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A Primer for Primary Care Clinicians Caring for Sexually Active Adolescents

eScholarship@UMMS - 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

eScholarship@UMMS - 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

eScholarship@UMMS - 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

eScholarship@UMMS - 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

eScholarship@UMMS - 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

eScholarship@UMMS - 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

eScholarship@UMMS - 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

eScholarship@UMMS - 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

eScholarship@UMMS - 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

eScholarship@UMMS - 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

eScholarship@UMMS - 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.

Wide Variation Found in Care of Opioid-Exposed Newborns

eScholarship@UMMS - Tue, 06/20/2017 - 2:36pm

OBJECTIVE: Standardized practices for the management of neonatal abstinence syndrome (NAS) are associated with shorter lengths of stay, but optimal protocols are not established. We sought to identify practice variations for newborns with in utero chronic opioid exposure among hospitals in the Better Outcomes Through Research for Newborns (BORN) network.

METHODS: Nursery site leaders completed a survey about hospitals' policies and practices regarding care for infants with chronic opioid exposure (>/=3 weeks).

RESULTS: The 76 (80%) of 95 respondent hospitals were in 34 states, varied in size (8000 births and 200 opioid-exposed infants per year), with most affiliated with academic centers (89%). Most (80%) had protocols for newborn drug exposure screening; 90% used risk-based approaches. Specimens included urine (85%), meconium (76%), and umbilical cords (10%). Of sites (88%) with NAS management protocols, 77% addressed medical management, 72% nursing care, 72% pharmacologic treatment, and 58% supportive care. Morphine was the most common first-line pharmacotherapy followed by methadone. Observation periods for opioid-exposed newborns varied; 57% observed short-acting opioid exposure for 2 to 3 days, while 30% observed for >/=5 days. For long-acting opioids, 71% observed for 4 to 5 days, 19% for 2 to 3 days, and 8% for >/=7 days. Observation for NAS occurred mostly in level 1 nurseries (86%); however, most (87%) transferred to NICUs when pharmacologic treatment was indicated.

CONCLUSIONS: Most BORN hospitals had protocols for the care of opioid-exposed infants, but policies varied widely and characterized areas of needed research. Identification of variation is the first step toward establishing best practice standards to improve care for this rapidly growing population.

Infant Nutritional Status and Markers of Environmental Enteric Dysfunction are Associated with Midchildhood Anthropometry and Blood Pressure in Tanzania

eScholarship@UMMS - Tue, 06/20/2017 - 2:36pm

OBJECTIVE: To assess whether growth and biomarkers of environmental enteric dysfunction in infancy are related to health outcomes in midchildhood in Tanzania.

STUDY DESIGN: Children who participated in 2 randomized trials of micronutrient supplements in infancy were followed up in midchildhood (4.6-9.8 years of age). Anthropometry was measured at age 6 and 52 weeks in both trials, and blood samples were available from children at 6 weeks and 6 months from 1 trial. Linear regression was used for height-for-age z-score, body mass index-for-age z-score, and weight for age z-score, and blood pressure analyses; log-binomial models were used to estimate risk of overweight, obesity, and stunting in midchildhood.

RESULTS: One hundred thirteen children were followed-up. Length-for-age z-score at 6 weeks and delta length-for-age z-score from 6 to 52 weeks were associated independently and positively with height-for-age z-score and inversely associated with stunting in midchildhood. Delta weight-for-length and weight-for-age z-score were also positively associated with midchildhood height-for-age z-score. The 6-week and delta weight-for-length z-scores were associated independently and positively with midchildhood body mass index-for-age z-score and overweight, as was the 6-week and delta weight-for-age z-score. Delta length-for-age z-score was also associated with an increased risk of overweight in midchildhood. Body mass index-for-age z-score in midchildhood was associated positively with systolic blood pressure. Serum anti-flagellin IgA concentration at 6 weeks was also associated with increased blood pressure in midchildhood.

CONCLUSIONS: Anthropometry at 6 weeks and growth in infancy independently predict size in midchildhood, while anti-flagellin IgA, a biomarker of environmental enteric dysfunction, in early infancy is associated with increased blood pressure in midchildhood. Interventions in early life should focus on optimizing linear growth while minimizing excess weight gain and environmental enteric dysfunction.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT00197730 and NCT00421668.

Laurence A. Boxer, MD, 1940-2017

eScholarship@UMMS - Tue, 06/20/2017 - 2:36pm

Obituary for Laurence A. Boxer, MD, retired professor from the University of Michigan Medical School, where he held the Henry and Mala Dorfman Family Chair in Pediatric Hematology/Oncology.

Cardiac Devices Come In Handy for the Coroner

Headlines from MedPage Today® - Tue, 06/20/2017 - 2:30pm
(MedPage Today) -- Device memory can often supply time and cause of death, study shows

Cardiac Devices Come In Handy for the Coroner

Headlines from MedPage Today® - Tue, 06/20/2017 - 2:30pm
(MedPage Today) -- Device memory can often supply time and cause of death, study shows

Risk Tool IDs Candidates for Adjuvant RT in Prostate Cancer (CME/CE)

Headlines from MedPage Today® - Tue, 06/20/2017 - 2:00pm
(MedPage Today) -- Combines tumor pathology, genomic data to reduce overtreatment

Risk Tool IDs Candidates for Adjuvant RT in Prostate Cancer (CME/CE)

Headlines from MedPage Today® - Tue, 06/20/2017 - 2:00pm
(MedPage Today) -- Combines tumor pathology, genomic data to reduce overtreatment

Clinical Challenges: Managing Gout

Headlines from MedPage Today® - Tue, 06/20/2017 - 1:30pm
(MedPage Today) -- Wealth of knowledge and effective treatments notwithstanding, condition remains all too common
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