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Five Key Points • Subglottic stenosis (SGS) is the commonest tracheobronchial manifestation of granulomatosis with polyangiitis (GPA), with early recognition and treatment key to preventing its vasculitic progression and fibrosis. • Previous studies have shown SGS to be the first feature of GPA in 4% of cases. It is not uncommon to see negative biochemical (10% ANCA negative) and negative histological biopsies (77% of head and neck specimens are negative). • Our management strategy emphasized rapid SGS-GPA treatment with limited surgical manipulation of the airway and systemic immunosuppression (IS) to prevent evolution of SGS & concurrent systemic vasculitic relapse. • In our study early multi-disciplinary team involvement to deliver induction IS in the presence of active SGS-GPA led to a procedure free interval (PFI) of 31.3 months. This is a significant increase compared to other published studies. • Nineteen percent (4/21) of the cohort did not require any surgical input following induction IS.

The purpose of the present study was to investigate the impact of student behavior on vocabulary knowledge development across three groups of kindergarteners: Intervention, Control, and Reference. Kindergarten students (n = 1132) from forty schools across Rhode Island, Connecticut, and Oregon completed a vocabulary program approximately 20 weeks in duration, including an additional vocabulary intervention for students in the Intervention group. Each student was assessed on four different vocabulary knowledge measures before and after completion of the vocabulary program, using both standardized and experimenter-developed formats: Target Receptive, Target Expressive, PPVT-4, and EVT-2. Results showed significant impact on vocabulary outcomes by classroom behavior and across groups of students. Students who received the supplemental vocabulary intervention performed as well, or better than reference peers on experimenter-developed measures of target words. Additionally, intervention student behavior was considered between whole-class and small group settings; however, no significant effects were found on vocabulary knowledge outcomes. These results suggest that while behavior did not have an impact on vocabulary knowledge outcomes in this study, all students successfully made considerable gains in vocabulary knowledge upon completion of this vocabulary program and intervention.

The purpose of the present study was to examine kindergarten student performance on a story retell task across at-risk and typically achieving groups (Intervention, Control, Reference) and language status (English-only, Englishlanguage learners). Additionally, the current study examined the relationship between vocabulary knowledge and the quality of production on a Story Retell task. Kindergarten students (n = 540) from twenty-two schools across Rhode Island, Connecticut, and Oregon completed a vocabulary program approximately 20 weeks in duration, including an additional vocabulary intervention for students in the Intervention group. Each student was assessed on vocabulary knowledge measures before and after completion of the vocabulary program, using both standardized and experimenter-developed formats: PPVT-4, Receptive Target Word, and Expressive Target Word. In addition, a Story Retell measure was completed with all students at the end of the school year. Results showed that language status had no impact when considering Story Retell performance across different groups of students within the course of an academic program. The students in the Intervention group performed better on the Story Retell task than the students in the Control group and the students in the Reference group performed better than both Intervention and Control groups. Further, the current study demonstrated that all vocabulary measures were positively correlated with the Story Retell comprehension measure and that PPVT-4 growth accounted for more unique variance in Story Retell performance than initial PPVT-4 scores. It was also established that student performance on the Expressive Target Word measure was the best predictor of the quality of Story Retell.

We evaluated current trends of pediatric urology exposure during the 3-year pediatric residency period nationwide. We also evaluated the opinions of urology and pediatric residency program directors regarding the need for additional exposure to pediatric urology.From February to October 2011 we administered 2 concurrent electronic surveys. One set was sent to urology residency program directors and the other was sent to pediatric residency program directors. The surveys consisted of 6 and 12 questions, respectively. The questions were created to best evaluate exposure to pediatric urology from the perspective of each cohort. Response data were analyzed using the chi-square test and case-control methods.Of the 117 accredited urology residency program directors and 190 pediatric residency program directors 51 (43.5%) and 78 (41.1%), respectively, completed the survey. Urology program directors answered favorably by a margin of 66% toward increased involvement with pediatric residents, while 84.6% of pediatric residency directors would like increased exposure to pediatric urology. Furthermore, 87% of pediatric residency directors reported that they do not require residents to have a formal pediatric urology rotation. However, in 65% of pediatric programs residents received some form of didactic education.These results show the desire on the part of urology and pediatric residency program directors for pediatric residents to have greater exposure to pediatric urology, particularly didactic and bedside teaching in the management of pediatric urological disorders. Increasing pediatric resident exposure to pediatric urological pathology and treatment during training would have a positive impact on the subsequent diagnosis and care of pediatric urological conditions.

Multiple reports have shown that echocardiograms are neither cost-effective nor of high diagnostic yield for a number of indications. This study sought to evaluate the impact of indications and provider type on the diagnostic yield of first-time outpatient pediatric echocardiograms. All initial echocardiograms interpreted at our institution from February 2009 to December 2014 were reviewed retrospectively. Positive findings were defined as any abnormality of structure or function. Ordering physicians were grouped as Primary Care, Subspecialist, or Cardiologist. A cost analysis of cardiac consultation versus direct echocardiogram ordering was performed using 2014 Arkansas Medicaid office-based allowables. A total of 7854 echocardiograms had complete data and were included in the study. Median age was 7.2 years (range 2 days to 18.9 years). There were 1179 (15%) abnormal first-time echocardiograms. Diagnostic yields were particularly low for the indications of chest pain (4.9%), syncope (5.3%), and palpitations (9.1%). When ordered by the Cardiology group, echocardiographic yields were increased 35% for all indications (p

Background. Agitation and aggression are common behaviors that often lead to psychiatric emergency center (PEC) admission of nursing home patients with dementia or Alzheimer’s disease. However, few if any data are available that adequately describe characteristics and psychosocial triggers of agitation and aggression leading to transport and admission to a PEC. Methods. A preliminary investigation to explore all possible characteristics and psychosocial predictors of PEC transport and length of stay in men and women nursing home patients with dementia or Alzheimer’s disease was designed. Frequency distributions, chi-square, analyses of variance, and regression analyses were used to analyze the data. Results. One hundred PEC patient charts were reviewed, of which 58 charts were missing information and 42 charts provided evaluable data. Nursing homes located in impoverished areas transported patients to the PEC significantly more often than those in affluent areas. A disconnect between the agitated/aggressive mental state reported by nursing home staff leading to the PEC transport and the calm/cooperative mental status PEC clinicians observed during the admission process was evident. Data from the charts also showed that 74% of patients received off-label antipsychotics rather than FDA-approved medications to treat dementia or Alzheimer’s disease. Conclusions. This is one of the few studies to identify characteristics and psychosocial triggers of PEC use and length of stay in nursing home patients. We also highlight potentially dangerous antipsychotic use in dementia and Alzheimer disease. Thus, our data add to the existing knowledge base regarding PEC utilization, length of stay, and pharmacotherapy in nursing home patients with dementia and Alzheimer’s disease. Given the preliminary nature of this study, however, the results should be interpreted with caution.

Parents rely on pediatricians to monitor their child's development. The American Academy of Pediatrics recommends routine developmental screening with both broadband and autism-specific instruments at specified ages. If broadband screeners can detect autism risk, this might minimize the burden of administering autism-specific screens to all children. The current study examines the ability of the Ages and Stages Questionnaire-Third Edition (ASQ-3) to identify children at risk for autism. We looked at ASQ-3 scores of children who screen positive on the Modified Checklist for Autism in Toddlers-Revised (M-CHAT-R), children who continue to screen positive on the M-CHAT-R Follow-up Interview, and children diagnosed with autism spectrum disorder (ASD).A total of 2848 toddlers, aged 16 to 30 months, were screened with the ASQ-3 and M-CHAT-R across 20 pediatric sites. Children who screened positive on the M-CHAT-R and its follow-up interview were offered a diagnostic evaluation.Using the "monitor and/or fail" cutoff on any domain, the ASQ-3 identified 87% of the children who screened positive on the M-CHAT-R with follow-up and 95% (20/21) of those diagnosed with an ASD. Monitor and/or fail on the Communication domain alone also identified 95% of the diagnosed children.Scores below the "monitor" cutoff on the Communication domain of the ASQ-3 can indicate initial concern requiring autism-specific follow-up. If these results are confirmed with a sample large enough to separately examine toddlers of different ages and different cultural backgrounds, it may be feasible to implement a 2-stage screening strategy, with autism-specific screening reserved for those who are positive on a broadband screen.

Background The purpose of this study was to assess swallowing outcomes in a cohort of patients with oropharyngeal squamous cell carcinoma (SCC) undergoing nonoperative treatment. Methods We conducted a retrospective study of patients who completed videofluoroscopic swallowing studies (VFSS) after nonoperative treatment of oropharyngeal SCC. All patients received intensity-modulated radiation therapy (IMRT) ± chemotherapy. Swallowing abnormalities were recorded and the Penetration Aspiration Scale (PAS) quantified airway infiltration. Results Posttreatment VFSS (n = 71) occurred at an average of 4.69 months posttreatment. Abnormal PAS was noted in 45% of swallow studies. Swallowing decompensations included reduced pharyngeal constriction (75%), epiglottic tilt (70%), cricopharyngeal opening (42%), and hyoid excursion (42%). The only variable independently associated with abnormal PAS was pretreatment swallowing difficulty (odds ratio [OR] = 4.02; p = .009). Conclusion This study demonstrates that patients undergoing nonsurgical treatment for oropharyngeal SCC are at risk for posttreatment dysphagia. This suggests a need for dysphagia evaluation/management and refinement of interventions to minimize dysphagia. © 2014 Wiley Periodicals, Inc. Head Neck, 36: 1392–1397, 2014

The purpose of this study was to assess swallowing outcomes in a cohort of patients with oropharyngeal squamous cell carcinoma (SCC) undergoing nonoperative treatment.We conducted a retrospective study of patients who completed videofluoroscopic swallowing studies (VFSS) after nonoperative treatment of oropharyngeal SCC. All patients received intensity-modulated radiation therapy (IMRT) ± chemotherapy. Swallowing abnormalities were recorded and the Penetration Aspiration Scale (PAS) quantified airway infiltration.Posttreatment VFSS (n = 71) occurred at an average of 4.69 months posttreatment. Abnormal PAS was noted in 45% of swallow studies. Swallowing decompensations included reduced pharyngeal constriction (75%), epiglottic tilt (70%), cricopharyngeal opening (42%), and hyoid excursion (42%). The only variable independently associated with abnormal PAS was pretreatment swallowing difficulty (odds ratio [OR] = 4.02; p = .009).This study demonstrates that patients undergoing nonsurgical treatment for oropharyngeal SCC are at risk for posttreatment dysphagia. This suggests a need for dysphagia evaluation/management and refinement of interventions to minimize dysphagia.

There is evidence of a worldwide increase in the prevalence of, and mortality from, asthma. Suggested causes of these increases include environmental and medical factors. There are implications for nursing practice. The nurse has a role to play in health education and promotion for asthmatics. Research is being carried out but there is a need for further work.

The prospect of maternity and moments of birth are frequent narrative elements in twentieth-century American science fiction and horror. In narratives like that of the Alien film series, human bodies become grotesque wombs for alien fetuses, and the moment of birth is lethal and terrifying. If at times these images of birth refuse to correspond to actual female anatomy, the new life that emerges is almost always figured as infantile, even if it is monstrous. In many such fictions, both the alien fetus and the body that carries it come to represent the ultimate threat to human society. The space of the mother’s body, accordingly, is the focus for description, visualization, and imaginative speculation.

One of the West’s most enduring icons of motherhood, the Madonna with child, is represented on the cover of this book within a number of conceptual frames, each inflecting the image differently. Most immediately the figure of the Madonna belongs to a religious institution that has served for more than two millennia as a scaffolding for social relations across the Western world. The image proper, we are informed by the small print on the lower left-hand side, was painted by Lorenzo Costa and now belongs to the Philadelphia Museum of Art, circulating thus as a commodity in the art world and public domain. The painting in turn was “acquired” by the government of the United States to serve as a postage stamp, to be sent out to millions of households across the nation, indeed across the world, at Christmas time. While the religious, economic, and artistic meaning of the painting changes as it passes from context to context, the cultural meaning of the painting s subject, the woman with child, appears to remain stable throughout: we do not question it. In fact, we seem intuitively to know what it signifies.

Experiments using microarrays abound in genomic research, yet one factor remains in question. Without replication, how much stock can we put into the findings of microarray experiments? In addition, there is a growing desire to integrate microarray data with other molecular databases. To accomplish this in a scientifically acceptable manner, we must be able to measure the validity and quality of microarray data. Otherwise, it would be the weakest link in any integration process. Validating and evaluating the quality of data requires the ability to determine the reproducibility of results. Data obtained from a microarray experiment designed as a feasibility test provided a unique opportunity to partition and quantify several sources of variation that are likely to be present in most microarray experiments. We use this opportunity to discuss the origins of variability observed in microarray experiments and provide some suggestions for how to minimize or avoid them when designing an experiment.

The pedigree disequilibrium test (PDT) has been proposed recently as a test for association in general pedigrees [Martin et al., Am J Hum Genet 67:146-54, 2000]. The Genetic Analysis Workshop (GAW) 12 simulated data, with many extended pedigrees, is an example the type of data to which the PDT is ideally suited. In replicate 42 from the general population the PDT correctly identifies candidate genes 1, 2, and 6 as containing single nucleotide polymorphisms (SNPs) that are significantly associated with the disease. We also applied the truncated product method (TPM) [Zaykin et al., Genet Epidemiol, in press] to combine p-values in overlapping windows across the genes. Our results show that the TPM is helpful in identifying significant SNPs as well as removing spurious false positives. Our results indicate that, using the PDT, functional disease-associated SNPs can be successfully identified with a dense map of moderately polymorphic SNPs.

Recent literature regarding microarray technology has focused on the need to incorporate classical statistical practices in experimental design in order to utilize more robust, classical statistical methodologies in data analysis. We have demonstrated that classical statistical methods are applicable to analysis of data previously presented by Golub, et al. 1999. Our preliminary analysis of all 6817 genes involves simple t-tests for statistically significant separation of means of gene expression level in two cancer types. Our subsets of genes that distinguish AML types from ALL types are relatively consistent with those published by Golub. We select those predictor genes based on the t-values and stepwise discriminant analysis, and evaluate the resulting model’s performance in predicting 34 test samples by linear discriminant analysis. Only two samples were not correctly predicted (samples 61 and 66) with 25 predictor genes we chose. We also evaluate the parsimony of our model by evaluating, through a stepwise method, the minimum number of genes required to maintain a high level of accuracy in predicting cancer types.

This prospective environmental intervention study was conducted to determine the impact of low-technology lead hazard reduction activities among children with mildly elevated blood lead levels. Children whose homes had severe lead hazards were automatically assigned to the intervention group. Children whose homes had lesser hazards were randomly assigned to the intervention group or comparison group. The one-time intervention focused mainly on cleaning and repainting window areas and educating caregivers to maintain effective housekeeping techniques. Changes in blood lead and dust lead loading levels were observed following the interventions. Analysis of covariance was used to adjust comparisons of postintervention levels for preintervention levels and other variables. The lead hazard reduction activities were associated with a modest decline in blood lead levels among children with severe hazards. The magnitude of the decline depended on the confounder that was controlled; the majority ranged from −1.1 to −1.6 μg/dL. A moderate reduction in window well dust lead loading levels was also observed. While low-technology lead hazard reduction measures appeared to be an effective secondary prevention strategy among children with severe household lead hazards, larger studies are needed to confirm these results.

We evaluated a panel of AAV serotypes for their ability to transduce hematopoietic stem and progenitor cells of human and murine origin. rAAV-2 genomes encoding either dsRed1 or firefly luciferase under the control of the hybrid CBA promoter were packaged into capsids derived from AAV-1, AAV-5, AAV-7, AAV-8 and AAV-9 and purified by successive rounds of cesium chloride gradient centrifugation. Hematopoietic cells were transduced overnight at low cytokine concentrations, following which cells were assayed in vitro for transgene expression or transplanted into sublethally irradiated NOD/SCID mice. For murine marrow cells, AAV-7 and AAV-showed the highest levels of expression as compared with the other serotypes. For analysis of human cells, hematopoietic stem/progenitor cells were purified from cord blood, cytokine-primed peripheral blood and bone marrow samples obtained using IRB approved protocols. CD34 cells were immunomagnetically purified and transduced with rAAV-dsRed. Flow cytometric analyses revealed that AAV-7 consistently showed the highest level of transgene expression in vitro in CD34 cells derived from cord blood and bone marrow with levels ranging from 36-64% 24 hours after transduction. This was followed by AAV-8 and AAV-1, at 10-43% expression at 24 hours post-transduction, while the other serotypes exhibited lower levels of transgene expression. We next compared transduction of the CD34+CD3//Q-population, which is highly enriched for stem cells. CD34+CD3//Q-cells were flow sorted to purity prior to transduction with the different serotypes. Notably, this primitive population yielded higher levels of transduction than the more heterogeneous CD34 population, with approximately 60-70% of CD34+CD3//Q-cells from cord blood and cytokine primed peripheral blood showing dsRed expression 24 hours after transduction with AAV-7. As with CD34 cells, transduction with AAV-8 and AAV-1 were the next most efficient. We have previously demonstrated that although rAAV-2 transduction in vitro results in poor expression at early time points, possibly due to defined limitations in uncoating, nuclear entry and second strand synthesis, long term studies and in vivo assays demonstrate that rAAV-2 efficiently transduces primitive human hematopoietic stem cells capable of serial engraftment in immune deficient mice. Since in vitro assays may not reflect true stem cell activity, we initiated in vivo transplantation studies of stem cells transduced with different AAV serotypes to determine the relative long term engraftment and gene expression potentials of AAV genomes packaged in the different serotype capsids. Initial results following live imaging of luciferase-transduced recipients confirm both the early onset of gene expression with AAV-7 and AAV-8 and the hierarchy of transgene expression seen with the serotypes in vitro. Overall, our results suggest that rAAV genomes pseudotyped in AAV-7 and AAV-8 capsids are very promising for gene transfer into hematopoietic stem cells.

The search for the ideal vector for stem cell gene therapy continues as recognized problems remain with all existing viral vectors. The recent identification of over 100 new serotypes of AAV significantly expands the repertoire of available gene transfer vectors. Additionally, the capacity to pseudotype rAAV2 genomes in novel capsids facilitates evaluation. We and others have analyzed rAAV2-mediated gene transfer into hematopoietic stem cells (HSC). However, despite efficient gene-marking of primitive HSCs, there are identified limitations to transgene expression especially at early time points. The use of novel capsids has been shown to overcome these limitations in other tissues and expand the host range of AAV. We tested transduction of CD34+ cells from cytokine-primed peripheral blood, CD34+CD38|[minus]| cells from cord blood (CB) and the CD34+CD38- cell line TF1a with AAV2-dsRed pseudotyped in capsids of AAV1, 2, 5, 7, 8 and 9. Transduced cells were analyzed by flow cytometry 24 and 48 hours post transduction. Results revealed that the highest level of transgene expression was observed with AAV7 in HSCs from all sources while AAV 2 and 9 showed the lowest. The hierarchy of transgene expression in vitro was: AAV7>AAV8|[ge]|AAV1>AAV5>AAV2=AAV9 regardless of the source of CD34+cells. These results indicate that the use of certain novel capsids allows circumvention of limitations to expression from AAV2. We next evaluated in vivo engraftment of human HSCs transduced with pseudotyped rAAV in a NOD/SCID xenotransplant model. Transduced CD34+ cells purified from either CB or cytokine primed peripheral blood were transplanted into sublethally irradiated mice. The pseudotyped rAAV2 genome encoded the firefly luciferase gene under the control of the CBA promoter. Serial live imaging of recipients revealed transgene expression from each of the 6 serotypes tested. However the levels and trends for long term expression variedby serotype. At early time points, the highest initial expression was observed with AAV9 followed by AAV7 and 8. AAV2 showed the lowest level of initial expression. However differences emerged over time. AAV7, 9 and 8 capsids emerged as the best serotypes for long-term expression in vivo, followed by AAV2. AAV5 and 1 showed a rapid decline in expression after initial moderately high levels of expression. These differences suggest that the processing of pseudotyped rAAV in vivo varies with the capsid. AAV serotypes also appear to have different transduction properties in vivo as compared with in vitro. The mechanisms underlying these differences are being investigated. The rapid and robust expression seen in vivo with certain serotypes is highly promising and underscores the need for further evaluation of pseudotyped rAAV for stem cell gene transfer.

Apo A-1 Milano, an Arg173 to Cys point mutation of apo A-1, has demonstrated marked efficacy in the reduction of atherosclerotic lesions in animal models. A recent human trial testing recombinant apo A-1Milano infusions has similarly shown significant and rapid reduction in coronary atheroma volumes. In this project, we tested the utility of rAAV vectors encoding apo A-1 Milano for gene therapy of atherosclerosis in vivo following either intra-muscular injection or transplantation of rAAV-transduced bone marrow cells. ApoE-/- mice were injected with approximately 1012 vector genomes/kg at 6–8 weeks of age and placed on a high fat diet two weeks later. No major differences in body weight were observed between the treatment groups. 20–24 weeks after injection, the mice were harvested, aortas were cleaned, fixed, mounted, stained with oil red O and atherosclerotic plaque areas quantified. Control untreated mice or mice treated with an irrelevant rAAV vector showed marked atherosclerotic lesion formation. In contrast, the rAAV-2-apo A-1Milano and rAAV-5-apo A-1Milano injected groups showed significant reductions in plaque formation, 58% and 50% respectively, despite a lack of major differences in total plasma cholesterol levels. Since marrow-derived monocytes and macrophages play a pivotal role in atherogenesis, we tested the hypothesis that transplantation of rAAV apo A-1 Milano-transduced marrow cells would also result in a decline in plaque formation, possibly due to the localization of transduced macrophages within atherosclerotic lesions. Lethally irradiated Apo E-/- mice were transplanted with rAAV transduced cells, and high fat diet was initiated two weeks later. Twenty two to 24 weeks after transplantation, the mice were euthanized, and aortas were analyzed for atherosclerotic plaques. Untransplanted mice, and mice transplanted with untransduced and control rAAV transduced marrow served as negative controls. Wild type B6 to Apo E-/- transplants served as positive controls for plaque reduction. Results revealed a 41% and 47% reduction in atheroma formation following transplantation with cells transduced with rAAV-2 and rAAV5 vectors encoding apo A-1 Milano, respectively. These results suggest that either intramuscular injection of rAAV Apo A-1 Milano or transplantation of rAAV transduced marrow cells results in significant long-term inhibition of atherogenesis following a single treatment with an rAAV vector.