eScholarship@UMMS

Syndicate content
Recent documents in eScholarship@UMMS
Updated: 2 hours 24 min ago

WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects

Wed, 11/16/2016 - 9:02pm

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

Impact of Microbiota on Resistance to Ocular Pseudomonas aeruginosa-Induced Keratitis

Wed, 11/16/2016 - 9:02pm

The existence of the ocular microbiota has been reported but functional analyses to evaluate its significance in regulating ocular immunity are currently lacking. We compared the relative contribution of eye and gut commensals in regulating the ocular susceptibility to Pseudomonas aeruginosa-induced keratitis. We find that in health, the presence of microbiota strengthened the ocular innate immune barrier by significantly increasing the concentrations of immune effectors in the tear film, including secretory IgA and complement proteins. Consistent with this view, Swiss Webster (SW) mice that are typically resistant to P. aeruginosa-induced keratitis become susceptible due to the lack of microbiota. This was exemplified by increased corneal bacterial burden and elevated pathology of the germ free (GF) mice when compared to the conventionally maintained SW mice. The protective immunity was found to be dependent on both eye and gut microbiota with the eye microbiota having a moderate, but significant impact on the resistance to infection. These events were IL-1ss-dependent as corneal IL-1ss levels were decreased in the infected GF and antibiotic-treated mice when compared to the SPF controls, and neutralization of IL-1ss increased the ocular bacterial burden in the SPF mice. Monocolonizing GF mice with Coagulase Negative Staphylococcus sp. isolated from the conjunctival swabs was sufficient to restore resistance to infection. Cumulatively, these data underline a previously unappreciated role for microbiota in regulating susceptibility to ocular keratitis. We predict that these results will have significant implications for contact lens wearers, where alterations in the ocular commensal communities may render the ocular surface vulnerable to infections.

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

Wed, 11/16/2016 - 9:02pm

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.

And the survey said.... evaluating rationale for participation in gun buybacks as a tool to encourage higher yields

Wed, 11/16/2016 - 9:02pm

BACKGROUND: Gun buyback programs represent one arm of a multipronged approach to raise awareness and education about gun safety.

METHODS: The city of Worcester, MA has conducted an annual gun buyback at the Police Department Headquarters since 2002. We analyzed survey responses from a voluntary, 18-question, face-to-face structured interview from December 2009 to June 2015 using descriptive statistics to determine participant demographics and motivations for participation.

RESULTS: A total of 943 guns were collected, and 273 individuals completed surveys. The majority of participants were white males older than 55years (42.4%). Participants represented 61 zip codes across Worcester County, with 68% having prior gun safety training and 61% with weapons remaining in the home (27% of which children could potentially access). The top reasons for turning in guns were "no longer needed" (48%) and "fear of children accessing the gun" (14%). About 1 in 3 respondents knew someone injured/killed by gun violence. Almost all (96%) respondents claimed the program raised community awareness of firearm risk.

CONCLUSION: The Worcester Goods for Guns Buyback has collected more than 900 guns between 2009 and 2015. The buyback removes unwanted guns from homes and raises community awareness about firearm safety.

Differences in the Quality of Pediatric Resuscitative Care Across a Spectrum of Emergency Departments

Wed, 11/16/2016 - 9:02pm

Importance: The quality of pediatric resuscitative care delivered across the spectrum of emergency departments (EDs) in the United States is poorly described. In a recent study, more than 4000 EDs completed the Pediatric Readiness Survey (PRS); however, the correlation of PRS scores with the quality of simulated or real patient care has not been described.

Objective: To measure and compare the quality of resuscitative care delivered to simulated pediatric patients across a spectrum of EDs and to examine the correlation of PRS scores with quality measures.

Design, Setting, and Participants: This prospective multicenter cohort study evaluated 58 interprofessional teams in their native pediatric or general ED resuscitation bays caring for a series of 3 simulated critically ill patients (sepsis, seizure, and cardiac arrest).

Main Outcomes and Measures: A composite quality score (CQS) was measured as the sum of 4 domains: (1) adherence to sepsis guidelines, (2) adherence to cardiac arrest guidelines, (3) performance on seizure resuscitation, and (4) teamwork. Pediatric Readiness Survey scores and health care professional demographics were collected as independent data. Correlations were explored between CQS and individual domain scores with PRS.

Results: Overall, 58 teams from 30 hospitals participated (8 pediatric EDs [PEDs], 22 general EDs [GEDs]). The mean CQS was 71 (95% CI, 68-75); PEDs had a higher mean CQS (82; 95% CI, 79-85) vs GEDs (66; 95% CI, 63-69) and outperformed GEDs in all domains. However, when using generalized estimating equations to estimate CQS controlling for clustering of the data, PED status did not explain a higher CQS (beta = 4.28; 95% CI, -4.58 to 13.13) while the log of pediatric patient volume did explain a higher CQS (beta = 9.57; 95% CI, 2.64-16.49). The correlation of CQS to PRS was moderate (r = 0.51; P < .001). The correlation was weak for cardiac arrest (r = 0.24; P = .07), weak for sepsis (rho = 0.45; P < .001) and seizure (rho = 0.43; P = .001), and strong for teamwork (rho = 0.71; P < .001).

Conclusions and Relevance: This multicenter study noted significant differences in the quality of simulated pediatric resuscitative care across a spectrum of EDs. The CQS was higher in PEDs compared with GEDs. However, when controlling for pediatric patient volume and other variables in a multivariable model, PED status does not explain a higher CQS while pediatric patient volume does. The correlation of the PRS was moderate for simulation-based measures of quality.

Medicare Facility Diagnosis Related Groups Have Outpaced Individual Physician Payment

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

INTRODUCTION: We set out to compare the rates of Medicare reimbursement to physicians versus hospitals for several major vascular procedures over a period of five years.

METHODS: We queried the Wolters Luwer MediRegs database to collect Medicare reimbursement data from fiscal years 2011 to 2015. We surveyed reimbursements for carotid endarterectomy (CEA), carotid angioplasty and stenting (CAS), femoropopliteal bypass, and lower extremity fem-pop revascularization with stenting. Based on data availability, we surveyed physician reimbursement data on the national level and in both medically over-served and underserved areas. Hospital reimbursement rates were examined on a national level and by hospitals' teaching and wage index statuses.

RESULTS: We found that for all four vascular procedures, Medicare reimbursements to hospitals increased by a greater percentage than to physicians. By region, underserved areas had lower physician reimbursements than the national average, while the opposite was true for overserved areas. Additionally, for hospital Medicare reimbursements, location in a high wage index accounted for a significant increase in reimbursement over the national average, with teaching status contributing to this increase to a smaller extent.

CONCLUSIONS: This data on Medicare reimbursements indicate that payments to hospitals are increasing more significantly than to physicians. This disparity in pay changes affects both independent and academic vascular surgeons. Medicare should consider pay increases to independent providers in accordance to the hospital pay increase.

Poor Adherence to Lung-Protective Mechanical Ventilation in Pediatric Acute Respiratory Distress Syndrome

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

OBJECTIVES: To determine the frequency of low-tidal volume ventilation in pediatric acute respiratory distress syndrome and assess if any demographic or clinical factors improve low-tidal volume ventilation adherence.

DESIGN: Descriptive post hoc analysis of four multicenter pediatric acute respiratory distress syndrome studies.

SETTING: Twenty-six academic PICU.

PATIENTS: Three hundred fifteen pediatric acute respiratory distress syndrome patients.

MEASUREMENTS AND MAIN RESULTS: All patients who received conventional mechanical ventilation at hours 0 and 24 of pediatric acute respiratory distress syndrome who had data to calculate ideal body weight were included. Two cutoff points for low-tidal volume ventilation were assessed: less than or equal to 6.5 mL/kg of ideal body weight and less than or equal to 8 mL/kg of ideal body weight. Of 555 patients, we excluded 240 for other respiratory support modes or missing data. The remaining 315 patients had a median PaO2-to-FIO2 ratio of 140 (interquartile range, 90-201), and there were no differences in demographics between those who did and did not receive low-tidal volume ventilation. With tidal volume cutoff of less than or equal to 6.5 mL/kg of ideal body weight, the adherence rate was 32% at hour 0 and 33% at hour 24. A low-tidal volume ventilation cutoff of tidal volume less than or equal to 8 mL/kg of ideal body weight resulted in an adherence rate of 58% at hour 0 and 60% at hour 24. Low-tidal volume ventilation use was no different by severity of pediatric acute respiratory distress syndrome nor did adherence improve over time. At hour 0, overweight children were less likely to receive low-tidal volume ventilation less than or equal to 6.5 mL/kg ideal body weight (11% overweight vs 38% nonoverweight; p = 0.02); no difference was noted by hour 24. Furthermore, in the overweight group, using admission weight instead of ideal body weight resulted in misclassification of up to 14% of patients as receiving low-tidal volume ventilation when they actually were not.

CONCLUSIONS: Low-tidal volume ventilation is underused in the first 24 hours of pediatric acute respiratory distress syndrome. Age, Pediatric Risk of Mortality-III, and pediatric acute respiratory distress syndrome severity were not associated with improved low-tidal volume ventilation adherence nor did adherence improve over time. Overweight children were less likely to receive low-tidal volume ventilation strategies in the first day of illness.

Barriers to Care Coordination and Medical Home Implementation

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

BACKGROUND: Pediatricians are central in leading the family-centered medical home (FCMH), yet little is known about how provider-perceived barriers to and attitudes toward the FCMH affect implementation. This study aims to assess the relationship between pediatrician-perceived barriers to and attitudes toward FCMH and reported care coordination.

METHODS: Pediatricians working in ambulatory care responded to the American Academy of Pediatrics Periodic Survey of Fellows #79 (N = 572, response rate, 59%). Our primary care coordination outcomes were whether pediatricians were: (1) leading a multidisciplinary team; (2) developing care plans; and (3) connecting with support services. Independent variables included barriers to FCMH implementation (lack of communication skills, support services, and time). Associations between outcomes and barriers were assessed by multivariate logistic regression, controlling for pediatrician and practice characteristics.

RESULTS: Lack of sufficient personnel was significantly associated with fewer care coordination activities: leading a multidisciplinary team (odds ratio [OR], 0.53), developing care plans (OR, 0.51), and connecting with support services (OR, 0.42). Lacking communication skills was significantly associated with lower odds of development of care plans (OR, 0.56) and assistance with support services (OR, 0.64). Lack of time was significantly associated with lower odds of leading a multidisciplinary team (OR, 0.53). A pediatrician's belief that the FCMH encourages the use of preventive services was significantly associated with increased support services (OR, 2.06).

CONCLUSIONS: Pediatricians report a need for sufficient personnel and communication skills to provide care coordination, a core component of the FCMH. Interventions to boost FCMH implementation should focus on providing resources to develop these characteristics.

Multiple Cafe au Lait Spots in a Group of Fair-Skinned Children without Signs or Symptoms of Neurofibromatosis Type 1

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

BACKGROUND: The presence of six or more cafe au lait (CAL) spots is a criterion for the diagnosis of neurofibromatosis type 1 (NF-1). Children with multiple CAL spots are often referred to dermatologists for NF-1 screening. The objective of this case series is to characterize a subset of fair-complected children with red or blond hair and multiple feathery CAL spots who did not meet the criteria for NF-1 at the time of their last evaluation.

METHODS: We conducted a chart review of eight patients seen in our pediatric dermatology clinic who were previously identified as having multiple CAL spots and no other signs or symptoms of NF-1.

RESULTS: We describe eight patients ages 2 to 9 years old with multiple, irregular CAL spots with feathery borders and no other signs or symptoms of NF-1. Most of these patients had red or blond hair and were fair complected. All patients were evaluated in our pediatric dermatology clinic, some with a geneticist. The number of CAL spots per patient ranged from 5 to 15 (mean 9.4, median 9).

CONCLUSION: A subset of children, many with fair complexions and red or blond hair, has an increased number of feathery CAL spots and appears unlikely to develop NF-1, although genetic testing was not conducted. It is important to recognize the benign nature of CAL spots in these patients so that appropriate screening and follow-up recommendations may be made.

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.