US cases. Conclusions: Presentation and outcomes of COVID-19 among individuals with DS were more severe for patients from India than for those from HIC. Global efforts should especially target vaccination campaigns and other risk-reducing interventions for individuals with DS from low-income countries

COVID-19 in children with down syndrome: data from the trisomy 21 Research Society Survey

Adults with Down Syndrome (DS) are at higher risk for severe outcomes of coronavirus disease 2019 (COVID-19) than the general population, but evidence is required to understand the risks for children with DS, which is necessary to inform COVID-19 shielding advice and vaccination priorities. We aimed to determine the epidemiological and clinical characteristics of COVID-19 in children with DS. Using data from an international survey obtained from a range of countries and control data from the United States, we compared the prevalence of symptoms and medical complications and risk factors for severe outcomes between DS and non-DS paediatric populations with COVID-19. Hospitalised COVID-19 patients <18 years with DS had a higher incidence of respiratory symptoms, fever, and several medical complications from COVID-19 than control patients without DS <18 years. Older age, obesity, and epilepsy were significant risk factors for hospitalisation among paediatric COVID-19 patients with DS, and age and thyroid disorder were significant risk factors for acute respiratory distress syndrome. Mortality rates were low in all paediatric COVID-19 patients (with and without DS), contrasting with previous findings in adults with DS (who exhibit higher mortality than those without DS). Children with DS are at increased risk for more severe presentations of COVID-19. Efforts should be made to ensure the comprehensive and early detection of COVID-19 in this population and to identify children with DS who present comorbidities that pose a risk for a severe course of COVID-19. Our results emphasize the importance of vaccinating children with DS as soon as they become eligible.This work is supported by grants from the following bodies: Down Syndrome Affiliates in Action, Down Syndrome Medical Interest Group-USA, GiGi’s Playhouse, Jerome Lejeune Foundation, LuMind IDSC Foundation, The Matthew Foundation, National Down Syndrome Society, National Task Group on Intellectual Disabilities and Dementia Practices. AH is supported by the HERCULES Center (NIEHS P30ES019776). The REDCap survey and database management system at Emory University was supported by Library Information Technology Services grant support (UL1 TR000424). MD is supported by the Centre for Genomic Regulation Severo Ochoa excellence grant, the CIBER of Rare Diseases, and DURSI 2017SGR595, and acknowledges the Spanish Ministry of Science, Innovation and Universities (MSIU) to the EMBL partnership, the Centro de Excelencia Severo Ochoa and CERCA (GenCat). AS is supported by the MRC (MR/S011277/1; MR/S005145/1; MR/R024901/1), Lumind IDSC, The LeJeune Foundation and the European Commission (H2020 SC1 Gene overdosage and comorbidities during the early lifetime in Down Syndrome GO-DS21- 848077). ML was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at UCL Great Ormond Street Institute of Child Health/Great Ormond Street Hospital NHS Foundation Trust). The Research Programme on Biomedical Informatics (GRIB) is a member of the Spanish National Bioinformatics Institute (INB), funded by ISCIII and EDER (PT17/0009/0014). The DCEXS is a “Unidad de Excelencia María de Maeztu”, funded by the AEI (CEX2018-000782-M). The GRIB is also supported by the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya (2017 SGR 00519). This study was also supported by the Fondo de Investigaciones Sanitario (FIS), Instituto de Salud Carlos III (PI18/00335 to MCI, PI14/01126 and PI17/01019 to JF), partly jointly funded by Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa; the Jérôme Lejeune Foundation (No. 1319 Cycle 2019B to MCI); the National Institutes of Health (NIA grants 1R01AG056850 - 01A1; R21AG056974 and R01AG061566 to JF); Departament de Salut de la Generalitat de Catalunya, Pla Estratègic de Recerca i Innovació en Salut (SLT006/17/00119 to JF); and Fundació La Marató de TV3 (20141210 to JF

Medical vulnerability of individuals with Down syndrome to severe COVID-19-data from the Trisomy 21 Research Society and the UK ISARIC4C survey

Background: Health conditions, immune dysfunction, and premature aging associated with trisomy 21 (Down syndrome, DS) may impact the clinical course of COVID-19. Methods: The T21RS COVID-19 Initiative launched an international survey for clinicians or caregivers on patients with COVID-19 and DS. Data collected between April and October 2020 (N=1046) were analysed and compared with the UK ISARIC4C survey of hospitalized COVID-19 patients with and without DS. Findings: The mean age of COVID-19 patients with DS in the T21RS survey was 29 years (SD = 18). Similar to the general population, the most frequent signs and symptoms of COVID-19 were fever, cough, and shortness of breath. Joint/muscle pain and vomiting or nausea were less frequent (p \u3c 0.01), whereas altered consciousness/confusion were more frequent (p \u3c 0.01). Risk factors for hospitalization and mortality were similar to the general population with the addition of congenital heart defects as a risk factor for hospitalization. Mortality rates showed a rapid increase from age 40 and were higher in patients with DS (T21RS DS versus non-DS patients: risk ratio (RR) = 3.5 (95%-CI=2.6;4.4), ISARIC4C DS versus non-DS patients: RR = 2.9 (95%-CI=2.1;3.8)) even after adjusting for known risk factors for COVID-19 mortality. Interpretation: Leading signs/symptoms of COVID-19 and risk factors for severe disease course are similar to the general population. However, individuals with DS present significantly higher rates of medical complications and mortality, especially from age 40. Funding: Down Syndrome Affiliates in Action, DSMIG-USA, GiGi\u27s Playhouse, Jerome Lejeune Foundation, LuMind IDSC Foundation, The Matthew Foundation, NDSS, National Task Group on Intellectual Disabilities and Dementia Practices