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Autistic children are less likely to be jointly engaged with a play partner than nonautistic children, negatively impacting social communication development. Promoting joint engagement during play can be an important target for educators of autistic students, but educator perceptions of autistic students may affect their interactions with students. This secondary data analysis investigated educator perceptions of the behaviors of their autistic students, their relationship on educator behavior, and their relationship on the implementation of an intervention promoting joint engagement. Participants included 66 autistic preschool students, and twelve educators from six preschools. Schools were randomized to educator training or a waitlist. Before training, educators rated their students controllability over autism related behaviors. To observe educator behavior, they were filmed playing for ten minutes with students, before and after receiving training. Ratings of controllability were positively correlated with cognitive scores, and negatively correlated with ADOS (Autism Diagnostic Observation Schedule) comparison scores. Furthermore, educator ratings of controllability predicted joint engagement strategies used by educators during play. Educators tended to use strategies promoting joint engagement for students perceived as more able to control their autism spectrum disorder behavior. Among educators that received JASPER (Joint Attention, Symbolic Play, Engagement, and Regulation) training, ratings of controllability did not predict changes in strategy scores after training. Educators were able to learn and implement new joint engagement strategies despite their initial perceptions.

Early intervention can provide a great benefit for children with autism spectrum disorder (ASD). However, no single intervention is effective for all children. Even when an intervention is effective overall, individual child response varies. Some children make incredible progress, and others make slow or no progress. Therefore, it is important that the field move towards developing methods to personalize intervention. Operationalizing meaningful change and predicting intervention response are critical steps in designing systematic and personalized early intervention. The present research used improvement in expressive language to group children that received a targeted social communication early intervention, Joint Attention, Symbolic Play, Engagement, and Regulation (JASPER), into super responders and slow responders. Using baseline data from traditional standardized assessments of cognition and behavioral data from validated experimental measures of play and social communication, we used conditional inference tree models to predict responder status. From a sample of 99 preschool age, limited language children with ASD, play diversity was the most significant predictor of responder status. Children that played functionally with a wider variety of toys had increased odds of being a super responder to JASPER. A combination of lower play diversity and impairments in fine motor abilities increased the odds of children being slow responders to JASPER. Results from the present study can inform future efforts to individualize intervention and systematic approaches to augmenting treatment in real time. LAY SUMMARY: To help us answer the question of for whom an intervention works best, we examined 99 children, age three to five, who qualified as being limited spoken language communicators, and received a targeted intervention for social communication and language. We used child characteristics before intervention to predict which children would improve their language the most and found that the ability to play appropriately with a wider variety of toys predicted the best improvements in expressive language. These findings will help better inform future work to individualize intervention based on the unique needs of each child.

Zika virus (ZIKV) is unique among mosquito-borne flaviviruses in that it is also vertically and sexually transmitted by humans. The male reproductive tract is thought to be a ZIKV reservoir; however, the reported magnitude and duration of viral persistence in male genital tissues vary widely in humans and non-human primate models. ZIKV tissue and cellular tropism and potential effects on male fertility also remain unclear. The objective of this study was to resolve these questions by analyzing archived genital tissues from 51 ZIKV-inoculated male macaques and correlating data on plasma viral kinetics, tissue tropism, and ZIKV-induced pathological changes in the reproductive tract. We hypothesized that ZIKV would persist in the male macaque genital tract for longer than there was detectable viremia, where it would localize to germ and epithelial cells and associate with lesions. We detected ZIKV RNA and infectious virus in testis, epididymis, seminal vesicle, and prostate gland. In contrast to prepubertal males, sexually mature macaques were significantly more likely to harbor persistent ZIKV RNA or infectious virus somewhere in the genital tract, with detection as late as 60 days post-inoculation. ZIKV RNA localized primarily to testicular stem cells/sperm precursors and epithelial cells, including Sertoli cells, epididymal duct epithelium, and glandular epithelia of the seminal vesicle and prostate gland. ZIKV infection was associated with microscopic evidence of inflammation in the epididymis and prostate gland of sexually mature males, pathologies that were absent in uninfected controls, which could have significant effects on male fertility. The findings from this study increase our understanding of persistent ZIKV infection which can inform risk of sexual transmission during assisted reproductive therapies as well as potential impacts on male fertility.

BackgroundGlobal gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context.MethodsWe used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments & Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age.ResultsThe SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10- 9), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10- 8). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells.ConclusionFocusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids.

Actinotignum schaalii is an anaerobic, gram-positive commensal organism of the urogenital tract. A. schaalii typically causes urinary tract infections, predominantly in the elderly. Here, we describe the first case of A. schaalii infection presenting as cellulitis and abscess in a patient with common variable immunodeficiency. The patient was successfully treated with an incision and drainage and a prolonged antibiotic course. A. schaalii infection should be considered in sterile abscesses, and anaerobic cultures should be requested in the absence of positive routine cultures.

Efforts to decrease disparity in diagnosis and treatment for under-resourced children with developmental delays, such as autism spectrum disorder, have led to increased interest in developing programs in community settings. One potential setting that has already demonstrated feasibility in conducting universal screening is the childcare setting. The current study conducted developmental screening in a total of 116 children ages 16-80 months of age in an urban low-income community childcare center. Parents of 20 children who screened positive were enrolled in the intervention phase of the study, where children received a staff-delivered targeted early intervention or a waitlist control condition. Given the small and imbalanced sample sizes, confidence intervals from mixed effect models were used to measure changes across time for each group. Of the children who received treatment, there was an average increase in child initiated joint engagement, symbolic play, and language use. This study provides initial feasibility data for the implementation of a screening and early intervention program to service a predominantly low-resource and ethnically diverse population within the childcare system in a large metropolitan city. Autism Res 2019, 12: 1423-1433. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Identifying and delivering treatment services for young children with developmental delays, such as autism spectrum disorder, may be most successful in community settings, especially for those children from under-resourced areas. This study found preliminary evidence that the childcare setting is a good place to conduct screening and deliver early interventions for children at risk for autism and other developmental delays.

ObjectivesNonalcoholic fatty liver disease (NAFLD) is common; however, no information is available on how pediatric gastroenterologists in the United States manage NAFLD. Therefore, study objectives were to understand how pediatric gastroenterologists in the US approach the management of NAFLD, and to identify barriers to care for children with NAFLD.MethodsWe performed structured one-on-one interviews to ascertain each individual pediatric gastroenterologist's approach to the management of NAFLD in children. Responses were recorded from open-ended questions regarding screening for comorbidities, recommendations regarding nutrition, physical activity, medications, and perceived barriers to care.ResultsResponse rate was 72.0% (486/675). Mean number of patients examined per week was 3 (standard deviation [SD] 3.5). Dietary intervention was recommended by 98.4% of pediatric gastroenterologists. Notably, 18 different dietary recommendations were reported. A majority of physicians provided targets for exercise frequency (72.6%, mean 5.6 days/wk, SD 1.6) and duration (69.9%, mean 40.2 minutes/session, SD 16.4). Medications were prescribed by 50.6%. Almost one-half of physicians (47.5%) screened for type 2 diabetes, dyslipidemia, and hypertension. Providers who spent more than 25 minutes at the initial visit were more likely to screen for comorbidities (P = 0.003). Barriers to care were reported by 92.8% with 29.0% reporting ≥3 barriers.ConclusionsThe majority of US pediatric gastroenterologists regularly encounter children with NAFLD. Varied recommendations regarding diet and exercise highlight the need for prospective clinical trials. NAFLD requires a multidimensional approach with adequate resources in the home, community, and clinical setting.

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection.

The association of bullous pemphigoid with melanoma remains controversial and poorly understood. Recent studies report the presence of the bullous pemphigoid antigen, BP180, in melanoma cells, yet not normal melanocytes, suggesting an underlying mechanism for cases of melanoma-associated bullous pemphigoid. We report on an 88-year-old woman who showed a temporal relationship between the development of bullous pemphigoid and melanoma. The patient did not receive programmed death ligand 1 inhibitor therapy and improved rapidly following complete excision of her melanoma, with clobetasol, doxycycline, and niacinamide. We review the literature on the relationship between bullous pemphigoid and melanoma, and propose a mechanism underlying a melanoma-associated bullous pemphigoid.

In Drosophila, P-element transposition causes mutagenesis and genome instability during hybrid dysgenesis. The P-element 31-bp terminal inverted repeats (TIRs) contain sequences essential for transposase cleavage and have been implicated in DNA repair via protein-DNA interactions with cellular proteins. The identity and function of these cellular proteins were unknown. Biochemical characterization of proteins that bind the TIRs identified a heterodimeric basic leucine zipper (bZIP) complex between an uncharacterized protein that we termed "Inverted Repeat Binding Protein (IRBP) 18" and its partner Xrp1. The reconstituted IRBP18/Xrp1 heterodimer binds sequence-specifically to its dsDNA-binding site within the P-element TIRs. Genetic analyses implicate both proteins as critical for repair of DNA breaks following transposase cleavage in vivo. These results identify a cellular protein complex that binds an active mobile element and plays a more general role in maintaining genome stability.

UnlabelledWe used an osteopenic adult ovariectomized (OVX) rat model to evaluate various sequential treatments for osteoporosis, using FDA-approved agents with complementary tissue-level mechanisms of action. Sequential treatment for 3 months each with alendronate (Aln), followed by PTH, followed by resumption of Aln, created the highest trabecular bone mass, best microarchitecture, and highest bone strength.IntroductionIndividual agents used to treat human osteoporosis reduce fracture risk by ∼ 50-60%. As agents that act with complementary mechanisms are available, sequential therapies that mix antiresorptive and anabolic agents could improve fracture risk reduction, when compared with monotherapies.MethodsWe evaluated bone mass, bone microarchitecture, and bone strength in adult OVX, osteopenic rats, during different sequences of vehicle (Veh), parathyroid hormone (PTH), Aln, or raloxifene (Ral) in three 90-day treatment periods, over 9 months. Differences among groups were evaluated. The interrelationships of bone mass and microarchitecture endpoints and their relationship to bone strength were studied.ResultsEstrogen deficiency caused bone loss. OVX rats treated with Aln monotherapy had significantly better bone mass, microarchitecture, and bone strength than untreated OVX rats. Rats treated with an Aln drug holiday had bone mass and microarchitecture similar to the Aln monotherapy group but with significantly lower bone strength. PTH-treated rats had markedly higher bone endpoints, but all were lost after PTH withdrawal without follow-up treatment. Rats treated with PTH followed by Aln had better bone endpoints than those treated with Aln monotherapy, PTH monotherapy, or an Aln holiday. Rats treated initially with Aln or Ral, then switched to PTH, also had better bone endpoints, than monotherapy treatment. Rats treated with Aln, then PTH, and returned to Aln had the highest values for all endpoints.ConclusionOur data indicate that antiresorptive therapy can be coupled with an anabolic agent, to produce and maintain better bone mass, microarchitecture, and strength than can be achieved with any monotherapy.

Aging reduces the number of mesenchymal stem cells (MSCs) that can differentiate into osteoblasts in the bone marrow, which leads to impairment of osteogenesis. However, if MSCs could be directed toward osteogenic differentiation, they could be a viable therapeutic option for bone regeneration. We have developed a method to direct MSCs to the bone surface by attaching a synthetic high-affinity and specific peptidomimetic ligand (LLP2A) against integrin α4β1 on the MSC surface to a bisphosphonate (alendronate, Ale) that has a high affinity for bone. LLP2A-Ale induced MSC migration and osteogenic differentiation in vitro. A single intravenous injection of LLP2A-Ale increased trabecular bone formation and bone mass in both xenotransplantation studies and in immunocompetent mice. Additionally, LLP2A-Ale prevented trabecular bone loss after peak bone acquisition was achieved or as a result of estrogen deficiency. These results provide proof of principle that LLP2A-Ale can direct MSCs to the bone to form new bone and increase bone strength.

Although a highly heritable and disabling disease, bipolar disorder's (BD) genetic variants have been challenging to identify. We present new genotype data for 1,190 cases and 401 controls and perform a genome-wide association study including additional samples for a total of 2,191 cases and 1,434 controls. We do not detect genome-wide significant associations for individual loci; however, across all SNPs, we show an association between the power to detect effects calculated from a previous genome-wide association study and evidence for replication (P = 1.5×10(-7)). To demonstrate that this result is not likely to be a false positive, we analyze replication rates in a large meta-analysis of height and show that, in a large enough study, associations replicate as a function of power, approaching a linear relationship. Within BD, SNPs near exons exhibit a greater probability of replication, supporting an enrichment of reproducible associations near functional regions of genes. These results indicate that there is likely common genetic variation associated with BD near exons (±10 kb) that could be identified in larger studies and, further, provide a framework for assessing the potential for replication when combining results from multiple studies.

Osteoporotic patients treated with antiresorptive or anabolic agents experience an increase in bone mass and a reduction in incident fractures. However, the effects of these medications on bone quality and strength after a prolonged discontinuation of treatment are not known. We evaluated these effects in an osteoporotic rat model. Six-month-old ovariectomized (OVX) rats were treated with placebo, alendronate (ALN, 2 µg/kg), parathyroid hormone [PTH(1-34); 20 µg/kg], or raloxifene (RAL, 2 mg/kg) three times a week for 4 months and withdrawn from the treatments for 8 months. Treatment with ALN, PTH, and RAL increased the vertebral trabecular bone volume (BV/TV) by 47%, 53%, and 31%, with corresponding increases in vertebral compression load by 27%, 51%, and 31%, respectively (p