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Data from the Head Start Impact Study (N = 3,185, age = 3-4 years) were used to determine whether 1 year of Head Start differentially benefited children from homes with high, middle, and low levels of parental preacademic stimulation on three academic outcome domains-early math, early literacy, and receptive vocabulary. Results from residualized growth models showed positive impacts of random assignment to Head Start on all three outcomes, and positive associations between parental preacademic stimulation and academic performance. Two moderated effects were also found. Head start boosted early math skills the most for children receiving low parental preacademic stimulation. Effects of Head Start on early literacy skills were largest for children receiving moderate levels of parental preacademic stimulation. Implications for Head Start are discussed. © 2014 Society for Research in Child Development, Inc.

Objective: The authors carried out a genomewide linkage scan to identify chromosomal regions likely to contain genes that contribute to susceptibility to recurrent early-onset major depressive disorder, the form of the disorder with the greatest reported risk to relatives of index cases.Method: Microsatellite DNA markers were studied in 656 families with two or more such cases (onset before age 31 in probands and age 41 in other relatives), including 1,494 informative "all possible" affected relative pairs (there were 894 independent affected sibling pairs). Analyses included a primary multipoint allele-sharing analysis (with ALLEGRO) and a secondary logistic regression analysis taking the sex of each relative pair into account (male-male, male-female, female-female).Results: Genomewide suggestive evidence for linkage was observed on chromosome 15q25-q26 (at 105.4 centimorgans [cM]). The authors previously reported genomewide significant linkage in this region in the first 297 families. In the secondary analysis, after empirical genomewide correction for multiple testing, suggestive linkage results were observed on chromosome 17p12 (28.0 cM, excess sharing in male-male and male-female pairs) and on chromosome 8p22-p21.3 (25.1 cM, excess sharing in male-male pairs).Conclusions: These regions of chromosomes 15q, 17p, and 8p might contain genes that contribute to susceptibility to major depression and related disorders. Evidence for linkage has been reported independently in the same regions of chromosome 15q for major depression and of chromosome 8p for related personality traits. [ABSTRACT FROM AUTHOR]

BACKGROUND: Sjogren's syndrome (SS) is a common autoimmune disorder in which liver involvement is frequent, but generally mild and subclinical. Multiple hepatic histologies have been reported, but to our knowledge an association with granulomatous hepatitis (GH) has never been described. We recently evaluated an individual in whom biopsy-proven GH was associated with concomitant SS. OBJECTIVE: To clarify the possible association between GH and SS. METHODS: We retrospectively reviewed all cases of biopsy-proven GH seen in our institution from 1991 to 2004. Overall, there were 16 individuals with GH identified of which 4 were considered idiopathic in origin. These individuals underwent an extensive evaluation for the presence of SS as well as other disorders known to be associated with GH. RESULTS: Of the 4 identified cases with a previously suspected idiopathic GH, 3 met criteria for primary SS. All 3 individuals underwent minor salivary gland biopsy, which was diagnostic for this condition. CONCLUSIONS: These results suggest a likely association between these 2 conditions. Further epidemiological studies will be necessary to confirm this finding. Copyright © 2006 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

Early adversity increases risk for child mental health difficulties. Stressors in the home environment (e.g., parental mental illness, household socioeconomic challenges) may be particularly impactful. Attending out-of-home childcare may buffer or magnify negative effects of such exposures. Using a longitudinal observational design, we leveraged data from the NIH Environmental influences on Child Health Outcomes Program to test whether number of hours in childcare, defined as 1) any type of nonparental care and 2) center-based care specifically, was associated with child mental health, including via buffering or magnifying associations between early exposure to psychosocial and socioeconomic risks (age 0-3 years) and later internalizing and externalizing symptoms (age 3-5.5 years), in a diverse sample of N = 2,024 parent-child dyads. In linear regression models, childcare participation was not associated with mental health outcomes, nor did we observe an impact of childcare attendance on associations between risk exposures and symptoms. Psychosocial and socioeconomic risks had interactive effects on internalizing and externalizing symptoms. Overall, the findings did not indicate that childcare attendance positively or negatively influenced child mental health and suggested that psychosocial and socioeconomic adversity may need to be considered as separate exposures to understand child mental health risk in early life.

Objective: To examine associations between cognitive stimulation in the home at 6 months and maternal feeding styles at 24 months, direct intervention effects of Smart Beginnings (SB) on feeding styles, and potential indirect effects of SB on feeding styles via earlier intervention effects on cognitive stimulation., Methods: Single-blind, two-site randomized clinical trial (RCT) of the SB intervention. SB integrates PlayReadVIP, a universal, pediatric primary care-based program, and Family Check-Up (FCU), a targeted secondary home-based parenting intervention. Mother-infant dyads (N = 327) were randomized at birth to standard pediatric care or the SB intervention. Linear regression analyses determined associations between cognitive stimulation at 6 months and maternal feeding styles at 24 months, a secondary data analysis. Direct intervention impacts on feeding styles, a secondary RCT outcome, were also assessed and mediation analyses explored intervention effects on feeding styles via earlier intervention impacts on cognitive stimulation., Results: Cognitive stimulation was significantly associated with higher responsive and lower indulgent feeding styles. SB mothers were less likely to exhibit pressuring styles compared with controls (Effect Size [ES]=-0.12, P = 0.02). Although no direct intervention effects were found on responsive or indulgent feeding styles, indirect effects of SB were evident on these feeding styles through intervention-induced increases in cognitive stimulation in the SB group., Conclusions: This study found positive linkages between cognitive stimulation in the home and later feeding styles. Additionally, the SB intervention was associated with less pressured feeding and indirect pathways mediated by intervention effects on cognitive stimulation. Implications for early childhood parenting interventions are discussed., Competing Interests: Declaration of Competing Interest The authors have no potential conflicts of interest to disclose, including financial relationships relevant to this article., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Abstract: A 29-year-old Korean woman with chronic aplastic anemia presented with seizures due to cyclosporine-induced posterior reversible encephalopathy syndrome, caused by unpredictable oral cyclosporine (CS) accumulation and prolonged elimination. This case demonstrates the need to monitor CS drug levels with careful dose adjustments., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Parenting is a critical mediator of children's school readiness. In line with this theory of change, data from the randomized clinical trial of Smart Beginnings (tiered Video Interaction Project and Family Check-Up; N = 403, treatment arm n = 201) were used to examine treatment impacts on early language and literacy skills at child age 4 years (n Latinx  = 168, n Black  = 198, n Male  = 203), as well as indirect impacts through parental support of cognitive stimulation at child age 2 years. Although results did not reveal direct effects on children's early skills, there were significant indirect effects for early literacy (β = .03, p = .05) and early language (β = .04, p = .04) via improvements in parental cognitive stimulation. Implications for interventions targeting parenting to improve children's school readiness beginning at birth are discussed., (© 2023 The Authors. Child Development © 2023 Society for Research in Child Development.)

Introduction: Children and adolescents with elevated internalizing symptoms are at increased risk for depression, anxiety, and other psychopathology later in life. The present study examined the predictive links between two bioecological factors in early childhood-parental hostility and socioeconomic stress-and children's internalizing symptom class outcomes, while considering the effects of child sex assigned at birth on internalizing symptom development from childhood to adolescence., Materials and Methods: The study used a sample of 1,534 children to test the predictive effects of socioeconomic stress at ages 18 and 27 months; hostile parenting measured at child ages 4-5; and sex assigned at birth on children's internalizing symptom latent class outcomes at child ages 7-9, 10-12, 13-15, and 16-19. Analyses also tested the mediating effect of parenting on the relationship between socioeconomic stress and children's symptom classes. Other covariates included parent depressive symptoms at child ages 4-5 and child race and ethnicity., Results: Analyses identified three distinct heterogenous internalizing symptom classes characterized by relative symptom levels and progression: low (35%); moderate and increasing (41%); and higher and increasing (24%). As anticipated, higher levels of parental hostility in early childhood predicted membership in the higher and increasing symptom class, compared with the low symptom class (odds ratio (OR) = .61, 95% confidence interval (CI) [.48,.77]). Higher levels of early childhood socioeconomic stress were also associated with the likelihood of belonging to the higher-increasing symptom class compared to the low and moderate-increasing classes (OR = .46, 95% CI [.35,.60] and OR = .56, 95% CI [.44,.72], respectively). The total ( c = .61) and direct ( c' = .57) effects of socioeconomic stress on children's symptom class membership in the mediation analysis were significant ( p <.001)., Discussion: Study findings suggest that intervening on modifiable bioecological stressors-including parenting behaviors and socioeconomic stressors-may provide important protective influences on children's internalizing symptom trajectories., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Williams, Oro, Blackwell, Liu, Miller, Ganiban, Neiderhiser, DeGarmo, Shaw, Chen, Natsuaki and Leve.)

Controlling malaria requires new drugs against Plasmodium falciparum . The P. falciparum cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite's life cycle. We defined the structure-activity relationship (SAR) of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. In vitro potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. P. berghei sporozoites and P. falciparum asexual blood stages were used to assay multistage antiparasitic activity. Cellular specificity of compounds was evaluated using transgenic parasites expressing PfPKG carrying a substituted "gatekeeper" residue. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.

Introduction: As paediatric intensive care unit (PICU) mortality declines, there is growing recognition of the morbidity experienced by children surviving critical illness and their families. A comprehensive understanding of the adverse physical, cognitive, emotional and social sequelae common to PICU survivors is limited, however, and the trajectory of recovery and risk factors for morbidity remain unknown., Methods and Analysis: The Post-Intensive Care Syndrome - paediatrics Longitudinal Cohort Study will evaluate child and family outcomes over 2 years following PICU discharge and identify child and clinical factors associated with impaired outcomes. We will enrol 750 children from 30 US PICUs during their first PICU hospitalisation, including 500 case participants experiencing ≥3 days of intensive care that include critical care therapies (eg, mechanical ventilation, vasoactive infusions) and 250 age-matched, sex-matched and medical complexity-matched control participants experiencing a single night in the PICU with no intensive care therapies. Children, parents and siblings will complete surveys about health-related quality of life, physical function, cognitive status, emotional health and peer and family relationships at multiple time points from baseline recall through 2 years post-PICU discharge. We will compare outcomes and recovery trajectories of case participants to control participants, identify risk factors associated with poor outcomes and determine the emotional and social health consequences of paediatric critical illness on parents and siblings., Ethics and Dissemination: This study has received ethical approval from the University of Pennsylvania Institutional Review Board (protocol #843844). Our overall objective is to characterise the ongoing impact of paediatric critical illness to guide development of interventions that optimise outcomes among children surviving critical illness and their families. Findings will be presented at key disciplinary meetings and in peer-reviewed publications at fixed data points. Published manuscripts will be added to our public study website to ensure findings are available to families, clinicians and researchers., Trials Registration Number: NCT04967365., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: This study aimed to identify contextual factors associated with life satisfaction during the COVID-19 pandemic for adolescents with mental, emotional, behavioral, and developmental (MEBD) disabilities., Methods: Data were collected from a sample of 1084 adolescents aged 11-21 years from April 2020 to August 2021. This cross-sectional study used a sequential machine learning workflow, consisting of random forest regression and evolutionary tree regression, to identify subgroups of adolescents in the Environmental influences on Child Health Outcomes (ECHO) consortium who demonstrated enhanced vulnerability to lower life satisfaction as described by intersecting risk factors, protective factors, and MEBD disabilities., Results: Adolescents with a history of depression, anxiety, autism, and attention-deficit/hyperactivity disorder were particularly susceptible to decreased life satisfaction in response to unique combinations of stressors experienced during the COVID-19 pandemic. These stressors included decreased social connectedness, decreased family engagement, stress related to medical care access, pandemic-related traumatic stress, and single-caregiver households., Conclusion: Findings from this study highlight the importance of interventions aimed specifically at increasing adolescent social connectedness, family engagement, and access to medical support for adolescents with MEBD disabilities, particularly in the face of stressors, such as a global pandemic., Impact: Through a machine learning process, we identified contextualized risks associated with life satisfaction among adolescents with neurodevelopmental disabilities during the COVID-19 pandemic. The COVID-19 pandemic resulted in large-scale social disruptions for children and families. Such disruptions were associated with worse mental health outcomes in the general pediatric population, but few studies have examined specific subgroups who may be at heightened risk. We endeavored to close that gap in knowledge. This study highlights the importance of social connectedness, family engagement, and access to medical support as contributing factors to life satisfaction during the COVID-19 pandemic for adolescents with neurodevelopmental disabilities., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

High-quality predicted structures enable structure-based approaches to an expanding number of drug discovery programs. We propose that by utilizing free energy perturbation (FEP), predicted structures can be confidently employed to achieve drug design goals. We use structure-based modeling of hERG inhibition to illustrate this value of FEP., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Free energy perturbation (FEP) remains an indispensable method for computationally assaying prospective compounds in advance of synthesis. However, before FEP can be deployed prospectively, it must demonstrate retrospective recapitulation of known experimental data where the subtle details of the atomic ligand-receptor model are consequential. An open question is whether AlphaFold models can serve as useful initial models for FEP in the regime where there exists a congeneric series of known chemical matter but where no experimental structures are available either of the target or of close homologues. As AlphaFold structures are provided without a bound ligand, we employ induced fit docking to refine the AlphaFold models in the presence of one or more congeneric ligands. In this work, we first validate the performance of our latest induced fit docking technology, IFD-MD, on a retrospective set of public experimental GPCR structures with 95% of cross-docks producing a pose with a ligand RMSD ≤ 2.5 Å in the top two predictions. We then apply IFD-MD and FEP on AlphaFold models of the somatostatin receptor family of GPCRs. We use AlphaFold models produced prior to the availability of any experimental structure from this family. We arrive at FEP-validated models for SSTR2, SSTR4, and SSTR5, with RMSE around 1 kcal/mol, and explore the challenges of model validation under scenarios of limited ligand data, ample ligand data, and categorical data.

Greater maternal depressive symptoms are consistently associated with higher levels of behavioral difficulties in children, emerging in early childhood and with long-lasting consequences for children's development. Interventions promoting early relational health have been shown to have benefits for children's behavior; however, these impacts are not always realized in the context of maternal depression. This study examined whether tiered programs could address this limitation by focusing on both parenting, through universal primary prevention, and psychosocial stressors and parent mental health, through tailored secondary prevention. Analysis of a randomized controlled trial (RCT) of the Smart Beginnings (SB) intervention was conducted to determine whether SB attenuated the association between maternal depression and early childhood internalizing and externalizing behaviors. Maternal depression significantly predicted both internalizing and externalizing behaviors in linear regression models. Further, there was a significant interaction between maternal depression and treatment group, such that among mothers with higher depressive symptoms, the SB treatment attenuated the magnitude of the association between depression and child behavior. Findings suggest that while parenting support is important for all families, it may be particularly critical for those with higher levels of depression and underscores the need to consider multidimensional family processes in both research and clinical practice.

Reaching population-level impact for families in poverty requires moving beyond a sole focus on individuals, to a wider focus on interactions between individuals and their broader environmental contexts. Place-based initiatives have emerged as a policy response to promote community-level change around these broader interactions between individuals and their local communities through addressing long-standing disparities in housing, employment, education, and health. Together Growing Strong (TGS) is one such place-based initiative focused on transforming the health, wellbeing, and development of young children and their families in Sunset Park, Brooklyn. The Children, Caregivers, and Community (C3) Study is an outcomes-based study designed to assess the trajectories of children and families in Sunset Park along indicators such as family health and wellbeing and child development in relation to TGS program participation. The aims, scope, and protocol of the C3 Study are the subjects of this paper., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Miller et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To test the impact of the fully integrated Smart Beginnings model on parental support of cognitive stimulation from 6 to 24 months across infancy and toddlerhood., Study Design: This was a single-blind, 2-site randomized clinical trial of the Smart Beginnings intervention. Enrollment took place at birth in postpartum units of hospitals in New York City and Pittsburgh, Pennsylvania, with a consecutive sample of 403 mother-infant dyads. Smart Beginnings combines a Video Interaction Project-14-session universal primary prevention program delivered in the pediatric clinic at the time of well-child visits birth-36 months-with potential for Family Check-Up-3-4 sessions targeted secondary prevention home-visiting program. The principal outcome was parental support of cognitive stimulation assessed via parent survey and video-recorded observations of parent-child interactions. Ordinary least squares and mixed effects regressions were conducted., Results: Families were mostly Black/African-American (50%) or Latinx (42%); all were Medicaid eligible (100%). Smart Beginnings significantly promoted cognitive stimulation during infancy and toddlerhood for most survey outcomes across time, including StimQ common total (effect size [ES] = 0.25, P = .01) and READ Quantity (ES = .19, P = .04) and Quality (ES = .30, P = .001). For the observations, the impact of Smart Beginnings varied by time, with significant impacts at 6 (ES = 0.37-.40, P < .001) and 24 (ES = 0.27-.30, P < .001) months, but not 18 months., Conclusions: Smart Beginnings positively promotes cognitive stimulation from infancy through toddlerhood using the integrated model. This study adds to the body of research showing preventive interventions in pediatric primary care and home visiting can support early relational health including parental support of cognitive stimulation., Trial Registration: NCT02459327., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The recently developed AlphaFold2 (AF2) algorithm predicts proteins' 3D structures from amino acid sequences. The open AlphaFold protein structure database covers the complete human proteome. Using an industry-leading molecular docking method (Glide), we investigated the virtual screening performance of 37 common drug targets, each with an AF2 structure and known holo and apo structures from the DUD-E data set. In a subset of 27 targets where the AF2 structures are suitable for refinement, the AF2 structures show comparable early enrichment of known active compounds (avg. EF 1%: 13.0) to apo structures (avg. EF 1%: 11.4) while falling behind early enrichment of the holo structures (avg. EF 1%: 24.2). With an induced-fit protocol (IFD-MD), we can refine the AF2 structures using an aligned known binding ligand as the template to improve the performance in structure-based virtual screening (avg. EF 1%: 18.9). Glide-generated docking poses of known binding ligands can also be used as templates for IFD-MD, achieving similar improvements (avg. EF 1% 18.0). Thus, with proper preparation and refinement, AF2 structures show considerable promise for in silico hit identification.

This study evaluated the collateral, or unanticipated, impacts of Smart Beginnings (SB), a two-site, tiered intervention designed to promote responsive parenting and school readiness, on breastfeeding intensity in a low-income sample. Impact analyses for the SB intervention were conducted using an intent-to-treat design leveraging a two-arm random assignment structure. Mothers assigned to the SB intervention group were more than three times more likely to give breastmilk as the only milk source at infant age 6 months than mothers assigned to the control group at one site, an effect not evident at the other study site. As development and growth are the two most salient domains of child health, understanding how interventions impact subsequent parenting practices across both domains is critical to address long-term economic and racial/ethnic disparities. Implications of the findings are discussed for improving the efficacy of interventions based on paediatric primary care., (© 2022 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) are imaging technologies invented in the 1980s that have revolutionized the field of in vivo retinal diagnostics and are now commonly used in ophthalmology clinics as well as in vision science research. Adaptive optics (AO) technology enables high-fidelity correction of ocular aberrations, resulting in improved resolution and sensitivity for both SLO and OCT systems. The potential of gathering multi-modal cellular-resolution information in a single instrument is of great interest to the ophthalmic imaging community. Although similar instruments have been developed for imaging the human retina, developing such a system for mice will benefit basic science research and should help with further dissemination of AO technology. Here, we present our work integrating OCT into an existing mouse retinal AO-SLO system, resulting in a multi-modal AO-enhanced imaging system of the living mouse eye. The new system allows either independent or simultaneous data acquisition of AO-SLO and AO-OCT, depending on the requirements of specific scientific experiments. The system allows a data acquisition speed of 200 kHz A-scans/pixel rate for OCT and SLO, respectively. It offers ∼6 µm axial resolution for AO-OCT and a ∼1 µm lateral resolution for AO-SLO-OCT imaging., Competing Interests: The authors declare that there are no conflicts of interest., (© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Accurate prediction of the p K a 's of protein residues is crucial to many applications in biological simulation and drug discovery. Here, we present the use of free energy perturbation (FEP) calculations for the prediction of single-protein residue p K a values. We begin with an initial set of 191 residues with experimentally determined p K a values. To isolate sampling limitations from force field inaccuracies, we develop an algorithm to classify residues whose environments are significantly affected by crystal packing effects. We then report an approach to identify buried histidines that require significant sampling beyond what is achieved in typical FEP calculations. We therefore define a clean data set not requiring algorithms capable of predicting major conformational changes on which other p K a prediction methods can be tested. On this data set, we report an RMSE of 0.76 p K a units for 35 ASP residues, 0.51 p K a units for 44 GLU residues, and 0.67 p K a units for 76 HIS residues.

Homology models have been used for virtual screening and to understand the binding mode of a known active compound; however, rarely have the models been shown to be of sufficient accuracy, comparable to crystal structures, to support free-energy perturbation (FEP) calculations. We demonstrate here that the use of an advanced induced-fit docking methodology reliably enables predictive FEP calculations on congeneric series across homology models ≥30% sequence identity. Furthermore, we show that retrospective FEP calculations on a congeneric series of drug-like ligands are sufficient to discriminate between predicted binding modes. Results are presented for a total of 29 homology models for 14 protein targets, showing FEP results comparable to those obtained using experimentally determined crystal structures for 86% of homology models with template structure sequence identities ranging from 30 to 50%. Implications for the use and validation of homology models in drug discovery projects are discussed.

This study examined predictors of TV use at bedtime and associations with toddlers' sleep and behavior using data from the Smart Beginnings study with 403 Medicaid-eligible, racial/ethnic minority participants from two cities in the United States. We first estimated predictors of TV use at bedtime at 18 months. We then examined whether TV at bedtime was associated with concurrent parent-report of nighttime sleep duration and quality, and later problem behavior at 24 months. Results showed that around half of the sample reported using TV at bedtime with their toddlers, and particularly first-time mothers and those receiving public assistance. We also found that use of TV at bedtime was related to concurrent sleep issues and increases in later problem behavior. Mediational path analyses revealed that TV at bedtime affected behavior via sleep quality. Despite the heterogeneity within this Medicaid-eligible sample, the results underscore the universally harmful effects of TV use at bedtime and lend support for structuring nighttime routines for toddlers to promote better sleep and behavioral outcomes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The ability to track individual immune cells within the central nervous system has revolutionized our understanding of the roles that microglia and monocytes play in synaptic maintenance, plasticity, and neurodegenerative diseases. However, distinguishing between similar subpopulations of mobile immune cells over time during episodes of neuronal death and tissue remodeling has proven to be challenging., Methods: We recombineered a photoconvertible fluorescent protein (Dendra2; D2) downstream of the Cx3cr1 promoter commonly used to drive expression of fluorescent markers in microglia and monocytes. Like the popular Cx3cr1-GFP line (Cx3cr1 +/GFP ), naïve microglia in Cx3cr1-Dendra2 mice (Cx3cr1 +/D2 ) fluoresce green and can be noninvasively imaged in vivo throughout the CNS. In addition, individual D2-expressing cells can be photoconverted, resulting in red fluorescence, and tracked unambiguously within a field of green non-photoconverted cells for several days in vivo., Results: Dendra2-expressing retinal microglia were noninvasively photoconverted in both ex vivo and in vivo conditions. Local in vivo D2 photoconversion was sufficiently robust to quantify cell subpopulations by flow cytometry, and the protein was stable enough to survive tissue processing for immunohistochemistry. Simultaneous in vivo fluorescence imaging of Dendra2 and light scattering measurements (Optical Coherence Tomography, OCT) were used to assess responses of individual microglial cells to localized neuronal damage and to identify the infiltration of monocytes from the vasculature in response to large scale neurodegeneration., Conclusions: The ability to noninvasively and unambiguously track D2-expressing microglia and monocytes in vivo through space and time makes the Cx3cr1-Dendra2 mouse model a powerful new tool for disentangling the roles of distinct immune cell subpopulations in neuroinflammation., (© 2021. The Author(s).)

Objective: Ischemic stroke (IS) in young patients may differ in etiology and prognosis from later-life IS, which is much more common. A number of single-center and population-based cohorts of affected individuals have been published, but information on the long-term prognosis of these patients is limited., Methods: IS patients (≤55 years), discharged over a 10-year period, were evaluated and prospectively followed. Subgroups were evaluated for type of stroke, antecedent risk factors (RF), long-term outcomes, and occupational status over several years of follow-up., Results: 178 IS individuals from 2001-2010 were divided into older (46-55, n = 118) and younger (18-45, n = 60) age groups. Traditional RF-hypertension, diabetes mellitus, hyperlipidemia-were significantly associated with IS, and increased with age. The distribution and type of IS were similar in both groups, except for an increase in small vessel IS among the older subgroup (p = .003). Of the evaluable patients at 5.1 ± 2.5 years of follow-up (n = 138), a similar proportion of patients in both subgroups had a recurrent IS, but no significant differences were found in most disability indices. Approximately one third of patients suffered from moderate to severe disability, and were unable to return to their prior work., Conclusions: Younger and older IS patients are generally predisposed from the same traditional RF which progress with age. Long-term disabilities tend to worsen over time due to recurrent vascular events. These data emphasize the need for a strategy for early identification of the already well-known stroke RF in younger stroke patients., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

We present a reliable and accurate solution to the induced fit docking problem for protein-ligand binding by combining ligand-based pharmacophore docking, rigid receptor docking, and protein structure prediction with explicit solvent molecular dynamics simulations. This novel methodology in detailed retrospective and prospective testing succeeded to determine protein-ligand binding modes with a root-mean-square deviation within 2.5 Å in over 90% of cross-docking cases. We further demonstrate these predicted ligand-receptor structures were sufficiently accurate to prospectively enable predictive structure-based drug discovery for challenging targets, substantially expanding the domain of applicability for such methods.

Poverty remains a critical predictor of children's school readiness, health and longer term outcomes. Early relational health (ERH) (ie, parenting practices and relationship quality) mediates the impact of poverty on child development, and thus has been the focus of many parenting interventions. Despite the documented efficacy of parenting interventions at reducing poverty-related disparities in child health and development, several key barriers prevent achieving population-level reach to families with young children. In the current paper we highlight several of these barriers including gaining population-level access to young children and families, reaching families only through single points of access, addressing the significant heterogeneity of risk that exists among families living in poverty, as well as addressing each of these barriers in combination. We suggest that understanding and confronting these barriers will allow family-centered interventions to more effectively address issues related to ERH at a population level, which in turn will reduce poverty-related disparities in child development., (Copyright © 2020 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Heterogeneity in risk among low-income families suggests the need for tiered interventions to prevent disparities in school readiness. Smart Beginnings (SB) integrates two interventions: Video Interaction Project (VIP) (birth to 3 years), delivered universally to low-income families in pediatric primary care, and Family Check-Up (6 months to 3 years), targeted home visiting for families with additional family risks. Our objective was to assess initial SB impacts on parent-child activities and interactions at 6 months, reflecting early VIP exposure., Methods: Two-site randomized controlled trial in New York City (84% Latinx) and Pittsburgh (81% Black), with postpartum enrollment and random assignment to treatment (SB) or control. At 6 months, we assessed parent-child interactions through surveys (StimQ, Parenting Your Baby) and observation (video-recorded play, coded by using Parent-Child Interaction Rating Scales - Infant Adaptation)., Results: A total of 403 families were enrolled at child's birth (201 treatment) with 362 (89.8%) assessed at 6 months. Treatment families had increased StimQ, including total score (Cohen's d = 0.28; P < .001) and domains reflecting reading ( d = 0.23; P = .02) and teaching ( d = 0.25; P = .01), and Parent-Child Interaction Rating Scales - Infant Adaptation, including a cognitive stimulation factor ( d = 0.40; P < .001) and domains reflecting support for cognitive development ( d = 0.36; P < .001), and language quantity (0.40; P < .001) and quality ( d = 0.37; P < .001). Thus, significant effects emerged across a broad sample by using varied methodologies., Conclusions: Findings replicate and extend previous VIP findings across samples and assessment methodologies. Examining subsequent assessments will determine impacts and feasibility of the full SB model, including potential additive impacts of Family Check-Up for families at elevated risk., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)

Vertebrate retinal photoreceptors signal light by suppressing a circulating "dark current" that maintains their relative depolarization in the dark. This dark current is composed of an inward current through CNG channels and NCKX transporters in the outer segment that is balanced by outward current exiting principally from the inner segment. It has been hypothesized that Kv2.1 channels carry a predominant fraction of the outward current in rods. We examined this hypothesis by comparing whole cell, suction electrode, and electroretinographic recordings from Kv2.1 knockout (Kv2.1-/-) and wild-type (WT) mouse rods. Single cell recordings revealed flash responses with unusual kinetics, and reduced dark currents that were quantitatively consistent with the measured depolarization of the membrane resting potential in the dark. A two-compartment (outer and inner segment) physiological model based on known ionic mechanisms revealed that the abnormal Kv2.1-/- rod photoresponses arise principally from the voltage dependencies of the known conductances and the NCKX exchanger, and a highly elevated fraction of inward current carried by Ca2+ through CNG channels due to the aberrant depolarization. Kv2.1-/- rods had shorter outer segments than WT and dysmorphic mitochondria in their inner segments. Optical coherence tomography of knockout animals demonstrated a slow photoreceptor degeneration over a period of 6 mo. Overall, these findings reveal that Kv2.1 channels carry 70-80% of the non-NKX outward dark current of the mouse rod, and that the depolarization caused by the loss of Kv2.1 results in elevated Ca2+ influx through CNG channels and elevated free intracellular Ca2+, leading to progressive degeneration., (© 2021 Fortenbach et al.)

Bartonella henselae endocarditis mimicking systemic vasculitis has been reported in patients with valvulopathy. Herein, we describe a patient with B. henselae endocarditis involving a prosthetic pulmonic valve with positive anti-dsDNA antibodies misdiagnosed with systemic lupus erythematosus (SLE) based on the revised classification SLE criteria.

Photoreceptors are highly specialized sensory neurons with unique metabolic and physiological requirements. These requirements are partially met by Müller glia and cells of the retinal pigment epithelium (RPE), which provide essential metabolites, phagocytose waste, and control the composition of the surrounding microenvironment. A third vital supporting cell type, the retinal microglia, can provide photoreceptors with neurotrophic support or exacerbate neuroinflammation and hasten neuronal cell death. Understanding the physiological requirements for photoreceptor homeostasis and the factors that drive microglia to best promote photoreceptor survival has important implications for the treatment and prevention of blinding degenerative diseases like retinitis pigmentosa and age-related macular degeneration.

The retinal ganglion cell (RGC) competence factor ATOH7 is dynamically expressed during retinal histogenesis. ATOH7 transcription is controlled by a promoter-adjacent primary enhancer and a remote shadow enhancer (SE). Deletion of the ATOH7 human SE causes nonsyndromic congenital retinal nonattachment (NCRNA) disease, characterized by optic nerve aplasia and total blindness. We used genome editing to model NCRNA in mice. Deletion of the murine SE reduces Atoh7 messenger RNA (mRNA) fivefold but does not recapitulate optic nerve loss; however, SE del /knockout (KO) trans heterozygotes have thin optic nerves. By analyzing Atoh7 mRNA and protein levels, RGC development and survival, and chromatin landscape effects, we show that the SE ensures robust Atoh7 transcriptional output. Combining SE deletion and KO and wild-type alleles in a genotypic series, we determined the amount of Atoh7 needed to produce a normal complement of adult RGCs, and the secondary consequences of graded reductions in Atoh7 dosage. Together, these data reveal the workings of an evolutionary fail-safe, a duplicate enhancer mechanism that is hard-wired in the machinery of vertebrate retinal ganglion cell genesis., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

This study examined the interrelated and longitudinal impacts of parent-child shared book reading, parenting stress, and early relational health, as measured by both parental warmth and parent sensitivity, from infancy to toddlerhood. To extend findings from previous studies of collateral effects that have been conducted in parenting interventions, we examined parenting behaviors in a broader context to determine whether shared book reading would confer collateral benefits to the parent and parent-child relationship beyond those expected (i.e., language and literacy). It was hypothesized that positive parent-child interactions, such as shared reading, would have positive impacts on parent outcomes such as parenting stress, parental warmth, and sensitivity. The sample consisted of 293 low-income mothers and their children who participated in a randomized controlled trial. Shared book reading, parenting stress, and parental warmth were assessed when children were 6 and 18 months old. We computed a series of cross-lagged structural equation models to examine longitudinal interrelations among these three factors. Results indicated that shared book reading at 6 months was associated with increases in observed and reported parental warmth and observed sensitivity and decreases in parenting stress at 18 months, controlling for baseline risk factors and treatment group status. These findings suggest that early parent-child book reading can have positive collateral impacts on parents' stress and the parent-child relationship over time. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Objective: To examine the associations between breastfeeding intensity and underexplored features of maternal-child interaction quality over and above the influence of breastfeeding initiation., Methods: The current study leveraged an on-going, multisite randomized controlled trial of a tiered parenting program for 462 Medicaid-eligible mothers and their infants in the United States. We examined whether breastfeeding intensity and exclusivity was associated with observed maternal sensitivity, intrusiveness, and detachment, as well as self-reported maternal verbal responsiveness, 6 months infant age. Analyses controlled for breastfeeding initiation, demographics, and early parenting experiences., Results: Higher intensity breastfeeding at 6 months was significantly related to higher maternal sensitivity (β = 0.12, p = 0.004) and lower maternal intrusiveness (β = -0.10, p = 0.045). There was no significant association between breastfeeding intensity at 6 months and detachment (β = -0.02, no significant [ns]) or self-reported verbal responsiveness (β = 0.11, ns). Results were the same when intensity was measured as a dichotomous indicator for exclusive breastfeeding. Effect sizes were small-to-moderate, ranging from Cohen's d = 0.26 to 0.31. Associations did not vary by site, race/ethnicity, infant difficultness, or household poverty., Conclusion: The finding that breastfeeding intensity was significantly and independently associated with maternal sensitivity and intrusiveness is novel in the literature on low-income families from the United States. These findings have implications for breastfeeding promotion strategies and indicate that future research should explore synergistic or spillover effects of interventions aimed at maternal-child interaction quality into the infant feeding domain, particularly in the primary care setting.

Past research on predictors of participation in early childhood parenting programs suggest that families experiencing higher levels of sociodemographic adversity (e.g., younger maternal age, single parenthood, lower income or education) are less likely to participate in parenting programs. This is significant, as it may indicate that those most in need of additional support are the least likely to receive it. Data from a randomized control trial (RCT) of Smart Beginnings, an integrated, tiered model for school readiness, were used to explore predictors of attendance in Video Interaction Project (VIP) through 6 months. VIP is a primary preventive intervention delivered in tandem with pediatric well-child visits, aimed at reducing income-based disparities in early child development through promotion of responsive parent-child interactions. Using Poisson distribution models (N = 403; treatment arm, n = 201), we find that demographic, socioeconomic status (SES), and psychosocial variables are associated with program attendance but not always in the expected direction. While analyses show that first-time mothers have higher levels of program attendance as expected, we find that less-educated mothers and those with lower parenting self-efficacy have higher levels of attendance as well. The latter findings may imply that the VIP intervention is, by some indicators, effectively targeting families who are more challenging to engage and retain. Implications for pediatric-based interventions with population-level accessibility are discussed.

It has been recently demonstrated that structures corresponding to the cell bodies of highly transparent cells in the retinal ganglion cell layer could be visualized noninvasively in the living human eye by optical coherence tomography (OCT) via temporal averaging. Inspired by this development, we explored the application of volumetric temporal averaging in mice, which are important models for studying human retinal diseases and therapeutic interventions. A general framework of temporal speckle-averaging (TSA) of OCT and optical coherence tomography angiography (OCTA) is presented and applied to mouse retinal volumetric data. Based on the image analysis, the eyes of mice under anesthesia exhibit only minor motions, corresponding to lateral displacements of a few micrometers and rotations of a fraction of 1 deg. Moreover, due to reduced eye movements under anesthesia, there is a negligible amount of motion artifacts within the volumes that need to be corrected to achieve volume coregistration. In addition, the relatively good optical quality of the mouse ocular media allows for cellular-resolution imaging without adaptive optics (AO), greatly simplifying the experimental system, making the proposed framework feasible for large studies. The TSA OCT and TSA OCTA results provide rich information about new structures previously not visualized in living mice with non-AO-OCT. The mechanism of TSA relies on improving signal-to-noise ratio as well as efficient suppression of speckle contrast due to temporal decorrelation of the speckle patterns, enabling full utilization of the high volumetric resolution offered by OCT and OCTA.

Microglia respond to damage and microenvironmental changes within the central nervous system by morphologically transforming and migrating to the lesion, but the real-time behavior of populations of these resident immune cells and the neurons they support have seldom been observed simultaneously. Here, we have used in vivo high-resolution optical coherence tomography (OCT) and scanning laser ophthalmoscopy with and without adaptive optics to quantify the 3D distribution and dynamics of microglia in the living retina before and after local damage to photoreceptors. Following photoreceptor injury, microglia migrated both laterally and vertically through the retina over many hours, forming a tight cluster within the area of visible damage that resolved over 2 wk. In vivo OCT optophysiological assessment revealed that the photoreceptors occupying the damaged region lost all light-driven signaling during the period of microglia recruitment. Remarkably, photoreceptors recovered function to near-baseline levels after the microglia had departed the injury locus. These results demonstrate the spatiotemporal dynamics of microglia engagement and restoration of neuronal function during tissue remodeling and highlight the need for mechanistic studies that consider the temporal and structural dynamics of neuron-microglia interactions in vivo., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Neuroinflammation commonly accompanies neurodegeneration, but the specific roles of resident and infiltrating immune cells during degeneration remains controversial. Much of the difficulty in assessing myeloid cell-specific functions during disease progression arises from the inability to clearly distinguish between activated microglia and bone marrow-derived monocytes and macrophages in various stages of differentiation and activation within the central nervous system. Using an inducible model of photoreceptor cell death, we investigated the prevalence of infiltrating monocytes and macrophage subpopulations after the initiation of degeneration in the mouse retina. In vivo retinal imaging revealed infiltration of CCR2 + leukocytes across retinal vessels and into the parenchyma within 48 hours of photoreceptor degeneration. Immunohistochemistry and flow cytometry confirmed and characterized these leukocytes as CD11b + CD45 + cells. Single-cell mRNA sequencing of the entire CD11b + CD45 + population revealed the presence of resting microglia, activated microglia, monocytes, and macrophages as well as 12 distinct subpopulations within these four major cell classes. Our results demonstrate a previously immeasurable degree of molecular heterogeneity in the innate immune response to cell-autonomous degeneration within the central nervous system and highlight the necessity of unbiased high-throughput and high-dimensional molecular techniques like scRNAseq to understand the complex and changing landscape of immune responders during disease progression.

Speckle is an inevitable consequence of the use of coherent light in imaging and acts as noise that corrupts image formation in most applications. Optical coherence tomographic imaging, as a technique employing coherence time gating, suffers from speckle. We present here a novel method of suppressing speckle noise intrinsically compatible with adaptive optics (AO) for confocal coherent imaging: modulation of the phase in the system pupil aperture with a segmented deformable mirror (DM) to introduce minor perturbations in the point spread function. This approach creates uncorrelated speckle patterns in a series of images, enabling averaging to suppress speckle noise while maintaining structural detail. A method is presented that efficiently determines the optimal range of modulation of DM segments relative to their AO-optimized position so that speckle noise is reduced while image resolution and signal strength are preserved. The method is active and independent of sample properties. Its effectiveness and efficiency are quantified and demonstrated by both ex vivo non-biological and in vivo biological applications., Competing Interests: R.J.Z, E.N.P and P. Z are listed as inventors on a patent application related to the work presented in this manuscript.

Background: Activation of resident microglia accompanies every known form of neurodegeneration, but the involvement of peripheral monocytes that extravasate and rapidly transform into microglia-like macrophages within the central nervous system during degeneration is far less clear., Methods: Using a combination of in vivo ocular imaging, flow cytometry, and immunohistochemistry, we investigated the response of infiltrating cells in a light-inducible mouse model of photoreceptor degeneration., Results: Within 24 h, resident microglia became activated and began migrating to the site of degeneration. Retinal expression of CCL2 increased just prior to a transient period of CCR2 + cell extravasation from the retinal vasculature. Proliferation of microglia and monocytes occurred concurrently; however, there was no indication of proliferation in either population until 72-96 h after neurodegeneration began. Eliminating CCL2-CCR2 signaling blocked monocyte recruitment, but did not alter the extent of retinal degeneration., Conclusions: These results demonstrate that the immune response to photoreceptor degeneration includes both resident microglia and monocytes, even at very early times. Surprisingly, preventing monocyte infiltration did not block neurodegeneration, suggesting that in this model, degeneration is limited by cell clearance from other phagocytes or by the timing of intrinsic cell death programs. These results show monocyte involvement is not limited to disease states that overwhelm or deplete the resident microglial population and that interventions focused on modulating the peripheral immune system are not universally beneficial for staving off degeneration.

Rods and cones mediate visual perception over 9 log units of light intensities, with both photoreceptor types contributing to a middle 3-log unit range that comprises most night-time conditions. Rod function in this mesopic range has been difficult to isolate and study in vivo because of the paucity of mutants that abolish cone signaling without causing photoreceptor degeneration. Here we describe a novel Gnat2 knockout mouse line (Gnat2 -/- ) ideal for dissecting rod and cone function. In this line, loss of Gnat2 expression abolished cone phototransduction, yet there was no loss of cones, disruption of the photoreceptor mosaic, nor change in general retinal morphology up to at least 9 months of age. Retinal microglia and Müller glia, which are highly sensitive to neuronal pathophysiology, were distributed normally with morphologies indistinguishable between Gnat2 -/- and wildtype adult mice. ERG recordings demonstrated complete loss of cone-driven a-waves in Gnat2 -/- mice; comparison to WT controls revealed that rods of both strains continue to function at light intensities exceeding 10 4 photoisomerizations rod -1 s -1 . We conclude that the Gnat2 -/- mouse is a preferred model for functional studies of rod pathways in the retina when degeneration could be an experimental confound., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Data from the Head Start Impact Study ( N = 1,141) and the Head Start Family and Child Experiences Survey, 2009 Cohort ( N = 825) were used to investigate whether Spanish instruction in Head Start differentially increased Spanish-speaking Dual Language Learners' (DLLs) academic achievement. Although hypothesized that Spanish instruction would be beneficial for DLLs' early literacy and math skills, results from residualized growth models showed there were no such positive associations. Somewhat surprisingly, DLL children instructed in Spanish had higher English receptive vocabulary skills at the end of the Head Start year than those not instructed, with children randomly assigned to Head Start and instructed in Spanish having the highest scores. Policy implications for Head Start-eligible Spanish-speaking DLLs are discussed.

Background: Retinal detachment (RD) can lead to proliferative vitreoretinopathy (PVR), a leading cause of intractable vision loss. PVR is associated with a cytokine storm involving common proinflammatory molecules like IL6, but little is known about the source and downstream signaling of IL6 and the consequences for the retina. Here, we investigated the early immune response and resultant cytokine signaling following RD in mice., Methods: RD was induced in C57BL/6 J and IL6 knockout mice, and the resulting inflammatory response was examined using immunohistochemistry and flow cytometry. Cytokines and signaling proteins of vitreous and retinas were quantified by multiple cytokine arrays and Western blotting. To attempt to block IL6 signaling, a neutralizing antibody of IL6 receptor α (IL6Rα) or IL6 receptor β (gp-130) was injected intravitreally immediately after RD., Results: Within one day of RD, bone marrow-derived Cd11b + monocytes had extravasated from the vasculature and lined the vitreal surface of the retina, while the microglia, the resident macrophages of the retina, were relatively unperturbed. Cytokine arrays and Western blot analysis revealed that this sterile inflammation did not cause activation of IL6 signaling in the neurosensory retina, but rather only in the vitreous and aqueous humor. Monocyte infiltration was inhibited by blocking gp130, but not by IL6 knockout or IL6Rα blockade., Conclusions: Together, our results demonstrate that monocytes are the primary immune cell mediating the cytokine storm following RD, and that any resulting retinal damage is unlikely to be a direct result of retinal IL6 signaling, but rather gp130-mediated signaling in the monocytes themselves. These results suggest that RD should be treated immediately, and that gp130-directed therapies may prevent PVR and promote retinal healing.

Introduction: The Weck Hem-o-lok™ Ligating clip is a routinely used hemostatic tool in robotic and laparoscopic surgery. It has been the practice in our institution to use such clips for hemostasis of the vascular bundles during robotic prostatectomy. Migration of such clips has been reported in the literature as single case reports. In this study, we present a case series of intravesical Weck clip extrusions presenting as bladder calculi. Such events have led to a change in our practice, and more research is needed to assess the impact of this change., Materials and Methods: A retrospective chart review was conducted over the period 2006-2011. Patients included in the study required cystoscopic intervention for removal of encrusted or impacted Weck clips. Primary data points included type of intervention required, time to presentation, and number of presentations. Postoperative anastomotic leak, duration of postoperative hospital stay, and initial operative time were also investigated., Results: Out of 570 total men undergoing robotic-assisted laparoscopic radical prostatectomy (RALRP), eight required return to the operating room for clip extraction (1.4%). Extraction methods included laser lithotripsy, blunt litholapaxy, and grasper extraction. Men experiencing clip migration were hospitalized for a longer period of time (7.6 days vs. 2.1 days, P < .01) and they required more blood transfusions (1.4 units vs. 0.05 units, P < .01) than men who did not experience clip migration. The most common site for clip intrusion was the bladder neck. Average time to presentation was 1.75 years., Discussion: Weck clip migration is a recognized complication of robotic-assisted radical prostatectomy. Men with recurrent urinary tract infection, bothersome voiding symptoms, or hematuria following RALRP should be considered for cystoscopic evaluation. Increased length of hospital stays and the need for a larger volume blood transfusion following prostatectomy were significant predictors of clip migration. More research is needed to determine if implemented changes to our surgical technique have mitigated these risks.

Ligand docking is a widely used tool for lead discovery and binding mode prediction based drug discovery. The greatest challenges in docking occur when the receptor significantly reorganizes upon small molecule binding, thereby requiring an induced fit docking (IFD) approach in which the receptor is allowed to move in order to bind to the ligand optimally. IFD methods have had some success but suffer from a lack of reliability. Complementing IFD with all-atom molecular dynamics (MD) is a straightforward solution in principle but not in practice due to the severe time scale limitations of MD. Here we introduce a metadynamics plus IFD strategy for accurate and reliable prediction of the structures of protein-ligand complexes at a practically useful computational cost. Our strategy allows treating this problem in full atomistic detail and in a computationally efficient manner and enhances the predictive power of IFD methods. We significantly increase the accuracy of the underlying IFD protocol across a large data set comprising 42 different ligand-receptor systems. We expect this approach to be of significant value in computationally driven drug design.

G-CSF is a myeloid growth factor produced by monocytes, macrophages, fibroblasts, and endothelial cells. Clinical uses of G-CSF includes mobilization of peripheral blood progenitor cells from healthy donors before hematopoietic stem cell transplantation, acceleration of neutrophil recovery following chemotherapy, and in the management of neutropenia due to other causes including AIDS and genetic disorders of granulocyte production. G-CSF is well tolerated and reports to be safe in healthy donors, although follow-up studies are limited in duration (D'Souza et al. in Transfus Med Rev 22(4):280-290, 2008).Isolated abdominal aortitis (IAA) is a rare disorder most commonly caused by the large-vessel vasculitides giant cell arteritis (GCA) and Takayasu arteritis, although it may also be associated with several other rheumatologic diseases and infections (Gornik and Creager in Circulation 117:3039-3051, 2008). To our knowledge, there only two cases have been published of IAA occurring in patients who had received G-CSF therapy (Dariea et al. in Rev Med Interne 25(3):225-229, 2004; Adiga et al. in Clin Drug Investig 29:821-825, 2009).We describe a case of a 55-year-old male, with peripheral vascular disease who after receiving Neupogen (G-CSF) developed a latent case of IAA. After further investigation and exclusion of other possible causative factors, we conclude that the most probable etiology is induction by G-CSF.

Unlabelled: The adeno-associated viruses (AAVs), which are being developed as gene delivery vectors, display differential cell surface glycan binding and subsequent tissue tropisms. For AAV serotype 1 (AAV1), the first viral vector approved as a gene therapy treatment, and its closely related AAV6, sialic acid (SIA) serves as their primary cellular surface receptor. Toward characterizing the SIA binding site(s), the structure of the AAV1-SIA complex was determined by X-ray crystallography to 3.0 Å. Density consistent with SIA was observed in a pocket located at the base of capsid protrusions surrounding icosahedral 3-fold axes. Site-directed mutagenesis substitution of the amino acids forming this pocket with structurally equivalent residues from AAV2, a heparan sulfate binding serotype, followed by cell binding and transduction assays, further mapped the critical residues conferring SIA binding to AAV1 and AAV6. For both viruses five of the six binding pocket residues mutated (N447S, V473D, N500E, T502S, and W503A) abolished SIA binding, whereas S472R increased binding. All six mutations abolished or decreased transduction by at least 50% in AAV1. Surprisingly, the T502S substitution did not affect transduction efficiency of wild-type AAV6. Furthermore, three of the AAV1 SIA binding site mutants-S472R, V473D, and N500E-escaped recognition by the anti-AAV1 capsid antibody ADK1a. These observations demonstrate that common key capsid surface residues dictate both virus binding and entry processes, as well as antigenic reactivity. This study identifies an important functional capsid surface "hot spot" dictating receptor attachment, transduction efficiency, and antigenicity which could prove useful for vector engineering., Importance: The adeno-associated virus (AAV) vector gene delivery system has shown promise in several clinical trials and an AAV1-based vector has been approved as the first gene therapy treatment. However, limitations still exist with respect to transduction efficiency and the detrimental effects of preexisting host antibodies. This study aimed to identify key capsid regions which can be engineered to overcome these limitations. A sialic glycan receptor recognition pocket was identified in AAV1 and its closely related AAV6, using X-ray crystallography. The site was confirmed by mutagenesis followed by cell binding and transduction assays. Significantly, residues controlling gene expression efficiency, as well as antibody escape variants, were also identified. This study thus provides, at the amino acid level, information for rational structural engineering of AAV vectors with improved therapeutic efficacy., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Data from the Head Start Impact Study ( N = 1,141) and the Head Start Family and Child Experiences Survey, 2009 Cohort ( N = 825) were used to describe child care enrollment decisions among Spanish-speaking Dual Language Learner (DLL) families. In particular, logistic regression models tested which child, family, and institutional characteristics predicted enrollment in early care and education (ECE) settings that used Spanish for instruction versus enrollment in settings that did not use Spanish. Results showed that whether the child's first language was exclusively Spanish and whether other DLL families previously attended the ECE arrangement strongly predicted whether that child enrolled. Policy implications for Head Start-eligible Spanish-speaking DLLs are discussed.