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Retro-Orbital Venous Sinus Delivery of rAAV9 Mediates High-Level Transduction of Brain and Retina Compared with Temporal Vein Delivery in Neonatal Mouse Pups

Tue, 06/20/2017 - 2:38pm

In order to pursue a clinical gene therapy for a human neurologic disease, it is often necessary to perform proof-of-concept trials in mouse models of that disease. In order to demonstrate a potential clinical efficacy, one must be able to select an appropriate vector and route of delivery for the appropriate age group in the disease model. Since many diseases require correction early in life, investigators often need to deliver recombinant adeno-associated viral (rAAV) vectors to neonatal mice. Herein, general central nervous system expression patterns of nuclear GFP following delivery of rAAV by three different routes are reported.

An oral HemokineTM, alpha-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo

Tue, 06/20/2017 - 2:37pm

An oral therapeutic which reduces duration of cytopenias and is active following accidental radiation exposures is an unmet need in radiation countermeasures. Alpha methylhydrocinnamate (ST7) prolongs STAT-5 phosphorylation, reduces growth-factor dependency of multi-lineage cell lines, and stimulates erythropoiesis. Here, ST7 and its isomers were studied for their effects on myeloid progenitors and hematopoietic stem cells (HSCs) following radiation, in nonhuman primates, and murine irradiation models. Addition of ST7 or ST7-S increased CFU-GM production by 1.7-fold (p<0.001), reduced neutrophil apoptosis comparable to G-CSF, and enhanced HSC survival post-radiation by 2-fold, (p=0.028). ST7 and ST7-S administered in normal baboons increased ANC and platelet counts by 50-400%. In sub-lethally-irradiated mice, ANC nadir remained > 200/mm3 and neutropenia recovered in 6days with ST7 treatment and 18days in controls (p<0.05). In lethally-irradiated mice, marrow pathology at 15days was hypocellular (10% cellularity) in controls, but normal (55-75% cellularity) with complete neutrophil maturation with ST7-S treatment. Following lethal irradiation, ST7, given orally for 4days, reduced mortality, with 30% survival in ST7-animals vs 8% in controls, (p<0.05). Collectively, the studies indicate that ST7 and ST7-S enhance myeloid recovery post-radiation and merit further evaluation to accelerate hematologic recovery in conditions of radiation-related and other marrow hypoplasias.

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 1 Efficacy: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations

Tue, 06/20/2017 - 2:37pm

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the US Food and Drug Administration, convened a meeting of sedation experts from a variety of clinical specialties and research backgrounds with the objective of developing recommendations for procedural sedation research. Four core outcome domains were recommended for consideration in sedation clinical trials: (1) safety, (2) efficacy, (3) patient-centered and/or family-centered outcomes, and (4) efficiency. This meeting identified core outcome measures within the efficacy and patient-centered and/or family-centered domains. Safety will be addressed in a subsequent meeting, and efficiency will not be addressed at this time. These measures encompass depth and levels of sedation, proceduralist and patient satisfaction, patient recall, and degree of pain experienced. Consistent use of the recommended outcome measures will facilitate the comprehensive reporting across sedation trials, along with meaningful comparisons among studies and interventions in systematic reviews and meta-analyses.

Restrictive Lung Disease in the Cu/Zn Superoxide-Dismutase 1 G93A Amyotrophic Lateral Sclerosis Mouse Model

Tue, 06/20/2017 - 2:37pm

This study is the first to show progressive restrictive pulmonary disease in the most commonly used ALS mouse model—the SOD1G93A mouse.

Airway smooth muscle dysfunction in Pompe (Gaa-/-) mice

Tue, 06/20/2017 - 2:37pm

Pompe disease is an autosomal recessive disorder caused by a deficiency of acid alpha-glucosidase (GAA) - an enzyme responsible for hydrolyzing lysosomal glycogen. Deficiency of GAA leads to systemic glycogen accumulation in the lysosomes of skeletal muscle, motor neurons and smooth muscle. Skeletal muscle and motor neuron pathology are known to contribute to respiratory insufficiency in Pompe disease, but the role of airway pathology has not been evaluated. Here we propose that GAA enzyme deficiency disrupts the function of the trachea and bronchi, and this lower airway pathology contributes to respiratory insufficiency in Pompe disease. Using an established mouse model of Pompe disease - the Gaa-/- mouse - we compared histology, pulmonary mechanics, airway smooth muscle function and calcium signaling between Gaa-/- and age matched wild type (WT) mice. Lysosomal glycogen accumulation was observed in the smooth muscle of both the bronchi and the trachea in Gaa-/- but not WT mice. Furthermore, Gaa-/- mice had hyporesponsive airway resistance and bronchial ring contraction to the bronchoconstrictive agents methacholine (Mch) and potassium chloride (KCl), and to a bronchodilator (albuterol). Finally, calcium signaling during bronchiolar smooth muscle contraction was impaired in Gaa-/- mice indicating impaired extracellular calcium influx. We conclude that GAA enzyme deficiency leads to glycogen accumulation in the trachea and bronchi, and impairs the ability of lower airway smooth muscle to regulate calcium and respond appropriately to bronchodilator or constrictors. Accordingly, airway smooth muscle dysfunction may contribute to respiratory impairments in Pompe disease.

Human Papillomavirus Vaccine Update

Tue, 06/20/2017 - 2:37pm

Rates of cancers attributable to human papillomavirus (HPV) are rising. A safe and extremely effective vaccine is available to prevent many of these cancers. Studies have shown that health care providers' recommendation to immunize is the most important factor in parents' decision. Parents of all adolescent boys and girls should receive a strong and unequivocal recommendation to vaccinate their child against HPV at the 11- or 12-year-old well child visit. Ideally, adolescents complete their HPV vaccine series by their 13th birthday, leading to greater immune response and protection before most adolescents are exposed to sexually transmitted HPV.

Adolescent Sexuality: Updates to the Sexually Transmitted Infection Guidelines

Tue, 06/20/2017 - 2:37pm

Adolescents are at high risk for acquisition and transmission of sexually transmitted infections (STI) secondary to both cognitive and biological susceptibility. The prevention, diagnosis, and treatment of STIs are a critical part of adolescent health care. This article discusses the most common bacterial, parasitic, and viral STIs encountered in this age group with an emphasis on new guidelines for screening and management.

Treating Youths in the Juvenile Justice System

Tue, 06/20/2017 - 2:37pm

Adolescents involved with the juvenile justice system have higher rates of risky sexual behaviors, resulting in high rates of sexually transmitted infections and increased risk of human immunodeficiency virus, early or complicated pregnancy, and parenting issues. Comorbid substance abuse, gang association, mental health issues, and history of having been abused as children result in further elevated rates. Girls and lesbian, gay, bisexual, and transgender youths represent growing subpopulations with special risks. Increasingly diverted to community-based alternatives, juvenile justice-involved teens obtain most of their medical care from community providers, who need to understand their risks to provide appropriate, optimal care.

A Primer for Primary Care Clinicians Caring for Sexually Active Adolescents

Tue, 06/20/2017 - 2:37pm

Issue preface: This slim issue of thirteen articles was specifically designed with the needs of the General Pediatrician in mind. The list of topics covers a broad scope of clinical issues that are common among adolescent patients, particularly adolescents who are sexually active. Many pediatricians feel poorly equipped to address sexual matters in teens either because they do not have updated knowledge about them or because the issues are complicated and take more time than usually scheduled in a busy practice. This issue will help pediatricians feel more confident caring for their adolescent patients. All the authors have made a concerted effort to provide a concise review of the topic assigned to them coupled with practical suggestions for the clinician to consider.

CAR T-Cell Therapy: Progress and Prospects

Tue, 06/20/2017 - 2:37pm

Lentivirus-mediated transduction of autologous T cells with a chimeric antigen receptor (CAR) to confer a desired epitope specificity as a targeted immunotherapy for cancer has been among the first human gene therapy techniques to demonstrate widespread therapeutic efficacy. Other approaches to using gene therapy to enhance antitumor immunity have been less specific and less effective. These have included amplification, marking, and cytokine transduction of tumor infiltrating lymphocytes, recombinant virus-based expression of tumor antigens as a tumor vaccine, and transduction of antigen-presenting cells with tumor antigens. Unlike any of those methods, the engineering of CAR T cells combine specific monoclonal antibody gene sequences to confer epitope specificity and other T-cell receptor and activation domains to create a self-contained single vector approach to produce a very specific antitumor response, as is seen with CD19-directed CAR T cells used to treat CD19-expressing B-cell malignancies. Recent success with these therapies is the culmination of a long step-wise iterative process of improvement in the design of CAR vectors. This review aims to summarize this long series of advances in the development of effective CAR vector since their initial development in the 1990s, and to describe emerging approaches to design that promise to enhance and widen the human gene therapy relevance of CAR T-cell therapy in the future.

The role of endoscopy in subepithelial lesions of the GI tract

Tue, 06/20/2017 - 2:37pm

This is one of a series of statements discussing the use of GI endoscopy in common clinical situations. The Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy (ASGE) prepared this text.

Gene Therapy 2017: Progress and Future Directions

Tue, 06/20/2017 - 2:37pm

Introduction: Gene therapy has changed dramatically in the 28 years since the first human gene transfer experiment in 1989. Alipogene tiparvovec, GlyberaR®, a recombinant adeno-associated virus (rAAV) product for lipoprotein lipase deficiency, and Strimvelis®, a lentivirus vector for severe combined immune deficiency are approved in Europe. An rAAV2 product for a congenital form of blindness is currently under review in the United States, likely to be followed by numerous other gene therapies.

Care Coordination and Comprehensive Electronic Health Records are Associated with Increased Transition Planning Activities

Tue, 06/20/2017 - 2:37pm

OBJECTIVE: Youth with Special Health Care Needs (YSHCN) require assistance from their pediatricians to transition to adult care. There is little data on what transition resources pediatricians have. This paper studies if care coordination and/or comprehensive electronic health record (CEHR) implementation are associated with improved transition processes. METHODS: Using AAP Periodic Survey #79, we report whether practices generated written transition plans, assisted in finding adult providers, and discussed confidentiality issues. Descriptive statistics and a logistic regression model were done to evaluate whether CEHR, care coordination, or practice and physician characteristics improve transition planning. RESULTS: Transition planning support in practices is low. Pediatricians with any care coordinator report more written transition plans for YSHCN (23% vs. 6%, p<0.001), assistance identifying adult providers (59% vs. 39%, p<0.001), and discussing confidentiality issues (50% vs. 33%, p<0.001). Pediatricians with a CEHR compared to those without are more likely to report written transition plans for YSHCN (24% vs. 12 % p<0.05) and discussing confidentiality issues (51% vs. 39%, p<0.05). In the logistic regression model, having care coordination (AOR 11.1, 95% CI 5.9-21.3) and CEHR (AOR 2.6, 95% CI 1.5-5.0) are independently associated with higher odds of having a written transition plan. CONCLUSIONS: Only 1 in 5 pediatricians have a transition coordinator in their practice and just 15% have a CEHR, even as these resources are associated with improved transition processes for YSHCN. Policy decisions should be made to help practices with supports, such as care coordination and EHR implementation, in order to improve transitions to adulthood.

KAT-Independent Gene Regulation by Tip60 Promotes ESC Self-Renewal but Not Pluripotency

Tue, 06/20/2017 - 2:37pm

Although histone-modifying enzymes are generally assumed to function in a manner dependent on their enzymatic activities, this assumption remains untested for many factors. Here, we show that the Tip60 (Kat5) lysine acetyltransferase (KAT), which is essential for embryonic stem cell (ESC) self-renewal and pre-implantation development, performs these functions independently of its KAT activity. Unlike ESCs depleted of Tip60, KAT-deficient ESCs exhibited minimal alterations in gene expression, chromatin accessibility at Tip60 binding sites, and self-renewal, thus demonstrating a critical KAT-independent role of Tip60 in ESC maintenance. In contrast, KAT-deficient ESCs exhibited impaired differentiation into mesoderm and endoderm, demonstrating a KAT-dependent function in differentiation. Consistent with this phenotype, KAT-deficient mouse embryos exhibited post-implantation developmental defects. These findings establish separable KAT-dependent and KAT-independent functions of Tip60 in ESCs and during differentiation, revealing a complex repertoire of regulatory functions for this essential chromatin remodeling complex.

Are "Goods for Guns" Good for the Community? An Update of a Community Gun Buyback Program

Tue, 06/20/2017 - 2:36pm

BACKGROUND: Gun violence remains a leading cause of death in the United States. Community gun buyback programs provide an opportunity to dispose of extraneous firearms. The purpose of this study was to understand the demographics, motivation, child access to firearms and household mental illness of buyback participants in hopes of improving the program's effectiveness.

METHODS: A 2015 Injury Free Coalition for Kids gun buyback program which collaborated with local police departments was studied. We administered a 23-item questionnaire survey to gun buyback participants assessing demographic characteristics, motivation for relinquishing firearms, child firearm accessibility, and mental illness/domestic violence history.

RESULTS: A total of 186 individuals from Central/Western Massachusetts turned in 339 weapons. Participants received between $25 and $75 in gift cards dependent on what type of gun was turned in, with an average cost of $41/gun. A total of 109 participants (59%) completed the survey. Respondents were mostly white (99%), male (90%) and first-time participants in the program (85.2%). Among survey respondents, 54% turned in firearms "for safety reasons". Respondents reported no longer needing/wanting their weapons (47%) and approximately one in eight participants were concerned the firearm(s) were accessible to children. Most respondents (87%) felt the program encouraged neighborhood awareness of firearm safety. Three out of every five participants reported that guns still remained in their homes, additionally; 21% where children could potentially access them and 14% with a history of mental illness/suicide/domestic violence in the home.

CONCLUSIONS: Gun buybacks can provide a low-cost means of removing unwanted firearms from the community. Most participants felt their homes were safer after turning in the firearm(s). In homes still possessing guns, emphasis on secure gun storage should continue increasing the safety of children and families. The results of this survey also provided new insights into the association between mental illness/suicide and gun ownership.

LEVEL OF EVIDENCE: Level III, Prognostic and Epidemiological.

A novel homozygous VPS45 p.P468L mutation leading to severe congenital neutropenia with myelofibrosis

Tue, 06/20/2017 - 2:36pm

VPS45-associated severe congenital neutropenia (SCN) is a rare disorder characterized by life-threating infections, neutropenia, neutrophil and platelet dysfunction, poor response to filgrastim, and myelofibrosis with extramedullary hematopoiesis. We present a patient with SCN due to a homozygous c.1403C>T (p.P468L) mutation in VPS45, critical regulator of SNARE-dependent membrane fusion. Structural modeling indicates that P468, like the T224 and E238 residues affected by previously reported mutations, cluster in a VPS45 "hinge" region, indicating its critical role in membrane fusion and VPS45-associated SCN. Bone marrow transplantation, complicated by early graft failure rescued with stem cell boost, led to resolution of the hematopoietic phenotype.

Understanding predictors of continued long-term pediatric cancer care across the region: A report from the Consortium for New England Childhood Cancer Survivors

Tue, 06/20/2017 - 2:36pm

BACKGROUND: Many survivors of childhood cancer do not receive recommended longitudinal oncology care. Factors present at the time of childhood cancer diagnosis may identify patients who are vulnerable to poor adherence to follow-up.

METHODS: This cohort of survivors of acute lymphoblastic leukemia (ALL) diagnosed from 1996 to 1999 at seven Consortium for New England Childhood Cancer Survivors institutions was evaluated for attendance at oncology clinics at 5 and 10 years from diagnosis. Demographic, socioeconomic, disease, and treatment characteristics were analyzed as risk factors for nonadherence to follow-up.

RESULTS: Of 317 patients, 90% were alive 5 years from diagnosis and 88% of those remained in active follow-up. At 10 years from diagnosis, 88% were alive, 73% of whom continued in active follow-up. Insurance status at diagnosis was significantly associated with adherence at both 5 and 10 years. At 10 years, initial enrollment on therapeutic study was associated with increased attendance and central nervous system (CNS) leukemia with decreased attendance. In multivariable modeling of follow-up at 5 years, patients who were adults were less likely to participate and those with private insurance at diagnosis more likely to participate. At 10 years, insurance status at diagnosis remained a predictor of adherence to follow-up.

CONCLUSIONS: In this regional cohort, many patients who are survivors of ALL continue to participate in oncology care at 5 and 10 years from diagnosis. Factors known at diagnosis including insurance status, CNS leukemia, older age, and enrollment on therapeutic study were associated with differential attendance to follow-up visits.

Bilateral native nephrectomy reduces systemic oxalate level after combined liver-kidney transplant: A case report

Tue, 06/20/2017 - 2:36pm

Primary hyperoxaluria type 1 (PH1) is a rare liver enzymatic defect that causes overproduction of plasma oxalate. Accumulation of oxalate in the kidney and subsequent renal failure are fatal to PH1 patients often in pediatric age. Combined liver and kidney transplantation is the therapy of choice for end-stage renal disease due to PH1. Levels of plasma oxalate remain elevated for several months after liver transplantation, as the residual body oxalate is slowly excreted. Patients with persistent hyperoxaluria after transplant often require hemodialysis, and accumulation of residual oxalate in the kidney can induce graft dysfunction. As the native kidneys are the main target of calcium oxalate accumulation, we postulated that removal of native kidneys could drastically decrease total body oxalate levels after transplantation. Here, we report a case of bilateral nephrectomy at the time of combined liver-kidney transplantation in a pediatric PH1 patient. Bilateral nephrectomy induced a rapid decrease in plasma oxalate to normal levels in less than 20 days, compared to the several months reported in the literature. Our results suggest that removal of native kidneys could be an effective strategy to decrease the need for hemodialysis and the risk of renal dysfunction after combined liver-kidney transplantation in patients with PH1.

Outcomes From Pediatric Gastroenterology Maintenance of Certification Using Web-based Modules

Tue, 06/20/2017 - 2:36pm

OBJECTIVES: Beginning in 2013, the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) sponsored and developed subspecialty field-specific quality improvement (QI) activities to provide Part 4 Maintenance of Certification (MOC) credit for ongoing certification of pediatric gastroenterologists by the American Board of Pediatrics. Each activity was a Web-based module that measured clinical practice data repeatedly over at least 3 months as participants implemented rapid cycle change. Here, we examine existing variations in clinical practice among participating pediatric gastroenterologists and determine whether completion of Web-based MOC activities improves patient care processes and outcomes.

METHODS: We performed a cross-sectional and prospective analysis of physician and parent-reported clinical practice data abstracted from Web-based MOC modules on the topics of upper endoscopy, colonoscopy, and informed consent collected from pediatric gastroenterologists from North America from 2013 to 2016.

RESULTS: Among 134 participating pediatric gastroenterologists, 56% practitioners practiced at an academic institution and most (94%) were NASPGHAN members. Participating physicians reported data from 6300 procedures. At baseline, notable practice variation across measured activities was demonstrated. Much of the rapid cycle changes implemented by participants involved individual behaviors, rather than system/team-based improvement activities. Participants demonstrated significant improvements on most targeted process and quality care outcomes.

CONCLUSIONS: Pediatric gastroenterologists and parents reported baseline practice variation, and improvement in care processes and outcomes measured during NASPGHAN-sponsored Web-based MOC QI activities. Subspecialty-oriented Web-based MOC QI activities can reveal targets for reducing unwarranted variation in clinical pediatric practice, and can effectively improve care and patient outcomes.