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Down syndrome (DS) is a complex condition associated with multiple medical, developmental, and behavioral concerns. A prospective, longitudinal clinical database was integrated into a specialty Down Syndrome Program, with the goals of better understanding the incidence, course, and impact of co-occurring medical, neurodevelopmental, and mental health conditions in DS. We describe the process of developing the database, including a systematic approach to data collection and database infrastructure, and report on feasibility, challenges, and solutions of initial implementation. Between March 2018 and November 2021, data from 842 patients (ages 4.8 months to 26 years) was collected. Challenges included caregiver form completion as well as time and personnel required for successful implementation. With full integration into clinical visit flow, the database proved to be feasible. The database enables identification of patterns of development and health throughout the lifespan and it facilitates future data sharing and collaborative research to advance care.

Abstract Antibodies are engineerable quantities in medicine. Learning antibody molecular recognition would enable the in silico design of high affinity binders against nearly any proteinaceous surface. Yet, publicly available experiment antibody sequence-binding datasets may not contain the mutagenic, antigenic, or antibody sequence diversity necessary for deep learning approaches to capture molecular recognition. In part, this is because limited experimental platforms exist for assessing quantitative and simultaneous sequence-function relationships for multiple antibodies. Here we present MAGMA-seq, an integrated technology that combines multiple antigens and multiple antibodies and determines quantitative biophysical parameters using deep sequencing. We demonstrate MAGMA-seq on two pooled libraries comprising mutants of nine different human antibodies spanning light chain gene usage, CDR H3 length, and antigenic targets. We demonstrate the comprehensive mapping of potential antibody development pathways, sequence-binding relationships for multiple antibodies simultaneously, and identification of paratope sequence determinants for binding recognition for broadly neutralizing antibodies (bnAbs). MAGMA-seq enables rapid and scalable antibody engineering of multiple lead candidates because it can measure binding for mutants of many given parental antibodies in a single experiment.

OBJECTIVES: To document the level of vaccine hesitancy in caregivers of children younger than 12 years of age over the course of the pandemic in Pediatric Emergency Departments (ED). Study design Ongoing multicenter, cross-sectional survey of caregivers presenting to 19 pediatric EDs in the USA, Canada, Israel, and Switzerland during first months of the pandemic (phase1), when vaccines were approved for adults (phase2) and most recently when vaccines were approved for children (phase3). RESULTS: Willingness to vaccinate rate declined over the study period (59.7%, 56.1% and 52.1% in the three phases). Caregivers who are fully vaccinated, who have higher education, and those worried their child had COVID-19 upon arrival to the ED, were more likely to plan to vaccinate in all three phases. Mothers were less likely to vaccinate early in the pandemic, but this hesitancy attenuated in later phases. Older caregivers were more willing to vaccinate, and caregivers of older children were less likely to vaccinate their children in phase 3. During the last phase, willingness to vaccinate was lowest in those who had a primary care provider but did not rely on their advice for medical decisions (34%). Those with no primary care provider and those who do and rely on their medical advice, had similar rates of willingness to vaccinate (55.1% and 52.1%, respectively). CONCLUSIONS: COVID-19 vaccine hesitancy is widespread and growing over time, and public health measures should further try to leverage identified factors associated with hesitancy in order to enhance vaccination rates among children.

OBJECTIVES: To assess differences in willingness to vaccinate children against COVID-19, and factors that may be associated with increased acceptance, among US caregivers of various racial and ethnic identities who presented with their child to the Emergency Department (ED) after emergency use authorization of vaccines for children ages 5-11. STUDY DESIGN: A multicenter, cross-sectional survey of caregivers presenting to 11 pediatric EDs in the United States in November-December 2021. Caregivers were asked about their identified race and ethnicity and if they planned to vaccinate their child. We collected demographic data and inquired about caregiver concerns related to COVID-19. We compared responses by race/ethnicity. Multivariable logistic regression models served to determine factors that were independently associated with increased vaccine acceptance overall and among racial/ethnic groups. RESULTS: Among 1916 caregivers responding, 54.67% planned to vaccinate their child against COVID-19. Large differences in acceptance were noted by race/ethnicity, with highest acceptance among Asian caregivers (61.1%) and those who did not specify a listed racial identity (61.1%); caregivers identifying as Black (44.7%) or Multi-racial (44.4%) had lower acceptance rates. Factors associated with intent to vaccinate differed by racial/ethnic group, and included caregiver COVID-19 vaccine receipt (all groups), caregiver concerns about COVID-19 (White caregivers), and having a trusted primary provider (Black caregivers). CONCLUSIONS: Caregiver intent to vaccinate children against COVID-19 varied by race/ethnicity, but race/ethnicity did not independently account for these differences. Caregiver COVID-19 vaccination status, concerns about COVID-19, and presence of a trusted primary provider are important in vaccination decisions.

BackgroundPrior research has characterized neurodevelopmental phenotypes for Down syndrome (DS), but there is variability in age of milestone attainment and limited identification of early predictors of developmental trajectories. Additionally, less is known about receipt of education and services in relation to development.ObjectiveThis study describes the delivery of education and therapies in the setting of general developmental and behavioral needs in a large clinical cohort of children with DS seen in a specialized Down Syndrome Program (DSP).MethodThe clinically collected data included 814 patients with DS who were seen at a specialty DSP at a large, tertiary pediatric care center from March 2018 to January 2023. Data were collected through caregiver-and clinician-reported history at clinical visits to the program. Descriptive frequencies were utilized to describe participant demographics, skills and behaviors, and receipt of services, across age groups in childhood.ResultsDelays were present across all developmental domains; in particular delays in language, communication, and academic skills, and behavioral challenges were commonly reported. Almost all children received Early Intervention (EI) services, and many young children received non-public therapies after completing EI. Older participants demonstrated more impairments than younger age groups, yet received services at lower rates, particularly behavioral and speech language interventions.ConclusionA snapshot of developmental skill attainment in individuals with DS is provided. Therapies to support the levels of need were reported at much lower frequencies than the level of need reported to target aspects of development and behavior. Several gaps in therapies and educational services were identified. There is an important need for tailoring supports, based on developmental level, to meet individual needs. These findings may help to inform policy change related to developmental and educational services for individuals with DS.

Down syndrome (DS) is the most common cause of intellectual disability, yet little is known about the neurobiological pathways leading to cognitive impairments. Electroencephalographic (EEG) measures are commonly used to study neurodevelopmental disorders, but few studies have focused on young children with DS. Here we assess resting state EEG data collected from toddlers/preschoolers with DS (n = 29, age 13–48 months old) and compare their aperiodic and periodic EEG features with both age-matched (n = 29) and developmental-matched (n = 58) comparison groups. DS participants exhibited significantly reduced aperiodic slope, increased periodic theta power, and decreased alpha peak amplitude. A majority of DS participants displayed a prominent peak in the theta range, whereas a theta peak was not present in age-matched participants. Overall, similar findings were also observed when comparing DS and developmental-matched groups, suggesting that EEG differences are not explained by delayed cognitive ability.

Triply Periodic Minimal Surfaces (TPMS), such as Gyroid, are widely accepted for bone tissue engineering due to their interconnected porous structures with tunable properties that enable high surface area to volume ratios, energy absorption, and relative strength. Among these topologies, the Fischer-Koch-S (FKS) has also been suggested for compact bone scaffolds, but few studies have investigated these structures beyond computer simulations. FKS scaffolds have been fabricated in metal and polymer, but to date none have been fabricated in a ceramic used in bone tissue engineering (BTE) scaffolds. This study is the first to fabricate ceramic FKS scaffolds and compare them with the more common Gyroid topology. Results showed that FKS scaffolds were 32% stronger, absorbed 49% more energy, and had only 11% lower permeability than Gyroid scaffolds when manufactured at high porosity (70%). Both FKS and Gyroid scaffolds displayed strength and permeability in the low range of trabecular long bones with high reliability (Weibull failure probability) in the normal direction. Fracture modes were further investigated to explicate the quasi-brittle failure exhibited by both scaffold topologies, exploring stress-strain relationships along with scanning electron microscopy for failure analysis. Considering the physical aspects of successful bone tissue engineering scaffolds, FKS scaffolds appear to be more promising for further study as bone regeneration scaffolds than Gyroid due to their higher compressive strength and reliability, at only a small penalty to permeability. In the context of BTE, FKS scaffolds may be better suited than Gyroids to applications where denser bone and strength is prioritized over permeability, as suggested by earlier simulation studies.

A general method to generate biosensors for user-defined molecules could provide detection tools for a wide range of biological applications. Here, we describe an approach for the rapid engineering of biosensors using PYR1 (Pyrabactin Resistance 1), a plant abscisic acid (ABA) receptor with a malleable ligand-binding pocket and a requirement for ligand-induced heterodimerization, which facilitates the construction of sense-response functions. We applied this platform to evolve 21 sensors with nanomolar to micromolar sensitivities for a range of small molecules, including structurally diverse natural and synthetic cannabinoids and several organophosphates. X-ray crystallography analysis revealed the mechanistic basis for new ligand recognition by an evolved cannabinoid receptor. We demonstrate that PYR1-derived receptors are readily ported to various ligand-responsive outputs, including enzyme-linked immunosorbent assay (ELISA)-like assays, luminescence by protein-fragment complementation and transcriptional circuits, all with picomolar to nanomolar sensitivity. PYR1 provides a scaffold for rapidly evolving new biosensors for diverse sense-response applications.

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.

Background and objectivesStandard therapies (adrenocorticotropic hormone [ACTH], oral steroids, or vigabatrin) fail to control infantile spasms in almost half of children. Early identification of nonresponders could enable rapid initiation of sequential therapy. We aimed to determine the time to clinical remission after appropriate infantile spasms treatment initiation and identify predictors of the time to infantile spasms treatment response.MethodsThe National Infantile Spasms Consortium prospectively followed children aged 2-24 months with new-onset infantile spasms at 23 US centers (2012-2018). We included children treated with standard therapy (ACTH, oral steroids, or vigabatrin). Sustained treatment response was defined as having the last clinically recognized infantile spasms on or before treatment day 14, absence of hypsarrhythmia on EEG 2-4 weeks after treatment, and persistence of remission to day 30. We analyzed the time to treatment response and assessed clinical characteristics to predict sustained treatment response.ResultsAmong 395 infants, clinical infantile spasms remission occurred in 43% (n = 171) within the first 2 weeks of treatment, of which 81% (138/171) responded within the first week of treatment. There was no difference in the median time to response across standard therapies (ACTH: median 4 days, interquartile range [IQR] 3-7; oral steroids: median 3 days, IQR 2-5; vigabatrin: median 3 days, IQR 1-6). Individuals without hypsarrhythmia on the pretreatment EEG (i.e., abnormal but not hypsarrhythmia) were more likely to have early treatment response than infants with hypsarrhythmia at infantile spasms onset (hazard ratio 2.23, 95% CI 1.39-3.57). No other clinical factors predicted early responders to therapy.DiscussionRemission after first infantile spasms treatment can be identified by treatment day 7 in most children. Given the importance of early and effective treatment, these data suggest that children who do not respond to standard infantile spasms therapy within 1 week should be reassessed immediately for additional standard treatment. This approach could optimize outcomes by facilitating early sequential therapy for children with infantile spasms.

Abstract Transcranial magnetic stimulation paired with electroencephalography (TMS–EEG) can measure local excitability and functional connectivity. To address trial-to-trial variability, responses to multiple TMS pulses are recorded to obtain an average TMS evoked potential (TEP). Balancing adequate data acquisition to establish stable TEPs with feasible experimental duration is critical when applying TMS–EEG to clinical populations. Here we aim to investigate the minimum number of pulses (MNP) required to achieve stable TEPs in children with epilepsy. Eighteen children with Self-Limited Epilepsy with Centrotemporal Spikes, a common epilepsy arising from the motor cortices, underwent multiple 100-pulse blocks of TMS to both motor cortices over two days. TMS was applied at 120% of resting motor threshold (rMT) up to a maximum of 100% maximum stimulator output. The average of all 100 pulses was used as a “gold-standard” TEP to which we compared “candidate” TEPs obtained by averaging subsets of pulses. We defined TEP stability as the MNP needed to achieve a concordance correlation coefficient of 80% between the candidate and “gold-standard” TEP. We additionally assessed whether experimental or clinical factors affected TEP stability. Results show that stable TEPs can be derived from fewer than 100 pulses, a number typically used for designing TMS-EEG experiments. The early segment (15–80 ms) of the TEP was less stable than the later segment (80–350 ms). Global mean field amplitude derived from all channels was less stable than local TEP derived from channels overlying the stimulated site. TEP stability did not differ depending on stimulated hemisphere, block order, or antiseizure medication use, but was greater in older children. Stimulation administered with an intensity above the rMT yielded more stable local TEPs. Studies of TMS-EEG in pediatrics have been limited by the complexity of experimental set-up and time course. This study serves as a critical starting point, demonstrating the feasibility of designing efficient TMS–EEG studies that use a relatively small number of pulses to study pediatric epilepsy and potentially other pediatric groups.

Abstract Background Patients requiring coronary artery bypass grafting (CABG) are often loaded with antithrombotic drugs (AT) and are at an increased risk for perioperative bleeding complications. Active AT removal by a hemoadsorption cartridge integrated in the cardiopulmonary bypass circuit is increasingly used in this setting to reduce bleeding, and herein we describe the extension of this application in patients on AT undergoing off-pump coronary artery bypass (OPCAB). Methods Ten patients (80% male; mean age: 67.4 ± 9.2years) were treated with ticagrelor (eight patients), rivaroxaban and ticagrelor (one patient), and rivaroxaban (one patient) prior to OPCAB surgery. AT’s were discontinued one day before surgery in nine patients and on the day of surgery in one patient, and all patients were also on aspirin. The cohort mean EuroSCORE-II was 2.9 ± 1.5%. A hemoadsorption cartridge was integrated into a dialysis device (n=4) or a stand-alone apheresis pump (n=6) periprocedural, for a treatment time of 145 ± 33 min. Outcome measures included bleeding according to Bleeding Academic Research Consortium (BARC)-4 and 24-hour chest-tube-drainage (CTD). Results Mean operation time was 184 ± 35 min. All patients received a left internal thoracic artery with a mean of 2.3 ± 0.9 total grafts. One patient had a BARC-4 bleeding event and there were no surgical re-explorations for bleeding. Mean 24-hours CTD was 680 ± 307mL. During follow-up of 19.5 ± 17.0 months, none of the patients died or required further reinterventions. No device-related adverse events were reported. Conclusions Hemoadsorption via a stand-alone apheresis pump during OPCAB surgery was feasible and safe. This innovative and new approach showed favorable bleeding rates in patients on antithrombotic drugs requiring bypass surgery.