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Antibodies to Toxin B Are Protective Against Clostridium difficile Infection Recurrence

Wed, 11/16/2016 - 9:01pm

BACKGROUND: Although newer studies have evaluated risk factors for recurrent Clostridium difficile infection (CDI), the vast majority did not measure important biomarkers such as endogenous anti-toxin A and anti-toxin B antibody levels.

METHODS: Data from the placebo group of a phase 2 trial testing monoclonal antibodies to C. difficile toxins A and B for preventing CDI recurrence (rCDI) were analyzed to assess risk factors associated with rCDI. Patients with symptomatic CDI taking metronidazole or vancomycin were enrolled. The primary outcome was rCDI within 84 days of treatment start. Univariate and multivariate logistic regression was used to examine associations between potential risk factors and rCDI. At baseline, demographic and clinical characteristics were recorded; endogenous antibody levels were assessed using 2 enzyme-linked immunosorbent assays.

RESULTS: A predictor of recurrence was age > /=65 years, and an antibody-mediated immune response to toxin B appears to be protective against rCDI.

CONCLUSIONS: Our findings demonstrate the importance of clinical as well as immunological risk factors in rCDI and provide more robust evidence for the protective effects of antibody to toxin B in the prevention of rCDI.

CLINICAL TRIALS REGISTRATION: NCT00350298.

Impact of Weight Extremes on Clinical Outcomes in Pediatric Acute Respiratory Distress Syndrome

Wed, 11/16/2016 - 9:01pm

OBJECTIVES: To determine whether weight extremes impact clinical outcomes in pediatric acute respiratory distress syndrome.

DESIGN: Post hoc analysis of a cohort created by combining five multicenter pediatric acute respiratory distress syndrome studies.

SETTING: Forty-three academic PICUs worldwide.

PATIENTS: A total of 711 subjects prospectively diagnosed with pediatric acute respiratory distress syndrome.

INTERVENTION: Subjects more than 2 years were included and categorized by Center for Disease Control and Prevention body mass index z score criteria: underweight (< -1.89), normal weight (-1.89 to +1.04), overweight (+1.05 to +1.64), and obese ( > /= +1.65). Subjects were stratified by direct versus indirect lung injury leading to pediatric acute respiratory distress syndrome. The primary outcome was in-hospital mortality. In survivors, secondary analyses included duration of mechanical ventilation and ICU length of stay.

MEASUREMENTS AND MAIN RESULTS: A total of 331 patients met inclusion criteria; 12% were underweight, 50% normal weight, 11% overweight, and 27% obese. Overall mortality was 20%. By multivariate analysis, body mass index category was independently associated with mortality (p = 0.004). When stratified by lung injury type, there was no mortality difference between body mass index groups with direct lung injury; however, in the indirect lung injury group, the odds of mortality in the obese were significantly lower than normal weight subjects (odds ratio, 0.11; 95% CI, 0.02-0.84). Survivors with direct lung injury had no difference in the duration of mechanical ventilation or ICU length of stay; however, those with indirect lung injury, the overweight required longer duration of mechanical ventilation than other groups (p < 0.001).

CONCLUSIONS: These data support the obesity paradox in pediatric acute respiratory distress syndrome. Obese children with indirect lung injury pediatric acute respiratory distress syndrome have a lower risk of mortality. Importantly, among survivors, the overweight with indirect lung injury requires longer duration of mechanical ventilation. Our data require prospective validation to further elucidate the pathobiology of this phenomenon.

Newborn screening for X-linked adrenoleukodystrophy: evidence summary and advisory committee recommendation

Wed, 11/16/2016 - 9:01pm

The secretary of the US Department of Health and Human Services in February 2016 recommended that X-linked adrenoleukodystrophy (X-ALD) be added to the recommended uniform screening panel for state newborn screening programs. This decision was informed by data presented on the accuracy of screening from New York, the only state that currently offers X-ALD newborn screening, and published and unpublished data showing health benefits of earlier treatment (hematopoietic stem cell transplantation and adrenal hormone replacement therapy) for the childhood cerebral form of X-ALD. X-ALD newborn screening also identifies individuals with later-onset disease, but poor genotype-phenotype correlation makes predicting health outcomes difficult and might increase the risk of unnecessary treatment. Few data are available regarding the harms of screening and presymptomatic identification. Significant challenges exist for implementing comprehensive X-ALD newborn screening, including incorporation of the test, coordinating follow-up diagnostic and treatment care, and coordination of extended family testing after case identification.

Modeling altered T-cell development with induced pluripotent stem cells from patients with RAG1-dependent immune deficiencies

Wed, 11/16/2016 - 9:01pm

Primary immunodeficiency diseases comprise a group of heterogeneous genetic defects that affect immune system development and/or function. Here we use in vitro differentiation of human induced pluripotent stem cells (iPSCs) generated from patients with different recombination-activating gene 1 (RAG1) mutations to assess T-cell development and T-cell receptor (TCR) V(D)J recombination. RAG1-mutants from severe combined immunodeficient (SCID) patient cells showed a failure to sustain progression beyond the CD3(--)CD4(-)CD8(-)CD7(+)CD5(+)CD38(-)CD31(-/lo)CD45RA(+) stage of T-cell development to reach the CD3(-/+)CD4(+)CD8(+)CD7(+)CD5(+)CD38(+)CD31(+)CD45RA(-) stage. Despite residual mutant RAG1 recombination activity from an Omenn syndrome (OS) patient, similar impaired T-cell differentiation was observed, due to increased single-strand DNA breaks that likely occur due to heterodimers consisting of both an N-terminal truncated and a catalytically dead RAG1. Furthermore, deep-sequencing analysis of TCR-beta (TRB) and TCR-alpha (TRA) rearrangements of CD3(-)CD4(+)CD8(-) immature single-positive and CD3(+)CD4(+)CD8(+) double-positive cells showed severe restriction of repertoire diversity with preferential usage of few Variable, Diversity, and Joining genes, and skewed length distribution of the TRB and TRA complementary determining region 3 sequences from SCID and OS iPSC-derived cells, whereas control iPSCs yielded T-cell progenitors with a broadly diversified repertoire. Finally, no TRA/delta excision circles (TRECs), a marker of TRA/delta locus rearrangements, were detected in SCID and OS-derived T-lineage cells, consistent with a pre-TCR block in T-cell development. This study compares human T-cell development of SCID vs OS patients, and elucidates important differences that help to explain the wide range of immunologic phenotypes that result from different mutations within the same gene of various patients.

A framework for assessing outcomes from newborn screening: on the road to measuring its promise

Wed, 11/16/2016 - 9:01pm

Newborn screening (NBS) is intended to identify congenital conditions prior to the onset of symptoms in order to provide early intervention that leads to improved outcomes. NBS is a public health success, providing reduction in mortality and improved developmental outcomes for screened conditions. However, it is less clear to what extent newborn screening achieves the long-term goals relating to improved health, growth, development and function. We propose a framework for assessing outcomes for the health and well-being of children identified through NBS programs. The framework proposed here, and this manuscript, were approved for publication by the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). This framework can be applied to each screened condition within the Recommended Uniform Screening Panel (RUSP), recognizing that the data elements and measures will vary by condition. As an example, we applied the framework to sickle cell disease and phenylketonuria (PKU), two diverse conditions with different outcome measures and potential sources of data. Widespread and consistent application of this framework across state NBS and child health systems is envisioned as useful to standardize approaches to assessment of outcomes and for continuous improvement of the NBS and child health systems. SIGNIFICANCE: Successful interventions for newborn screening conditions have been a driving force for public health newborn screening for over fifty years. Organizing interventions and outcome measures into a standard framework to systematically assess outcomes has not yet come into practice. This paper presents a customizable outcomes framework for organizing measures for newborn screening condition-specific health outcomes, and an approach to identifying sources and challenges to populating those measures.

Utilizing Idea Boards as an Evaluation Tool

Wed, 11/16/2016 - 3:40pm

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

The Importance of Learning Objectives in Program Design and Evaluation

Wed, 11/16/2016 - 3:33pm

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

Quality Improvement (QI) in Evaluation: Ask Why Again and Again and Again

Wed, 11/16/2016 - 3:32pm

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

Making Your Webinar Accessible

Wed, 11/16/2016 - 11:18am

Blog post to AEA365, a blog sponsored by the American Evaluation Association (AEA) dedicated to highlighting Hot Tips, Cool Tricks, Rad Resources, and Lessons Learned for evaluators. The American Evaluation Association is an international professional association of evaluators devoted to the application and exploration of program evaluation, personnel evaluation, technology, and many other forms of evaluation. Evaluation involves assessing the strengths and weaknesses of programs, policies, personnel, products, and organizations to improve their effectiveness.

In the proper context: Neuropeptide regulation of behavioral transitions during food searching

Wed, 11/16/2016 - 9:57am

Neuromodulation enables transient restructuring of anatomically fixed neural circuits, generating alternate outputs and distinct states that allow for flexible organismal responses to changing conditions. We recently identified a requirement for the neuropeptide-like protein NLP-12, a Caenorhabditis elegans homolog of mammalian Cholecystokinin (CCK), in the control of behavioral responses to altered food availability. We showed that deletion of nlp-12 impairs turning during local food searching while nlp-12 overexpression is sufficient to induce deep body bends and enhance turning. nlp-12 is solely expressed in the DVA interneuron that is located postsynaptic to the dopaminergic PDE neurons and presynaptic to premotor and motor neurons, well-positioned for modulating sensorimotor tasks. Interestingly, DVA was previously implicated in a NLP-12 mediated proprioceptive feedback loop during C. elegans locomotion. Here, we discuss the modulatory effects of NLP-12 with an emphasis on the potential for circuit level integration with olfactory information about food availability. In addition, we propose potential mechanisms by which DVA may integrate distinct forms of sensory information to regulate NLP-12 signaling and mediate context-dependent modulation of the motor circuit.

The Genetic Basis of Natural Variation in Caenorhabditis elegans Telomere Length

Wed, 11/16/2016 - 9:57am

Telomeres are involved in the maintenance of chromosomes and the prevention of genome instability. Despite this central importance, significant variation in telomere length has been observed in a variety of organisms. The genetic determinants of telomere-length variation and their effects on organismal fitness are largely unexplored. Here, we describe natural variation in telomere length across the Caenorhabditis elegans species. We identify a large-effect variant that contributes to differences in telomere length. The variant alters the conserved oligonucleotide/oligosaccharide-binding fold of protection of telomeres 2 (POT-2), a homolog of a human telomere-capping shelterin complex subunit. Mutations within this domain likely reduce the ability of POT-2 to bind telomeric DNA, thereby increasing telomere length. We find that telomere-length variation does not correlate with offspring production or longevity in C. elegans wild isolates, suggesting that naturally long telomeres play a limited role in modifying fitness phenotypes in C. elegans.

Improving Care for Neonatal Abstinence Syndrome

Wed, 11/16/2016 - 8:57am

BACKGROUND AND OBJECTIVE: Care for neonatal abstinence syndrome (NAS), a postnatal drug withdrawal syndrome, remains variable. We designed and implemented a multicenter quality improvement collaborative for infants with NAS. Our objective was to determine if the collaborative was effective in standardizing hospital policies and improving patient outcomes.

METHODS: From 2012 to 2014, data were collected through serial cross-sectional audits of participating centers. Hospitals assessed institutional policies and patient-level data for infants with NAS requiring pharmacotherapy, including length of pharmacologic treatment and length of hospital stay (LOS). Models were fit, clustered according to hospital, to evaluate changes in patient outcomes over time.

RESULTS: Among 199 participating centers, the mean number of NAS-focused guidelines increased from 3.7 to 5.1 of a possible 6 (P < .001), with improvements noted in all measured domains. Among infants cared for at participating centers, decreases occurred in median (interquartile range) length of pharmacologic treatment, from 16 days (10 to 27 days) to 15 days (10 to 24 days; P = .02), and LOS from 21 days (14 to 33 days) to 19 days (15 to 28 days; P = .002). In addition, there was a statistically significant decrease in the proportion of infants discharged on medication for NAS, from 39.7% to 26.5% (P = .02). After adjusting for potential confounders, standardized NAS scoring process was associated with shorter LOS (-3.3 days,95% confidence interval, -4.9 to -1.4).

CONCLUSIONS: Involvement in a multicenter, multistate quality improvement collaborative focused on infants requiring pharmacologic treatment for NAS was associated with increases in standardizing hospital patient care policies and decreases in health care utilization.

The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families

Wed, 11/16/2016 - 8:56am

PURPOSE: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients' phenotypes was questioned, as MAGEL2 whole-gene deletions seem to cause little or no clinical phenotype.

METHODS: Here we report a total of 18 newly identified individuals with Schaaf-Yang syndrome from 14 families, including 1 family with 3 individuals found to be affected with a truncating variant of MAGEL2, 11 individuals who are clinically affected but were not tested molecularly, and a presymptomatic fetal sibling carrying the pathogenic MAGEL2 variant.

RESULTS: All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and 1 fetus harboring a c.1996dupC (p.Q666fs) mutation and 2 fetuses harboring a c.1996delC (p.Q666fs) mutation. The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to neurobehavioral disease and contractures of the small finger joints.

CONCLUSION: This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling for affected families.

Sleep Disorders Associated With Traumatic Brain Injury-A Review

Wed, 11/16/2016 - 8:56am

BACKGROUND: Sleep disorders are common are common following traumatic brain injury.

METHODS: In this article we review the spectrum and proposed mechanisms of traumatic brain injury associated sleep disorders and discuss the clinical approach to diagnosis and management of these disorders.

RESULT: Disordered sleep and wakefulness after traumatic brain injury is common. Sleep disruption contributes to morbidity, such as the development of neurocognitive and neurobehavioral deficits, and prolongs the recovery phase after injury. Early recognition and correction of these problems may limit the secondary effects of traumatic brain injury and improve patient outcomes.

CONCLUSION: Evaluating sleep disorders in traumatic brain injury should be an important component of post-traumatic brain injury assessment and management.

American Society of Pediatric Nephrology Position Paper: Standard Resources Required for a Pediatric Nephrology Practice

Wed, 11/16/2016 - 8:56am

This document aims to describe the essential resources needed for all pediatric nephrology divisions, regardless of the number of pediatric nephrologists in the division. The recommendations in this position paper are the work of authors representing the American Society of Pediatric Nephrology (ASPN) and are endorsed by the ASPN Council.

De novo mutations in PURA are associated with hypotonia and developmental delay

Wed, 11/16/2016 - 8:56am

PURA is the leading candidate gene responsible for the developmental phenotype in the 5q31.3 microdeletion syndrome. De novo mutations in PURA were recently reported in 15 individuals with developmental features similar to the 5q31.3 microdeletion syndrome. Here we describe six unrelated children who were identified by clinical whole-exome sequencing (WES) to have novel de novo variants in PURA with a similar phenotype of hypotonia and developmental delay and frequently associated with seizures. The protein Puralpha (encoded by PURA) is involved in neuronal proliferation, dendrite maturation, and the transport of mRNA to translation sites during neuronal development. Mutations in PURA may alter normal brain development and impair neuronal function, leading to developmental delay and the seizures observed in patients with mutations in PURA.

Mild Microcytic Anemia in an Infant with a Compound Heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB: c.157G > A)

Wed, 11/16/2016 - 8:56am

We report an infant with a compound heterozygosity for Hb C (HBB: c.19G > A) and Hb Osu Christiansborg (HBB: c.157G > A) and a phenotype of mild microcytic anemia with target cell morphology but without overt hemolysis.

Self-Complementary Adeno-Associated Virus Vectors Improve Transduction Efficiency of Corneal Endothelial Cells

Wed, 11/16/2016 - 8:56am

Transplantation of a donor cornea to restore vision is the most frequently performed transplantation in the world. Corneal endothelial cells (CEC) are crucial for the outcome of a graft as they maintain corneal transparency and avoid graft failure due to corneal opaqueness. Given the characteristic of being a monolayer and in direct contact with culture medium during cultivation in eye banks, CEC are specifically suitable for gene therapeutic approaches prior to transplantation. Recombinant adeno-associated virus 2 (rAAV2) vectors represent a promising tool for gene therapy of CEC. However, high vector titers are needed to achieve sufficient gene expression. One of the rate-limiting steps for transgene expression is the conversion of single-stranded (ss-) DNA vector genome into double-stranded (ds-) DNA. This step can be bypassed by using self-complementary (sc-) AAV2 vectors. Aim of this study was to compare for the first time transduction efficiencies of ss- and scAAV2 vectors in CEC. For this purpose AAV2 vectors containing enhanced green fluorescent protein (GFP) as transgene were used. Both in CEC and in donor corneas, transduction with scAAV2 resulted in significantly higher transgene expression compared to ssAAV2. The difference in transduction efficiency decreased with increasing vector titer. In most cases, only half the vector titer of scAAV2 was required for equal or higher gene expression rates than those of ssAAV2. In human donor corneas, GFP expression was 64.7+/-11.3% (scAAV) and 38.0+/-8.6% (ssAAV) (p < 0.001), respectively. Furthermore, transduced cells maintained their viability and showed regular morphology. Working together with regulatory authorities, a translation of AAV2 vector-mediated gene therapy to achieve a temporary protection of corneal allografts during cultivation and transplantation could therefore become more realistic.