Resident Dyads Providing Transition Care to Adolescents and Young Adults With Chronic Illnesses and Neurodevelopmental Disabilities.

PubMed

Chung, Richard J; Jasien, Joan; Maslow, Gary R

2017-04-01

Youth with special health care needs often experience difficulty transitioning from pediatric to adult care. These difficulties may derive in part from lack of physician training in transition care and the challenges health care providers experience establishing interdisciplinary partnerships to support these patients. This educational innovation sought to improve pediatrics and adult medicine residents' interdisciplinary communication and collaboration. Residents from pediatrics, medicine-pediatrics, and internal medicine training programs participated in a transitions clinic for patients with chronic health conditions aged 16 to 26 years. Residents attended 1 to 4 half-day clinic sessions during 1-month ambulatory rotations. Pediatrics/adult medicine resident dyads collaboratively performed psychosocial and medical transition consultations that addressed health care navigation, self-care, and education and vocation topics. Two to 3 attending physicians supervised each clinic session (4 hours) while concurrently seeing patients. Residents completed a preclinic survey about baseline attitudes and experiences, and a postclinic survey about their transitions clinic experiences, changes in attitudes, and transition care preparedness. A total of 46 residents (100% of those eligible) participated in the clinic and completed the preclinic survey, and 25 (54%) completed the postclinic survey. A majority of respondents to the postclinic survey reported positive experiences. Residents in both pediatrics and internal medicine programs reported improved preparedness for providing transition care to patients with chronic health conditions and communicating effectively with colleagues in other disciplines. A dyadic model of collaborative transition care training was positively received and yielded improvements in immediate self-assessed transition care preparedness.

Initial Testing (Stage 1) of SGI-1776, a PIM1 Kinase Inhibitor, by the Pediatric Preclinical Testing Program

PubMed Central

Batra, Vandana; Maris, John M.; Kang, Min H.; Reynolds, C. Patrick; Houghton, Peter J.; Alexander, Denise; Kolb, E. Anders; Gorlick, Richard; Keir, Stephen T.; Carol, Hernan; Lock, Richard; Billups, Catherine A.; Smith, Malcolm A.

2011-01-01

The PIM kinase inhibitor, SGI-1776, was tested against the PPTP in vitro (1.0 nM to 10 μM) and in vivo panels (148 mg/kg daily x 5 days for 3 weeks). SGI-1776 exhibited cytotoxic activity in vitro with a median relative IC50 of 3.1 μM. SGI-1776 induced significant differences in EFS distribution in vivo in 9 of 31 solid tumor xenografts and in 1 of 8 of the evaluable ALL xenografts. SGI-1776 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 1 of 39 evaluable models. In contrast, SGI-1776 induced complete responses of subcutaneous MV4;11 (B myeloid leukemia). PMID:22052829

[A short history of pediatric neurology in Jagiellonian University].

PubMed

Kaciński, Marek

2016-01-01

The author reminded preclinical years and the work of children's neu- rologists at that time. And next he de- scribed the work of people which from creating the Department of Pediatric Neurology in 1996 created structures of the Department, its 6 Laboratories and the Outpatients Clinic. From 2008 the Department was a part a Chair of Pediatric and Adolescent Neurology, from here the Author also checked teaching and scientific activity of the Chair, the Department, and 2 academic Laboratories of the Neurophysiology and the Clinical Electrophysiology. He pointed at effective efforts for financed research projects.

Initial testing (stage 1) of SGI-1776, a PIM1 kinase inhibitor, by the pediatric preclinical testing program.

PubMed

Batra, Vandana; Maris, John M; Kang, Min H; Reynolds, C Patrick; Houghton, Peter J; Alexander, Denise; Kolb, E Anders; Gorlick, Richard; Keir, Stephen T; Carol, Hernan; Lock, Richard; Billups, Catherine A; Smith, Malcolm A

2012-10-01

The PIM kinase inhibitor, SGI-1776, was tested against the PPTP in vitro (1.0 nM-10 µM) and in vivo panels (148 mg/kg daily × 5 days for 3 weeks). SGI-1776 exhibited cytotoxic activity in vitro with a median relative IC(50) of 3.1 µM. SGI-1776 induced significant differences in EFS distribution in vivo in 9 of 31 solid tumor xenografts and in 1 of 8 of the evaluable ALL xenografts. SGI-1776 induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 1 of 39 evaluable models. In contrast, SGI-1776 induced complete responses of subcutaneous MV4;11 (B myeloid leukemia). Copyright © 2011 Wiley Periodicals, Inc.

Applications of Genomic Sequencing in Pediatric CNS Tumors.

PubMed

Bavle, Abhishek A; Lin, Frank Y; Parsons, D Williams

2016-05-01

Recent advances in genome-scale sequencing methods have resulted in a significant increase in our understanding of the biology of human cancers. When applied to pediatric central nervous system (CNS) tumors, these remarkable technological breakthroughs have facilitated the molecular characterization of multiple tumor types, provided new insights into the genetic basis of these cancers, and prompted innovative strategies that are changing the management paradigm in pediatric neuro-oncology. Genomic tests have begun to affect medical decision making in a number of ways, from delineating histopathologically similar tumor types into distinct molecular subgroups that correlate with clinical characteristics, to guiding the addition of novel therapeutic agents for patients with high-risk or poor-prognosis tumors, or alternatively, reducing treatment intensity for those with a favorable prognosis. Genomic sequencing has also had a significant impact on translational research strategies in pediatric CNS tumors, resulting in wide-ranging applications that have the potential to direct the rational preclinical screening of novel therapeutic agents, shed light on tumor heterogeneity and evolution, and highlight differences (or similarities) between pediatric and adult CNS tumors. Finally, in addition to allowing the identification of somatic (tumor-specific) mutations, the analysis of patient-matched constitutional (germline) DNA has facilitated the detection of pathogenic germline alterations in cancer genes in patients with CNS tumors, with critical implications for genetic counseling and tumor surveillance strategies for children with familial predisposition syndromes. As our understanding of the molecular landscape of pediatric CNS tumors continues to advance, innovative applications of genomic sequencing hold significant promise for further improving the care of children with these cancers.

Evaluation of Cytarabine Against Ewing Sarcoma Xenografts by the Pediatric Preclinical Testing Program

PubMed Central

Houghton, Peter J.; Morton, Christopher L.; Kang, Min; Reynolds, C. Patrick; Billups, Catherine A.; Favours, Edward; Payne-Turner, Debbie; Tucker, Chandra; Smith, Malcolm A.

2015-01-01

Treatment with the nucleoside analog cytarabine has been shown to mimic changes in gene expression associated with down-regulation of the EWS-FLI1 oncogene in Ewing sarcoma cell lines, selectively inhibit their growth in vitro, and cause tumor regression in athymic nude mice. For this report cytarabine was studied in vitro against a panel of 23 pediatric cancer cell lines and in vivo against 6 Ewing sarcoma xenografts. Acute lymphoblastic leukemia cell lines were the most sensitive to cytarabine in vitro (median IC50 9 nM), while Ewing sarcoma cell lines showed intermediate sensitivity (median IC50 232 nM). Cytarabine at a dose of 150 mg/kg administered daily 5× failed to significantly inhibit growth of five xenograft models, but reduced growth rate of the A673 xenograft by 50%. Cytarabine shows no differential in vitro activity against Ewing sarcoma cell lines and is ineffective in vivo against Ewing sarcoma xenografts at the dose and schedule studied. PMID:20979180

Accelerating drug development in pediatric cancer: a novel Phase I study design of venetoclax in relapsed/refractory malignancies.

PubMed

Place, Andrew E; Goldsmith, Kelly; Bourquin, Jean-Pierre; Loh, Mignon L; Gore, Lia; Morgenstern, Daniel A; Sanzgiri, Yeshwant; Hoffman, David; Zhou, Ying; Ross, Jeremy A; Prine, Betty; Shebley, Mohamad; McNamee, Megan; Farazi, Thalia; Kim, Su Young; Verdugo, Maria; Lash-Fleming, Leanne; Zwaan, C Michel; Vormoor, Josef

2018-03-29

Venetoclax is a highly selective, potent BCL-2 inhibitor that is approved for some patients previously treated for chronic lymphocytic leukemia, and has shown promising activity in adult studies across several hematologic malignancies. Preclinical studies have demonstrated venetoclax activity in pediatric patient-derived xenograft models and cell lines; however, clinical studies in pediatric patients have yet to be conducted. The prognosis is poor for children with most relapsed/refractory malignancies, and limited treatment options result in unmet clinical need. Herein, we describe the rationale and design of the first study of venetoclax in pediatric patients with relapsed/refractory malignancies: a Phase I trial investigating the safety and pharmacokinetics of venetoclax monotherapy followed by the addition of chemotherapy (Trial registration: EudraCT 2017-000439-14; NCT03236857).

Development of Confidence in Child Behavior Management through Role Playing.

ERIC Educational Resources Information Center

Kress, Gerard C., Jr.; Ehrlichs, Melvin A.

1990-01-01

In a preclinical course in pediatric dentistry, 76 students were taught child behavior management through role playing of 7-10 common management situations. Pre- and postcourse measures of student confidence found that, although older students were more confident, all gained significantly from the training. Other student characteristics were also…

Identification of targets for rational pharmacological therapy in childhood craniopharyngioma.

PubMed

Gump, Jacob M; Donson, Andrew M; Birks, Diane K; Amani, Vladimir M; Rao, Karun K; Griesinger, Andrea M; Kleinschmidt-DeMasters, B K; Johnston, James M; Anderson, Richard C E; Rosenfeld, Amy; Handler, Michael; Gore, Lia; Foreman, Nicholas; Hankinson, Todd C

2015-05-21

Pediatric adamantinomatous craniopharyngioma (ACP) is a histologically benign but clinically aggressive brain tumor that arises from the sellar/suprasellar region. Despite a high survival rate with current surgical and radiation therapy (75-95 % at 10 years), ACP is associated with debilitating visual, endocrine, neurocognitive and psychological morbidity, resulting in excheptionally poor quality of life for survivors. Identification of an effective pharmacological therapy could drastically decrease morbidity and improve long term outcomes for children with ACP. Using mRNA microarray gene expression analysis of 15 ACP patient samples, we have found several pharmaceutical targets that are significantly and consistently overexpressed in our panel of ACP relative to other pediatric brain tumors, pituitary tumors, normal pituitary and normal brain tissue. Among the most highly expressed are several targets of the kinase inhibitor dasatinib - LCK, EPHA2 and SRC; EGFR pathway targets - AREG, EGFR and ERBB3; and other potentially actionable cancer targets - SHH, MMP9 and MMP12. We confirm by western blot that a subset of these targets is highly expressed in ACP primary tumor samples. We report here the first published transcriptome for ACP and the identification of targets for rational therapy. Experimental drugs targeting each of these gene products are currently being tested clinically and pre-clinically for the treatment of other tumor types. This study provides a rationale for further pre-clinical and clinical studies of novel pharmacological treatments for ACP. Development of mouse and cell culture models for ACP will further enable the translation of these targets from the lab to the clinic, potentially ushering in a new era in the treatment of ACP.

Pediatric Traumatic Brain Injury and Autism: Elucidating Shared Mechanisms

PubMed Central

Singh, Rahul; Nguyen, Linda; Motwani, Kartik; Swatek, Michelle

2016-01-01

Pediatric traumatic brain injury (TBI) and autism spectrum disorder (ASD) are two serious conditions that affect youth. Recent data, both preclinical and clinical, show that pediatric TBI and ASD share not only similar symptoms but also some of the same biologic mechanisms that cause these symptoms. Prominent symptoms for both disorders include gastrointestinal problems, learning difficulties, seizures, and sensory processing disruption. In this review, we highlight some of these shared mechanisms in order to discuss potential treatment options that might be applied for each condition. We discuss potential therapeutic and pharmacologic options as well as potential novel drug targets. Furthermore, we highlight advances in understanding of brain circuitry that is being propelled by improved imaging modalities. Going forward, advanced imaging will help in diagnosis and treatment planning strategies for pediatric patients. Lessons from each field can be applied to design better and more rigorous trials that can be used to improve guidelines for pediatric patients suffering from TBI or ASD. PMID:28074078

A Model Program for Translational Medicine in Epilepsy Genetics

PubMed Central

Smith, Lacey A.; Ullmann, Jeremy F. P.; Olson, Heather E.; El Achkar, Christelle M.; Truglio, Gessica; Kelly, McKenna; Rosen-Sheidley, Beth; Poduri, Annapurna

2017-01-01

Recent technological advances in gene sequencing have led to a rapid increase in gene discovery in epilepsy. However, the ability to assess pathogenicity of variants, provide functional analysis, and develop targeted therapies has not kept pace with rapid advances in sequencing technology. Thus, although clinical genetic testing may lead to a specific molecular diagnosis for some patients, test results often lead to more questions than answers. As the field begins to focus on therapeutic applications of genetic diagnoses using precision medicine, developing processes that offer more than equivocal test results is essential. The success of precision medicine in epilepsy relies on establishing a correct genetic diagnosis, analyzing functional consequences of genetic variants, screening potential therapeutics in the preclinical laboratory setting, and initiating targeted therapy trials for patients. We describe the structure of a comprehensive, pediatric Epilepsy Genetics Program that can serve as a model for translational medicine in epilepsy. PMID:28056630

O8.10A MODEL FOR RESEARCH INITIATIVES FOR RARE CANCERS: THE COLLABORATIVE EPENDYMOMA RESEARCH NETWORK (CERN)

PubMed Central

Armstrong, T.S.; Aldape, K.; Gajjar, A.; Haynes, C.; Hirakawa, D.; Gilbertson, R.; Gilbert, M.R.

2014-01-01

Ependymoma represents less than 5% of adult central nervous system (CNS) tumors and a higher percentage of pediatric CNS tumors, but it remains an orphan disease. The majority of the laboratory-based research and clinical trials have been conducted in the pediatric setting, a reflection of the relative incidence and funding opportunities. CERN, created in 2006, was designed to establish a collaborative effort between laboratory and clinical research and pediatric and adult investigators. The organization of CERN is based on integration and collaboration among five projects. Project 1 contains the clinical trials network encompassing both adult and pediatric centers. This group has completed 2 clinical trials with more underway. Project 2 is focused on molecular classification of human ependymoma tumor tissues and also contains the tumor repository which has now collected over 600 fully clinically annotated CNS ependymomas from adults and children. Project 3 is focused on drug discovery utilizing robust laboratory models of ependymoma to perform high throughput screening of drug libraries, then taking promising agents through extensive preclinical testing including monitoring of drug delivery to tumor using state of the art microdialysis. Project 4 contains the basic research efforts evaluating the molecular pathogenesis of ependymoma and has successfully translated these findings by generating the first mouse models of ependymoma that are employed in preclinical drug development in Project 3. Project 5 studies patient outcomes, including the incorporation of these measures in the clinical trials. This project also contains an online Ependymoma Outcomes survey, collecting data on the consequences of the disease and its treatment. These projects have been highly successful and collaborative. For example, the serial measurement of symptom burden (Project 5) has greatly contributed to the evaluation of treatment efficacy of a clinical trial (Project 1) and investigators from Project 2 are evaluating potential predictive markers from tumor tissue from the same clinical trial. Results from genomic and molecular discoveries generated by Project 4 were evaluated using the clinical material from the Tumor Registry (Project 2). Agents identified from the high throughput screening in Project 3 are being used to create novel clinical trials (Project 1). As a complimentary effort, CERN's community outreach efforts provide a major gateway to patients, families, caregivers and healthcare providers, contributing to greater awareness of ependymoma, and supporting clinical trial accrual in Project 1. In summary, CERN has successfully created a collaborative, multi-national integrated effort combining pediatric- and adult-focused investigators spanning from basic science to patient outcomes measures. This research paradigm may be an effective approach for other rare cancers.

Molecular profiling of childhood cancer: Biomarkers and novel therapies.

PubMed

Saletta, Federica; Wadham, Carol; Ziegler, David S; Marshall, Glenn M; Haber, Michelle; McCowage, Geoffrey; Norris, Murray D; Byrne, Jennifer A

2014-06-01

Technological advances including high-throughput sequencing have identified numerous tumor-specific genetic changes in pediatric and adolescent cancers that can be exploited as targets for novel therapies. This review provides a detailed overview of recent advances in the application of target-specific therapies for childhood cancers, either as single agents or in combination with other therapies. The review summarizes preclinical evidence on which clinical trials are based, early phase clinical trial results, and the incorporation of predictive biomarkers into clinical practice, according to cancer type. There is growing evidence that molecularly targeted therapies can valuably add to the arsenal available for treating childhood cancers, particularly when used in combination with other therapies. Nonetheless the introduction of molecularly targeted agents into practice remains challenging, due to the use of unselected populations in some clinical trials, inadequate methods to evaluate efficacy, and the need for improved preclinical models to both evaluate dosing and safety of combination therapies. The increasing recognition of the heterogeneity of molecular causes of cancer favors the continued development of molecularly targeted agents, and their transfer to pediatric and adolescent populations.

Preclinical profile of cabazitaxel

PubMed Central

Vrignaud, Patricia; Semiond, Dorothée; Benning, Veronique; Beys, Eric; Bouchard, Hervé; Gupta, Sunil

2014-01-01

First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with docetaxel. In conclusion, the demonstrated activity of cabazitaxel in tumors with innate or acquired resistance to docetaxel, CNS tumors, and pediatric tumors made this agent a candidate for further clinical evaluation in a broader range of patient populations compared with first-generation taxanes. PMID:25378905

A tailored mouse model of CLN2 disease: A nonsense mutant for testing personalized therapies

PubMed Central

Geraets, Ryan D.; Beraldi, Rosanna; Weimer, Jill M.; Pearce, David A.

2017-01-01

The Neuronal Ceroid Lipofuscinoses (NCLs), also known as Batten disease, result from mutations in over a dozen genes. Although, adults are susceptible, the NCLs are frequently classified as pediatric neurodegenerative diseases due to their greater pediatric prevalence. Initial clinical presentation usually consists of either seizures or retinopathy but develops to encompass both in conjunction with declining motor and cognitive function. The NCLs result in premature death due to the absence of curative therapies. Nevertheless, preclinical and clinical trials exist for various therapies. However, the genotypes of NCL animal models determine which therapeutic approaches can be assessed. Mutations of the CLN2 gene encoding a soluble lysosomal enzyme, tripeptidyl peptidase 1 (TPP1), cause late infantile NCL/CLN2 disease. The genotype of the original mouse model of CLN2 disease, Cln2-/-, excludes mutation guided therapies like antisense oligonucleotides and nonsense suppression. Therefore, the purpose of this study was to develop a model of CLN2 disease that allows for the assessment of all therapeutic approaches. Nonsense mutations in CLN2 disease are frequent, the most common being CLN2R208X. Thus, we created a mouse model that carries a mutation equivalent to the human p.R208X mutation. Molecular assessment of Cln2R207X/R207X tissues determined significant reduction in Cln2 transcript abundance and TPP1 enzyme activity. This reduction leads to the development of neurological impairment (e.g. tremors) and neuropathology (e.g. astrocytosis). Collectively, these assessments indicate that the Cln2R207X/R207X mouse is a valid CLN2 disease model which can be used for the preclinical evaluation of all therapeutic approaches including mutation guided therapies. PMID:28464005

SU-C-303-03: Dosimetric Model of the Beagle Needed for Pre-Clinical Testing of Radiopharmaceuticals

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shang, M; Sands, M; Bolch, W

2015-06-15

Purpose: Large animal models, most popularly beagles, have been crucial surrogates to humans in determining radiation safety levels of radiopharmaceuticals. This study aims to develop a detailed beagle phantom to accurately approximate organ absorbed doses for therapy nuclear medicine preclinical studies. Methods: A 3D NURBS model was created subordinate to a whole body CT of an adult beagle. Bones were harvested and CT imaged to offer macroscopic skeletal detail. Samples of trabecular spongiosa were cored and imaged to offer microscopic skeletal detail for bone trabeculae and marrow volume fractions. Results: Organ masses in the model are typical of an adultmore » beagle. Trends in volume fractions for skeletal dosimetry are fundamentally similar to those found in existing models of other canine species. Conclusion: This work warrants its use in further investigations of radiation transport calculation for electron and photon dosimetry. This model accurately represents the anatomy of a beagle, and can be directly translated into a useable geometry for a voxel-based Monte Carlo radiation transport program such as MCNP6. Work supported by a grant from the Hyundai Hope on Wheels Foundation for Pediatric Cancer Research.« less

Evaluation of patritumab with or without erlotinib in combination with standard cytotoxic agents against pediatric sarcoma xenograft models.

PubMed

Bandyopadhyay, Abhik; Favours, Edward; Phelps, Doris A; Pozo, Vanessa Del; Ghilu, Samson; Kurmashev, Dias; Michalek, Joel; Trevino, Aron; Guttridge, Denis; London, Cheryl; Hirotani, Kenji; Zhang, Ling; Kurmasheva, Raushan T; Houghton, Peter J

2018-02-01

Integrating molecularly targeted agents with cytotoxic drugs used in curative treatment of pediatric cancers is complex. An evaluation was undertaken with the ERBB3/Her3-specific antibody patritumab (P) either alone or with the ERBB1/epidermal growth factor receptor inhibitor erlotinib (E) in combination with standard cytotoxic agents, cisplatin, vincristine, and cyclophosphamide, in pediatric sarcoma xenograft models that express receptors and ligands targeted by these agents. Tumor models were selected based upon ERBB3 expression and phosphorylation, and ligand (heregulin) expression. Patritumab, E, or these agents combined was evaluated without or with concomitant cytotoxic agents using procedures developed by the Pediatric Preclinical Testing Program. Full doses of cytotoxic agents were tolerated when combined with P, whereas dose reductions of 25% (vincristine, cisplatin) or 50% (cyclophosphamide) were required when combined with P + E. Patritumab, E alone, or in combination did not significantly inhibit growth of any tumor model, except for Rh18 xenografts (E alone). Patritumab had no single-agent activity and marginally enhanced the activity of vincristine and cisplatin only in Ewing sarcoma ES-4. P + E did not increase the antitumor activity of vincristine or cisplatin, whereas dose-reduced cyclophosphamide was significantly less active than cyclophosphamide administered at its maximum tolerated dose when combined with P + E. P had no single-agent activity, although it marginally potentiated the activity of vincristine and cisplatin in one of three models studied. However, the addition of E necessitated dose reduction of each cytotoxic agent, abrogating the enhancement observed with P alone. © 2017 Wiley Periodicals, Inc.

Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion

PubMed Central

Hussein, Deema; Punjaruk, Wiyada; Storer, Lisa C.D.; Shaw, Lucy; Ottoman, Ramadan; Peet, Andrew; Miller, Suzanne; Bandopadhyay, Gagori; Heath, Rachel; Kumari, Rajendra; Bowman, Karen J.; Braker, Paul; Rahman, Ruman; Jones, George D.D.; Watson, Susan; Lowe, James; Kerr, Ian D.; Grundy, Richard G.; Coyle, Beth

2011-01-01

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neuroectodermal tumor) was thoroughly characterized. Comparison of DNA copy number with the original corresponding tumor demonstrated that genomic changes present in the original tumor, typical of that particular tumor type, were retained in culture. In each case, the CSC component was approximately 3–4-fold enriched in neurosphere culture compared with monolayer culture, and a higher capacity for multilineage differentiation was observed for neurosphere-derived cells. DNA content profiles of neurosphere-derived cells expressing the CSC marker nestin demonstrated the presence of cells in all phases of the cell cycle, indicating that not all CSCs are quiescent. Furthermore, neurosphere-derived cells demonstrated an increased resistance to etoposide compared with monolayer-derived cells, having lower initial DNA damage, potentially due to a combination of increased drug extrusion by ATP-binding cassette multidrug transporters and enhanced rates of DNA repair. Finally, orthotopic xenograft models reflecting the tumor of origin were established from these cell lines. In summary, these cell lines and the approach taken provide a robust model system that can be used to develop our understanding of the biology of CSCs in pediatric brain tumors and other cancer types and to preclinically test therapeutic agents. PMID:20978004

Pediatric brain tumor cancer stem cells: cell cycle dynamics, DNA repair, and etoposide extrusion.

PubMed

Hussein, Deema; Punjaruk, Wiyada; Storer, Lisa C D; Shaw, Lucy; Othman, Ramadhan; Ottoman, Ramadan; Peet, Andrew; Miller, Suzanne; Bandopadhyay, Gagori; Heath, Rachel; Kumari, Rajendra; Bowman, Karen J; Braker, Paul; Rahman, Ruman; Jones, George D D; Watson, Susan; Lowe, James; Kerr, Ian D; Grundy, Richard G; Coyle, Beth

2011-01-01

Reliable model systems are needed to elucidate the role cancer stem cells (CSCs) play in pediatric brain tumor drug resistance. The majority of studies to date have focused on clinically distinct adult tumors and restricted tumor types. Here, the CSC component of 7 newly established primary pediatric cell lines (2 ependymomas, 2 medulloblastomas, 2 gliomas, and a CNS primitive neuroectodermal tumor) was thoroughly characterized. Comparison of DNA copy number with the original corresponding tumor demonstrated that genomic changes present in the original tumor, typical of that particular tumor type, were retained in culture. In each case, the CSC component was approximately 3-4-fold enriched in neurosphere culture compared with monolayer culture, and a higher capacity for multilineage differentiation was observed for neurosphere-derived cells. DNA content profiles of neurosphere-derived cells expressing the CSC marker nestin demonstrated the presence of cells in all phases of the cell cycle, indicating that not all CSCs are quiescent. Furthermore, neurosphere-derived cells demonstrated an increased resistance to etoposide compared with monolayer-derived cells, having lower initial DNA damage, potentially due to a combination of increased drug extrusion by ATP-binding cassette multidrug transporters and enhanced rates of DNA repair. Finally, orthotopic xenograft models reflecting the tumor of origin were established from these cell lines. In summary, these cell lines and the approach taken provide a robust model system that can be used to develop our understanding of the biology of CSCs in pediatric brain tumors and other cancer types and to preclinically test therapeutic agents.

Neuroprotection and neurotoxicity in the developing brain: an update on the effects of dexmedetomidine and xenon.

PubMed

Alam, Azeem; Suen, Ka Chun; Hana, Zac; Sanders, Robert D; Maze, Mervyn; Ma, Daqing

Growing and consistent preclinical evidence, combined with early clinical epidemiological observations, suggest potentially neurotoxic effects of commonly used anesthetic agents in the developing brain. This has prompted the FDA to issue a safety warning for all sedatives and anesthetics approved for use in children under three years of age. Recent studies have identified dexmedetomidine, the potent α2-adrenoceptor agonist, and xenon, the noble gas, as effective anesthetic adjuvants that are both less neurotoxic to the developing brain, and also possess neuroprotective properties in neonatal and other settings of acute ongoing neurologic injury. Dexmedetomidine and xenon are effective anesthetic adjuvants that appear to be less neurotoxic than other existing agents and have the potential to be neuroprotective in the neonatal and pediatric settings. Although results from recent clinical trials and case reports have indicated the neuroprotective potential of xenon and dexmedetomidine, additional randomized clinical trials corroborating these studies are necessary. By reviewing both the existing preclinical and clinical evidence on the neuroprotective effects of dexmedetomidine and xenon, we hope to provide insight into the potential clinical efficacy of these agents in the management of pediatric surgical patients. Copyright © 2017 Elsevier Inc. All rights reserved.

National Library of Medicine Classification: A Scheme for the Shelf Arrangement of Books in a Field of Medicine and Its Related Sciences. Fourth Edition.

ERIC Educational Resources Information Center

Wiggins, Emilie, Ed.

Outlined is the National Library of Medicine classification system for medicine and related sciences. In this system each preclinical science, such as human anatomy, biochemistry or pathology, and each medical subject, such as infectious diseases or pediatrics, receives a two-letter classification. Under each of these main headings numbered minor…

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

PubMed Central

Talekar, Mala K; Allen, Joshua E; Dicker, David T; El-Deiry, Wafik S

2015-01-01

ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin's lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin's lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL. PMID:26030065

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells.

PubMed

Talekar, Mala K; Allen, Joshua E; Dicker, David T; El-Deiry, Wafik S

2015-08-03

ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin's lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin's lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL.

Rationale and Design of a Phase 1 Clinical Trial to Evaluate HSV G207 Alone or with a Single Radiation Dose in Children with Progressive or Recurrent Malignant Supratentorial Brain Tumors.

PubMed

Waters, Alicia M; Johnston, James M; Reddy, Alyssa T; Fiveash, John; Madan-Swain, Avi; Kachurak, Kara; Bag, Asim K; Gillespie, G Yancey; Markert, James M; Friedman, Gregory K

2017-03-01

Primary central nervous system tumors are the most common solid neoplasm of childhood and the leading cause of cancer-related death in pediatric patients. Survival rates for children with malignant supratentorial brain tumors are poor despite aggressive treatment with combinations of surgery, radiation, and chemotherapy, and survivors often suffer from damaging lifelong sequelae from current therapies. Novel innovative treatments are greatly needed. One promising new approach is the use of a genetically engineered, conditionally replicating herpes simplex virus (HSV) that has shown tumor-specific tropism and potential efficacy in the treatment of malignant brain tumors. G207 is a genetically engineered HSV-1 lacking genes essential for replication in normal brain cells. Safety has been established in preclinical investigations involving intracranial inoculation in the highly HSV-sensitive owl monkey (Aotus nancymai), and in three adult phase 1 trials in recurrent/progressive high-grade gliomas. No dose-limiting toxicities were seen in the adult studies and a maximum tolerated dose was not reached. Approximately half of the 35 treated adults had radiographic or neuropathologic evidence of response at a minimum of one time point. Preclinical studies in pediatric brain tumor models indicate that a variety of pediatric tumor types are highly sensitive to killing by G207. This clinical protocol outlines a first in human children study of intratumoral inoculation of an oncolytic virus via catheters placed directly into recurrent or progressive supratentorial malignant tumors.

Preclinical examination of clofarabine in pediatric ependymoma: intratumoral concentrations insufficient to warrant further study.

PubMed

Patel, Yogesh T; Jacus, Megan O; Boulos, Nidal; Dapper, Jason D; Davis, Abigail D; Vuppala, Pradeep K; Freeman, Burgess B; Mohankumar, Kumarasamypet M; Throm, Stacy L; Gilbertson, Richard J; Stewart, Clinton F

2015-05-01

Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m(2). Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (K pt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.12 ± 0.05. The model-predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-h IC50 (407 ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued.

Preclinical examination of clofarabine in pediatric ependymoma: Intratumoral concentrations insufficient to warrant further study

PubMed Central

Patel, Yogesh T.; Jacus, Megan O.; Boulos, Nidal; Dapper, Jason D.; Davis, Abigail D.; Vuppala, Pradeep K.; Freeman, Burgess B.; Mohankumar, Kumarasamypet M.; Throm, Stacy L.; Gilbertson, Richard J.; Stewart, Clinton F.

2015-01-01

Clofarabine, a deoxyadenosine analog, was an active anticancer drug in our in vitro high-throughput screening against mouse ependymoma neurospheres. To characterize the clofarabine disposition in mice for further preclinical efficacy studies, we evaluated the plasma and central nervous system (CNS) disposition in a mouse model of ependymoma. A plasma pharmacokinetic study of clofarabine (45 mg/kg, IP) was performed in CD1 nude mice bearing ependymoma to obtain initial plasma pharmacokinetic parameters. These estimates were used to derive D-optimal plasma sampling time-points for cerebral microdialysis studies. A simulation of clofarabine pharmacokinetics in mice and pediatric patients suggested that a dosage of 30 mg/kg, IP in mice would give exposures comparable to that in children at a dosage of 148 mg/m2. Cerebral microdialysis was performed to study the tumor extracellular fluid (ECF) disposition of clofarabine (30 mg/kg, IP) in the ependymoma cortical allografts. Plasma and tumor ECF concentration-time data were analyzed using a nonlinear mixed effects modeling approach. The median unbound fraction of clofarabine in mouse plasma was 0.79. The unbound tumor to plasma partition coefficient (Kpt,uu: ratio of tumor to plasma AUCu,0-inf) of clofarabine was 0.12±0.05. The model predicted mean tumor ECF clofarabine concentrations were below the in vitro 1-hr IC50 (407 ng/mL) for ependymoma neurospheres. Thus, our results show the clofarabine exposure reached in the tumor ECF was below that associated with an antitumor effect in our in vitro washout study. Therefore, clofarabine was de-prioritized as an agent to treat ependymoma, and further preclinical studies were not pursued. PMID:25724157

Concise Review: Mesenchymal Stem Cell Therapy for Pediatric Disease: Perspectives on Success and Potential Improvements

PubMed Central

Nitkin, Christopher R.

2016-01-01

Abstract Mesenchymal stem cells (MSCs) represent a potentially revolutionary therapy for a wide variety of pediatric diseases, but the optimal cell‐based therapeutics for such diversity have not yet been specified. The published clinical trials for pediatric pulmonary, cardiac, orthopedic, endocrine, neurologic, and hematologic diseases provide evidence that MSCs are indeed efficacious, but the significant heterogeneity in therapeutic approaches between studies raises new questions. The purpose of this review is to stimulate new preclinical and clinical trials to investigate these factors. First, we discuss recent clinical trials for pediatric diseases studying MSCs obtained from bone marrow, umbilical cord and umbilical cord blood, placenta, amniotic fluid, and adipose tissue. We then identify factors, some unique to pediatrics, which must be examined to optimize therapeutic efficacy, including route of administration, dose, timing of administration, the role of ex vivo differentiation, cell culture techniques, donor factors, host factors, and the immunologic implications of allogeneic therapy. Finally, we discuss some of the practicalities of bringing cell‐based therapy into the clinic, including regulatory and manufacturing considerations. The aim of this review is to inform future studies seeking to maximize therapeutic efficacy for each disease and for each patient. Stem Cells Translational Medicine 2017;6:539–565 PMID:28191766

Pre-Clinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies

PubMed Central

Waters, Alicia M.; Stewart, Jerry E.; Atigadda, Venkatram R.; Mroczek-Musulman, Elizabeth; Muccio, Donald D.; Grubbs, Clinton J.; Beierle, Elizabeth A.

2016-01-01

Rare tumors of solid organs remain some of the most difficult pediatric cancers to cure. These difficult tumors include rare pediatric renal malignancies such as malignant rhabdoid kidney tumors (MRKT) and non-osseous renal Ewing sarcoma, and hepatoblastoma, a pediatric liver tumor that arises from immature liver cells. There are data in adult renal and hepatic malignancies demonstrating the efficacy of retinoid therapy. The investigation of retinoic acid therapy in cancer is not a new strategy, but the widespread adoption of this therapy has been hindered by toxicities. Our laboratory has been investigating a novel synthetic rexinoid, UAB30, which exhibits a more favorable side effect profile. In this current study, we hypothesized that UAB30 would diminish the growth of tumor cells from both rare renal and liver tumors in vitro and in vivo. We successfully demonstrated decreased cellular proliferation, invasion and migration, cell cycle arrest and increased apoptosis after treatment with UAB30. Additionally, in in vivo murine models of human hepatoblastoma or rare human renal tumors, there were significantly decreased tumor xenograft growth and increased animal survival after UAB30 treatment. UAB30 should further be investigated as a developing therapeutic in these rare and difficult to treat, pediatric solid organ tumors. PMID:26873726

[Use of cognitive aids in pediatric emergency care : Interdisciplinary consensus statement].

PubMed

Wirtz, S; Eich, C; Becke, K; Brenner, S; Callies, A; Harding, U; Höhne, C; Hoffmann, F; Kaufmann, J; Landsleitner, B; Marung, H; Nicolai, T; Reifferscheid, F; Trappe, U; Jung, P

2017-05-01

Preclinical pediatric emergencies are rare events and are therefore often associated with stress and uncertainty for emergency medical service personnel. To ensure adequate treatment of pediatric patients a variety of different cognitive aids exist (e.g. books, apps, rulers, weight-adapted bag systems). Especially the size specifications of the medical equipment and the dosage of emergency medication are individually very different in children and are dependent on parameters, such as body height and weight. Therefore, cognitive aids often enable length measurement whereby it is possible to draw conclusions on body weight for calculating the child's medication dosage. These aids may help to avoid the wrong medication dose or the wrong therapy of children but uncritical and untrained usage of these aids carries a potential risk of mistakes. This recommendation gives an overview of the general requirements and different problems of cognitive aids and should help improve the general framework and the rational basis for the use and further development of cognitive aids in emergency medicine.

Opportunistic Screening for Exposure to Bullying in the Pediatric Emergency Department

PubMed Central

Seltzer, Marlene; Menoch, Margaret; Chen, Charity

2017-01-01

To assess opportunistic screening for exposure to bullying in the pediatric emergency department (ED), an anonymous survey inquiring about exposure to physical, verbal, social, and cyber bullying behaviors was given to ED patients 5 to 18 years old. The survey asked about being the recipient, perpetrator, and/or witness of bullying; the frequency of exposure; liking school; missing school; and presenting complaint. Either the child or parent could complete the survey. A total of 909 surveys were analyzed. Exposure was 78.7%. A greater proportion of females reported being victims and witnesses. Youth who reported being both victims and witnesses represented the largest group, with witness-only the second largest. Parents reported less cyber-bullying and witness status to all types of bullying. For children who did not like school, there was a significant difference in exposure versus nonexposure. There was no association with presenting complaint. Opportunistic screening for bullying exposure in pediatric ED patients warrants consideration as it may increase detection of preclinical status and clinical sequelae. PMID:28680945

Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism Phenotypes

DTIC Science & Technology

2014-09-01

AD_________________ Award Number: TITLE: Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism ...AUG 2013-7 Aug 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism ...a genetic mouse model of autism -like phenotypes, the Grin1 knockdown mouse. The Grin1 gene encodes the NR1 subunit of the NMDA receptor . In the

Extraluminal biodegradable splint to treat upper airway anterior malacia: A preclinical proof of principle.

PubMed

Gorostidi, François; Courbon, Cécile; Burki, Marco; Reinhard, Antoine; Sandu, Kishore

2018-02-01

Upper airway malacia highly complicates the treatment of benign laryngotracheal stenosis, and no ideal option is available to date. We here explore the use of extraluminal biodegradable splints in an animal model of long-segment anterior tracheomalacia (TM). We show the efficacy, as well as the tissue tolerance, of a custom-made biodegradable extraluminal device surgically inserted around the trachea. Preclinical animal study. Anterior TM was induced in rabbits through an anterior neck approach by removing eight consecutive anterior tracheal rings without damaging the underlying mucosa. Malacia was corrected during the same surgery by pexy sutures, suspending the tracheal mucosa to an experimental biodegradable device. Symptoms, survival, and tissue reaction were compared to healthy and sham surgery controls. The model induced death by respiratory failure within minutes. Ten animals received the experimental treatment, and those who survived the perioperative period remained asymptomatic with a maximum follow-up of 221 days. Histological studies at programmed euthanasia showed complete degradation of the prosthesis, with significant remnant fibrosis around the trachea. However, the tracheal stiffness of test segments was comparatively less than that of control segments. Extraluminal biodegradable splints rescued animals with a condition otherwise incompatible with life. It was well tolerated, leaving peritracheal fibrosis that was not as stiff as normal trachea. The external tracheal stiffening was sufficient for the test animals to live through the phase of severe acute hypercollapsibility. This represents a valid option to help pediatric patients with laryngotracheal stenosis and associated cartilaginous airway malacia. NA. Laryngoscope, 128:E53-E58, 2018. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

Pre-Clinical Testing of Real-Time PCR Assays for Diarrheal Disease Agents of Genera Escherichia and Shigella

DTIC Science & Technology

2014-05-16

FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA May 16, 2014 Reporting Period: October 1, 2010 to September 30, 2013...10-2010 - 30-09-2013 PRE-CLINICAL TESTING OF REAL-TIME PCR ASSAYS FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA ...Texas (MOA 2007 - 2013. Agreement No.: DODI 4000.19; AFI 25-201). Pre-clinical test results qualify ETEC and Shigella real-time PCR assays as lead

Gastroenterology Curriculum in the Canadian Medical School System.

PubMed

Dang, ThucNhi Tran; Wong, Clarence; Bistritz, Lana

2017-01-01

Background and Purpose. Gastroenterology is a diverse subspecialty that covers a wide array of topics. The preclinical gastroenterology curriculum is often the only formal training that medical students receive prior to becoming residents. There is no Canadian consensus on learning objectives or instructional methods and a general lack of awareness of curriculum at other institutions. This results in variable background knowledge for residents and lack of guidance for course development. Objectives. (1) Elucidate gastroenterology topics being taught at the preclinical level. (2) Determine instructional methods employed to teach gastroenterology content. Results . A curriculum map of gastroenterology topics was constructed from 10 of the medical schools that responded. Topics often not taught included pediatric GI diseases, surgery and trauma, food allergies/intolerances, and obesity. Gastroenterology was taught primarily by gastroenterologists and surgeons. Didactic and small group teaching was the most employed teaching method. Conclusion. This study is the first step in examining the Canadian gastroenterology curriculum at a preclinical level. The data can be used to inform curriculum development so that topics generally lacking are better incorporated in the curriculum. The study can also be used as a guide for further curriculum design and alignment across the country.

Wire-bending test as a predictor of preclinical performance by dental students.

PubMed

Kao, E C; Ngan, P W; Wilson, S; Kunovich, R

1990-10-01

Traditional Dental Aptitude Test and academic grade point average have been shown to be poor predictors of clinical performance by dental students. To refine predictors of psychomotor skills, a wire-bending test was given to 105 freshmen at the beginning of their dental education. Grades from seven restorative preclinical courses in their freshman and sophomore years were compared to scores on wire bending and the three traditional predictors: GPA, academic aptitude, and perceptual aptitude scores. Wire-bending scores correlated significantly with six out of seven preclinical restorative courses. The predictive power for preclinical performance was doubled when wire bending was added to traditional predictors in stepwise multiple regression analysis. Wire-bending scores identified students of low performance. These preliminary results suggest that the wire-bending test shows some potential as a screening test for identifying students who may hae psychomotor difficulties, early in their dental education.

Drugs for the treatment of pediatric type 2 diabetes mellitus and related co-morbidities.

PubMed

Tabatabaei-Malazy, Ozra; Nikfar, Shekoufeh; Larijani, Bagher; Abdollahi, Mohammad

2016-12-01

The continuing global epidemic of obesity in adolescents has raised the prevalence of type 2 diabetes mellitus (T2DM). Despite the wealth of information concerning T2DM in adults, rare data are available targeting treatment of T2DM in pediatric. Areas covered: This article has reviewed clinical practice guidelines, particularly the American Diabetes Association and the Pediatric Endocrine Society consensus, jointly with clinical trial data available in databases with respect to the use of available pharmacological options to treat T2DM and its complications in youth. Expert opinion: The use of other pharmacological treatments of T2DM in addition to metformin and insulin entails several problems. Since rare studies have been conducted on the medications available to manage T2DM in children, treating them may be more difficult than that of adults. It needs longer and larger size clinical trials along with better pharmacological agents to affect various pathophysiological mechanisms of diabetes. Meanwhile, the efficacy and safety of combinations therapies should be completed in preclinical and clinical phases.

Preclinical testing for aortic endovascular grafts: results of a Food and Drug Administration workshop.

PubMed

Abel, Dorothy B; Beebe, Hugh G; Dedashtian, Mark M; Morton, Michael C; Moynahan, Megan; Smith, Loius J; Weinberg, Steven L

2002-05-01

Since their introduction into clinical trials in the United States, endovascular aortic grafts have shown various types of problems. Although details of design and construction vary between different endovascular grafts and failure modes have had a variety of causes and clinical effects, the inability of preclinical testing to predict these failures remains common to all endovascular grafts. The need to improve preclinical testing in an attempt to reduce clinical device failures resulted in a Food and Drug Administration-sponsored workshop on endovascular graft preclinical testing held in Rockville, Md, from July 31 to August 1, 2001. FORMAT: The workshop was not designed as a consensus conference. Instead, it provided a forum for bringing stakeholders together to define problems and identify areas of agreement and disagreement. The workshop had 34 invited participants who represented device manufacturers, the medical community, the Food and Drug Administration, and testing facilities, and international attendance was more than 120 people. Discussion centered on: 1, defining the physiologic, anatomic, and morphologic characteristics of abdominal aortic aneurysms before and after endovascular graft treatment; 2, identifying the types of failures that have been observed clinically; and 3, determining which characteristics should be considered during preclinical modeling to better predict clinical performance. Attendees agreed to the need to better define and address anatomic characteristics and changes in the aneurysm after endograft treatment to optimize preclinical testing. Much discussion and little agreement occurred on the importance of flow-related forces on graft performance or the need or ability to define and model physiologic compliance during durability testing. The discussion and conclusions are summarized in this paper and are provided in detail at: http://www.fda.gov/cdrh/meetings/073101workshop.html. The workshop raised awareness of significant performance issues and the challenges of modeling the extremely variable and relatively undefined environment of abdominal aortic aneurysms. Through the interactive format of the workshop, participants identified areas of preclinical testing, device design, and aspects of the simulated environment that need further consideration.

Bioengineering targeted nanodrugs for hematologic malignancies: An innovation in pediatric oncology

NASA Astrophysics Data System (ADS)

Krishnan, Vinu

Chemotherapy for pediatric cancers employs combinations of highly toxic drugs. This has achieved 5-year survival rates exceeding 90% in children treated for leukemia -- the most prominent form of pediatric cancer. However, delayed onset of harmful side effects in more than 60% of survivors result in death or low quality of life post therapy. This is primarily due to the non-specific effect of drugs on healthy dividing cells in a growing child. Nanomedicine has advanced tremendously to improve adult cancer therapy, but as yet has had minimal impact in pediatric oncology. There is a pressing need for innovative therapeutic strategies that can reduce life-threatening side effects caused by conventional chemotherapy in the clinic. Targeting chemotherapeutic agents specifically to leukemia cells may alleviate treatment-related toxicity in children. The research objective of this dissertation is to bioengineer and advance preclinically a novel nanotherapeutic approach that can specifically target and deliver drugs into leukemic cells. Dexamethasone (Dex) is one of the most commonly used chemotherapeutic drugs in treating pediatric leukemia. For the first part in this study, we encapsulated Dex in polymeric NPs and validated its anti-leukemic potential in vitro and in vivo. NPs with an average diameter of 110 nm were assembled from an amphiphilic block copolymer of poly(ethylene glycol) (PEG) and poly-caprolactone (PCL) bearing pendant cyclic ketals (ECT2). The blank NPs were nontoxic to cultured cells in vitro and to mice in vivo. Encapsulation of Dex into the NPs (Dex-NP) did not compromise the bioactivity of the drug. Dex-NPs induced glucocorticoid phosphorylation and showed cytotoxicity similar to free drug when treated with leukemic cells. Studies using NPs labeled with fluorescent dyes revealed leukemic cell surface binding and internalization. In vivo biodistribution studies showed NP accumulation in the liver and spleen with subsequent clearance of particles with time. In a preclinical model of leukemia, Dex-NPs significantly improved the quality of life and survival of mice compared to the group treated with free Dex. In the second section, we demonstrate, that doxorubicin (DOX, an anthracycline commonly used in pediatric leukemia therapy) when encapsulated within 80 nm sized NPs and modified with targeting ligands against CD19 (a B-lymbhoblast antigen, CD19-DOX-NPs) can be delivered in a CD19-specific manner to leukemic cells. The CD19-DOX-NPs were internalized via receptor-mediated endocytosis and imparted cytotoxicity in a CD19-dependent manner in CD19 positive (CD19+) leukemic cells. Leukemic mice treated with CD19-DOX-NPs survived significantly longer and manifested a higher degree of agility indicating reduced apparent systemic toxicity during treatment compared to mice treated with free DOX. This study for the first time shows the efficacy of polymeric NPs to target and deliver chemotherapeutic drugs in pediatric oncology and suggests that targeted nanotherapy can potentially improve the therapeutic efficacy of conventional chemotherapy and reduce treatment-related side effects in children.

Aortic, carotid intima-media thickness and flow- mediated dilation as markers of early atherosclerosis in a cohort of pediatric patients with rheumatic diseases.

PubMed

Del Giudice, Emanuela; Dilillo, Anna; Tromba, Luciana; La Torre, Giuseppe; Blasi, Sara; Conti, Fabrizio; Viola, Franca; Cucchiara, Salvatore; Duse, Marzia

2018-06-01

The aims of this study were to identify the presence of endothelial dysfunction as a marker of early atherosclerosis by measuring aortic and carotid intimal-medial thickness (aIMT and cIMT) and flow-mediated dilation (FMD) and their correlation with traditional and no traditional risk factors for atherosclerosis in children with rheumatic diseases. Thirty-nine patients (mean age 15.3 ± 5.7 years), 23 juvenile idiopathic arthritis, 9 juvenile spondyloarthropathies, 7 connective tissue diseases (mean disease duration and onset respectively 5 ± 3.6 and 10 ± 5 years), and 52 healthy children matched for sex and age were enrolled. Demographic data (age, sex, familiarity for cardiovascular disease), traditional risk factors for atherosclerosis (BMI, active and passive smoking, dyslipidemia), activity disease indexes (reactive count protein, erythrocyte sedimentation rate) autoantibodies, and complement tests were collected. aIMT, cIMT, and FMD were assessed following a standardized protocol by high-resolution ultrasonography. Patients resulted significantly more exposed to passive smoking and had a lower BMI and higher homocysteine level than controls. cIMT and aIMT were significantly higher in patients than controls (p < 0.001) and correlated with age at diagnosis (p < 0.001 r 0.516 and 0.706, respectively) but not with mean disease duration. FMD % was significantly reduced in patients compared to controls (p < 0.001). Subclinical atherosclerosis occurs in pediatric rheumatic diseases, mainly in early onset forms, and aIMT is an earlier marker of preclinical atherosclerosis. Premature endothelial dysfunction could be included in the follow-up of children with rheumatic disorders to plan prevention strategies of cardiovascular disease already in pediatrics.

Benznidazole Extended-Release Tablets for Improved Treatment of Chagas Disease: Preclinical Pharmacokinetic Study

PubMed Central

Campos, Michel Leandro; Rosa, Talita Atanazio; Padilha, Elias Carvalho; Alzate, Alejandro Henao; Rolim, Larissa Araújo; Rolim-Neto, Pedro José

2016-01-01

Benznidazole (BNZ) is the first-line drug for the treatment of Chagas disease. The drug is available in the form of immediate-release tablets for 100-mg (adult) and 12.5-mg (pediatric) doses. The drug is administered two or three times daily for 60 days. The high frequency of daily administrations and the long period of treatment are factors that significantly contribute to the abandonment of therapy, affecting therapeutic success. Accordingly, this study aimed to evaluate the preclinical pharmacokinetics of BNZ administered as extended-release tablets (200-mg dose) formulated with different types of polymers (hydroxypropyl methylcellulose K4M and K100M), compared to the tablets currently available. The studies were conducted with rabbits, and BNZ quantification was performed in plasma and urine by ultraperformance liquid chromatography methods previously validated. The bioavailability of BNZ was adequate in the administration of extended-release tablets; however, with the administration of the pediatric tablet, the bioavailability was lower than with other tablets, which showed that the clinical use of this formulation should be monitored. The pharmacokinetic parameters demonstrated that the extended-release tablets prolonged drug release from the pharmaceutical matrix and provided an increase in the maintenance of the drug concentration in vivo, which would allow the frequency of administration to be reduced. Thus, a relative bioavailability study in humans will be planned for implementation of a new product for the treatment of Chagas disease. PMID:26883698

The neuropsychology of normal aging and preclinical Alzheimer’s disease

PubMed Central

Caselli, Richard J.; Locke, Dona E.C.; Dueck, Amylou C.; Knopman, David S.; Woodruff, Bryan K.; Hoffman-Snyder, Charlene; Rademakers, Rosa; Fleisher, Adam S.; Reiman, Eric M.

2013-01-01

Background An NIA-sponsored workgroup on preclinical Alzheimer’s disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. Methods 71 apolipoprotein E (APOE) e4 homozygotes (HMZ), 194 e3/4 heterozygotes (HTZ), and 356 e4 noncarriers (NC) aged 21–87 years who were cognitively healthy underwent neuropsychological testing every two years. Longitudinal trajectories of test scores were compared between APOE subgroups. Results There was a significant effect of age on all cognitive domains in both APOE e4 carriers and NC. A significant effect of APOE e4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross sectional comparisons did not discriminate the groups. Conclusions While cognitive aging patterns are similar in APOE e4 carriers and NC, preclinical AD is characterized by a significant e4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory sensitive measures and longitudinal design. PMID:23541188

The neuropsychology of normal aging and preclinical Alzheimer's disease.

PubMed

Caselli, Richard J; Locke, Dona E C; Dueck, Amylou C; Knopman, David S; Woodruff, Bryan K; Hoffman-Snyder, Charlene; Rademakers, Rosa; Fleisher, Adam S; Reiman, Eric M

2014-01-01

A National Institute on Aging-sponsored work group on preclinical Alzheimer's disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD. Seventy-one apolipoprotein E (APOE) ε4 homozygotes, 194 ε3/ε4 heterozygotes, and 356 ε4 noncarriers age 21 to 87 years who were cognitively healthy underwent neuropsychological testing every 2 years. Longitudinal trajectories of test scores were compared between APOE subgroups. There was a significant effect of age on all cognitive domains in both APOE ε4 carriers and noncarriers. A significant effect of APOE ε4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross-sectional comparisons did not discriminate the groups. Although cognitive aging patterns are similar in APOE ε4 carriers and noncarriers, preclinical AD is characterized by a significant ε4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory-sensitive measures and longitudinal design. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Stakeholders' Perspectives on Preclinical Testing for Alzheimer's Disease.

PubMed

Arias, Jalayne J; Cummings, Jeffrey; Grant, Alexander Rae; Ford, Paul J

2015-01-01

Progress towards validating amyloid beta as an early indicator of Alzheimer's disease (AD) heightens the need for evaluation of stakeholders' perspectives of the benefits and harms of preclinical testing in asymptomatic individuals. Investigators conducted and analyzed 14 semi-structured interviews with family members of patients diagnosed with AD. Participants reported benefits, including the potential to seek treatment, make lifestyle changes, and prepare for cognitive impairment. Participants identified harms, including social harms, adverse life decisions, and psychological harms. Nine participants reported either a "positive global perspective" or a "positive global perspective (qualified)." Results from this study characterized stakeholders' perspectives on the potential benefits and harms of clinical use of preclinical testing for AD. Investigators used data from this study to develop a framework that contributes to ongoing discussions that will evaluate widespread adoption of preclinical testing and will inform future research. Copyright 2015 The Journal of Clinical Ethics. All rights reserved.

Omega-3 fatty acid supplementation delays the progression of neuroblastoma in vivo.

PubMed

Gleissman, Helena; Segerström, Lova; Hamberg, Mats; Ponthan, Frida; Lindskog, Magnus; Johnsen, John Inge; Kogner, Per

2011-04-01

Epidemiological and preclinical studies have revealed that omega-3 fatty acids have anticancer properties. We have previously shown that the omega-3 fatty acid docosahexaenoic acid (DHA) induces apoptosis of neuroblastoma cells in vitro by mechanisms involving intracellular peroxidation of DHA by means of 15-lipoxygenase or autoxidation. In our study, the effects of DHA supplementation on neuroblastoma tumor growth in vivo were investigated using two complementary approaches. For the purpose of prevention, DHA as a dietary supplement was fed to athymic rats before the rats were xenografted with human neuroblastoma cells. For therapeutic purposes, athymic rats with established neuroblastoma xenografts were given DHA daily by gavage and tumor growth was monitored. DHA levels in plasma and tumor tissue were analyzed by gas liquid chromatography. DHA delayed neuroblastoma xenograft development and inhibited the growth of established neuroblastoma xenografts in athymic rats. A revised version of the Pediatric Preclinical Testing Program evaluation scheme used as a measurement of treatment response showed that untreated control animals developed progressive disease, whereas treatment with DHA resulted in stable disease or partial response, depending on the DHA concentration. In conclusion, prophylactic treatment with DHA delayed neuroblastoma development, suggesting that DHA could be a potential agent in the treatment of minimal residual disease and should be considered for prevention in selected cases. Treatment results on established aggressive neuroblastoma tumors suggest further studies aiming at a clinical application in children with high-risk neuroblastoma. Copyright © 2010 UICC.

An Economic Evaluation of Preclinical Testing Strategies Compared to the Compulsory Scrapie Flock Scheme in the Control of Classical Scrapie

PubMed Central

Hawkins, Neil; Houston, Fiona; Fryer, Helen; Kao, Rowland

2012-01-01

Cost-benefit is rarely combined with nonlinear dynamic models when evaluating control options for infectious diseases. The current strategy for scrapie in Great Britain requires that all genetically susceptible livestock in affected flocks be culled (Compulsory Scrapie Flock Scheme or CSFS). However, this results in the removal of many healthy sheep, and a recently developed pre-clinical test for scrapie now offers a strategy based on disease detection. We explore the flock level cost-effectiveness of scrapie control using a deterministic transmission model and industry estimates of costs associated with genotype testing, pre-clinical tests and the value of a sheep culled. Benefit was measured in terms of the reduction in the number of infected sheep sold on, compared to a baseline strategy of doing nothing, using Incremental Cost Effectiveness analysis to compare across strategies. As market data was not available for pre-clinical testing, a threshold analysis was used to set a unit-cost giving equal costs for CSFS and multiple pre-clinical testing (MT, one test each year for three consecutive years). Assuming a 40% within-flock proportion of susceptible genotypes and a test sensitivity of 90%, a single test (ST) was cheaper but less effective than either the CSFS or MT strategies (30 infected-sales-averted over the lifetime of the average epidemic). The MT strategy was slightly less effective than the CSFS and would be a dominated strategy unless preclinical testing was cheaper than the threshold price of £6.28, but may be appropriate for flocks with particularly valuable livestock. Though the ST is not currently recommended, the proportion of susceptible genotypes in the national flock is likely to continue to decrease; this may eventually make it a cost-effective alternative to the MT or CSFS. PMID:22412943

Prediction of practical performance in preclinical laboratory courses - the return of wire bending for admission of dental students in Hamburg.

PubMed

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2014-01-01

Although some recent studies concluded that dexterity is not a reliable predictor of performance in preclinical laboratory courses in dentistry, they could not disprove earlier findings which confirmed the worth of manual dexterity tests in dental admission. We developed a wire bending test (HAM-Man) which was administered during dental freshmen's first week in 2008, 2009, and 2010. The purpose of our study was to evaluate if the HAM-Man is a useful selection criterion additional to the high school grade point average (GPA) in dental admission. Regression analysis revealed that GPA only accounted for a maximum of 9% of students' performance in preclinical laboratory courses, in six out of eight models the explained variance was below 2%. The HAM-Man incrementally explained up to 20.5% of preclinical practical performance over GPA. In line with findings from earlier studies the HAM-Man test of manual dexterity showed satisfactory incremental validity. While GPA has a focus on cognitive abilities, the HAM-Man reflects learning of unfamiliar psychomotor skills, spatial relationships, and dental techniques needed in preclinical laboratory courses. The wire bending test HAM-Man is a valuable additional selection instrument for applicants of dental schools.

The Ontogeny of Cytochrome P450 Enzyme Activity and Protein Abundance in Conventional Pigs in Support of Preclinical Pediatric Drug Research.

PubMed

Millecam, Joske; De Clerck, Laura; Govaert, Elisabeth; Devreese, Mathias; Gasthuys, Elke; Schelstraete, Wim; Deforce, Dieter; De Bock, Lies; Van Bocxlaer, Jan; Sys, Stanislas; Croubels, Siska

2018-01-01

Since the implementation of several legislations to improve pediatric drug research, more pediatric clinical trials are being performed. In order to optimize these pediatric trials, adequate preclinical data are necessary, which are usually obtained by juvenile animal models. The growing piglet has been increasingly suggested as a potential animal model due to a high degree of anatomical and physiological similarities with humans. However, physiological data in pigs on the ontogeny of major organs involved in absorption, distribution, metabolism, and excretion of drugs are largely lacking. The aim of this study was to unravel the ontogeny of porcine hepatic drug metabolizing cytochrome P450 enzyme (CYP450) activities as well as protein abundances. Liver microsomes from 16 conventional pigs (8 males and 8 females) per age group: 2 days, 4 weeks, 8 weeks, and 6-7 months were prepared. Activity measurements were performed with substrates of major human CYP450 enzymes: midazolam (CYP3A), tolbutamide (CYP2C), and chlorzoxazone (CYP2E). Next, the hepatic scaling factor, microsomal protein per gram liver (MPPGL), was determined to correct for enzyme losses during the fractionation process. Finally, protein abundance was determined using proteomics and correlated with enzyme activity. No significant sex differences within each age category were observed in enzyme activity or MPPGL. The biotransformation rate of all three substrates increased with age, comparable with human maturation of CYP450 enzymes. The MPPGL decreased from birth till 8 weeks of age followed by an increase till 6-7 months of age. Significant sex differences in protein abundance were observed for CYP1A2, CYP2A19, CYP3A22, CYP4V2, CYP2C36, CYP2E_1, and CYP2E_2. Midazolam and tolbutamide are considered good substrates to evaluate porcine CYP3A/2C enzymes, respectively. However, chlorzoxazone is not advised to evaluate porcine CYP2E enzyme activity. The increase in biotransformation rate with age can be attributed to an increase in absolute amount of CYP450 proteins. Finally, developmental changes were observed regarding the involvement of specific CYP450 enzymes in the biotransformation of the different substrates.

Phase I Trial and Pharmacokinetic Study of Lexatumumab in Pediatric Patients With Solid Tumors

PubMed Central

Merchant, Melinda S.; Geller, James I.; Baird, Kristin; Chou, Alexander J.; Galli, Susana; Charles, Ava; Amaoko, Martha; Rhee, Eunice H.; Price, Anita; Wexler, Leonard H.; Meyers, Paul A.; Widemann, Brigitte C.; Tsokos, Maria; Mackall, Crystal L.

2012-01-01

Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. Patients and Methods This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one patient with recurrent progressive osteosarcoma who experienced resolution of clinical symptoms and positron emission tomography activity, ongoing more than 1 year off therapy. One patient with hepatoblastoma showed a dramatic biomarker response. Conclusion Pediatric patients tolerate 10 mg/kg of lexatumumab administered once every 14 days, the maximum-tolerated dose identified in adults. The drug seems to mediate some clinical activity in pediatric solid tumors and may work with radiation to enhance antitumor effects. PMID:23071222

A Multifaceted Approach to RSV Vaccination.

PubMed

Blanco, Jorge C G; Boukhvalova, Marina S; Morrison, Trudy G; Vogel, Stefanie N

2018-05-17

Respiratory Syncytial Virus (RSV) is the leading cause of pneumonia and bronchiolitis in infants, resulting in significant morbidity and mortality worldwide. In addition, RSV infections occur throughout different ages, thus, maintaining the virus in circulation, and increasing health risk to more susceptible populations such as infants, the elderly, and the immunocompromised. To date, there is no vaccine approved to prevent RSV infection or minimize symptoms of infection. Current clinical trials for vaccines against RSV are being carried out in four very different populations. There are vaccines that target two different pediatric populations, infants 2 to 6 month of age and seropositive children over 6 months of age, as well as women (non-pregnant or pregnant in their third trimester). There are vaccines that target adult and elderly populations. In this review, we will present and discuss RSV vaccine candidates currently in clinical trials. We will describe the preclinical studies instrumental for their advancement, with the goal of introducing new preclinical models that may more accurately predict the outcome of clinical vaccine studies.

Expert Opinion Editorial Tissue Engineered Blood Vessels as Promising Tools for Testing Drug Toxicity

PubMed Central

Truskey, George A.; Fernandez, Cristina E.

2015-01-01

Drug-induced vascular injury (DIVI) is a serious problem in preclinical studies of vasoactive molecules and for survivors of pediatric cancers. DIVI is often observed in rodents and some larger animals, primarily with drugs affecting vascular tone, but not in humans; however, DIVI observed in animal studies often precludes a drug candidate from continuing along the development pipeline. Thus, there is great interest by the pharmaceutical industry to identify quantifiable human biomarkers of DIVI. Small scale endothelialized tissue-engineered blood vessels using human cells represent a promising approach to screen drug candidates and developed alternatives to cancer therapeutics in vitro. We identify several technical challenges that remain to be addressed, including high throughput systems to screen large numbers of candidates, identification of suitable cell sources, and establishing and maintaining a differentiated state of the vessel wall cells. Adequately addressing these challenges should yield novel platforms to screen drugs and develop new therapeutics to treat cardiovascular disease. PMID:26028128

Preclinical to Clinical Translation of Studies of Transcranial Direct-Current Stimulation in the Treatment of Epilepsy: A Systematic Review

PubMed Central

Regner, Gabriela G.; Pereira, Patrícia; Leffa, Douglas T.; de Oliveira, Carla; Vercelino, Rafael; Fregni, Felipe; Torres, Iraci L. S.

2018-01-01

Epilepsy is a chronic brain syndrome characterized by recurrent seizures resulting from excessive neuronal discharges. Despite the development of various new antiepileptic drugs, many patients are refractory to treatment and report side effects. Non-invasive methods of brain stimulation, such as transcranial direct current stimulation (tDCS), have been tested as alternative approaches to directly modulate the excitability of epileptogenic neural circuits. Although some pilot and initial clinical studies have shown positive results, there is still uncertainty regarding the next steps of investigation in this field. Therefore, we reviewed preclinical and clinical studies using the following framework: (1) preclinical studies that have been successfully translated to clinical studies, (2) preclinical studies that have failed to be translated to clinical studies, and (3) clinical findings that were not previously tested in preclinical studies. We searched PubMed, Web of Science, Embase, and SciELO (2002–2017) using the keywords “tDCS,” “epilepsy,” “clinical trials,” and “animal models.” Our initial search resulted in 64 articles. After applying inclusion and exclusion criteria, we screened 17 full-text articles to extract findings about the efficacy of tDCS, with respect to the therapeutic framework used and the resulting reduction in seizures and epileptiform patterns. We found that few preclinical findings have been translated into clinical research (number of sessions and effects on seizure frequency) and that most findings have not been tested clinically (effects of tDCS on status epilepticus and absence epilepsy, neuroprotective effects in the hippocampus, and combined use with specific medications). Finally, considering that clinical studies on tDCS have been conducted for several epileptic syndromes, most were not previously tested in preclinical studies (Rasmussen's encephalitis, drug resistant epilepsy, and hippocampal sclerosis-induced epilepsy). Overall, most studies report positive findings. However, it is important to underscore that a successful preclinical study may not indicate success in a clinical study, considering the differences highlighted herein. Although most studies report significant findings, there are still important insights from preclinical work that must be tested clinically. Understanding these factors may improve the evidence for the potential use of this technique as a clinical tool in the treatment of epilepsy. PMID:29623027

[Acceptability of HIV testing provided to infants in pediatric services in Cote d'Ivoire, meanings for pediatric diagnostic coverage].

PubMed

Oga, Maxime; Brou, Hermann; Dago-Akribi, Hortense; Coffie, Patrick; Amani-Bossé, Clarisse; Ekouévi, Didier; Yapo, Vincent; Menan, Hervé; Ndondoki, Camille; Timité-Konan, M; Leroy, Valériane

2014-01-01

HIV testing in children had rarely been a central concern for researchers. When pediatric tracking retained the attention, it was more to inform on the diagnosis tools' performances rather than the fact the pediatric test can be accepted or refused. This article highlights the parents' reasons which explain why pediatric HIV test is accepted or refused. To study among parents, the explanatory factors of the acceptability of pediatric HIV testing among infant less than six months. Semi-structured interview with repeated passages in the parents of infants less than six months attending in health care facilities for the pediatric weighing/vaccination and consultations. We highlight that the parents' acceptance of the pediatric HIV screening is based on three elements. Firstly, the health care workers by his speech (which indicates its own knowledge and perceptions on the infection) directed towards mothers' influences their acceptance or not of the HIV test. Secondly, the mother who by her knowledge and perceptions on HIV, whose particular status, give an impression of her own wellbeing for her and her child influences any acceptance of the pediatric HIV test. Thirdly, the marital environment of the mother, particularly characterized by the ease of communication within the couple, to speak about the HIV test and its realization for the parents or the mother only are many factors which influence the effective realization of the pediatric HIV testing. The preventive principle of HIV transmission and the desire to realize the test in the newborn are not enough alone to lead to its effective realization, according to certain mothers confronted with the father's refusal. On the other hand, the other mothers refusing the realization of the pediatric test told to be opposed to it; of course, even if their partner would accept it. The mothers are the principal facing the pediatric HIV question and fear the reprimands and stigma. The father, the partner could be an obstacle, when he is opposed to the infant HIV testing, or also the facilitator with his realization if he is convinced. The father position thus remains essential face to the question of pediatric HIV testing acceptability. The mothers are aware of this and predict the difficulties of achieving their infant to be tested without the preliminary opinion of their partner at the same time father, and head of the family. The issue of pediatric HIV testing, at the end of our analysis, highlights three elements which require a comprehensive management to improve the coverage of pediatric HIV test. These three elements would not exist without being influenced; therefore they are constantly in interaction and prevent or support the realization or not pediatric test. Also, with the aim to improve the pediatric HIV test coverage, it is necessary to take into account the harmonious management of these elements. Firstly, the mother alone (with her knowledge, and perceptions), its marital environment (with the proposal of the HIV test integrating (1) the partner and/or father with his perceptions and knowledge on HIV infection and (2) facility of speaking about the test and its realization at both or one about the parents, the mother) and of the knowledge, attitudes and practices about the infection of health care workers of the sanitary institution. Our recommendations proposed taking into account a redefinition of the HIV/AIDS approach towards the families exposed to HIV and a more accentuated integration of the father facilitating their own HIV test acceptation and that of his child.

Prediction of practical performance in preclinical laboratory courses – the return of wire bending for admission of dental students in Hamburg

PubMed Central

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2014-01-01

Although some recent studies concluded that dexterity is not a reliable predictor of performance in preclinical laboratory courses in dentistry, they could not disprove earlier findings which confirmed the worth of manual dexterity tests in dental admission. We developed a wire bending test (HAM-Man) which was administered during dental freshmen’s first week in 2008, 2009, and 2010. The purpose of our study was to evaluate if the HAM-Man is a useful selection criterion additional to the high school grade point average (GPA) in dental admission. Regression analysis revealed that GPA only accounted for a maximum of 9% of students’ performance in preclinical laboratory courses, in six out of eight models the explained variance was below 2%. The HAM-Man incrementally explained up to 20.5% of preclinical practical performance over GPA. In line with findings from earlier studies the HAM-Man test of manual dexterity showed satisfactory incremental validity. While GPA has a focus on cognitive abilities, the HAM-Man reflects learning of unfamiliar psychomotor skills, spatial relationships, and dental techniques needed in preclinical laboratory courses. The wire bending test HAM-Man is a valuable additional selection instrument for applicants of dental schools. PMID:24872857

Interleukin-1 Receptor in Seizure Susceptibility after Traumatic Injury to the Pediatric Brain

PubMed Central

O'Brien, Terence J.; Gimlin, Kayleen; Wright, David K.; Kim, Shi Eun; Casillas-Espinosa, Pablo M.; Webster, Kyria M.; Petrou, Steven; Noble-Haeusslein, Linda J.

2017-01-01

Epilepsy after pediatric traumatic brain injury (TBI) is associated with poor quality of life. This study aimed to characterize post-traumatic epilepsy in a mouse model of pediatric brain injury, and to evaluate the role of interleukin-1 (IL-1) signaling as a target for pharmacological intervention. Male mice received a controlled cortical impact or sham surgery at postnatal day 21, approximating a toddler-aged child. Mice were treated acutely with an IL-1 receptor antagonist (IL-1Ra; 100 mg/kg, s.c.) or vehicle. Spontaneous and evoked seizures were evaluated from video-EEG recordings. Behavioral assays tested for functional outcomes, postmortem analyses assessed neuropathology, and brain atrophy was detected by ex vivo magnetic resonance imaging. At 2 weeks and 3 months post-injury, TBI mice showed an elevated seizure response to the convulsant pentylenetetrazol compared with sham mice, associated with abnormal hippocampal mossy fiber sprouting. A robust increase in IL-1β and IL-1 receptor were detected after TBI. IL-1Ra treatment reduced seizure susceptibility 2 weeks after TBI compared with vehicle, and a reduction in hippocampal astrogliosis. In a chronic study, IL-1Ra-TBI mice showed improved spatial memory at 4 months post-injury. At 5 months, most TBI mice exhibited spontaneous seizures during a 7 d video-EEG recording period. At 6 months, IL-1Ra-TBI mice had fewer evoked seizures compared with vehicle controls, coinciding with greater preservation of cortical tissue. Findings demonstrate this model's utility to delineate mechanisms underlying epileptogenesis after pediatric brain injury, and provide evidence of IL-1 signaling as a mediator of post-traumatic astrogliosis and seizure susceptibility. SIGNIFICANCE STATEMENT Epilepsy is a common cause of morbidity after traumatic brain injury in early childhood. However, a limited understanding of how epilepsy develops, particularly in the immature brain, likely contributes to the lack of efficacious treatments. In this preclinical study, we first demonstrate that a mouse model of traumatic injury to the pediatric brain reproduces many neuropathological and seizure-like hallmarks characteristic of epilepsy. Second, we demonstrate that targeting the acute inflammatory response reduces cognitive impairments, the degree of neuropathology, and seizure susceptibility, after pediatric brain injury in mice. These findings provide evidence that inflammatory cytokine signaling is a key process underlying epilepsy development after an acquired brain insult, which represents a feasible therapeutic target to improve quality of life for survivors. PMID:28724747

Pediatric Baseline Patch Test Series: Initial Findings of the Pediatric Contact Dermatitis Workgroup.

PubMed

Yu, JiaDe; Atwater, Amber Reck; Brod, Bruce; Chen, Jennifer K; Chisolm, Sarah S; Cohen, David E; de la Feld, Salma; Gaspari, Anthony A; Martin, Kari Lyn; Montanez-Wiscovich, Marjorie; Sheehan, Michael; Silverberg, Nanette; Lugo-Somolinos, Aida; Thakur, Binod K; Watsky, Kalman; Jacob, Sharon E

2018-06-21

Allergic contact dermatitis is a challenging diagnostic problem in children. Although epicutaneous patch testing is the diagnostic standard for confirmation of contact sensitization, it is less used in children by dermatologists treating children, pediatric dermatologists, and pediatricians, when compared with adult practitioners. The aim of the study was to create and evaluate standardization of a pediatric patch test series for children older than 6 years. We surveyed dermatologists and allergists conducting epicutaneous patch testing in children attending the 2017 American Contact Dermatitis Society meeting held in Washington, DC. This was followed by discussion of collected data and consensus review by a pediatric contact dermatitis working group at the conference. A baseline pediatric patch test panel was established through working group consensus.

EU-approved rapid tests might underestimate bovine spongiform encephalopathy infection in goats.

PubMed

Meloni, Daniela; Bozzetta, Elena; Langeveld, Jan P M; Groschup, Martin H; Goldmann, Wilfred; Andrèoletti, Olivier; Lantier, Isabelle; Van Keulen, Lucien; Bossers, Alex; Pitardi, Danilo; Nonno, Romolo; Sklaviadis, Theodoros; Ingravalle, Francesco; Peletto, Simone; Colussi, Silvia; Acutis, Pier Luigi

2017-03-01

We report the diagnostic sensitivity of 3 EU-approved rapid tests (ELISAs; 1 from IDEXX and 2 from Bio-Rad) for the detection of transmissible spongiform encephalopathy diseases in goats. Ninety-eight goat brainstem samples were tested. All the rapid tests had 100% specificity and ≥80% sensitivity, with the IDEXX test significantly more sensitive than the 2 Bio-Rad tests. All tests detected 100% of samples from goats with clinical scrapie, but missed 8% (IDEXX) to 33% (Bio-Rad SG) of samples from preclinical goats. Importantly, only IDEXX picked up all samples from clinical bovine spongiform encephalopathy (BSE)-infected goats, whereas the other 2 rapid tests missed 15% (Bio-Rad SG) to 25% (Bio-Rad SAP). These results show that a fraction of preclinical scrapie infections are likely missed by EU surveillance, with sensitivity of detection strongly dependent on the choice of the rapid test. Moreover, a significant proportion of clinical BSE infections are underestimated by using either Bio-Rad test. Assuming that the same sensitivity on preclinical goats would also occur in BSE-infected goats, our data suggest that IDEXX is likely the most sensitive test for detecting preclinical field cases of BSE infection in goats, although with an 8% failure rate. These results raise some concerns about the reliability of current EU surveillance figures on BSE infection in goats.

An empirically derived composite cognitive test score with improved power to track and evaluate treatments for preclinical Alzheimer's disease.

PubMed

Langbaum, Jessica B; Hendrix, Suzanne B; Ayutyanont, Napatkamon; Chen, Kewei; Fleisher, Adam S; Shah, Raj C; Barnes, Lisa L; Bennett, David A; Tariot, Pierre N; Reiman, Eric M

2014-11-01

There is growing interest in the evaluation of preclinical Alzheimer's disease (AD) treatments. As a result, there is a need to identify a cognitive composite that is sensitive to track preclinical AD decline to be used as a primary endpoint in treatment trials. Longitudinal data from initially cognitively normal, 70- to 85-year-old participants in three cohort studies of aging and dementia from the Rush Alzheimer's Disease Center were examined to empirically define a composite cognitive endpoint that is sensitive to detect and track cognitive decline before the onset of cognitive impairment. The mean-to-standard deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of cognitive tests/subtests drawn from the neuropsychological battery in cognitively normal participants who subsequently progressed to clinical stages of AD during 2- and 5-year periods, using data from those who remained unimpaired during the same period to correct for aging and practice effects. Combinations that performed well were then evaluated for representation of relevant cognitive domains, robustness across individual years before diagnosis, and occurrence of selected items within top performing combinations. The optimal composite cognitive test score comprised seven cognitive tests/subtests with an MSDR = 0.964. By comparison, the most sensitive individual test score was Logical Memory Delayed Recall with an MSDR = 0.64. We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared with the most sensitive single test item to track preclinical AD decline and evaluate preclinical AD treatments. We are confirming the power of the composite in independent cohorts and with other analytical approaches, which may result in refinements, have designated it as the primary endpoint in the Alzheimer's Prevention Initiative's preclinical treatment trials for individuals at high imminent risk for developing symptoms due to late-onset AD. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap.

PubMed

Snigdha, Shikha; Milgram, Norton W; Willis, Sherry L; Albert, Marylin; Weintraub, S; Fortin, Norbert J; Cotman, Carl W

2013-07-01

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer's disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer's disease. Copyright © 2013 Elsevier Inc. All rights reserved.

A preclinical cognitive test battery to parallel the National Institute of Health Toolbox in humans: bridging the translational gap

PubMed Central

Snigdha, Shikha; Milgram, Norton W.; Willis, Sherry L.; Albert, Marylin; Weintraub, S.; Fortin, Norbert J.; Cotman, Carl W.

2013-01-01

A major goal of animal research is to identify interventions that can promote successful aging and delay or reverse age-related cognitive decline in humans. Recent advances in standardizing cognitive assessment tools for humans have the potential to bring preclinical work closer to human research in aging and Alzheimer’s disease. The National Institute of Health (NIH) has led an initiative to develop a comprehensive Toolbox for Neurologic Behavioral Function (NIH Toolbox) to evaluate cognitive, motor, sensory and emotional function for use in epidemiologic and clinical studies spanning 3 to 85 years of age. This paper aims to analyze the strengths and limitations of animal behavioral tests that can be used to parallel those in the NIH Toolbox. We conclude that there are several paradigms available to define a preclinical battery that parallels the NIH Toolbox. We also suggest areas in which new tests may benefit the development of a comprehensive preclinical test battery for assessment of cognitive function in animal models of aging and Alzheimer’s disease. PMID:23434040

An Oral Formulation of YK-4-279: Preclinical Efficacy and Acquired Resistance Patterns in Ewing Sarcoma.

PubMed

Lamhamedi-Cherradi, Salah-Eddine; Menegaz, Brian A; Ramamoorthy, Vandhana; Aiyer, Ramani A; Maywald, Rebecca L; Buford, Adrianna S; Doolittle, Dannette K; Culotta, Kirk S; O'Dorisio, James E; Ludwig, Joseph A

2015-07-01

Ewing sarcoma is a transcription factor-mediated pediatric bone tumor caused by a chromosomal translocation of the EWSR1 gene and one of several genes in the ETS family of transcription factors, typically FLI1 or ERG. Full activity of the resulting oncogenic fusion protein occurs only after binding RNA helicase A (RHA), and novel biologically targeted small molecules designed to interfere with that interaction have shown early promise in the preclinical setting. Herein, we demonstrate marked preclinical antineoplastic activity of an orally bioavailable formulation of YK-4-279 and identify mechanisms of acquired chemotherapy resistance that may be exploited to induce collateral sensitivity. Daily enteral administration of YK-4-279 led to significant delay in Ewing sarcoma tumor growth within a murine model. In advance of anticipated early-phase human clinical trials, we investigated both de novo and acquired mechanism(s) by which Ewing sarcoma cells evade YK-4-279-mediated cell death. Drug-resistant clones, formed by chronic in vitro exposure to steadily increased levels of YK-4-279, overexpressed c-Kit, cyclin D1, pStat3(Y705), and PKC isoforms. Interestingly, cross-resistance to imatinib and enzastaurin (selective inhibitors of c-Kit and PKC-β, respectively), was observed and the use of YK-4-279 with enzastaurin in vitro led to marked drug synergy, suggesting a potential role for combination therapies in the future. By advancing an oral formulation of YK-4-279 and identifying prominent mechanisms of resistance, this preclinical research takes us one step closer to a shared goal of curing adolescents and young adults afflicted by Ewing sarcoma. ©2015 American Association for Cancer Research.

Establishment of primary cell culture and an intracranial xenograft model of pediatric ependymoma: a prospect for therapy development and understanding of tumor biology.

PubMed

Pavon, Lorena Favaro; Sibov, Tatiana Tais; Caminada de Toledo, Silvia Regina; Mara de Oliveira, Daniela; Cabral, Francisco Romero; Gabriel de Souza, Jean; Boufleur, Pamela; Marti, Luciana C; Malheiros, Jackeline Moraes; Ferreira da Cruz, Edgar; Paiva, Fernando F; Malheiros, Suzana M F; de Paiva Neto, Manoel A; Tannús, Alberto; Mascarenhas de Oliveira, Sérgio; Silva, Nasjla Saba; Cappellano, Andrea Maria; Petrilli, Antonio Sérgio; Chudzinski-Tavassi, Ana Marisa; Cavalheiro, Sérgio

2018-04-24

Ependymoma (EPN), the third most common pediatric brain tumor, is a central nervous system (CNS) malignancy originating from the walls of the ventricular system. Surgical resection followed by radiation therapy has been the primary treatment for most pediatric intracranial EPNs. Despite numerous studies into the prognostic value of histological classification, the extent of surgical resection and adjuvant radiotherapy, there have been relatively few studies into the molecular and cellular biology of EPNs. We elucidated the ultrastructure of the cultured EPN cells and characterized their profile of immunophenotypic pluripotency markers (CD133, CD90, SSEA-3, CXCR4). We established an experimental EPN model by the intracerebroventricular infusion of EPN cells labeled with multimodal iron oxide nanoparticles (MION), thereby generating a tumor and providing a clinically relevant animal model. MRI analysis was shown to be a valuable tool when combined with effective MION labeling techniques to accompany EPN growth. We demonstrated that GFAP/CD133+CD90+/CD44+ EPN cells maintained key histopathological and growth characteristics of the original patient tumor. The characterization of EPN cells and the experimental model could facilitate biological studies and preclinical drug screening for pediatric EPNs. In this work, we established notoriously challenging primary cell culture of anaplastic EPNs (WHO grade III) localized in the posterior fossa (PF), using EPNs obtained from 1 to 10-year-old patients ( n = 07), and then characterized their immunophenotype and ultrastructure to finally develop a xenograft model.

Antibiotic-Induced Depletion of Anti-inflammatory Clostridia Is Associated with the Development of Graft-versus-Host Disease in Pediatric Stem Cell Transplantation Patients.

PubMed

Simms-Waldrip, Tiffany R; Sunkersett, Gauri; Coughlin, Laura A; Savani, Milan R; Arana, Carlos; Kim, Jiwoong; Kim, Minsoo; Zhan, Xiaowei; Greenberg, David E; Xie, Yang; Davies, Stella M; Koh, Andrew Y

2017-05-01

Adult stem cell transplantation (SCT) patients with graft-versus-host-disease (GVHD) exhibit significant disruptions in gut microbial communities. These changes are associated with higher overall mortality and appear to be driven by specific antibiotic therapies. It is unclear whether pediatric SCT patients who develop GVHD exhibit similar antibiotic-induced gut microbiota community changes. Here, we show that pediatric SCT patients (from Children's Medical Center Dallas, n = 8, and Cincinnati Children's Hospital, n = 7) who developed GVHD showed a significant decline, up to 10-log fold, in gut anti-inflammatory Clostridia (AIC) compared with those without GVHD. In fact, the development of GVHD is significantly associated with this AIC decline and with cumulative antibiotic exposure, particularly antibiotics effective against anaerobic bacteria (P = .003, Firth logistic regression analysis). Using metagenomic shotgun sequencing analysis, we were able to identify specific commensal bacterial species, including AIC, that were significantly depleted in GVHD patients. We then used a preclinical GVHD model to verify our clinical observations. Clindamycin depleted AIC and exacerbated GVHD in mice, whereas oral AIC supplementation increased gut AIC levels and mitigated GVHD in mice. Together, these data suggest that an antibiotic-induced AIC depletion in the gut microbiota is associated with the development of GVHD in pediatric SCT patients. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Current status of new tuberculosis vaccine in children

PubMed Central

Pang, Yu; Zhao, Aihua; Cohen, Chad; Kang, Wanli; Lu, Jie; Wang, Guozhi; Zhao, Yanlin; Zheng, Suhua

2016-01-01

ABSTRACT Pediatric tuberculosis contributes significantly to the burden of TB disease worldwide. In order to achieve the goal of eliminating TB by 2050, an effective TB vaccine is urgently needed to prevent TB transmission in children. BCG vaccination can protect children from the severe types of TB such as TB meningitis and miliary TB, while its efficacy against pediatric pulmonary TB ranged from no protection to very high protection. In recent decades, multiple new vaccine candidates have been developed, and shown encouraging safety and immunogenicity in the preclinical experiments. However, the limited data on protective efficacy in infants evaluated by clinical trials has been disappointing, an example being MVA85A. To date, no vaccine has been shown to be clinically safer and more effective than the presently licensed BCG vaccine. Hence, before a new vaccine is developed with more promising efficacy, we must reconsider how to better use the current BCG vaccine to maximize its effectiveness in children. PMID:27002369

Pediatric oral formulation of dendrimer-N-acetyl-l-cysteine conjugates for the treatment of neuroinflammation.

PubMed

Yellepeddi, Venkata K; Mohammadpour, Raziye; Kambhampati, Siva P; Sayre, Casey; Mishra, Manoj K; Kannan, Rangaramanujam M; Ghandehari, Hamidreza

2018-04-20

N-Acetyl-l-cysteine (NAC) commonly used as an antidote in acetaminophen poisoning has shown promise in the treatment of neurological disorders such as cerebral palsy (CP). However, NAC suffers from drawbacks such as poor oral bioavailability and suboptimal blood-brain-barrier (BBB) permeability limiting its clinical success. It was previously demonstrated that intravenous administration of dendrimer-NAC (D-NAC) conjugates have shown significant promise in the targeted treatment of neuroinflammation, in multiple preclinical models. Development of an oral formulation of D-NAC may open new administrative routes for this compound. Here, we report the gastrointestinal stability, in vitro transepithelial permeability, and in vivo oral absorption and pharmacokinetics in rats of a pediatric formulation of D-NAC containing Capmul MCM (glycerol monocaprylate) as a penetration enhancer. D-NAC was stable for 6 h in all five simulated gastrointestinal fluids with no signs of chemical degradation. The apparent permeability (P app ) of D-NAC increased 9-fold in the formulation containing Capmul. The area under the curve [AUC] 0-∞ of D-NAC with Capmul increased by 47% when compared to D-NAC alone. These results indicate that an oral pediatric formulation containing D-NAC and Capmul can be an effective option for the treatment of neuroinflammation. Copyright © 2018 Elsevier B.V. All rights reserved.

Preclinical Evaluation of Engineered Oncolytic Herpes Simplex Virus for the Treatment of Pediatric Solid Tumors

PubMed Central

Megison, Michael L.; Gillory, Lauren A.; Stewart, Jerry E.; Nabers, Hugh C.; Mroczek-Musulman, Elizabeth; Waters, Alicia M.; Coleman, Jennifer M.; Kelly, Virginia; Markert, James M.; Gillespie, G. Yancey; Friedman, Gregory K.; Beierle, Elizabeth A.

2014-01-01

Recently, investigators showed that mice with syngeneic murine gliomas that were treated with a neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal cells. Previous studies have shown antitumor effects of other oHSV against a number of adult tumors including hepatocellular carcinoma and renal cell carcinoma. The purpose of the current study was to investigate the oncolytic potential of M002 against difficult to treat pediatric liver and kidney tumors. We showed that the oHSV, M002, infected, replicated, and decreased cell survival in hepatoblastoma, malignant rhabdoid kidney tumor, and renal sarcoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly increased survival and decreased tumor growth. Finally, these studies showed that the primary entry protein for oHSV, CD111 (nectin-1) was present in human hepatoblastoma and malignant rhabdoid kidney tumor specimens. We concluded that M002 effectively targeted these rare aggressive tumor types and that M002 may have potential for use in children with unresponsive or relapsed pediatric solid tumors. PMID:24497984

Insights into cerebellar development and medulloblastoma.

PubMed

Bihannic, Laure; Ayrault, Olivier

2016-01-01

Cerebellar development is an extensive process that begins during early embryonic stages and persists more than one year after birth in human. Therefore, the cerebellum is susceptible to acquire various developmental abnormalities leading to numerous diseases such as medulloblastoma, the most common pediatric malignant brain tumor. One third of the patients with medulloblastoma are incurable and survivors have a poor quality of life due to the aggressiveness of the broad-spectrum treatments. Within the past few years, it has been highlighted that medulloblastoma is a heterogeneous disease that is divided in four molecular subgroups. This recent advance in the field, combined with the development of associated preclinical models for each subgroup, should enable, in the future, the discovery and use of targeted therapy in clinical treatments for each subtype of medulloblastoma. In this review, we first aim to show how deregulation of cerebellar development can lead to medulloblastoma formation and then to present the advances in the molecular subgrouping of medulloblastoma and the associated preclinical models. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

International variation in the prevalence of preclinical colorectal cancer: Implications for predictive values of noninvasive screening tests and potential target populations for screening

PubMed Central

Stock, Christian; Brenner, Hermann

2017-01-01

Screening for colorectal cancer (CRC) is implemented in an increasing number of countries. We aimed to assess international variation in the prevalence of preclinical CRC and the resulting variation in positive and negative predictive values (PPVs, NPVs) of existing and potential CRC screening tests in various countries. Using age‐ and sex‐specific CRC incidence data and transition rates from preclinical to clinical CRC we estimated overall and age‐ and sex‐specific prevalence of preclinical CRC in the target population aged 50–74 years in different parts of the world. These prevalence estimates were used to derive PPVs and NPVs for existing and potential noninvasive screening tests with varying levels of sensitivity and specificity. Within all regions and countries, prevalence strongly increases with age and is higher in men than in women. In addition, major variation was seen between regions and countries, with overall prevalence varying between 1 and 0.1%. As a result, PPVs are expected to strongly vary between ∼10% for men in high incidence countries, such as Australia and Germany, and 1% for women in low incidence countries, whereas NPVs are expected to be consistently well above 99%. Variation in CRC prevalence profoundly affects expected PPVs of screening tests, and PPVs should be carefully considered when decisions on screening tests and strategies are made for specific populations and health care systems. Here, we provide estimates of preclinical CRC and expected PPVs and NPVs of noninvasive screening tests, which may enhance the empirical basis for planning of population‐based CRC screening strategies. PMID:28670788

Development of a Hampton University Program for Novel Breast Cancer Imaging and Therapy Research

DTIC Science & Technology

2013-04-01

intracavitary brachytherapy procedures during laboratory pre-clinical imaging and dosimetry equipment testing, calibration and data processing, in collaboration... electronics and detector instrumentation development; 4) breast phantom construction and implantation; 5) laboratory pre-clinical device testing...such as the ionization chamber, diode, radiographic verification 6 films and thermoluminescent dosimeters ( TLD ) but the scintillator fiber detectors

Preclinical safety testing for cell-based products using animals.

PubMed

McBlane, James W

2015-09-01

The objectives of preclinical testing include to show why there might be therapeutic benefit in patients and to provide information on the product's toxicity. For cell-based products, given even once, there may be long term exposure and this could imply, unlike for conventional drugs, that all preclinical studies may be needed prior to first human use. The duration of exposure to cells should be studied in animals to guide toxicity assessments. Distribution of cells after administration by a route resembling that intended in humans should be studied to understand potential risks. Risk of tumour formation with the product may also need to be characterised. To the extent that this information can be generated by in vitro testing, studies in animals may not be needed and limitations on the capability of preclinical data to predict human toxicity are recognised: species-specificity make some cell products act only in humans and a human cell-product might be expected to be rejected by immunocompetent animals. Does this suggest testing in immunosuppressed animals or of development of an animal-cell product supposedly similar to the human cell product? No single answer seems to fit every situation. Copyright © 2015.

Decision-Making in Pediatric Transport Team Dispatch Using Script Concordance Testing.

PubMed

Rajapreyar, Prakadeshwari; Marcdante, Karen; Zhang, Liyun; Simpson, Pippa; Meyer, Michael T

2017-11-01

Our objective was to compare decision-making in dispatching pediatric transport teams by Medical Directors of pediatric transport teams (serving as experts) to that of Pediatric Intensivists and Critical Care fellows who often serve as Medical Control physicians. Understanding decision-making around team composition and dispatch could impact clinical management, cost effectiveness, and educational needs. Survey was developed using Script Concordance Testing guidelines. The survey contained 15 transport case vignettes covering 20 scenarios (45 questions). Eleven scenarios assessed impact of intrinsic patient factors (e.g., procedural needs), whereas nine assessed extrinsic factors (e.g., weather). Pediatric Critical Care programs accredited by the Accreditation Council for Graduate Medical Education (the United States). Pediatric Intensivists and senior Critical Care fellows at Pediatric Critical Care programs were the target population with Transport Medical Directors serving as the expert panel. None. Survey results were scored per Script Concordance Testing guidelines. Concordance within groups was assessed using simple percentage agreement. There was little concordance in decision-making by Transport Medical Directors (median Script Concordance Testing percentage score [interquartile range] of 33.9 [30.4-37.3]). In addition, there was no statistically significant difference between the median Script Concordance Testing scores among the senior fellows and Pediatric Intensivists (31.1 [29.6-33.2] vs 29.7 [28.3-32.3], respectively; p = 0.12). Transport Medical Directors were more concordant on reasoning involving intrinsic patient factors rather than extrinsic factors (10/21 vs 4/24). Our study demonstrates pediatric transport team dispatch decision-making discordance by pediatric critical care physicians of varying levels of expertise and experience. Script Concordance Testing at a local level may better elucidate standards in medical decision-making within pediatric critical care physicians. The development of a curriculum, which provides education and trains our workforce on the logistics of pediatric transport team dispatch, would help standardize practice and evaluate outcomes based on decision-making.

Antitumor Efficacy Testing in Rodents

PubMed Central

2008-01-01

The preclinical research and human clinical trials necessary for developing anticancer therapeutics are costly. One contributor to these costs is preclinical rodent efficacy studies, which, in addition to the costs associated with conducting them, often guide the selection of agents for clinical development. If inappropriate or inaccurate recommendations are made on the basis of these preclinical studies, then additional costs are incurred. In this commentary, I discuss the issues associated with preclinical rodent efficacy studies. These include the identification of proper preclinical efficacy models, the selection of appropriate experimental endpoints, and the correct statistical evaluation of the resulting data. I also describe important experimental design considerations, such as selecting the drug vehicle, optimizing the therapeutic treatment plan, properly powering the experiment by defining appropriate numbers of replicates in each treatment arm, and proper randomization. Improved preclinical selection criteria can aid in reducing unnecessary human studies, thus reducing the overall costs of anticancer drug development. PMID:18957675

Adaptation of a Biomarker-Based Sepsis Mortality Risk Stratification Tool for Pediatric Acute Respiratory Distress Syndrome.

PubMed

Yehya, Nadir; Wong, Hector R

2018-01-01

The original Pediatric Sepsis Biomarker Risk Model and revised (Pediatric Sepsis Biomarker Risk Model-II) biomarker-based risk prediction models have demonstrated utility for estimating baseline 28-day mortality risk in pediatric sepsis. Given the paucity of prediction tools in pediatric acute respiratory distress syndrome, and given the overlapping pathophysiology between sepsis and acute respiratory distress syndrome, we tested the utility of Pediatric Sepsis Biomarker Risk Model and Pediatric Sepsis Biomarker Risk Model-II for mortality prediction in a cohort of pediatric acute respiratory distress syndrome, with an a priori plan to revise the model if these existing models performed poorly. Prospective observational cohort study. University affiliated PICU. Mechanically ventilated children with acute respiratory distress syndrome. Blood collection within 24 hours of acute respiratory distress syndrome onset and biomarker measurements. In 152 children with acute respiratory distress syndrome, Pediatric Sepsis Biomarker Risk Model performed poorly and Pediatric Sepsis Biomarker Risk Model-II performed modestly (areas under receiver operating characteristic curve of 0.61 and 0.76, respectively). Therefore, we randomly selected 80% of the cohort (n = 122) to rederive a risk prediction model for pediatric acute respiratory distress syndrome. We used classification and regression tree methodology, considering the Pediatric Sepsis Biomarker Risk Model biomarkers in addition to variables relevant to acute respiratory distress syndrome. The final model was comprised of three biomarkers and age, and more accurately estimated baseline mortality risk (area under receiver operating characteristic curve 0.85, p < 0.001 and p = 0.053 compared with Pediatric Sepsis Biomarker Risk Model and Pediatric Sepsis Biomarker Risk Model-II, respectively). The model was tested in the remaining 20% of subjects (n = 30) and demonstrated similar test characteristics. A validated, biomarker-based risk stratification tool designed for pediatric sepsis was adapted for use in pediatric acute respiratory distress syndrome. The newly derived Pediatric Acute Respiratory Distress Syndrome Biomarker Risk Model demonstrates good test characteristics internally and requires external validation in a larger cohort. Tools such as Pediatric Acute Respiratory Distress Syndrome Biomarker Risk Model have the potential to provide improved risk stratification and prognostic enrichment for future trials in pediatric acute respiratory distress syndrome.

Establishment of primary cell culture and an intracranial xenograft model of pediatric ependymoma: a prospect for therapy development and understanding of tumor biology

PubMed Central

Pavon, Lorena Favaro; Sibov, Tatiana Tais; Caminada de Toledo, Silvia Regina; Mara de Oliveira, Daniela; Cabral, Francisco Romero; Gabriel de Souza, Jean; Boufleur, Pamela; Marti, Luciana C.; Malheiros, Jackeline Moraes; Ferreira da Cruz, Edgar; Paiva, Fernando F.; Malheiros, Suzana M.F.; de Paiva Neto, Manoel A.; Tannús, Alberto; Mascarenhas de Oliveira, Sérgio; Silva, Nasjla Saba; Cappellano, Andrea Maria; Petrilli, Antonio Sérgio; Chudzinski-Tavassi, Ana Marisa; Cavalheiro, Sérgio

2018-01-01

Background Ependymoma (EPN), the third most common pediatric brain tumor, is a central nervous system (CNS) malignancy originating from the walls of the ventricular system. Surgical resection followed by radiation therapy has been the primary treatment for most pediatric intracranial EPNs. Despite numerous studies into the prognostic value of histological classification, the extent of surgical resection and adjuvant radiotherapy, there have been relatively few studies into the molecular and cellular biology of EPNs. Results We elucidated the ultrastructure of the cultured EPN cells and characterized their profile of immunophenotypic pluripotency markers (CD133, CD90, SSEA-3, CXCR4). We established an experimental EPN model by the intracerebroventricular infusion of EPN cells labeled with multimodal iron oxide nanoparticles (MION), thereby generating a tumor and providing a clinically relevant animal model. MRI analysis was shown to be a valuable tool when combined with effective MION labeling techniques to accompany EPN growth. Conclusions We demonstrated that GFAP/CD133+CD90+/CD44+ EPN cells maintained key histopathological and growth characteristics of the original patient tumor. The characterization of EPN cells and the experimental model could facilitate biological studies and preclinical drug screening for pediatric EPNs. Methods In this work, we established notoriously challenging primary cell culture of anaplastic EPNs (WHO grade III) localized in the posterior fossa (PF), using EPNs obtained from 1 to 10-year-old patients (n = 07), and then characterized their immunophenotype and ultrastructure to finally develop a xenograft model. PMID:29774098

The Hamburg Selection Procedure for Dental Students – Introduction of the HAM-Nat as subject-specific test for study aptitude

PubMed Central

Kothe, Christian; Hissbach, Johanna; Hampe, Wolfgang

2013-01-01

Introduction: The present study examines the question whether the selection of dental students should be based solely on average school-leaving grades (GPA) or whether it could be improved by using a subject-specific aptitude test. Methods: The HAM-Nat Natural Sciences Test was piloted with freshmen during their first study week in 2006 and 2007. In 2009 and 2010 it was used in the dental student selection process. The sample size in the regression models varies between 32 and 55 students. Results: Used as a supplement to the German GPA, the HAM-Nat test explained up to 12% of the variance in preclinical examination performance. We confirmed the prognostic validity of GPA reported in earlier studies in some, but not all of the individual preclinical examination results. Conclusion: The HAM-Nat test is a reliable selection tool for dental students. Use of the HAM-Nat yielded a significant improvement in prediction of preclinical academic success in dentistry. PMID:24282449

No Clinically Significant Difference Between Adult and Pediatric IKDC Subjective Knee Evaluation Scores in Adults.

PubMed

Stegmeier, Nicole; Oak, Sameer R; O'Rourke, Colin; Strnad, Greg; Spindler, Kurt P; Jones, Morgan; Farrow, Lutul D; Andrish, Jack; Saluan, Paul

Two versions of the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation form currently exist: the original version (1999) and a recently modified pediatric-specific version (2011). Comparison of the pediatric IKDC with the adult version in the adult population may reveal that either version could be used longitudinally. We hypothesize that the scores for the adult IKDC and pediatric IKDC will not be clinically different among adult patients aged 18 to 50 years. Randomized crossover study design. Level 2. The study consisted of 100 participants, aged 18 to 50 years, who presented to orthopaedic outpatient clinics with knee problems. All participants completed both adult and pediatric versions of the IKDC in random order with a 10-minute break in between. We used a paired t test to test for a difference between the scores and a Welch's 2-sample t test to test for equivalence. A least-squares regression model was used to model adult scores as a function of pediatric scores, and vice versa. A paired t test revealed a statistically significant 1.6-point difference between the mean adult and pediatric scores. However, the 95% confidence interval (0.54-2.66) for this difference did not exceed our a priori threshold of 5 points, indicating that this difference was not clinically important. Equivalence testing with an equivalence region of 5 points further supported this finding. The adult and pediatric scores had a linear relationship and were highly correlated with an R 2 of 92.6%. There is no clinically relevant difference between the scores of the adult and pediatric IKDC forms in adults, aged 18 to 50 years, with knee conditions. Either form, adult or pediatric, of the IKDC can be used in this population for longitudinal studies. If the pediatric version is administered in adolescence, it can be used for follow-up into adulthood.

No Clinically Significant Difference Between Adult and Pediatric IKDC Subjective Knee Evaluation Scores in Adults

PubMed Central

Stegmeier, Nicole; Oak, Sameer R.; O’Rourke, Colin; Strnad, Greg; Spindler, Kurt P.; Jones, Morgan; Farrow, Lutul D.; Andrish, Jack; Saluan, Paul

2017-01-01

Background: Two versions of the International Knee Documentation Committee (IKDC) Subjective Knee Evaluation form currently exist: the original version (1999) and a recently modified pediatric-specific version (2011). Comparison of the pediatric IKDC with the adult version in the adult population may reveal that either version could be used longitudinally. Hypothesis: We hypothesize that the scores for the adult IKDC and pediatric IKDC will not be clinically different among adult patients aged 18 to 50 years. Study Design: Randomized crossover study design. Level of Evidence: Level 2. Methods: The study consisted of 100 participants, aged 18 to 50 years, who presented to orthopaedic outpatient clinics with knee problems. All participants completed both adult and pediatric versions of the IKDC in random order with a 10-minute break in between. We used a paired t test to test for a difference between the scores and a Welch’s 2-sample t test to test for equivalence. A least-squares regression model was used to model adult scores as a function of pediatric scores, and vice versa. Results: A paired t test revealed a statistically significant 1.6-point difference between the mean adult and pediatric scores. However, the 95% confidence interval (0.54-2.66) for this difference did not exceed our a priori threshold of 5 points, indicating that this difference was not clinically important. Equivalence testing with an equivalence region of 5 points further supported this finding. The adult and pediatric scores had a linear relationship and were highly correlated with an R2 of 92.6%. Conclusion: There is no clinically relevant difference between the scores of the adult and pediatric IKDC forms in adults, aged 18 to 50 years, with knee conditions. Clinical Relevance: Either form, adult or pediatric, of the IKDC can be used in this population for longitudinal studies. If the pediatric version is administered in adolescence, it can be used for follow-up into adulthood. PMID:28080306

Bioengineered Temporomandibular Joint Disk Implants: Study Protocol for a Two-Phase Exploratory Randomized Preclinical Pilot Trial in 18 Black Merino Sheep (TEMPOJIMS)

PubMed Central

Monje, Florencio Gil; González-García, Raúl; Little, Christopher B; Mónico, Lisete; Pinho, Mário; Santos, Fábio Abade; Carrapiço, Belmira; Gonçalves, Sandra Cavaco; Morouço, Pedro; Alves, Nuno; Moura, Carla; Wang, Yadong; Jeffries, Eric; Gao, Jin; Sousa, Rita; Neto, Lia Lucas; Caldeira, Daniel; Salvado, Francisco

2017-01-01

Background Preclinical trials are essential to test efficacious options to substitute the temporomandibular joint (TMJ) disk. The contemporary absence of an ideal treatment for patients with severe TMJ disorders can be related to difficulties concerning the appropriate study design to conduct preclinical trials in the TMJ field. These difficulties can be associated with the use of heterogeneous animal models, the use of the contralateral TMJ as control, the absence of rigorous randomized controlled preclinical trials with blinded outcomes assessors, and difficulties involving multidisciplinary teams. Objective This study aims to develop a new, reproducible, and effective study design for preclinical research in the TMJ domain, obtaining rigorous data related to (1) identify the impact of bilateral discectomy in black Merino sheep, (2) identify the impact of bilateral discopexy in black Merino sheep, and (3) identify the impact of three different bioengineering TMJ discs in black Merino sheep. Methods A two-phase exploratory randomized controlled preclinical trial with blinded outcomes is proposed. In the first phase, nine sheep are randomized into three different surgical bilateral procedures: bilateral discectomy, bilateral discopexy, and sham surgery. In the second phase, nine sheep are randomized to bilaterally test three different TMJ bioengineering disk implants. The primary outcome is the histological gradation of TMJ. Secondary outcomes are imaging changes, absolute masticatory time, ruminant time per cycle, ruminant kinetics, ruminant area, and sheep weight. Results Previous preclinical studies in this field have used the contralateral unoperated side as a control, different animal models ranging from mice to a canine model, with nonrandomized, nonblinded and uncontrolled study designs and limited outcomes measures. The main goal of this exploratory preclinical protocol is to set a new standard for future preclinical trials in oromaxillofacial surgery, particularly in the TMJ field, by proposing a rigorous design in black Merino sheep. The authors also intend to test the feasibility of pilot outcomes. The authors expect to increase the quality of further studies in this field and to progress in future treatment options for patients undergoing surgery for TMJ disk replacement. Conclusions The study has commenced, but it is too early to provide results or conclusions. PMID:28254733

Interprofessional, multiple step simulation course improves pediatric resident and nursing staff management of pediatric patients with diabetic ketoacidosis

PubMed Central

Larson-Williams, Linnea M; Youngblood, Amber Q; Peterson, Dawn Taylor; Zinkan, J Lynn; White, Marjorie L; Abdul-Latif, Hussein; Matalka, Leen; Epps, Stephen N; Tofil, Nancy M

2016-01-01

AIM To investigate the use of a multidisciplinary, longitudinal simulation to educate pediatric residents and nurses on management of pediatric diabetic ketoacidosis. METHODS A multidisciplinary, multiple step simulation course was developed by faculty and staff using a modified Delphi method from the Pediatric Simulation Center and pediatric endocrinology department. Effectiveness of the simulation for the residents was measured with a pre- and post-test and a reference group not exposed to simulation. A follow up post-test was completed 3-6 mo after the simulation. Nurses completed a survey regarding the education activity. RESULTS Pediatric and medicine-pediatric residents (n = 20) and pediatric nurses (n = 25) completed the simulation course. Graduating residents (n = 16) were used as reference group. Pretest results were similar in the control and intervention group (74% ± 10% vs 76% ± 15%, P = 0.658). After completing the intervention, participants improved in the immediate post-test in comparison to themselves and the control group (84% ± 12% post study; P < 0.05). The 3-6 mo follow up post-test results demonstrated knowledge decay when compared to their immediate post-test results (78% ± 14%, P = 0.761). Residents and nurses felt the interdisciplinary and longitudinal nature of the simulation helped with learning. CONCLUSION Results suggest a multidisciplinary, longitudinal simulation improves immediate post-intervention knowledge but important knowledge decay occurs, future studies are needed to determine ways to decrease this decay. PMID:27896145

WAKE-Up Exoskeleton to Assist Children With Cerebral Palsy: Design and Preliminary Evaluation in Level Walking.

PubMed

Patane, Fabrizio; Rossi, Stefano; Del Sette, Fausto; Taborri, Juri; Cappa, Paolo

2017-07-01

This paper presents the modular design and control of a novel compliant lower limbmulti-joint exoskeleton for the rehabilitation of ankle kneemobility and locomotion of pediatric patients with neurological diseases, such as Cerebral Palsy (CP). The device consists of an untethered powered knee-ankle-foot orthosis (KAFO), addressed as WAKE-up (Wearable Ankle Knee Exoskeleton), characterized by a position control and capable of operating synchronously and synergistically with the human musculoskeletal system. The WAKE-up mechanical system, control architecture and feature extraction are described. Two test benches were used to mechanically characterize the device. The full system showed a maximum value of hysteresis equal to 8.8% and a maximum torque of 5.6 N m/rad. A pre-clinical use was performed, without body weight support, by four typically developing children and three children with CP. The aims were twofold: 1) to test the structure under weight-bearing conditions and 2) to ascertain its ability to provide appropriate assistance to the ankle and the knee during overground walking in a real environment. Results confirm the effectiveness of the WAKE-up design in providing torque assistance in accordance to the volitionalmovements especially in the recovery of correct foot landing at the start of the gait cycle.

Treatment of TBI with Hormonal and Pharmacological Support, Preclinical Validation Using Diffuse and Mechanical TBI Animal Models

DTIC Science & Technology

2016-05-01

Award Number: PT075653 (grant) W81XWH-08-2-0153 (contract) TITLE: Treatment of TBI with Hormonal and Pharmacological Support, Preclinical...TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-08-2-0153 Treatment of TBI with Hormonal and Pharmacological Support, Preclinical Validation Using...rats. Our in vivo tests also included MRI imaging, focusing on edema resolution and reduction of diffuse axonal damage (fractional anisotropy

Preclinical antivenom-efficacy testing reveals potentially disturbing deficiencies of snakebite treatment capability in East Africa

PubMed Central

Oluoch, George O.; Ainsworth, Stuart; Alsolaiss, Jaffer; Bolton, Fiona; Arias, Ana-Silvia; Gutiérrez, José-María; Rowley, Paul; Kalya, Stephen; Ozwara, Hastings; Casewell, Nicholas R.

2017-01-01

Background Antivenom is the treatment of choice for snakebite, which annually kills an estimated 32,000 people in sub-Saharan Africa and leaves approximately 100,000 survivors with permanent physical disabilities that exert a considerable socioeconomic burden. Over the past two decades, the high costs of the most polyspecifically-effective antivenoms have sequentially reduced demand, commercial manufacturing incentives and production volumes that have combined to create a continent-wide vacuum of effective snakebite therapy. This was quickly filled with new, less expensive antivenoms, many of which are of untested efficacy. Some of these successfully marketed antivenoms for Africa are inappropriately manufactured with venoms from non-African snakes and are dangerously ineffective. The uncertain efficacy of available antivenoms exacerbates the complexity of designing intervention measures to reduce the burden of snakebite in sub-Saharan Africa. The objective of this study was to preclinically determine the ability of antivenoms available in Kenya to neutralise the lethal effects of venoms from the most medically important snakes in East Africa. Methods We collected venom samples from the most medically important snakes in East Africa and determined their toxicity in a mouse model. Using a ‘gold standard’ comparison protocol, we preclinically tested the comparative venom-neutralising efficacy of four antivenoms available in Kenya with two antivenoms of clinically-proven efficacy. To explain the variant efficacies of these antivenoms we tested the IgG-venom binding characteristics of each antivenom using in vitro IgG titre, avidity and venom-protein specificity assays. We also measured the IgG concentration of each antivenom. Findings None of the six antivenoms are preclinically effective, at the doses tested, against all of the most medically important snakes of the region. The very limited snake polyspecific efficacy of two locally available antivenoms is of concern. In vitro assays of the abilities of ‘test’ antivenom IgGs to bind venom proteins were not substantially different from that of the ‘gold standard’ antivenoms. The least effective antivenoms had the lowest IgG content/vial. Conclusions Manufacture-stated preclinical efficacy statements guide decision making by physicians and antivenom purchasers in sub-Saharan Africa. This is because of the lack of both clinical data on the efficacy of most of the many antivenoms used to treat patients and independent preclinical assessment. Our preclinical efficacy assessment of antivenoms available in Kenya identifies important limitations for two of the most commonly-used antivenoms, and that no antivenom is preclinically effective against all the regionally important snakes. The potential implication to snakebite treatment is of serious concern in Kenya and elsewhere in sub-Saharan Africa, and underscores the dilemma physicians face, the need for clinical data on antivenom efficacy and the medical and societal value of establishing independent preclinical antivenom-efficacy testing facilities throughout the continent. PMID:29045429

Prediction of skull fracture risk for children 0-9 months old through validated parametric finite element model and cadaver test reconstruction.

PubMed

Li, Zhigang; Liu, Weiguo; Zhang, Jinhuan; Hu, Jingwen

2015-09-01

Skull fracture is one of the most common pediatric traumas. However, injury assessment tools for predicting pediatric skull fracture risk is not well established mainly due to the lack of cadaver tests. Weber conducted 50 pediatric cadaver drop tests for forensic research on child abuse in the mid-1980s (Experimental studies of skull fractures in infants, Z Rechtsmed. 92: 87-94, 1984; Biomechanical fragility of the infant skull, Z Rechtsmed. 94: 93-101, 1985). To our knowledge, these studies contained the largest sample size among pediatric cadaver tests in the literature. However, the lack of injury measurements limited their direct application in investigating pediatric skull fracture risks. In this study, 50 pediatric cadaver tests from Weber's studies were reconstructed using a parametric pediatric head finite element (FE) model which were morphed into subjects with ages, head sizes/shapes, and skull thickness values that reported in the tests. The skull fracture risk curves for infants from 0 to 9 months old were developed based on the model-predicted head injury measures through logistic regression analysis. It was found that the model-predicted stress responses in the skull (maximal von Mises stress, maximal shear stress, and maximal first principal stress) were better predictors than global kinematic-based injury measures (peak head acceleration and head injury criterion (HIC)) in predicting pediatric skull fracture. This study demonstrated the feasibility of using age- and size/shape-appropriate head FE models to predict pediatric head injuries. Such models can account for the morphological variations among the subjects, which cannot be considered by a single FE human model.

The predictive validity of the BioMedical Admissions Test for pre-clinical examination performance.

PubMed

Emery, Joanne L; Bell, John F

2009-06-01

Some medical courses in the UK have many more applicants than places and almost all applicants have the highest possible previous and predicted examination grades. The BioMedical Admissions Test (BMAT) was designed to assist in the student selection process specifically for a number of 'traditional' medical courses with clear pre-clinical and clinical phases and a strong focus on science teaching in the early years. It is intended to supplement the information provided by examination results, interviews and personal statements. This paper reports on the predictive validity of the BMAT and its predecessor, the Medical and Veterinary Admissions Test. Results from the earliest 4 years of the test (2000-2003) were matched to the pre-clinical examination results of those accepted onto the medical course at the University of Cambridge. Correlation and logistic regression analyses were performed for each cohort. Section 2 of the test ('Scientific Knowledge') correlated more strongly with examination marks than did Section 1 ('Aptitude and Skills'). It also had a stronger relationship with the probability of achieving the highest examination class. The BMAT and its predecessor demonstrate predictive validity for the pre-clinical years of the medical course at the University of Cambridge. The test identifies important differences in skills and knowledge between candidates, not shown by their previous attainment, which predict their examination performance. It is thus a valid source of additional admissions information for medical courses with a strong scientific emphasis when previous attainment is very high.

Tau and Amyloid Positron Emission Tomography Imaging Predict Driving Performance Among Older Adults with and without Preclinical Alzheimer's Disease.

PubMed

Roe, Catherine M; Babulal, Ganesh M; Mishra, Shruti; Gordon, Brian A; Stout, Sarah H; Ott, Brian R; Carr, David B; Ances, Beau M; Morris, John C; Benzinger, Tammie L S

2018-01-01

Abnormal levels of Alzheimer's disease (AD) biomarkers, measured by positron emission tomography imaging using amyloid-based radiotracers and cerebrospinal fluid, are associated with impaired driving performance in older adults. We examined whether preclinical AD staging, defined using amyloid imaging and tau imaging using the radiotracer T807 (AKA flortaucipir or AV-1451), was associated with receiving a marginal/fail rating on a standardized road test (n = 42). Participants at Stage 2 (positive amyloid and tau scans) of preclinical AD were more likely to receive a marginal/fail rating compared to participants at Stage 0 or 1. Stage 2 preclinical AD may manifest in worse driving performance.

Pre-admission criteria and pre-clinical achievement: Can they predict medical students performance in the clinical phase?

PubMed

Salem, Raneem O; Al-Mously, Najwa; AlFadil, Sara; Baalash, Amal

2016-01-01

Various factors affect medical students' performance during clinical phase. Identifying these factors would help in mentoring weak students and help in selection process for residency programmes. Our study objective is to evaluate the impact of pre-admission criteria, and pre-clinical grade point average (GPA) on undergraduate medical students' performance during clinical phase. This study has a cross-sectional design that includes fifth- and sixth-year female medical students (71). Data of clinical and pre-clinical GPA in medical school and pre-admission to medical school tests scores were collected. A significant correlation between clinical GPA with the pre-clinical GPA was observed (p < 0.05). Such significant correlation was not seen with other variables under study. A regression analysis was performed, and the only significant predictor of students clinical performance was the pre-clinical GPA (p < 0.001). However, no significant difference between students' clinical and pre-clinical GPA for both cohorts was observed (p > 0.05). Pre-clinical GPA is strongly correlated with and can predict medical students' performance during clinical years. Our study highlighted the importance of evaluating the academic performances of students in pre-clinical years before they move into clinical years in order to identify weak students to mentor them and monitor their progress.

Pediatric material properties: a review of human child and animal surrogates.

PubMed

Franklyn, Melanie; Peiris, Sujanie; Huber, Christina; Yang, King H

2007-01-01

Because pediatric tissue is difficult for researchers to obtain, the biomechanical responses of adult humans have been studied much more extensively than those of children. Piglets, chimpanzees, and other animals have been used as child surrogates, but the tissue properties and responses to impact forces obtained from these animals may not directly correlate with the human child, and this correlation is not well understood. Consequently, only a handful of human pediatric tissue properties are known. Child anthropomorphic test devices employed in automotive safety have been developed largely by scaling data obtained from adult human cadaveric tests, where various scaling methods have been used to account for differences in geometry, material properties, or a combination of these two parameters. Similar scaling techniques have also been implemented to develop injury assessment reference values for child anthropomorphic test devices. Nevertheless, these scaling techniques have not yet proven to be accurate, in part because of the lack of pediatric data. In this review, the properties of pediatric human and animal surrogate tissue that have been mechanically tested are evaluated. It was found that most of the pediatric tissue that has previously been tested pertains to the head, neck, cervical spine, and extremities. It is evident that some body regions, such as the head and neck, have been tested to some extent since injuries to these regions are critical from an injury perspective. On the other hand, there is limited pediatric data available for the thorax, abdomen, thoracic and lumbar spines and fetal-related tissue. This review presents the pediatric data available in the literature and highlights the body regions where further testing is needed.

Clinical applications of bioactive milk components

PubMed Central

Newburg, David S.

2015-01-01

Milk represents a unique resource for translational medicine: It contains a rich pool of biologically active molecules with demonstrated clinical benefits. The ongoing characterization of the mechanistic process through which milk components promote development and immunity has revealed numerous milk-derived compounds with potential applications as clinical therapies in infectious and inflammatory disease, cancer, and other conditions. Lactoferrin is an effective antimicrobial and antiviral agent in high-risk patient populations and a potentially potent adjuvant to chemotherapy in lung cancer. Enteric nutrition formulas supplemented with transforming growth factor β, a milk cytokine, have been shown to promote remission in pediatric Crohn's disease. A number of milk glycans, including human milk oligosaccharides, show promise in preclinical studies as antimicrobial and anti-inflammatory agents. While active preclinical investigations of human milk may soon result in large-scale production of human milk molecules, bovine milk components in many instances represent a practical source of bioactive milk compounds for use in clinical trials. This review summarizes current efforts to translate the compounds derived from human and bovine milk into effective clinical therapies. These efforts suggest a common pathway for the translation of milk-derived compounds into clinical applications. PMID:26011900

Update on the use of defibrotide.

PubMed

Guglielmelli, Tommasina; Bringhen, Sara; Palumbo, Antonio

2012-03-01

Defibrotide is a polydisperse oligonucleotide obtained from porcine intestinal mucosa and prepared by controlled depolymerization of DNA. It is a nucleic acid polymer, predominantly single-stranded, which has anti-ischemic and anti-thrombotic properties. The efficacy and safety of defibrotide in the treatment of veno-occlusive disease (VOD) occurring after high-dose chemotherapy and hematopoietic stem-cell transplantation is now well established in Phase II - III trials. A recent randomized, Phase III trial in pediatric patients has also demonstrated its role in the prevention of VOD. Preclinical studies reported the inhibitory effects of defibrotide on myeloma cells' growth through an antiangiogenic action and a regulation of the tumor-microenvironment interactions. A recent Phase II trial underlines the efficacy and safety of defibrotide-thalidomide-melphalan combination in the treatment of relapsed/refractory multiple myeloma. Defibrotide may be effective in the prophylaxis and the treatment of veno-occlusive disease. Recent experimental results suggest that defibrotide may belong to the new generation of anti-cancer drugs that can prevent tumor angiogenesis. In multiple myeloma, defibrotide may overcome the prothrombotic effect of thalidomide on endothelial cells. Further preclinical and clinical investigations are needed to assess the precise role of defibrotide in the treatment of patients with multiple myeloma.

Clinical applications of bioactive milk components.

PubMed

Hill, David R; Newburg, David S

2015-07-01

Milk represents a unique resource for translational medicine: It contains a rich pool of biologically active molecules with demonstrated clinical benefits. The ongoing characterization of the mechanistic process through which milk components promote development and immunity has revealed numerous milk-derived compounds with potential applications as clinical therapies in infectious and inflammatory disease, cancer, and other conditions. Lactoferrin is an effective antimicrobial and antiviral agent in high-risk patient populations and a potentially potent adjuvant to chemotherapy in lung cancer. Enteric nutrition formulas supplemented with transforming growth factor β, a milk cytokine, have been shown to promote remission in pediatric Crohn's disease. A number of milk glycans, including human milk oligosaccharides, show promise in preclinical studies as antimicrobial and anti-inflammatory agents. While active preclinical investigations of human milk may soon result in large-scale production of human milk molecules, bovine milk components in many instances represent a practical source of bioactive milk compounds for use in clinical trials. This review summarizes current efforts to translate the compounds derived from human and bovine milk into effective clinical therapies. These efforts suggest a common pathway for the translation of milk-derived compounds into clinical applications.

Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

PubMed

Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

2014-11-01

Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

National trends in safety performance of electronic health record systems in children's hospitals.

PubMed

Chaparro, Juan D; Classen, David C; Danforth, Melissa; Stockwell, David C; Longhurst, Christopher A

2017-03-01

To evaluate the safety of computerized physician order entry (CPOE) and associated clinical decision support (CDS) systems in electronic health record (EHR) systems at pediatric inpatient facilities in the US using the Leapfrog Group's pediatric CPOE evaluation tool. The Leapfrog pediatric CPOE evaluation tool, a previously validated tool to assess the ability of a CPOE system to identify orders that could potentially lead to patient harm, was used to evaluate 41 pediatric hospitals over a 2-year period. Evaluation of the last available test for each institution was performed, assessing performance overall as well as by decision support category (eg, drug-drug, dosing limits). Longitudinal analysis of test performance was also carried out to assess the impact of testing and the overall trend of CPOE performance in pediatric hospitals. Pediatric CPOE systems were able to identify 62% of potential medication errors in the test scenarios, but ranged widely from 23-91% in the institutions tested. The highest scoring categories included drug-allergy interactions, dosing limits (both daily and cumulative), and inappropriate routes of administration. We found that hospitals with longer periods since their CPOE implementation did not have better scores upon initial testing, but after initial testing there was a consistent improvement in testing scores of 4 percentage points per year. Pediatric computerized physician order entry (CPOE) systems on average are able to intercept a majority of potential medication errors, but vary widely among implementations. Prospective and repeated testing using the Leapfrog Group's evaluation tool is associated with improved ability to intercept potential medication errors. © The Author 2016. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com

New Breed of Mice May Improve Accuracy for Preclinical Testing of Cancer Drugs | FNLCR Staging

Cancer.gov

A new breed of lab animals, dubbed “glowing head mice,” may do a better job than conventional mice in predicting the success of experimental cancer drugs—while also helping to meet an urgent need for more realistic preclinical animal models. Th

Gliomatosis cerebri: A consensus summary report from the First International Gliomatosis cerebri Group Meeting, March 26-27, 2015, Paris, France.

PubMed

Greenfield, Jeffrey P; Castañeda Heredia, Alicia; George, Emilie; Kieran, Mark W; Morales La Madrid, Andres

2016-12-01

Gliomatosis cerebri (GC) is a universally fatal extensive and diffuse infiltration of brain parenchyma by a glial tumor. Many aspects of this phenomenon remain unknown. The First International Gliomatosis cerebri Group Meeting had the following goals: refine the clinical and radiologic diagnostic criteria for GC, suggest appropriate diagnostic procedures, standardize tissue manipulation for histologic and molecular characterization, and prioritize relevant preclinical projects. Also, general treatment recommendations were outlined for the pediatric population. Importantly, this meeting was the starting point for meaningful collaborative international research projects. This review is a consensus summary of discussions shared and conclusions derived from this meeting. © 2016 Wiley Periodicals, Inc.

Acquisition of dental skills in preclinical technique courses: influence of spatial and manual abilities.

PubMed

Schwibbe, Anja; Kothe, Christian; Hampe, Wolfgang; Konradt, Udo

2016-10-01

Sixty years of research have not added up to a concordant evaluation of the influence of spatial and manual abilities on dental skill acquisition. We used Ackerman's theory of ability determinants of skill acquisition to explain the influence of spatial visualization and manual dexterity on the task performance of dental students in two consecutive preclinical technique courses. We measured spatial and manual abilities of applicants to Hamburg Dental School by means of a multiple choice test on Technical Aptitude and a wire-bending test, respectively. Preclinical dental technique tasks were categorized as consistent-simple and inconsistent-complex based on their contents. For analysis, we used robust regression to circumvent typical limitations in dental studies like small sample size and non-normal residual distributions. We found that manual, but not spatial ability exhibited a moderate influence on the performance in consistent-simple tasks during dental skill acquisition in preclinical dentistry. Both abilities revealed a moderate relation with the performance in inconsistent-complex tasks. These findings support the hypotheses which we had postulated on the basis of Ackerman's work. Therefore, spatial as well as manual ability are required for the acquisition of dental skills in preclinical technique courses. These results support the view that both abilities should be addressed in dental admission procedures in addition to cognitive measures.

Assessment of programmed death-ligand 1 expression and tumor-associated immune cells in pediatric cancer tissues.

PubMed

Majzner, Robbie G; Simon, Jason S; Grosso, Joseph F; Martinez, Daniel; Pawel, Bruce R; Santi, Mariarita; Merchant, Melinda S; Geoerger, Birgit; Hezam, Imene; Marty, Virginie; Vielh, Phillippe; Daugaard, Mads; Sorensen, Poul H; Mackall, Crystal L; Maris, John M

2017-10-01

Programmed death 1 (PD-1) signaling in the tumor microenvironment dampens immune responses to cancer, and blocking this axis induces antitumor effects in several malignancies. Clinical studies of PD-1 blockade are only now being initiated in pediatric patients, and little is known regarding programmed death-ligand 1 (PD-L1) expression in common childhood cancers. The authors characterized PD-L1 expression and tumor-associated immune cells (TAICs) (lymphocytes and macrophages) in common pediatric cancers. Whole slide sections and tissue microarrays were evaluated by immunohistochemistry for PD-L1 expression and for the presence of TAICs. TAICs were also screened for PD-L1 expression. Thirty-nine of 451 evaluable tumors (9%) expressed PD-L1 in at least 1% of tumor cells. The highest frequency histotypes comprised Burkitt lymphoma (80%; 8 of 10 tumors), glioblastoma multiforme (36%; 5 of 14 tumors), and neuroblastoma (14%; 17 of 118 tumors). PD-L1 staining was associated with inferior survival among patients with neuroblastoma (P = .004). Seventy-four percent of tumors contained lymphocytes and/or macrophages. Macrophages were significantly more likely to be identified in PD-L1-positive versus PD-L1-negative tumors (P < .001). A subset of diagnostic pediatric cancers exhibit PD-L1 expression, whereas a much larger fraction demonstrates infiltration with tumor-associated lymphocytes. PD-L1 expression may be a biomarker for poor outcome in neuroblastoma. Further preclinical and clinical investigation will define the predictive nature of PD-L1 expression in childhood cancers both at diagnosis and after exposure to chemoradiotherapy. Cancer 2017;123:3807-3815. © 2017 American Cancer Society. © 2017 American Cancer Society.

An Adaptation of the Original Fresno Test to Measure Evidence-Based Practice Competence in Pediatric Bedside Nurses.

PubMed

Laibhen-Parkes, Natasha; Kimble, Laura P; Melnyk, Bernadette Mazurek; Sudia, Tanya; Codone, Susan

2018-06-01

Instruments used to assess evidence-based practice (EBP) competence in nurses have been subjective, unreliable, or invalid. The Fresno test was identified as the only instrument to measure all the steps of EBP with supportive reliability and validity data. However, the items and psychometric properties of the original Fresno test are only relevant to measure EBP with medical residents. Therefore, the purpose of this paper is to describe the development of the adapted Fresno test for pediatric nurses, and provide preliminary validity and reliability data for its use with Bachelor of Science in Nursing-prepared pediatric bedside nurses. General adaptations were made to the original instrument's case studies, item content, wording, and format to meet the needs of a pediatric nursing sample. The scoring rubric was also modified to complement changes made to the instrument. Content and face validity, and intrarater reliability of the adapted Fresno test were assessed during a mixed-methods pilot study conducted from October to December 2013 with 29 Bachelor of Science in Nursing-prepared pediatric nurses. Validity data provided evidence for good content and face validity. Intrarater reliability estimates were high. The adapted Fresno test presented here appears to be a valid and reliable assessment of EBP competence in Bachelor of Science in Nursing-prepared pediatric nurses. However, further testing of this instrument is warranted using a larger sample of pediatric nurses in diverse settings. This instrument can be a starting point for evaluating the impact of EBP competence on patient outcomes. © 2018 Sigma Theta Tau International.

The Alzheimer’s Prevention Initiative composite cognitive test score: Sample size estimates for the evaluation of preclinical Alzheimer’s disease treatments in presenilin 1 E280A mutation carriers

PubMed Central

Ayutyanont, Napatkamon; Langbaum, Jessica B.; Hendrix, Suzanne B.; Chen, Kewei; Fleisher, Adam S.; Friesenhahn, Michel; Ward, Michael; Aguirre, Camilo; Acosta-Baena, Natalia; Madrigal, Lucìa; Muñoz, Claudia; Tirado, Victoria; Moreno, Sonia; Tariot, Pierre N.; Lopera, Francisco; Reiman, Eric M.

2014-01-01

Objective There is a need to identify a cognitive composite that is sensitive to tracking preclinical AD decline to be used as a primary endpoint in treatment trials. Method We capitalized on longitudinal data, collected from 1995 to 2010, from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world’s largest known early-onset autosomal dominant AD (ADAD) kindred to identify a composite cognitive test with the greatest statistical power to track preclinical AD decline and estimate the number of carriers age 30 and older needed to detect a treatment effect in the Alzheimer’s Prevention Initiative’s (API) preclinical AD treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of one to seven cognitive tests/sub-tests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a two and five year follow-up period, using data from non-carriers during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top performing combinations and representation of relevant cognitive domains. Results This optimal test combination included CERAD Word List Recall, CERAD Boston Naming Test (high frequency items), MMSE Orientation to Time, CERAD Constructional Praxis and Ravens Progressive Matrices (Set A) with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR=0.38) or the entire CERAD-Col battery (MSDR=0.76). A sample size of 75 cognitively normal PSEN1-E280A mutation carriers age 30 and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, p=0.05). Conclusions We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared to the most sensitive single test item to track preclinical AD decline in ADAD mutation carriers and evaluate preclinical AD treatments. This API composite cognitive test score will be used as the primary endpoint in the first API trial in cognitively unimpaired ADAD carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset AD, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytical approaches. PMID:24816373

A randomized controlled trial of high-fidelity simulation versus lecture-based education in preclinical medical students.

PubMed

Alluri, Ram Kiran; Tsing, Pamela; Lee, Edward; Napolitano, Jason

2016-01-01

The purpose of this study was to compare the efficacy of simulation versus lecture-based education among preclinical medical students. Twenty medical students participated in this randomized, controlled crossover study. Students were randomized to four groups. Each group received two simulations and two lectures covering four different topics. Students were administered a pre-test, post-test and delayed post-test. The mean percentage of questions answered correctly on each test was calculated. The mean of each student's change in score across the three tests was used to compare simulation- versus lecture-based education. Students in both the simulation and lecture groups demonstrated improvement between the pre-test and post-test (p < 0.05). Students in the simulation group demonstrated improvement between the immediate post-test and delayed post-test (p < 0.05), while students in the lecture group did not demonstrate improvement (p > 0.05). When comparing interventions, the change in score between the pre-test and post-test was similar among both the groups (p > 0.05). The change in score between the post-test and delayed post-test was greater in the simulation group (p < 0.05). High-fidelity simulation may serve as a viable didactic platform for preclinical medical education. Our study demonstrated equivalent immediate knowledge gain and superior long-term knowledge retention in comparison to lectures.

Issues related to development of antiepileptogenic therapies.

PubMed

Pitkänen, Asla; Nehlig, Astrid; Brooks-Kayal, Amy R; Dudek, F Edward; Friedman, Daniel; Galanopoulou, Aristea S; Jensen, Frances E; Kaminski, Rafal M; Kapur, Jaideep; Klitgaard, Henrik; Löscher, Wolfgang; Mody, Istvan; Schmidt, Dieter

2013-08-01

Several preclinical proof-of-concept studies have provided evidence for positive treatment effects on epileptogenesis. However, none of these hypothetical treatments has advanced to the clinic. The experience in other fields of neurology such as stroke, Alzheimer's disease, or amyotrophic lateral sclerosis has indicated several problems in the design of preclinical studies, which likely contribute to failures in translating the positive preclinical data to the clinic. The Working Group on "Issues related to development of antiepileptogenic therapies" of the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES) has considered the possible problems that arise when moving from proof-of-concept antiepileptogenesis (AEG) studies to preclinical AEG trials, and eventually to clinical AEG trials. This article summarizes the discussions and provides recommendations on how to design a preclinical AEG monotherapy trial in adult animals. We specifically address study design, animal and model selection, number of studies needed, issues related to administration of the treatment, outcome measures, statistics, and reporting. In addition, we give recommendations for future actions to advance the preclinical AEG testing. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process

PubMed Central

An, Fan; Qu, Yueyang; Luo, Yong; Fang, Ning; Liu, Yang; Gao, Zhigang; Zhao, Weijie; Lin, Bingcheng

2016-01-01

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery. PMID:27122192

A Laminated Microfluidic Device for Comprehensive Preclinical Testing in the Drug ADME Process.

PubMed

An, Fan; Qu, Yueyang; Luo, Yong; Fang, Ning; Liu, Yang; Gao, Zhigang; Zhao, Weijie; Lin, Bingcheng

2016-04-28

New techniques are urgently needed to replace conventional long and costly pre-clinical testing in the new drug administration process. In this study, a laminated microfluidic device was fabricated to mimic the drug ADME response test in vivo. This proposed device was loaded and cultured with functional cells for drug response investigation and organ tissues that are involved in ADME testing. The drug was introduced from the top of the device and first absorbed by the Caco-2 cell layer, and then metabolized by the primary hepatocyte layer. It subsequently interacted with the MCF-7 cell layer, distributed in the lung, heart and fat tissues, and was finally eliminated through the dialysis membrane. Throughout this on-chip ADME process, the proposed device can be used as a reliable tool to simultaneously evaluate the drug anti-tumor activity, hepatotoxicity and pharmacokinetics. Furthermore, this device was proven to be able to reflect the hepatic metabolism of a drug, drug distribution in the target tissues, and the administration method of a drug. Furthermore, this microdevice is expected to reduce the number of drug candidates and accelerate the pre-clinical testing process subject to animal testing upon adaptation in new drug discovery.

Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder.

PubMed

Postuma, Ronald B; Gagnon, Jean-François; Vendette, Mélanie; Desjardins, Catherine; Montplaisir, Jacques Y

2011-05-01

For development of neuroprotective therapy, neurodegenerative disease must be identified as early as possible. However, current means of identifying "preclinical" neurodegeneration are limited. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are at >50% risk of synuclein-mediated neurodegenerative disease--this provides a unique opportunity to directly observe preclinical synucleinopathy and to test potential markers of preclinical disease. Patients with RBD without neurodegenerative disease were enrolled in a prospective cohort starting in 2004. Olfaction and color vision were tested at baseline, then annually for 5 years. Test results were compared between patients who developed neurodegenerative disease and those who remained disease-free. Out of 64 patients, 62 (97%) participated in annual follow-up. During follow-up, 21 developed disease, and 41 remained disease-free. Out of 21, 16 developed a combination of parkinsonism and dementia, 4 developed isolated parkinsonism (all with tremor), and 1 developed isolated dementia. Compared to those remaining disease-free, patients destined to develop disease had worse baseline olfaction (University of Pennsylvania Smell Identification Test [UPSIT] = 58.3 ± 27.0% age/sex-adjusted normal vs 80.2 ± 26.3%; p = 0.003) and color vision (Farnsworth-Munsell 100-Hue color test [FM-100] errors 153.0 ± 82.2% normal vs 120.2 ± 26.5%; p = 0.022). Kaplan-Meier 5-year-disease-free survival in those with normal olfaction was 86.0%, vs 35.4% with impaired olfaction (p = 0.029). Disease-free survival with normal color vision was 70.3%, vs 26.0% with impaired vision (p = 0.009). Both olfaction and color vision were reduced as much as 5 years before disease diagnosis, with only slight decline in preclinical stages. Olfaction and color vision identify early-stage synuclein-mediated neurodegenerative diseases. In most cases, abnormalities are measurable at least 5 years before disease onset, and progress slowly in the preclinical stages. Copyright © 2011 American Neurological Association.

Premise for Standardized Sepsis Models.

PubMed

Remick, Daniel G; Ayala, Alfred; Chaudry, Irshad; Coopersmith, Craig M; Deutschman, Clifford; Hellman, Judith; Moldawer, Lyle; Osuchowski, Marcin

2018-06-05

Sepsis morbidity and mortality exacts a toll on patients and contributes significantly to healthcare costs. Preclinical models of sepsis have been used to study disease pathogenesis and test new therapies, but divergent outcomes have been observed with the same treatment even when using the same sepsis model. Other disorders such as diabetes, cancer, malaria, obesity and cardiovascular diseases have used standardized, preclinical models that allow laboratories to compare results. Standardized models accelerate the pace of research and such models have been used to test new therapies or changes in treatment guidelines. The National Institutes of Health (NIH) mandated that investigators increase data reproducibility and the rigor of scientific experiments and has also issued research funding announcements about the development and refinement of standardized models. Our premise is that refinement and standardization of preclinical sepsis models may accelerate the development and testing of potential therapeutics for human sepsis, as has been the case with preclinical models for other disorders. As a first step towards creating standardized models, we suggest 1) standardizing the technical standards of the widely used cecal ligation and puncture model and 2) creating a list of appropriate organ injury and immune dysfunction parameters. Standardized sepsis models could enhance reproducibility and allow comparison of results between laboratories and may accelerate our understanding of the pathogenesis of sepsis.

Animal Models in Genomic Research: Techniques, Applications, and Roles for Nurses

PubMed Central

Osier, Nicole D.; Pham, Lan; Savarese, Amanda; Sayles, Kendra

2016-01-01

Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. PMID:27969037

Animal models in genomic research: Techniques, applications, and roles for nurses.

PubMed

Osier, Nicole D; Pham, Lan; Savarese, Amanda; Sayles, Kendra; Alexander, Sheila A

2016-11-01

Animal research has been conducted by scientists for over two millennia resulting in a better understanding of human anatomy, physiology, and pathology, as well as testing of novel therapies. In the molecular genomic era, pre-clinical models represent a key tool for understanding the genomic underpinnings of health and disease and are relevant to precision medicine initiatives. Nurses contribute to improved health by collecting and translating evidence from clinically relevant pre-clinical models. Using animal models, nurses can ask questions that would not be feasible or ethical to address in humans, and establish the safety and efficacy of interventions before translating them to clinical trials. Two advantages of using pre-clinical models are reduced variability between test subjects and the opportunity for precisely controlled experimental exposures. Standardized care controls the effects of diet and environment, while the availability of inbred strains significantly reduces the confounding effects of genetic differences. Outside the laboratory, nurses can contribute to the approval and oversight of animal studies, as well as translation to clinical trials and, ultimately, patient care. This review is intended as a primer on the use of animal models to advance nursing science; specifically, the paper discusses the utility of preclinical models for studying the pathophysiologic and genomic contributors to health and disease, testing interventions, and evaluating effects of environmental exposures. Considerations specifically geared to nurse researchers are also introduced, including discussion of how to choose an appropriate model and controls, potential confounders, as well as legal and ethical concerns. Finally, roles for nurse clinicians in pre-clinical research are also highlighted. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation and Improved Use of Fecal Occult Blood Test in the Constipated Child.

PubMed

Kilway, Denise M

2016-01-01

This quality improvement project examined the use of fecal occult blood test in the constipated child in a pediatric gastroenterology outpatient clinic. A retrospective chart review was completed on 100 children seen for an initial visit with the gastroenterology provider. The number of fecal occult blood tests performed and the child's coinciding symptoms were tallied and compared with the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition recommendations. An educational intervention was held with the pediatric gastroenterology providers consisting of a PowerPoint presentation summarizing aims of the quality improvement project and reviewing recommendations for use of fecal occult blood test in the constipated child. Pre- and post-intervention chart review data sets were compared. Results showed a 19.6% decrease in the use of fecal occult blood tests performed during the post-intervention timeframe. However, when used in conjunction with North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition recommendations, the appropriateness of fecal occult blood test use increased by 71.4% in the post-intervention patients. Reviewing the recommendations with gastroenterology providers assisted in optimizing the meaningful use of fecal occult blood test, improving quality and safety of care for children seen in the pediatric gastroenterology outpatient clinic.

Development of a Postacute Hospital Item Bank for the New Pediatric Evaluation of Disability Inventory-Computer Adaptive Test

ERIC Educational Resources Information Center

Dumas, Helene M.

2010-01-01

The PEDI-CAT is a new computer adaptive test (CAT) version of the Pediatric Evaluation of Disability Inventory (PEDI). Additional PEDI-CAT items specific to postacute pediatric hospital care were recently developed using expert reviews and cognitive interviewing techniques. Expert reviews established face and construct validity, providing positive…

MIDG-Emerging grid technologies for multi-site preclinical molecular imaging research communities.

PubMed

Lee, Jasper; Documet, Jorge; Liu, Brent; Park, Ryan; Tank, Archana; Huang, H K

2011-03-01

Molecular imaging is the visualization and identification of specific molecules in anatomy for insight into metabolic pathways, tissue consistency, and tracing of solute transport mechanisms. This paper presents the Molecular Imaging Data Grid (MIDG) which utilizes emerging grid technologies in preclinical molecular imaging to facilitate data sharing and discovery between preclinical molecular imaging facilities and their collaborating investigator institutions to expedite translational sciences research. Grid-enabled archiving, management, and distribution of animal-model imaging datasets help preclinical investigators to monitor, access and share their imaging data remotely, and promote preclinical imaging facilities to share published imaging datasets as resources for new investigators. The system architecture of the Molecular Imaging Data Grid is described in a four layer diagram. A data model for preclinical molecular imaging datasets is also presented based on imaging modalities currently used in a molecular imaging center. The MIDG system components and connectivity are presented. And finally, the workflow steps for grid-based archiving, management, and retrieval of preclincial molecular imaging data are described. Initial performance tests of the Molecular Imaging Data Grid system have been conducted at the USC IPILab using dedicated VMware servers. System connectivity, evaluated datasets, and preliminary results are presented. The results show the system's feasibility, limitations, direction of future research. Translational and interdisciplinary research in medicine is increasingly interested in cellular and molecular biology activity at the preclinical levels, utilizing molecular imaging methods on animal models. The task of integrated archiving, management, and distribution of these preclinical molecular imaging datasets at preclinical molecular imaging facilities is challenging due to disparate imaging systems and multiple off-site investigators. A Molecular Imaging Data Grid design, implementation, and initial evaluation is presented to demonstrate the secure and novel data grid solution for sharing preclinical molecular imaging data across the wide-area-network (WAN).

Pediatric Contact Dermatitis Registry Inaugural Case Data.

PubMed

Goldenberg, Alina; Mousdicas, Nico; Silverberg, Nanette; Powell, Douglas; Pelletier, Janice L; Silverberg, Jonathan I; Zippin, Jonathan; Fonacier, Luz; Tosti, Antonella; Lawley, Leslie; Wu Chang, Mary; Scheman, Andrew; Kleiner, Gary; Williams, Judith; Watsky, Kalman; Dunnick, Cory A; Frederickson, Rachel; Matiz, Catalina; Chaney, Keri; Estes, Tracy S; Botto, Nina; Draper, Michelle; Kircik, Leon; Lugo-Somolinos, Aida; Machler, Brian; Jacob, Sharon E

2016-01-01

Little is known about the epidemiology of allergic contact dermatitis (ACD) in US children. More widespread diagnostic confirmation through epicutaneous patch testing is needed. The aim was to quantify patch test results from providers evaluating US children. The study is a retrospective analysis of deidentified patch test results of children aged 18 years or younger, entered by participating providers in the Pediatric Contact Dermatitis Registry, during the first year of data collection (2015-2016). One thousand one hundred forty-two cases from 34 US states, entered by 84 providers, were analyzed. Sixty-five percent of cases had one or more positive patch test (PPT), with 48% of cases having 1 or more relevant positive patch test (RPPT). The most common PPT allergens were nickel (22%), fragrance mix I (11%), cobalt (9.1%), balsam of Peru (8.4%), neomycin (7.2%), propylene glycol (6.8%), cocamidopropyl betaine (6.4%), bacitracin (6.2%), formaldehyde (5.7%), and gold (5.7%). This US database provides multidisciplinary information on pediatric ACD, rates of PPT, and relevant RPPT reactions, validating the high rates of pediatric ACD previously reported in the literature. The registry database is the largest comprehensive collection of US-only pediatric patch test cases on which future research can be built. Continued collaboration between patients, health care providers, manufacturers, and policy makers is needed to decrease the most common allergens in pediatric consumer products.

Pediatric MATCH Infographic

Cancer.gov

Infographic explaining NCI-COG Pediatric MATCH, a cancer treatment clinical trial for children and adolescents, from 1 to 21 years of age, that is testing the use of precision medicine for pediatric cancers.

Preclinical Alzheimer's disease and longitudinal driving decline.

PubMed

Roe, Catherine M; Babulal, Ganesh M; Head, Denise M; Stout, Sarah H; Vernon, Elizabeth K; Ghoshal, Nupur; Garland, Brad; Barco, Peggy P; Williams, Monique M; Johnson, Ann; Fierberg, Rebecca; Fague, M Scot; Xiong, Chengjie; Mormino, Elizabeth; Grant, Elizabeth A; Holtzman, David M; Benzinger, Tammie L S; Fagan, Anne M; Ott, Brian R; Carr, David B; Morris, John C

2017-01-01

Links between preclinical AD and driving difficulty onset would support the use of driving performance as an outcome in primary and secondary prevention trials among older adults (OAs). We examined whether AD biomarkers predicted the onset of driving difficulties among OAs. 104 OAs (65+ years) with normal cognition took part in biomarker measurements, a road test, clinical and psychometric batteries and self-reported their driving habits. Higher values of CSF tau/Aβ 42 and ptau 181 /Aβ 42 ratios, but not uptake on PIB amyloid imaging (p=.12), predicted time to a rating of Marginal or Fail on the driving test using Cox proportional hazards models. Hazards ratios (95% confidence interval) were 5.75 (1.70-19.53), p=.005 for CSF tau/Aβ 42 ; 6.19 (1.75-21.88) and p=.005 for CSF ptau 181 /Aβ 42 . Preclinical AD predicted time to receiving a Marginal or Fail rating on an on-road driving test. Driving performance shows promise as a functional outcome in AD prevention trials.

The Use of Minipigs for Preclinical Safety Assessment by the Pharmaceutical Industry: Results of an IQ DruSafe Minipig Survey.

PubMed

Colleton, Curtis; Brewster, David; Chester, Anne; Clarke, David O; Heining, Peter; Olaharski, Andrew; Graziano, Michael

2016-04-01

The use of minipigs in preclinical safety testing of pharmaceuticals is considered an alternative to the more traditional dog and nonhuman primate (NHP) nonrodent species. Substantial evidence exists to suggest that the anatomy, physiology, and biochemistry of minipigs are similar enough to humans to consider them as valid nonrodent models for pharmaceutical safety testing. Since the utilization of minipigs was last assessed over 5 years ago, the Preclinical Safety Leadership Group (DruSafe) of the International Consortium for Innovation and Quality in Pharmaceutical Development conducted this survey to provide an updated assessment of the utility, perceived value, and impediments to the use of minipigs in preclinical safety testing. Of the 32 participating members of DruSafe, 15 responded to the survey representing both large and small companies. Respondents indicated that the minipig has been utilized mostly for short-term safety assessment studies with dermal, oral, and parenteral routes of administration. Minipigs are widely accepted as appropriate models for cardiovascular assessments and have been used to a limited extent for reproductive toxicology testing. Overall responses indicated that safety testing for large molecules using this species is relatively low due to a lack of background data, reagents or biomarkers, concerns regarding immune system characterization and poor suitability for developmental toxicity assessments. Most companies utilized contract research organizations for definitive safety toxicity assessment studies. Conclusions of this survey indicate that minipig is an acceptable nonrodent species largely limited to studies using small molecules, primarily dermal products, and results are comparable to those reported 5 years ago. © The Author(s) 2016.

Spatial reversal learning in preclinical scrapie-inoculated mice.

PubMed

Lysons, A M; Woollard, S J

1996-04-10

Acquisition and reversal of a two-choice spatial discrimination were tested in scrapie-inoculated mice. Both acquisition and reversal were normal in mice tested 138 and 103 days prior to the onset of clinical symptoms. At 65 days before onset of clinical symptoms, scrapie-inoculated mice required more trails to criterion in reversal learning, but this effect was not significant in a second experiment (68 days preclinical) and was transient: no effect was seen 33 days before symptoms. However, the course of reversal learning was abnormal in all three late preclinical groups (68, 65 and 33 days before symptoms). Reversal learning in these three groups was characterized by a rapid extinction of the original discrimination, followed by a period, absent in controls, during which performance showed no further improvement. This effect corresponds in time of onset to the appearance of characteristic neuropathological features.

Manufacture of Third-Generation Lentivirus for Preclinical Use, with Process Development Considerations for Translation to Good Manufacturing Practice.

PubMed

Gándara, Carolina; Affleck, Valerie; Stoll, Elizabeth Ann

2018-02-01

Lentiviral vectors are used in laboratories around the world for in vivo and ex vivo delivery of gene therapies, and increasingly clinical investigation as well as preclinical applications. The third-generation lentiviral vector system has many advantages, including high packaging capacity, stable gene expression in both dividing and post-mitotic cells, and low immunogenicity in the recipient organism. Yet, the manufacture of these vectors is challenging, especially at high titers required for direct use in vivo, and further challenges are presented by the process of translating preclinical gene therapies toward manufacture of products for clinical investigation. The goals of this paper are to report the protocol for manufacturing high-titer third-generation lentivirus for preclinical testing and to provide detailed information on considerations for translating preclinical viral vector manufacture toward scaled-up platforms and processes in order to make gene therapies under Good Manufacturing Practice that are suitable for clinical trials.

Manufacture of Third-Generation Lentivirus for Preclinical Use, with Process Development Considerations for Translation to Good Manufacturing Practice

PubMed Central

Gándara, Carolina; Affleck, Valerie; Stoll, Elizabeth Ann

2018-01-01

Lentiviral vectors are used in laboratories around the world for in vivo and ex vivo delivery of gene therapies, and increasingly clinical investigation as well as preclinical applications. The third-generation lentiviral vector system has many advantages, including high packaging capacity, stable gene expression in both dividing and post-mitotic cells, and low immunogenicity in the recipient organism. Yet, the manufacture of these vectors is challenging, especially at high titers required for direct use in vivo, and further challenges are presented by the process of translating preclinical gene therapies toward manufacture of products for clinical investigation. The goals of this paper are to report the protocol for manufacturing high-titer third-generation lentivirus for preclinical testing and to provide detailed information on considerations for translating preclinical viral vector manufacture toward scaled-up platforms and processes in order to make gene therapies under Good Manufacturing Practice that are suitable for clinical trials. PMID:29212357

Benefits attained from space flight in pre-clinical evaluation of candidate drugs

NASA Astrophysics Data System (ADS)

Stodieck, Louis S.; Bateman, Ted; Ayers, Reed; Ferguson, Virginia; Simske, Steve

1998-01-01

Modern medicine has made great strides in recent decades. The promises of biotechnology and advances in gene identification and manipulation offer tremendous potential for treatment of disease. However, developing new drug therapies by biotechnology and pharmaceutical companies is still a very costly and time consuming process. One of the important milestones in drug development is the successful completion of preclinical evaluation. During this phase, drug candidates must be shown to be safe, yet effective as a treatment of the target disease or disorder. Critical for preclinical testing is the availability of biomedical test models that adequately mimic the target disease. A good model will 1) allow confident prediction of a drug's effects before expensive clinical trials are begun, 2) provide convincing data for use in an FDA new drug application and 3) minimize the time required for testing. Space flight may offer a completely unique and new set of biomedical models for use in pharmaceutical testing. This paper highlights some examples of recent experiments done in space to test new compounds for Chiron, (Emmeryville, CA) and discusses the importance of the International Space Station to greatly expand such commercial opportunities.

Testing therapeutic potency of anticancer drugs in animal studies: a commentary.

PubMed

Den Otter, Willem; Steerenberg, Peter A; Van der Laan, Jan Willem

2002-04-01

Regulatory authorities for medicines in European countries deal with many applications for admission to the market of anticancer drugs. Each application must be supported by preclinical and clinical data, among which testing of the therapeutic activity of drugs in animals is important. Recently, the Committee for Proprietary Medicinal Products (CPMP) has released a note for guidance on the preclinical evaluation of anticancer medicinal products. This note provides only general statements regarding tests of anticancer drugs in rodents. This stimulates considerations on how to organize and how to evaluate these tests. In this article we describe our considerations regarding these items based on our experience with applications in The Netherlands since 1993. (c) 2002 Elsevier Science (USA).

Pediatric portal hypertension

PubMed Central

Vogel, Clarissa Barbon

2017-01-01

Abstract: Pediatric portal hypertension management is a team approach between the patient, the patient's family, the primary caregiver, and specialty providers. Evidence-based practice guidelines have not been established in pediatrics. This article serves as a review for the primary care NP in the management of pediatric portal hypertension, discussing the etiology, pathophysiology, and clinical presentation of pediatric portal hypertension, diagnostic tests, and treatment and management options. PMID:28406835

Quantitative Systems Pharmacology Modeling of Acid Sphingomyelinase Deficiency and the Enzyme Replacement Therapy Olipudase Alfa Is an Innovative Tool for Linking Pathophysiology and Pharmacology.

PubMed

Kaddi, Chanchala D; Niesner, Bradley; Baek, Rena; Jasper, Paul; Pappas, John; Tolsma, John; Li, Jing; van Rijn, Zachary; Tao, Mengdi; Ortemann-Renon, Catherine; Easton, Rachael; Tan, Sharon; Puga, Ana Cristina; Schuchman, Edward H; Barrett, Jeffrey S; Azer, Karim

2018-06-19

Acid sphingomyelinase deficiency (ASMD) is a rare lysosomal storage disorder with heterogeneous clinical manifestations, including hepatosplenomegaly and infiltrative pulmonary disease, and is associated with significant morbidity and mortality. Olipudase alfa (recombinant human acid sphingomyelinase) is an enzyme replacement therapy under development for the non-neurological manifestations of ASMD. We present a quantitative systems pharmacology (QSP) model supporting the clinical development of olipudase alfa. The model is multiscale and mechanistic, linking the enzymatic deficiency driving the disease to molecular-level, cellular-level, and organ-level effects. Model development was informed by natural history, and preclinical and clinical studies. By considering patient-specific pharmacokinetic (PK) profiles and indicators of disease severity, the model describes pharmacodynamic (PD) and clinical end points for individual patients. The ASMD QSP model provides a platform for quantitatively assessing systemic pharmacological effects in adult and pediatric patients, and explaining variability within and across these patient populations, thereby supporting the extrapolation of treatment response from adults to pediatrics. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Using tablet computers to teach evidence-based medicine to pediatrics residents: a prospective study.

PubMed

Soma, David B; Homme, Jason H; Jacobson, Robert M

2013-01-01

We sought to determine if tablet computers-supported by a laboratory experience focused upon skill-development-would improve not only evidence-based medicine (EBM) knowledge but also skills and behavior. We conducted a prospective cohort study where we provided tablet computers to our pediatric residents and then held a series of laboratory sessions focused on speed and efficiency in performing EBM at the bedside. We evaluated the intervention with pre- and postintervention tests and surveys based on a validated tool available for use on MedEdPORTAL. The attending pediatric hospitalists also completed surveys regarding their observations of the residents' behavior. All 38 pediatric residents completed the preintervention test and the pre- and postintervention surveys. All but one completed the posttest. All 7 attending pediatric hospitalists completed their surveys. The testing, targeted to assess EBM knowledge, revealed a median increase of 16 points out of a possible 60 points (P < .0001). We found substantial increases in individual resident's test scores across all 3 years of residency. Resident responses demonstrated statistically significant improvements in self-reported comfort with 6 out of 6 EBM skills and statistically significant increases in self-reported frequencies for 4 out of 7 EBM behaviors. Attending pediatric hospitalists reported improvements in 5 of 7 resident behaviors. This novel approach for teaching EBM to pediatric residents improved knowledge, skills, and behavior through the introduction of a tablet computer and laboratory sessions designed to teach the quick and efficient application of EBM at the bedside. Copyright © 2013 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.

Contextual considerations in implementing problem-based learning approaches in a Brazilian medical curriculum: the UNAERP experience

PubMed Central

Bestetti, Reinaldo Bulgarelli; Couto, Lucélio Bernardes; Romão, Gustavo Salata; Araújo, Guilherme Teixeira; Restini, Carolina Baraldi A.

2014-01-01

Background Despite being a well-established pedagogical approach in medical education, the implementation of problem-based learning (PBL) approaches hinges not only on educational aspects of the medical curriculum but also on the characteristics and necessities of the health system and the medical labor market within which it is situated. Aim To report our experiences implementing a PBL-based approach in a region of Brazil where: 1) all pre-university education and the vast majority of medical courses are based on traditional, lecture-based instructions; and 2) students’ career interests in primary care, arguably the prototypical PBL trainee, are heavily disfavored because of economics. Results Brazilian guidelines require that clinical training take place during the last 2 years of the medical program and include intensive, supervised, inpatient and outpatient rotations in pediatrics, family medicine, obstetrics and gynecology, internal medicine, and surgery. Throughout the pre-clinical curriculum, then, students learn to deal with progressively more difficult and complex cases – typically through the use of PBL tutors in a primary care context. However, because of curricular time constraints in the clerkships, and students’ general preoccupation with specialty practice, the continuation of PBL-based approaches in the pre-clinical years – and the expansion of PBL into the clerkships – has become exceedingly difficult. Discussion and conclusion Our experience illustrates the importance of context (both cultural and structural) in implementing certain pedagogies within one Brazilian training program. We plan to address these barriers by: 1) integrating units, whenever possible, within a spiral curriculum; 2) introducing real patients earlier in students’ pre-clinical coursework (primarily in a primary care setting); and 3) using subject experts as PBL tutors to better motivate students. PMID:24931596

Vaccination uptake by vaccine-hesitant parents attending a specialist immunization clinic in Australia.

PubMed

Forbes, Thomas A; McMinn, Alissa; Crawford, Nigel; Leask, Julie; Danchin, Margie

2015-01-01

Vaccine hesitancy (VH) is an issue of global concern. The quality of communication between healthcare providers and parents can influence parental immunization acceptance. We aimed to describe immunization uptake following specialist immunization clinic (SIC) consultation for Australian children of VH parents as a cohort, and according to pre-clinic parental position on immunization. At a single tertiary pediatric SIC (RCH, Melbourne) a retrospective descriptive study classified VH families according to 3 proposed parental positions on immunization at initial clinic attendance. Immunization status at follow up was ascertained via the Australian Children's Immunization Register and National HPV Program Register and compared between groups. Of the VH cohort, 13/38 (34%) families were classified as hesitant, 21 (55%) as late/selective vaccinators and 4 (11%) as vaccine refusers. Mean follow up post-SIC attendance was 14.5 months. For the overall VH cohort, the majority chose selective immunization (42%) following SIC consultation. When analyzed by pre-clinic parental position on immunization, there was a trend for hesitant families to proceed with full immunization, selective families to continue selective immunization and refusing families to remain unimmunised (p < 0.0001). The most commonly omitted vaccines were hepatitis B (66%) and Haemophilus influenzae type B (55%), followed by the meningococcal C conjugate vaccine (53%) and measles, mumps and rubella vaccine (53%). Immunization outcome appears to correlate with pre-clinic parental position on immunization for the majority of families attending a SIC in Australia, with selective immunization the most common outcome. Tailored communication approaches based on parental position on immunization may optimise clinic resources and engagement of families, but require prospective research evaluation.

Integration of preclinical and clinical knowledge to predict intravenous PK in human: bilastine case study.

PubMed

Vozmediano, Valvanera; Ortega, Ignacio; Lukas, John C; Gonzalo, Ana; Rodriguez, Monica; Lucero, Maria Luisa

2014-03-01

Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes.

Vaccination uptake by vaccine-hesitant parents attending a specialist immunization clinic in Australia

PubMed Central

Forbes, Thomas A; McMinn, Alissa; Crawford, Nigel; Leask, Julie; Danchin, Margie

2015-01-01

Vaccine hesitancy (VH) is an issue of global concern. The quality of communication between healthcare providers and parents can influence parental immunization acceptance. We aimed to describe immunization uptake following specialist immunization clinic (SIC) consultation for Australian children of VH parents as a cohort, and according to pre-clinic parental position on immunization. At a single tertiary pediatric SIC (RCH, Melbourne) a retrospective descriptive study classified VH families according to 3 proposed parental positions on immunization at initial clinic attendance. Immunization status at follow up was ascertained via the Australian Children's Immunization Register and National HPV Program Register and compared between groups. Of the VH cohort, 13/38 (34%) families were classified as hesitant, 21 (55%) as late/selective vaccinators and 4 (11%) as vaccine refusers. Mean follow up post-SIC attendance was 14.5 months. For the overall VH cohort, the majority chose selective immunization (42%) following SIC consultation. When analyzed by pre-clinic parental position on immunization, there was a trend for hesitant families to proceed with full immunization, selective families to continue selective immunization and refusing families to remain unimmunised (p < 0.0001). The most commonly omitted vaccines were hepatitis B (66%) and Haemophilus influenzae type B (55%), followed by the meningococcal C conjugate vaccine (53%) and measles, mumps and rubella vaccine (53%). Immunization outcome appears to correlate with pre-clinic parental position on immunization for the majority of families attending a SIC in Australia, with selective immunization the most common outcome. Tailored communication approaches based on parental position on immunization may optimise clinic resources and engagement of families, but require prospective research evaluation. PMID:26366978

Development and assessment of sterility of a closed-system pediatric peritoneal dialysis.

PubMed

Biazi, Ana Paula Pereira; Croti, Ulisses Alexandre; Braile, Domingo Marcolino; Oliveira, Marcos Aurélio Barboza de; Costa, Jane Gonçalves Soares; Cardoso, Lucas Monteiro

2009-01-01

To develop an easy-handling totally closed pediatric peritoneal dialysis system and assess the sterility assurance level. From February to December 2008 was designed and developed a closed-system pediatric peritoneal dialysis at the Bioengineering Division of Braile Biomédica Indústria, Comércio e Representações S/A. Twenty systems were manufactured and submitted to sterility assurance level testing, and were divided into Group A (10)--using the sterility test--and B (10)--ethylene oxide gas penetration. In Group A, the sterility test was negative for bacteria and fungi proliferation within 14 days in all systems. In Group B, the gas penetration test showed that there was gas penetration in all points assessed. It was possible to develop a new easy-handling closed-system pediatric peritoneal dialysis and ensure its sterility.

Developing Guidelines for HIV Antibody Testing among Victims of Pediatric Sexual Abuse.

ERIC Educational Resources Information Center

Gellert, George A.; And Others

1990-01-01

An interim set of human immunodeficiency virus (HIV) testing guidelines for victims of pediatric sexual abuse (PSA) is proposed. Guidelines are based on responses of 63 practitioners of PSA assessment to 7 hypothetical clinical profiles with 12 testing criteria. (Author/DB)

Balancing animal welfare and assisted reproduction: ethics of preclinical animal research for testing new reproductive technologies.

PubMed

Jans, Verna; Dondorp, Wybo; Goossens, Ellen; Mertes, Heidi; Pennings, Guido; de Wert, Guido

2018-02-07

In the field of medically assisted reproduction (MAR), there is a growing emphasis on the importance of introducing new assisted reproductive technologies (ARTs) only after thorough preclinical safety research, including the use of animal models. At the same time, there is international support for the three R's (replace, reduce, refine), and the European Union even aims at the full replacement of animals for research. The apparent tension between these two trends underlines the urgency of an explicit justification of the use of animals for the development and preclinical testing of new ARTs. Considering that the use of animals remains necessary for specific forms of ART research and taking account of different views on the moral importance of helping people to have a genetically related child, we argue that, in principle, the importance of safety research as part of responsible innovation outweighs the limited infringement of animal wellbeing involved in ART research.

Vestibular evoked myogenic potential testing for the diagnosis of conductive hearing loss: survey of pediatric otolaryngologists' knowledge and beliefs.

PubMed

Dargie, Jenna M; Zhou, Guangwei; Dornan, Briana K; Whittemore, Kenneth R

2014-11-01

To assess physicians' knowledge and beliefs regarding vestibular evoked myogenic potential (VEMP) testing in children. A survey was delivered via email in html format to 1069 members of the American Academy of Otolaryngology--Head and Neck Surgery who identified as pediatric otolaryngologists. Study data were collected and managed using the Research Electronic Data Capture (REDCap) tools. 443 (41.4%) physicians opened the email. 190 (42.9% of opens) initiated the survey, of which 117 (61.9%) fully completed the survey of the physicians who responded to a question regarding knowledge of VEMP, 16% of respondents had never heard of the test. 16% of participants would use it in the setting of diagnosing pediatric conductive hearing loss. Responses regarding the youngest age at which VEMP is possible ranged from younger than 6 months through greater than 13 years of age. Beliefs regarding utility and reliability of VEMP varied, with 'unsure' as the most frequent response. Additionally, only 26% of pediatric otolaryngologists indicated some access to the test. The knowledge and availability of VEMP testing in the pediatric otolaryngology community varies widely. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers.

PubMed

Ayutyanont, Napatkamon; Langbaum, Jessica B S; Hendrix, Suzanne B; Chen, Kewei; Fleisher, Adam S; Friesenhahn, Michel; Ward, Michael; Aguirre, Camilo; Acosta-Baena, Natalia; Madrigal, Lucìa; Muñoz, Claudia; Tirado, Victoria; Moreno, Sonia; Tariot, Pierre N; Lopera, Francisco; Reiman, Eric M

2014-06-01

To identify a cognitive composite that is sensitive to tracking preclinical Alzheimer's disease decline to be used as a primary end point in treatment trials. We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world's largest known early-onset autosomal dominant Alzheimer's disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimer's disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimer's Prevention Initiative's (API) preclinical Alzheimer's disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains. The optimal test combination included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Raven's Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05). We have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimer's disease decline in autosomal dominant Alzheimer's disease mutation carriers and to evaluate preclinical Alzheimer's disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimer's disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimer's disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches. © Copyright 2014 Physicians Postgraduate Press, Inc.

Cardiovascular photodynamic therapy: state of the art

NASA Astrophysics Data System (ADS)

Woodburn, Kathryn W.; Rockson, Stanley G.

2000-05-01

Photodynamic therapy (PDT) has been used traditionally for oncologic and ophthalmic indications. In addition, the enormous potential for the use of PDT agents in cardiovascular diseases is currently being translated into reality. Preclinical studies with various photosensitizers have demonstrated reduction in atheromatous plaque and prevention of intimal hyperplasia. With recent advances in light-based vascular devices and laser diode technology, the clinical use of cardiovascular photodynamic therapy is even more likely. Two photosensitizers, 5-aminolevulinic acid (ALA) and AntrinR (motexafin lutetium) Injection, are under clinical evaluation with many other agents in preclinical testing. Here, preclinical studies are reviewed and the clinical viability of cardiovascular photodynamic therapy is discussed.

A novel suction/coagulation integrated probe for achieving better hemostasis: development and clinical use.

PubMed

Takahashi, Hidekazu; Haraguchi, Naotsugu; Nishimura, Junichi; Hata, Taishi; Matsuda, Chu; Yamamoto, Hirofumi; Mizushima, Tsunekazu; Mori, Masaki; Doki, Yuichiro; Nakajima, Kiyokazu

2018-06-01

Modern electrosurgical tools have a specific coagulation mode called "soft coagulation". However, soft coagulation has not been widely accepted for surgical operations. To optimize the soft coagulation environment, we developed a novel suction device integrated with an electrosurgical probe, called the "Suction ball coagulator" (SBC). In this study, we aimed to optimize the SBC design with a prototyping process involving a bench test and preclinical study; then, we aimed to demonstrate the feasibility, safety, and potential effectiveness of the SBC for laparoscopic surgery in clinical settings. SBC prototyping was performed with a bench test. Device optimization was performed in a preclinical study with a domestic swine bleeding model. Then, SBC was tested in a clinical setting during 17 clinical laparoscopic colorectal surgeries. In the bench tests, two tip hole sizes and patterns showed a good suction capacity. The preclinical study indicated the best tip shape for accuracy. In clinical use, no device-related adverse event was observed. Moreover, the SBC was feasible for prompt hemostasis and blunt dissections. In addition, SBC could evacuate vapors generated by tissue ablation using electroprobe during laparoscopic surgery. We successfully developed a novel, integrated suction/coagulation probe for hemostasis and commercialized it.

A novel hypothesis on the sensitivity of the fecal occult blood test: Results of a joint analysis of 3 randomized controlled trials.

PubMed

Lansdorp-Vogelaar, Iris; van Ballegooijen, Marjolein; Boer, Rob; Zauber, Ann; Habbema, J Dik F

2009-06-01

Estimates of the fecal occult blood test (FOBT) (Hemoccult II) sensitivity differed widely between screening trials and led to divergent conclusions on the effects of FOBT screening. We used microsimulation modeling to estimate a preclinical colorectal cancer (CRC) duration and sensitivity for unrehydrated FOBT from the data of 3 randomized controlled trials of Minnesota, Nottingham, and Funen. In addition to 2 usual hypotheses on the sensitivity of FOBT, we tested a novel hypothesis where sensitivity is linked to the stage of clinical diagnosis in the situation without screening. We used the MISCAN-Colon microsimulation model to estimate sensitivity and duration, accounting for differences between the trials in demography, background incidence, and trial design. We tested 3 hypotheses for FOBT sensitivity: sensitivity is the same for all preclinical CRC stages, sensitivity increases with each stage, and sensitivity is higher for the stage in which the cancer would have been diagnosed in the absence of screening than for earlier stages. Goodness-of-fit was evaluated by comparing expected and observed rates of screen-detected and interval CRC. The hypothesis with a higher sensitivity in the stage of clinical diagnosis gave the best fit. Under this hypothesis, sensitivity of FOBT was 51% in the stage of clinical diagnosis and 19% in earlier stages. The average duration of preclinical CRC was estimated at 6.7 years. Our analysis corroborated a long duration of preclinical CRC, with FOBT most sensitive in the stage of clinical diagnosis. (c) 2009 American Cancer Society.

Free and cued memory in relation to biomarker-defined abnormalities in clinically normal older adults and those at risk for Alzheimer's disease.

PubMed

Papp, Kathryn V; Amariglio, Rebecca E; Mormino, Elizabeth C; Hedden, Trey; Dekhytar, Maria; Johnson, Keith A; Sperling, Reisa A; Rentz, Dorene M

2015-07-01

Furthering our understanding of the relationship between amyloidosis (Aβ), neurodegeneration (ND), and cognition is imperative for early identification and early intervention of Alzheimer's disease (AD). However, the subtle cognitive decline differentially associated with each biomarker-defined stage of preclinical AD has yet to be fully characterized. Recent work indicates that different components of memory performance (free and cued recall) may be differentially specific to memory decline in prodromal AD. We sought to examine the relationship between free and cued recall paradigms, in addition to global composites of memory, executive functioning, and processing speed in relation to stages of preclinical AD. A total of 260 clinically normal (CN) older adults (CDR=0) from the Harvard Aging Brain study were grouped according to preclinical AD stages including Stage 0 (Aβ-/ND-), Stage 1 (Aβ+/ND-), Stage 2 (Aβ+/ND+), and suspected non-Alzheimer's associated pathology (SNAP; Aβ-/ND+). General linear models controlling for age, sex, and education were used to assess for stage-based performance differences on cognitive composites of executive functioning, processing speed, and memory in addition to free and cued delayed recall on the Selective Reminding Test (SRT) and Memory Capacity Test (MCT). Global memory performance differed between preclinical stages with Stage 2 performing worse compared with Stage 0. When examining free and cued paradigms by memory test, only the MCT (and not the SRT) revealed group differences. More specifically, Stage 1 was associated with decrements in free recall compared with Stage 0 while Stage 2 was associated with decrements in both free and cued recall. There was a trend for the SNAP group to perform worse on free recall compared with Stage 0. Finally, there was no association between preclinical stage and global composites of executive functioning or processing speed. Clinically normal older adults with underlying evidence of amyloidosis and neurodegeneration exhibit subtle, yet measurable differences in memory performance, but only on a challenging associative test. The sensitivity of free vs. cued memory paradigms may be dependent on preclinical stage such that reduced free recall is associated with amyloidosis alone (Stage 1) while a decline in cued recall may represent progression to amyloidosis and neurodegeneration (Stage 2). These findings may have practical applications for clinical assessment and clinical trial design. Copyright © 2015. Published by Elsevier Ltd.

Free and Cued Memory in relation to Biomarker-Defined Abnormalities in Clinically Normal Older Adults and Those at Risk for Alzheimer’s Disease

PubMed Central

Papp, Kathryn V.; Amariglio, Rebecca E.; Mormino, Elizabeth; Hedden, Trey; Dekhytar, Maria; Johnson, Keith A.; Sperling, Reisa A.; Rentz, Dorene M.

2015-01-01

Objectives Furthering our understanding of the relationship between amyloidosis (Aβ), neurodegeneration (ND), and cognition is imperative for early identification and early intervention of Alzheimer’s disease (AD). However, the subtle cognitive decline differentially associated with each biomarker-defined stage of preclinical AD has yet to be fully characterized. Recent work indicates that different components of memory performance (free and cued recall) may be differentially specific to memory decline in prodromal AD. We sought to examine the relationship between free and cued recall paradigms, in addition to global composites of memory, executive functioning, and processing speed in relation to stages of preclinical AD. Methods A total of 260 clinically normal (CN) older adults (CDR=0) from the Harvard Aging Brain study were grouped according to preclinical AD stages including Stage 0 (Aβ−/ND−), Stage 1 (Aβ+/ND−), Stage 2 (Aβ+/ND+), and suspected non-Alzheimer’s associated pathology (SNAP; Aβ−/ND+). General linear models controlling for age, sex, and education were used to assess for stage-based performance differences on cognitive composites of executive functioning, processing speed, and memory in addition to free and cued delayed recall on the Selective Reminding Test (SRT) and Memory Capacity Test (MCT). Results Global memory performance differed between preclinical stages with Stage 2 performing worse compared with Stage 0. When examining free and cued paradigms by memory test, only the MCT (and not the SRT) revealed group differences. More specifically, Stage 1 was associated with decrements in free recall compared with Stage 0 while Stage 2 was associated with decrements in both free and cued recall. There was a trend for the SNAP group to perform worse on free recall compared with Stage 0. Finally, there was no association between preclinical stage and global composites of executive functioning or processing speed. Conclusions Clinically normal older adults with underlying evidence of amyloidosis and neurodegeneration exhibit subtle, yet measurable differences in memory performance, but only on a challenging associative test. The sensitivity of free vs. cued memory paradigms may be dependent on preclinical stage such that reduced free recall is associated with amyloidosis alone (Stage 1) while a decline in cued recall may represent progression to amyloidosis and neurodegeneration (Stage 2). These findings may have practical applications for clinical assessment and clinical trial design. PMID:26002757

Is There a Space-Based Technology Solution to Problems with Preclinical Drug Toxicity Testing?

PubMed

Hammond, Timothy; Allen, Patricia; Birdsall, Holly

2016-07-01

Even the finest state-of-the art preclinical drug testing, usually in primary hepatocytes, remains an imperfect science. Drugs continue to be withdrawn from the market due to unforeseen toxicity, side effects, and drug interactions. The space program may be able to provide a lifeline. Best known for rockets, space shuttles, astronauts and engineering, the space program has also delivered some serious medical science. Optimized suspension culture in NASA's specialized suspension culture devices, known as rotating wall vessels, uniquely maintains Phase I and Phase II drug metabolizing pathways in hepatocytes for weeks in cell culture. Previously prohibitively expensive, new materials and 3D printing techniques have the potential to make the NASA rotating wall vessel available inexpensively on an industrial scale. Here we address the tradeoffs inherent in the rotating wall vessel, limitations of alternative approaches for drug metabolism studies, and the market to be addressed. Better pre-clinical drug testing has the potential to significantly reduce the morbidity and mortality of one of the most common problems in modern medicine: adverse events related to pharmaceuticals.

Promising developments in neuropsychological approaches for the detection of preclinical Alzheimer's disease: a selective review.

PubMed

Rentz, Dorene M; Parra Rodriguez, Mario A; Amariglio, Rebecca; Stern, Yaakov; Sperling, Reisa; Ferris, Steven

2013-01-01

Recently published guidelines suggest that the most opportune time to treat individuals with Alzheimer's disease is during the preclinical phase of the disease. This is a phase when individuals are defined as clinically normal but exhibit evidence of amyloidosis, neurodegeneration and subtle cognitive/behavioral decline. While our standard cognitive tests are useful for detecting cognitive decline at the stage of mild cognitive impairment, they were not designed for detecting the subtle cognitive variations associated with this biomarker stage of preclinical Alzheimer's disease. However, neuropsychologists are attempting to meet this challenge by designing newer cognitive measures and questionnaires derived from translational efforts in neuroimaging, cognitive neuroscience and clinical/experimental neuropsychology. This review is a selective summary of several novel, potentially promising, approaches that are being explored for detecting early cognitive evidence of preclinical Alzheimer's disease in presymptomatic individuals.

Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy

PubMed Central

Grounds, Miranda D.; Radley, Hannah G.; Lynch, Gordon S.; Nagaraju, Kanneboyina; De Luca, Annamaria

2008-01-01

This review discusses various issues to consider when developing standard operating procedures for pre-clinical studies in the mdx mouse model of Duchenne muscular dystrophy (DMD). The review describes and evaluates a wide range of techniques used to measure parameters of muscle pathology in mdx mice and identifies some basic techniques that might comprise standardised approaches for evaluation. While the central aim is to provide a basis for the development of standardised procedures to evaluate efficacy of a drug or a therapeutic strategy, a further aim is to gain insight into pathophysiological mechanisms in order to identify other therapeutic targets. The desired outcome is to enable easier and more rigorous comparison of pre-clinical data from different laboratories around the world, in order to accelerate identification of the best pre-clinical therapies in the mdx mouse that will fast-track translation into effective clinical treatments for DMD. PMID:18499465

A laboratory silicone for preclinical training in ear prosthesis.

PubMed

Anand, Vijay; Haribabu; Vimala; Gnanasamband, Vimala

2013-07-01

This article describes an industrial elastic silicone as a material for the laboratory fabrication of ear prosthesis. It has been tested for toxicity in lab animals by the SGS India Pvt. Ltd and approved as a material to pass the parameter of abnormal toxicity. This material therefore can be safely recommended for laboratory exercise to fabricate facial prosthesis. The high cost of the maxillo facial silicone materials prohibits their use for facial prosthesis in pre-clinical training of post-graduate students in maxillofacial prosthodontics. For this reason, pre-clinical laboratory exercise in facial prosthesis is inadequate. A few institutions use polymethyl methacrylate resins which are rigid and do not have elastic characteristics of silicone, which is used for facial defects. This cost-effective industrial silicone material which mimics the elastic and color characteristics of the conventional silicones can be recommended for preclinical exercises.

Abuse liability assessment in preclinical drug development: predictivity of a translational approach for abuse liability testing using methylphenidate in four standardized preclinical study models.

PubMed

Teuns, Greet B A; Geys, Helena M; Geuens, Sonja M A; Stinissen, Piet; Meert, Theo F

2014-01-01

Preclinical abuse liability assessment of novel clinical CNS-active candidates involves several tests, addressing different aspects characteristic for abuse potential, which are considered predictive for substance abuse of these candidates, thus ensuring an appropriate translational approach. To demonstrate how such a strategy could work, a known drug of abuse, methylphenidate was evaluated in a full rodent test battery, comprising four test models, and in accordance with the requirements of the FDA, ICH and EMA guidelines. Methylphenidate was tested orally at 2.5, 5 or 10mg/kg for its physical dependence potential in a repeated dose non-precipitated withdrawal test, for its drug profiling in a drug discrimination learning procedure (single escalating doses), and for its reinforcing properties in a conditioned place preference test (alternate dosing days) and an intravenous self-administration procedure (0.05 to 1mg/kg/IV infusion during 5 daily 1-h test sessions). The stimulant d-amphetamine served as positive control and was administered subcutaneously at 0.8mg/kg in the first three test models. In the intravenous self-administration procedure rats were habituated to intravenously self-administer d-amphetamine at 0.06mg/kg/IV infusion prior to methylphenidate substitution. Cessation of subchronic dosing up to 10mg/kg methylphenidate led to sustained or even exacerbated effects on locomotion and behavior, body temperature, body weight, food consumption, and alteration of the diurnal rhythm during withdrawal. Clear generalization to d-amphetamine was obtained in the drug discrimination test at 5 and 10mg/kg. Distinct reinforcing properties were present in the conditioned place preference test at 10mg/kg and in the intravenous self-administration study from 0.05mg/kg/IV infusion onwards. The maximum plasma exposure after oral administration of methylphenidate over the dose ranges tested in the present rat studies covered at least 1.9-fold to 18.9-fold the recommended human therapeutic exposure of 10ng/ml, a plasma level that is considered representative of the human efficacious methylphenidate dose. The ratio Cmax Hu/rat calculated from the intravenous self-administration data ranged from 14.9 to 576.5. Consequently the regulatory requirements, stating that preclinical drug abuse liability studies should include high doses that produce plasma levels that are multiples of the therapeutic dose were fulfilled (FDA, EMA, ICH). The presented preclinical models, implemented within a drug development environment, were considered highly predictive to assess the abuse potential of methylphenidate, and in accordance with the regulatory requirements of drug licensing authorities in terms of appropriate methods, dose selection and subsequent plasma exposure. Copyright © 2014 Elsevier Inc. All rights reserved.

Social cognition in pediatric-onset multiple sclerosis (MS)

PubMed Central

Charvet, LE; Cleary, RE; Vazquez, K; Belman, A; Krupp, LB

2014-01-01

Background Pediatric-onset multiple sclerosis (MS) patients represent a subpopulation who are diagnosed during the course of development. Social cognitive deficits have recently been recognized in adults with MS. It is critical to identify if these youngest patients with the disorder are also at risk. Objective To determine whether pediatric-onset MS is associated with social cognitive deficits. Methods Consecutively-recruited participants with pediatric-onset MS were compared to a group of age- and gender-matched healthy controls on Theory of Mind (ToM) task performance. Tasks measured facial affect recognition (Reading the Mind in the Eyes Test), understanding social faux pas (Faux Pas Test), and understanding the perspective of another (False Beliefs Task). Results Twenty-eight (28) pediatric-onset MS participants (median age 17 years) and 32 healthy controls (median age 16 years) completed the study. The MS participants performed worse than controls on all three ToM tasks: Reading the Mind in the Eyes Test (p=0.008), the Faux-Pas Test (p=0.009), and the False Beliefs Task (p=0.06). While more MS than control participants were impaired on a measure of information processing speed (the Symbol Digit Modalities Test; 38% versus 6%), it did not account for the differences in ToM performance. Conclusions Social cognition may represent an area of cognitive functioning affected by MS in the pediatric-onset population. These processes are especially important to study in younger patients as these deficits could have long range implications on social adjustment, employment, and well-being. PMID:24647558

Social cognition in pediatric-onset multiple sclerosis (MS).

PubMed

Charvet, L E; Cleary, R E; Vazquez, K; Belman, A L; Krupp, L B

2014-10-01

Pediatric-onset multiple sclerosis (MS) patients represent a subpopulation who are diagnosed during the course of development. Social cognitive deficits have recently been recognized in adults with MS. It is critical to identify whether these youngest patients with the disorder are also at risk. To determine whether pediatric-onset MS is associated with social cognitive deficits. Consecutively-recruited participants with pediatric-onset MS were compared to a group of age- and gender-matched healthy controls on Theory of Mind (ToM) task performance. Tasks measured facial affect recognition (Reading the Mind in the Eyes Test), detecting social faux pas (Faux Pas Test), and understanding the perspective of another (False Beliefs Task). Twenty-eight (28) pediatric-onset MS participants (median age 17 years) and 32 healthy controls (median age 16 years) completed the study. The MS participants performed worse than controls on all three ToM tasks: Reading the Mind in the Eyes Test (p = 0.008), the Faux Pas Test (p = 0.009), and the False Beliefs Task (p = 0.06). While more MS than control participants were impaired on a measure of information processing speed (the Symbol Digit Modalities Test; 38% versus 6%), it did not account for the differences in ToM performance. Social cognition may represent an area of cognitive functioning affected by MS in the pediatric-onset population. These processes are especially important to study in younger patients as they may have long range implications for social adjustment, employment, and well-being. © The Author(s) 2014.

Study partners should be required in preclinical Alzheimer's disease trials.

PubMed

Grill, Joshua D; Karlawish, Jason

2017-12-06

In an effort to intervene earlier in Alzheimer's disease (AD), clinical trials are testing promising candidate therapies in preclinical disease. Preclinical AD trial participants are cognitively normal, functionally independent, and autonomous decision-makers. Yet, like AD dementia trials, preclinical trials require dual enrollment of a participant and a knowledgeable informant, or study partner. The requirement of dyadic enrollment is a barrier to recruitment and may present unique ethical challenges. Despite these limitations, the requirement should continue. Study partners may be essential to ensure participant safety and wellbeing, including overcoming distress related to biomarker disclosure and minimizing risk for catastrophic reactions and suicide. The requirement may maximize participant retention and ensure data integrity, including that study partners are the source of data that will ultimately instruct whether a new treatment has a clinical benefit and meaningful impact on the population health burden associated with AD. Finally, study partners are needed to ensure the scientific and clinical value of trials. Preclinical AD will represent a new model of care, in which persons with no symptoms are informed of probable cognitive decline and eventual dementia. The rationale for early diagnosis in symptomatic AD is equally applicable in preclinical AD-to minimize risk, maximize quality of life, and ensure optimal planning and communication. Family members and other sources of support will likely be essential to the goals of this new model of care for preclinical AD patients and trials must instruct this clinical practice.

Integrating Genomics Into Clinical Pediatric Oncology Using the Molecular Tumor Board at the Memorial Sloan Kettering Cancer Center.

PubMed

Ortiz, Michael V; Kobos, Rachel; Walsh, Michael; Slotkin, Emily K; Roberts, Stephen; Berger, Michael F; Hameed, Meera; Solit, David; Ladanyi, Marc; Shukla, Neerav; Kentsis, Alex

2016-08-01

Pediatric oncologists have begun to leverage tumor genetic profiling to match patients with targeted therapies. At the Memorial Sloan Kettering Cancer Center (MSKCC), we developed the Pediatric Molecular Tumor Board (PMTB) to track, integrate, and interpret clinical genomic profiling and potential targeted therapeutic recommendations. This retrospective case series includes all patients reviewed by the MSKCC PMTB from July 2014 to June 2015. Cases were submitted by treating oncologists and potential treatment recommendations were based upon the modified guidelines of the Oxford Centre for Evidence-Based Medicine. There were 41 presentations of 39 individual patients during the study period. Gliomas, acute myeloid leukemia, and neuroblastoma were the most commonly reviewed cases. Thirty nine (87%) of the 45 molecular sequencing profiles utilized hybrid-capture targeted genome sequencing. In 30 (73%) of the 41 presentations, the PMTB provided therapeutic recommendations, of which 19 (46%) were implemented. Twenty-one (70%) of the recommendations involved targeted therapies. Three (14%) targeted therapy recommendations had published evidence to support the proposed recommendations (evidence levels 1-2), eight (36%) recommendations had preclinical evidence (level 3), and 11 (50%) recommendations were based upon hypothetical biological rationales (level 4). The MSKCC PMTB enabled a clinically relevant interpretation of genomic profiling. Effective use of clinical genomics is anticipated to require new and improved tools to ascribe pathogenic significance and therapeutic actionability. The development of specific rule-driven clinical protocols will be needed for the incorporation and evaluation of genomic and molecular profiling in interventional prospective clinical trials. © 2016 Wiley Periodicals, Inc.

Enhancing TB case detection: experience in offering upfront Xpert MTB/RIF testing to pediatric presumptive TB and DR TB cases for early rapid diagnosis of drug sensitive and drug resistant TB.

PubMed

Raizada, Neeraj; Sachdeva, Kuldeep Singh; Nair, Sreenivas Achuthan; Kulsange, Shubhangi; Gupta, Radhey Shayam; Thakur, Rahul; Parmar, Malik; Gray, Christen; Ramachandran, Ranjani; Vadera, Bhavin; Ekka, Shobha; Dhawan, Shikha; Babre, Ameet; Ghedia, Mayank; Alavadi, Umesh; Dewan, Puneet; Khetrapal, Mini; Khanna, Ashwini; Boehme, Catharina; Paramsivan, Chinnambedu Nainarappan

2014-01-01

Diagnosis of pulmonary tuberculosis (PTB) in children is challenging due to difficulties in obtaining good quality sputum specimens as well as the paucibacillary nature of disease. Globally a large proportion of pediatric tuberculosis (TB) cases are diagnosed based only on clinical findings. Xpert MTB/RIF, a highly sensitive and specific rapid tool, offers a promising solution in addressing these challenges. This study presents the results from pediatric groups taking part in a large demonstration study wherein Xpert MTB/RIF testing replaced smear microscopy for all presumptive PTB cases in public health facilities across India. The study covered a population of 8.8 million across 18 programmatic sub-district level tuberculosis units (TU), with one Xpert MTB/RIF platform established at each study TU. Pediatric presumptive PTB cases (both TB and Drug Resistant TB (DR-TB)) accessing any public health facilities in study area were prospectively enrolled and tested on Xpert MTB/RIF following a standardized diagnostic algorithm. 4,600 pediatric presumptive pulmonary TB cases were enrolled. 590 (12.8%, CI 11.8-13.8) pediatric PTB were diagnosed. Overall 10.4% (CI 9.5-11.2) of presumptive PTB cases had positive results by Xpert MTB/RIF, compared with 4.8% (CI 4.2-5.4) who had smear-positive results. Upfront Xpert MTB/RIF testing of presumptive PTB and presumptive DR-TB cases resulted in diagnosis of 79 and 12 rifampicin resistance cases, respectively. Positive predictive value (PPV) for rifampicin resistance detection was high (98%, CI 90.1-99.9), with no statistically significant variation with respect to past history of treatment. Upfront access to Xpert MTB/RIF testing in pediatric presumptive PTB cases was associated with a two-fold increase in bacteriologically-confirmed PTB, and increased detection of rifampicin-resistant TB cases under routine operational conditions across India. These results suggest that routine Xpert MTB/RIF testing is a promising solution to present-day challenges in the diagnosis of PTB in pediatric patients.

An assessment of the utilization of the preclinical rodent model literature in clinical trials of putative therapeutics for the treatment of alcohol use disorders.

PubMed

Barajaz, Ashley M; Kliethermes, Christopher L

2017-12-01

Rodent models of Alcohol Use Disorders (AUD) are used extensively by preclinical researchers to develop new therapeutics for the treatment of AUD. Although these models play an important role in the development of novel, targeted therapeutics, their role in bringing therapeutics to clinical trials is unclear, as off-label use of existing medications not approved for the treatment of AUD is commonly seen in the clinic and clinical trials. In the current study, we used the Clinicaltrials.gov database to obtain a list of drugs that have been tested for efficacy in a clinical trial between 1997 and 2017. We then conducted a set of literature searches to determine which of the 98 unique drugs we identified had shown efficacy in a rodent model of an AUD prior to being tested in a clinical trial. We found that slightly less than half of the drugs tested in clinical trials (48%) had shown prior efficacy in any rodent model of an AUD, while the remaining 52% of drugs were used off-label, or in some cases, following non-published studies. This study raises the question of how clinical researchers incorporate results from preclinical studies in the decision to bring a drug to a clinical trial. Our results underscore the need for ongoing communication among preclinical and clinical researchers. Copyright © 2017 Elsevier B.V. All rights reserved.

21 CFR 812.35 - Supplemental applications.

Code of Federal Regulations, 2014 CFR

2014-04-01

... control procedures of § 820.30, preclinical/animal testing, peer reviewed published literature, or other... the verification and validation testing, as appropriate, demonstrated that the design outputs met the...

21 CFR 812.35 - Supplemental applications.

Code of Federal Regulations, 2011 CFR

2011-04-01

... control procedures of § 820.30, preclinical/animal testing, peer reviewed published literature, or other... the verification and validation testing, as appropriate, demonstrated that the design outputs met the...

21 CFR 812.35 - Supplemental applications.

Code of Federal Regulations, 2013 CFR

2013-04-01

... control procedures of § 820.30, preclinical/animal testing, peer reviewed published literature, or other... the verification and validation testing, as appropriate, demonstrated that the design outputs met the...

21 CFR 812.35 - Supplemental applications.

Code of Federal Regulations, 2012 CFR

2012-04-01

... control procedures of § 820.30, preclinical/animal testing, peer reviewed published literature, or other... the verification and validation testing, as appropriate, demonstrated that the design outputs met the...

Methotrexate Hypersensitivity Reactions in Pediatrics: Evaluation and Management

PubMed Central

Dilley, Meredith A.; Lee, Joyce P.; Broyles, Ana Dioun

2017-01-01

Reports of hypersensitivity reactions (HSRs) to MTX are limited to single case studies. We retrospectively reviewed HSRs to MTX during a 12-year period in our tertiary care pediatric center. Seven patients were evaluated for HSRs to MTX. Skin testing was positive in one of the 4 patients tested. One patient underwent successful graded challenge to MTX. Seventeen desensitizations to MTX were successfully performed in the other 6 patients. Skin testing, graded challenge, and desensitization were safe and effective procedures in the evaluation and management of patients with HSRs to MTX in our pediatric population. PMID:27786403

Upstairs downstairs: vertical integration of a pediatric service.

PubMed

Racine, A D; Stein, R E; Belamarich, P F; Levine, E; Okun, A; Porder, K; Rosenfeld, J L; Schechter, M

1998-07-01

The combined effects of recent changes in health care financing and training priorities have compelled academic medical centers to develop innovative structures to maintain service commitments yet conform to health care marketplace demands. In 1992, a municipal hospital in the Bronx, New York, affiliated with a major academic medical center reorganized its pediatric service into a vertically integrated system of four interdependent practice teams that provided comprehensive care in the ambulatory as well as inpatient settings. One of the goals of the new system was to conserve inpatient resources. To describe the development of a new vertically integrated pediatric service at an inner-city municipal hospital and to test whether its adoption was associated with the use of fewer inpatient resources. A descriptive analysis of the rationale, goals, implementation strategies, and structure of the vertically integrated pediatric service combined with a before-and-after comparison of in-hospital resource consumption. A before-and-after comparison was conducted for two periods: the period before vertical integration, from January 1989 to December 1991, and the period after the adoption of vertical integration, from July 1992 to December 1994. Four measures of inpatient resource use were compared after adjustment for case mix index: mean certified length of stay per case, mean number of radiologic tests per case, mean number of ancillary tests per case, and mean number of laboratory tests per case. Difference-in-differences-in-differences estimators were used to control for institution-wide trends throughout the time period and regional trends in inpatient pediatric practice occurring across institutions. Results. In 1992, the Department of Pediatrics at the Albert Einstein College of Medicine reorganized the pediatric service at Jacobi Medical Center, one of its principal municipal hospital affiliates, into a vertically integrated pediatric service that combines ambulatory and inpatient activities into four interdependent practice teams composed of attending pediatricians, allied health professionals, house officers, and social workers. The new vertically integrated service was designed to improve continuity of care for patients, provide a model of practice for professional trainees, conserve scarce resources, and create a clinical research infrastructure. The vertically integrated pediatric service augmented the role of attending pediatricians, extended the use of allied health professionals from the ambulatory to the inpatient sites, established interdisciplinary practice teams that unified the care of pediatric patients and their families, and used less inpatient resources. Controlling for trends within the study institution and trends in the practice of pediatrics across institutions throughout the time period, the vertical integration was associated with a decline in 0.6 days per case, the use of 0.62 fewer radiologic tests per case, 0.21 fewer ancillary tests per case, and 2.68 fewer laboratory tests per case. We conclude that vertical integration of a pediatric service at an inner-city municipal hospital is achievable; conveys advantages of improved continuity of care, enhanced opportunities for primary care training, and increased participation of senior clinicians; and has the potential to conserve significant amounts of inpatient resources.

A hemodynamic-directed approach to pediatric cardiopulmonary resuscitation (HD-CPR) improves survival.

PubMed

Morgan, Ryan W; Kilbaugh, Todd J; Shoap, Wesley; Bratinov, George; Lin, Yuxi; Hsieh, Ting-Chang; Nadkarni, Vinay M; Berg, Robert A; Sutton, Robert M

2017-02-01

Most pediatric in-hospital cardiac arrests (IHCAs) occur in ICUs where invasive hemodynamic monitoring is frequently available. Titrating cardiopulmonary resuscitation (CPR) to the hemodynamic response of the individual improves survival in preclinical models of adult cardiac arrest. The objective of this study was to determine if titrating CPR to systolic blood pressure (SBP) and coronary perfusion pressure (CoPP) in a pediatric porcine model of asphyxia-associated ventricular fibrillation (VF) IHCA would improve survival as compared to traditional CPR. After 7min of asphyxia followed by VF, 4-week-old piglets received either hemodynamic-directed CPR (HD-CPR; compression depth titrated to SBP of 90mmHg and vasopressor administration to maintain CoPP ≥20mmHg); or Standard Care (compression depth 1/3 of the anterior-posterior chest diameter and epinephrine every 4min). All animals received CPR for 10min prior to the first defibrillation attempt. CPR was continued for a maximum of 20min. Protocolized intensive care was provided to all surviving animals for 4h. The primary outcome was 4-h survival. Survival rate was greater with HD-CPR (12/12) than Standard Care (6/10; p=0.03). CoPP during HD-CPR was higher compared to Standard Care (point estimate +8.1mmHg, CI 95 : 0.5-15.8mmHg; p=0.04). Chest compression depth was lower with HD-CPR than Standard Care (point estimate -14.0mm, CI95: -9.6 to -18.4mm; p<0.01). Prior to the first defibrillation attempt, more vasopressor doses were administered with HD-CPR vs. Standard Care (median 5 vs. 2; p<0.01). Hemodynamic-directed CPR improves short-term survival compared to standard depth-targeted CPR in a porcine model of pediatric asphyxia-associated VF IHCA. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A Hemodynamic-Directed Approach to Pediatric Cardiopulmonary Resuscitation (HD-CPR) Improves Survival

PubMed Central

Morgan, Ryan W.; Kilbaugh, Todd J.; Shoap, Wesley; Bratinov, George; Lin, Yuxi; Hsieh, Ting-Chang; Nadkarni, Vinay M.; Berg, Robert A.; Sutton, Robert M.

2016-01-01

Aim Most pediatric in-hositalcardiac arrests(IHCAs) occur in ICUs where invasive hemodynamic monitoring is frequently available. Titrating cardiopulmonary resuscitation (CPR) to the hemodynamic response of the individual improves survival in preclinical models of adult cardiac arrest. The objective of this study was to determine if titrating CPR to systolic blood pressure (SBP) and coronary perfusion pressure (CoPP) in a pediatric porcine model of asphyxia-associated ventricular fibrillation (VF) IHCA would improve survival as compared to traditional CPR. Methods After 7 minutes of asphyxia followed by VF, 4-week-old piglets received either Hemodynamic-Directed CPR (HD-CPR; compression depth titrated to SBP of 90mmHg and vasopressor administration to maintain CoPP ≥20mmHg); or Standard Care (compression depth 1/3 of the anterior-posterior chest diameter and epinephrine every 4 minutes). All animals received CPR for 10 minutes prior to the first defibrillation attempt. CPR was continued for a maximum of 20 minutes. Protocolized intensive care was provided to all surviving animals for 4 hours. The primary outcome was 4-hour survival. Results Survival rate was greater with HD-CPR (12/12) than Standard Care (6/10; p=0.03). CoPP during HD-CPR was higher compared to Standard Care (point estimate +8.1mmHg, CI95: 0.5–15.8mmHg; p=0.04). Chest compression depth was lower with HD-CPR than Standard Care (point estimate 14.0mm, CI95: 9.6–18.4mm; p<0.01). Prior to the first defibrillation attempt, more vasopressor doses were administered with HD-CPR versus Standard Care (median 5 versus 2; p<0.01). Conclusions Hemodynamic-directed CPR improves short-term survival compared to standard depth-targeted CPR in a porcine model of pediatric asphyxia-associated VF IHCA. PMID:27923692

Preclinical Testing of Novel Oxytocin Receptor Activators in Models of Autism Phenotypes

DTIC Science & Technology

2015-11-01

evaluated one synthetic oxytocin agonist, Compound 39, and one oxytocin metabolite, for efficacy against social deficits in BALB/cByJ mice, and we are...currently evaluating a second oxytocin metabolite for prosocial effects. Overall, we have successfully validated three mouse models as preclinical...to, first, prioritize synthetic compounds that activate the oxytocin receptor using cell-based assays, and secondly, evaluate the therapeutic efficacy

New Breed of Mice May Improve Accuracy for Preclinical Testing of Cancer Drugs | Poster

Cancer.gov

A new breed of lab animals, dubbed “glowing head mice,” may do a better job than conventional mice in predicting the success of experimental cancer drugs—while also helping to meet an urgent need for more realistic preclinical animal models. The mice were developed to tolerate often-used light-emitting molecules, such as luciferase from fireflies and green fluorescent protein

Can evaluation of a dental procedure at the outset of learning predict later performance at the preclinical level? A pilot study.

PubMed

Polyzois, Ioannis; Claffey, Noel; McDonald, Albhe; Hussey, David; Quinn, Frank

2011-05-01

The purpose of this study was to examine the effectiveness of conventional pre-clinical training in dentistry and to determine if evaluation of a dental procedure at the beginning of dental training can be a predictor for future performance. A group of second year dental students with no previous experience in operative dentistry were asked to prepare a conventional class I cavity on a lower first molar typodont. Their first preparation was carried out after an introductory lecture and a demonstration and their second at the end of conventional training. The prepared typodonts were coded and blindly scored for the traditional assessment criteria of outline form, retention form, smoothness, cavity depth and cavity margin angulation. Once the codes were broken, a paired t-test was used to compare the difference between the means of before and after scores (P<0.0001) and a Pearson's linear correlation to test the association (r=0.4). From the results of this study, we could conclude that conventional preclinical training results in a significant improvement in the manual skills of the dental students and that the dental procedure used had only a limited predictive value for later performance at the preclinical level. © 2011 John Wiley & Sons A/S.

Statistical comparison of the pediatric versus adult IKDC subjective knee evaluation form in adolescents.

PubMed

Oak, Sameer R; O'Rourke, Colin; Strnad, Greg; Andrish, Jack T; Parker, Richard D; Saluan, Paul; Jones, Morgan H; Stegmeier, Nicole A; Spindler, Kurt P

2015-09-01

The International Knee Documentation Committee (IKDC) Subjective Knee Evaluation Form is a patient-reported outcome with adult (1998) and pediatric (2011) versions validated at different ages. Prior longitudinal studies of patients aged 13 to 17 years who tore their anterior cruciate ligament (ACL) have used the only available adult IKDC, whereas currently the pediatric IKDC is the accepted form of choice. This study compared the adult and pediatric IKDC forms and tested whether the differences were clinically significant. The hypothesis was that the pediatric and adult IKDC questionnaires would show no clinically significant differences in score when completed by patients aged 13 to 17 years. Cohort study (diagnosis); Level of evidence, 2. A total of 100 participants aged 13 to 17 years with knee injuries were split into 2 groups by use of simple randomization. One group answered the adult IKDC form first and then the pediatric form. The second group answered the pediatric IKDC form first and then the adult form. A 10-minute break was given between form administrations to prevent rote repetition of answers. Study design was based on established methods to compare 2 forms of patient-reported outcomes. A 5-point threshold for clinical significance was set below previously published minimum clinically important differences for the adult IKDC. Paired t tests were used to test both differences and equivalence between scores. By ordinary least-squares models, scores were modeled to predict adult scores given certain pediatric scores and vice versa. Comparison between adult and pediatric IKDC scores showed a statistically significant difference of 1.5 points; however, the 95% CI (0.3-2.6) fell below the threshold of 5 points set for clinical significance. Further equivalence testing showed the 95% CI (0.5-2.4) between adult and pediatric scores being within the defined 5-point equivalence region. The scores were highly correlated, with a linear relationship (R(2) = 92%). There was no clinically significant difference between the pediatric and adult IKDC form scores in adolescents aged 13 to 17 years. This result allows use of whichever form is most practical for long-term tracking of patients. A simple linear equation can convert one form into the other. If the adult questionnaire is used at this age, it can be consistently used during follow-up. © 2015 The Author(s).

Assessing Competence in Pediatric Cardiology

ERIC Educational Resources Information Center

Johnson, Apul E.; And Others

1976-01-01

In response to the need to assure physician competence, a rating scale was developed at the University of Minnesota Medical School for use in evaluating clinical competence in pediatric cardiology. It was tested on first- and second-year specialists. Development and testing procedures are described. (JT)

The opportunistic screening of refractive errors in school-going children by pediatrician using enhanced Brückner test.

PubMed

Jain, Piyush; Kothari, Mihir T; Gode, Vaibhav

2016-10-01

The aim of this study was to compare the results of enhanced Brückner test (EBT) performed by a pediatrician and an experienced pediatric ophthalmologist. In this prospective double-masked cohort study, a pediatrician and a pediatric ophthalmologist performed the EBT in a classroom of a school in semi-dark lighting condition using a direct ophthalmoscope. The results of the test were compared using 2 × 2 Bayesian table and kappa statistics. The findings of the pediatric ophthalmologists were considered gold standard. Two hundred and thirty-six eyes of 118 subjects, mean age 6.8 ± 0.5 years (range, 5.4-7.8 years), were examined. The time taken to complete this test was <10 s per subject. The ophthalmologist identified 59 eyes as ametropic (12 hyperopic and 47 myopic eyes) and 177 as emmetropic compared to 61 eyes as ametropic and 175 emmetropic by pediatrician. The prevalence of the test positive was 25.9%. The sensitivity of the pediatrician was 90.2%, specificity was 97.7%, predictive value of the positive test was 93.2%, and predictive value of the negative test was 96.6%. The clinical agreement (kappa) between the pediatric ophthalmologist and the pediatrician was 0.9. The results of the EBT performed by pediatrician were comparable to that of an experienced pediatric ophthalmologist. Opportunistic screening of refractive errors using EBT by a pediatrician can be an important approach in the detection of ametropia in children.

From Bench to Bedside: Utility of the Rabbit Elastase Aneurysm Model in Pre-Clinical Studies of Intracranial Aneurysm Treatment

PubMed Central

Brinjikji, Waleed; Ding, Yong H; Kallmes, David F; Kadirvel, Ramanathan

2016-01-01

Summary Pre-clinical studies are important in helping practitioners and device developers improve techniques and tools for endovascular treatment of intracranial aneurysms. Thus, an understanding of the major animal models used in such studies is important. The New Zealand rabbit elastase induced arterial aneurysm of the common carotid artery is one of the most commonly used models in testing the safety and efficacy of new endovascular devices. In this review we discuss 1) various techniques used to create the aneurysm, 2) complications of aneurysm creation, 3) natural history of the arterial aneurysm, 4) histopathologic and hemodynamic features of the aneurysm 5) devices tested using this model and 6) weaknesses of the model. We demonstrate how pre-clinical studies using this model are applied in treatment of intracranial aneurysms in humans. The model has a similar hemodynamic, morphological and histologic characteristics to human aneurysms and demonstrates similar healing responses to coiling as human aneurysms. Despite these strengths however, the model does have many weaknesses including the fact that the model does not emulate the complex inflammatory processes affecting growing and ruptured aneurysms. Furthermore the model’s extracranial location affects its ability to be used in preclinical safety assessments of new devices. We conclude that the rabbit elastase model has characteristics that make it a simple and effective model for preclinical studies on the endovascular treatment of intracranial aneurysms however further work is needed to develop aneurysm models that simulate the histopathologic and morphologic characteristics of growing and ruptured aneurysms. PMID:25904642

Preclinical, Clinical, and Over-the-Counter Postmarketing Experience with a New Vaginal Cup: Menstrual Collection

PubMed Central

North, Barbara B.

2011-01-01

Abstract Background Menstrual cups have been available for decades, but their use is limited by bulky design and the need for multiple sizes. The Softcup® (Instead, Inc., San Diego, CA) is a simple single-size disposable over-the-counter (OTC) menstrual cup that compresses to tampon shape to facilitate insertion and can be worn during coitus. This report describes preclinical evaluation, clinical testing, and postmarketing monitoring of the Softcup. Methods Preclinical testing complied with U.S. Food and Drug Administration (FDA) guidelines and used standard United States Pharmacopoeia methodologies for assessment of potential toxicity. Clinical testing enrolled 406 women in seven U.S. centers. A detailed written questionnaire assessed safety, acceptability, and effectiveness for menstrual collection. Study safety parameters included pelvic examinations, Pap smears, colposcopy, urinalysis, vaginal pH, wet mounts, gram stain, and vaginal microflora cultures. Postmarketing surveillance of over 100 million Softcups has been conducted by the manufacturer and by the FDA Medwatch system. Results No toxicity or mutagenicity was observed in preclinical evaluations. In clinical testing, after three cycles of cup use, 37% of subjects rated the cup as better than, 29% as worse than, and 34% as equal to pads or tampons. The cup was preferred for comfort, dryness, and less odor. Cups received lower ratings for disposal and convenience. Eighty-one percent of enrolled women were able to insert and remove their first cup using only written instructions. Use difficulties resulting in study discontinuations included cramping (1%), leakage (1%), and improper fit (3%). No safety parameters were adversely affected. No significant health risks were reported during postmarketing surveillance. Conclusions These results demonstrate that a single-size vaginal device has no significant health risks and is acceptable to many women without the need for fitting or other medical services. PMID:21194348

Preclinical, clinical, and over-the-counter postmarketing experience with a new vaginal cup: menstrual collection.

PubMed

North, Barbara B; Oldham, Michael J

2011-02-01

Menstrual cups have been available for decades, but their use is limited by bulky design and the need for multiple sizes. The Softcup® (Instead, Inc., San Diego, CA) is a simple single-size disposable over-the-counter (OTC) menstrual cup that compresses to tampon shape to facilitate insertion and can be worn during coitus. This report describes preclinical evaluation, clinical testing, and postmarketing monitoring of the Softcup. Preclinical testing complied with U.S. Food and Drug Administration (FDA) guidelines and used standard United States Pharmacopoeia methodologies for assessment of potential toxicity. Clinical testing enrolled 406 women in seven U.S. centers. A detailed written questionnaire assessed safety, acceptability, and effectiveness for menstrual collection. Study safety parameters included pelvic examinations, Pap smears, colposcopy, urinalysis, vaginal pH, wet mounts, gram stain, and vaginal microflora cultures. Postmarketing surveillance of over 100 million Softcups has been conducted by the manufacturer and by the FDA Medwatch system. No toxicity or mutagenicity was observed in preclinical evaluations. In clinical testing, after three cycles of cup use, 37% of subjects rated the cup as better than, 29% as worse than, and 34% as equal to pads or tampons. The cup was preferred for comfort, dryness, and less odor. Cups received lower ratings for disposal and convenience. Eighty-one percent of enrolled women were able to insert and remove their first cup using only written instructions. Use difficulties resulting in study discontinuations included cramping (1%), leakage (1%), and improper fit (3%). No safety parameters were adversely affected. No significant health risks were reported during postmarketing surveillance. These results demonstrate that a single-size vaginal device has no significant health risks and is acceptable to many women without the need for fitting or other medical services.

Predictive validity of pre-admission assessments on medical student performance.

PubMed

Dabaliz, Al-Awwab; Kaadan, Samy; Dabbagh, M Marwan; Barakat, Abdulaziz; Shareef, Mohammad Abrar; Al-Tannir, Mohamad; Obeidat, Akef; Mohamed, Ayman

2017-11-24

To examine the predictive validity of pre-admission variables on students' performance in a medical school in Saudi Arabia. In this retrospective study, we collected admission and college performance data for 737 students in preclinical and clinical years. Data included high school scores and other standardized test scores, such as those of the National Achievement Test and the General Aptitude Test. Additionally, we included the scores of the Test of English as a Foreign Language (TOEFL) and the International English Language Testing System (IELTS) exams. Those datasets were then compared with college performance indicators, namely the cumulative Grade Point Average (cGPA) and progress test, using multivariate linear regression analysis. In preclinical years, both the National Achievement Test (p=0.04, B=0.08) and TOEFL (p=0.017, B=0.01) scores were positive predictors of cGPA, whereas the General Aptitude Test (p=0.048, B=-0.05) negatively predicted cGPA. Moreover, none of the pre-admission variables were predictive of progress test performance in the same group. On the other hand, none of the pre-admission variables were predictive of cGPA in clinical years. Overall, cGPA strongly predict-ed students' progress test performance (p<0.001 and B=19.02). Only the National Achievement Test and TOEFL significantly predicted performance in preclinical years. However, these variables do not predict progress test performance, meaning that they do not predict the functional knowledge reflected in the progress test. We report various strengths and deficiencies in the current medical college admission criteria, and call for employing more sensitive and valid ones that predict student performance and functional knowledge, especially in the clinical years.

Predictive validity of pre-admission assessments on medical student performance

PubMed Central

Dabaliz, Al-Awwab; Kaadan, Samy; Dabbagh, M. Marwan; Barakat, Abdulaziz; Shareef, Mohammad Abrar; Al-Tannir, Mohamad; Obeidat, Akef

2017-01-01

Objectives To examine the predictive validity of pre-admission variables on students’ performance in a medical school in Saudi Arabia.  Methods In this retrospective study, we collected admission and college performance data for 737 students in preclinical and clinical years. Data included high school scores and other standardized test scores, such as those of the National Achievement Test and the General Aptitude Test. Additionally, we included the scores of the Test of English as a Foreign Language (TOEFL) and the International English Language Testing System (IELTS) exams. Those datasets were then compared with college performance indicators, namely the cumulative Grade Point Average (cGPA) and progress test, using multivariate linear regression analysis. Results In preclinical years, both the National Achievement Test (p=0.04, B=0.08) and TOEFL (p=0.017, B=0.01) scores were positive predictors of cGPA, whereas the General Aptitude Test (p=0.048, B=-0.05) negatively predicted cGPA. Moreover, none of the pre-admission variables were predictive of progress test performance in the same group. On the other hand, none of the pre-admission variables were predictive of cGPA in clinical years. Overall, cGPA strongly predict-ed students’ progress test performance (p<0.001 and B=19.02). Conclusions Only the National Achievement Test and TOEFL significantly predicted performance in preclinical years. However, these variables do not predict progress test performance, meaning that they do not predict the functional knowledge reflected in the progress test. We report various strengths and deficiencies in the current medical college admission criteria, and call for employing more sensitive and valid ones that predict student performance and functional knowledge, especially in the clinical years. PMID:29176032

Autoantibodies and their Judicious Use in Pediatric Rheumatology Practice.

PubMed

Saikia, Biman; Rawat, Amit; Vignesh, Pandiarajan

2016-01-01

Autoantibody testing forms an important part of diagnostic workup of patients in Pediatric rheumatology practice. However it is important to understand that the mere presence of autoantibodies does not necessarily mean the presence of an underlying autoimmune disease. Autoantibodies may be present decades before the development of clinical manifestations of an autoimmune disease and may be viewed as harbingers of Autoimmune disease. On the other hand, low-affinity autoantibodies may be present in normal healthy individuals; these natural autoantibodies serve an important function in immune regulation and tolerance. Autoantibody testing in pediatric practice mainly includes testing for anti-nuclear antibodies, anti-dsDNA antibodies, anti-neutrophil cytoplasmic autoantibodies and antiphospholipid antibodies. Rheumatoid factor and anti-CCP do not have much significance in the diagnostic schema in pediatric rheumatology, except perhaps for classification of juvenile idiopathic arthritis (JIA) and prognostication in late-onset polyarticular JIA. The positive predictive value (PPV) of any laboratory test depends on the prevalence of the disease in the population being tested. Hence, test ordering practices greatly impact the performance characteristics and positive predictive value of any laboratory test. A restricted test ordering only in patients with clinical signs and symptoms suggestive of autoimmune disease would thus greatly increase the PPV of tests such as antinuclear antibody used for diagnosing autoimmunity.

CAR T-cell therapy for glioblastoma: ready for the next round of clinical testing?

PubMed

Prinzing, Brooke L; Gottschalk, Stephen M; Krenciute, Giedre

2018-05-01

The outcome for patients with glioblastoma (GBM) remains poor, and there is an urgent need to develop novel therapeutic approaches. T cells genetically modified with chimeric antigen receptors (CARs) hold the promise to improve outcomes since they recognize and kill cells through different mechanisms than conventional therapeutics. Areas covered: This article reviews CAR design, tumor associated antigens expressed by GBMs that can be targeted with CAR T cells, preclinical and clinical studies conducted with CAR T cells, and genetic approaches to enhance their effector function. Expert commentary: While preclinical studies have highlighted the potent anti-GBM activity of CAR T cells, the initial foray of CAR T-cell therapies into the clinic resulted only in limited benefits for GBM patients. Additional genetic modification of CAR T cells has resulted in a significant increase in their anti-GBM activity in preclinical models. We are optimistic that clinical testing of these enhanced CAR T cells will be safe and result in improved anti-glioma activity in GBM patients.

Operation of the Preclinical Head Scanner for Proton CT.

PubMed

Sadrozinski, H F-W; Geoghegan, T; Harvey, E; Johnson, R P; Plautz, T E; Zatserklyaniy, A; Bashkirov, V; Hurley, R F; Piersimoni, P; Schulte, R W; Karbasi, P; Schubert, K E; Schultze, B; Giacometti, V

2016-09-21

We report on the operation and performance tests of a preclinical head scanner developed for proton computed tomography (pCT). After extensive preclinical testing, pCT is intended to be employed in support of proton therapy treatment planning and pre-treatment verification in patients undergoing particle-beam therapy. In order to assess the performance of the scanner, we have performed CT scans with 200 MeV protons from both the synchrotron of the Loma Linda University Medical Center (LLUMC) and the cyclotron of the Northwestern Medicine Chicago Proton Center (NMCPC). The very high sustained rate of data acquisition, exceeding one million protons per second, allowed a full 360° scan to be completed in less than 7 minutes. The reconstruction of various phantoms verified accurate reconstruction of the proton relative stopping power (RSP) and the spatial resolution in a variety of materials. The dose for an image with better than 1% uncertainty in the RSP is found to be close to 1 mGy.

A practical blueprint to systematically study life-long health consequences of novel medically assisted reproductive treatments

PubMed Central

Mulder, Callista L; Serrano, Joana B; Catsburg, Lisa A E; Roseboom, Tessa J; Repping, Sjoerd; van Pelt, Ans M M

2018-01-01

Abstract In medicine, safety and efficacy are the two pillars on which the implementation of novel treatments rest. To protect the patient from unnecessary or unsafe treatments, usually, a stringent path of (pre) clinical testing is followed before a treatment is introduced into routine patient care. However, in reproductive medicine several techniques have been clinically introduced without elaborate preclinical studies. Moreover, novel reproductive techniques may harbor safety risks not only for the patients undergoing treatment, but also for the offspring conceived through these techniques. If preclinical (animal) studies were performed, efficacy and functionality the upper hand. When a new medically assisted reproduction (MAR) treatment was proven effective (i.e. if it resulted in live birth) the treatment was often rapidly implemented in the clinic. For IVF, the first study on the long-term health of IVF children was published a decade after its clinical implementation. In more recent years, prospective follow-up studies have been conducted that provided the opportunity to study the health of large groups of children derived from different reproductive techniques. Although such studies have indicated differences between children conceived through MAR and children conceived naturally, results are often difficult to interpret due to the observational nature of these studies (and the associated risk of confounding factors, e.g. subfertility of the parents), differences in definitions of clinical outcome measures, lack of uniformity in assessment protocols and heterogeneity of the underlying reasons for fertility treatment. With more novel MARs waiting at the horizon, there is a need for a framework on how to assess safety of novel reproductive techniques in a preclinical (animal) setting before they are clinically implemented. In this article, we provide a blueprint for preclinical testing of safety and health of offspring generated by novel MARs using a mouse model involving an array of tests that comprise the entire lifespan. We urge scientists to perform the proposed extensive preclinical tests for novel reproductive techniques with the goal to acquire knowledge on efficacy and the possible health effects of to-be implemented reproductive techniques to safeguard quality of novel MARs. PMID:29635479

A Grading System To Evaluate Objectively the Strength of Pre-Clinical Data of Acute Neuroprotective Therapies for Clinical Translation in Spinal Cord Injury

PubMed Central

Okon, Elena B.; Tsai, Eve; Beattie, Michael S.; Bresnahan, Jacqueline C.; Magnuson, David K.; Reier, Paul J.; McTigue, Dana M.; Popovich, Phillip G.; Blight, Andrew R.; Oudega, Martin; Guest, James D.; Weaver, Lynne C.; Fehlings, Michael G.; Tetzlaff, Wolfram

2011-01-01

Abstract The past three decades have seen an explosion of research interest in spinal cord injury (SCI) and the development of hundreds of potential therapies that have demonstrated some promise in pre-clinical experimental animal models. A growing number of these treatments are seeking to be translated into human clinical trials. Conducting such a clinical trial, however, is extremely costly, not only for the time and money required to execute it, but also for the limited resources that will then no longer be available to evaluate other promising therapies. The decision about what therapies have sufficient pre-clinical evidence of efficacy to justify testing in humans is therefore of utmost importance. Here, we have developed a scoring system for objectively grading the body of pre-clinical literature on neuroprotective treatments for acute SCI. The components of the system include an evaluation of a number of factors that are thought to be important in considering the “robustness” of a therapy's efficacy, including the animal species and injury models that have been used to test it, the time window of efficacy, the types of functional improvements effected by it, and whether efficacy has been independently replicated. The selection of these factors was based on the results of a questionnaire that was performed within the SCI research community. A modified Delphi consensus-building exercise was then conducted with experts in pre-clinical SCI research to refine the criteria and decide upon how to score them. Finally, the grading system was applied to a series of potential neuroprotective treatments for acute SCI. This represents a systematic approach to developing an objective method of evaluating the extent to which the pre-clinical literature supports the translation of a particular experimental treatment into human trials. PMID:20507235

Regulatory considerations on new adjuvants and delivery systems.

PubMed

Sesardic, D

2006-04-12

New and improved vaccines and delivery systems are increasingly being developed for prevention, treatment and diagnosis of human diseases. Prior to their use in humans, all new biological products must undergo pre-clinical evaluation. These pre-clinical studies are important not only to establish the biological properties of the material and to evaluate its possible risk to the public, but also to plan protocols for subsequent clinical trials from which safety and efficacy can be evaluated. For vaccines, evaluation in pre-clinical studies is particularly important as information gained may also contribute to identifying the optimum composition and formulation process and provide an opportunity to develop suitable indicator tests for quality control. Data from pre-clinical and laboratory evaluation studies, which continue during clinical studies, is used to support an application for marketing authorisation. Addition of a new adjuvant and exploration of new delivery systems for vaccines presents challenges to both manufacturers and regulatory authorities. Because no adjuvant is licensed as a medicinal product in its own right, but only as a component of a particular vaccine, pre-clinical and appropriate toxicology studies need to be designed on a case-by-case basis to evaluate the safety profile of the adjuvant and adjuvant/vaccine combination. Current regulatory requirements for the pharmaceutical and pre-clinical safety assessment of vaccines are insufficient and initiatives are in place to develop more specific guidelines for evaluation of adjuvants in vaccines.

Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures.

PubMed

Lo Monaco, Melissa; Merckx, Greet; Ratajczak, Jessica; Gervois, Pascal; Hilkens, Petra; Clegg, Peter; Bronckaers, Annelies; Vandeweerd, Jean-Michel; Lambrichts, Ivo

2018-01-01

Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair.

Stem Cells for Cartilage Repair: Preclinical Studies and Insights in Translational Animal Models and Outcome Measures

PubMed Central

Ratajczak, Jessica; Gervois, Pascal; Clegg, Peter; Bronckaers, Annelies; Vandeweerd, Jean-Michel; Lambrichts, Ivo

2018-01-01

Due to the restricted intrinsic capacity of resident chondrocytes to regenerate the lost cartilage postinjury, stem cell-based therapies have been proposed as a novel therapeutic approach for cartilage repair. Moreover, stem cell-based therapies using mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been used successfully in preclinical and clinical settings. Despite these promising reports, the exact mechanisms underlying stem cell-mediated cartilage repair remain uncertain. Stem cells can contribute to cartilage repair via chondrogenic differentiation, via immunomodulation, or by the production of paracrine factors and extracellular vesicles. But before novel cell-based therapies for cartilage repair can be introduced into the clinic, rigorous testing in preclinical animal models is required. Preclinical models used in regenerative cartilage studies include murine, lapine, caprine, ovine, porcine, canine, and equine models, each associated with its specific advantages and limitations. This review presents a summary of recent in vitro data and from in vivo preclinical studies justifying the use of MSCs and iPSCs in cartilage tissue engineering. Moreover, the advantages and disadvantages of utilizing small and large animals will be discussed, while also describing suitable outcome measures for evaluating cartilage repair. PMID:29535784

Development of a canine model to enable the preclinical assessment of pH-dependent absorption of test compounds.

PubMed

Fancher, R Marcus; Zhang, Hongjian; Sleczka, Bogdan; Derbin, George; Rockar, Richard; Marathe, Punit

2011-07-01

A preclinical canine model capable of predicting a compound's potential for pH-dependent absorption in humans was developed. This involved the surgical insertion of a gastrostomy feeding tube into the stomach of a beagle dog. The tube was sutured in position to allow frequent withdrawal of gastric fluid for pH measurement. Therefore, it was possible to measure pH in the stomach and assess the effect of gastric pH-modifying agents on the absorption of various test compounds. Fasted gastric pH in the dog showed considerable inter- and intra-animal variability. Pretreatment of pentagastrin (6 µg/kg intramuscularly) 20 min prior to test compound administration was determined to be adequate for simulating fasting stomach pH in humans. Pretreatment with famotidine [40 mg orally] 1 h prior to test compound administration was determined to be adequate for simulating human gastric pH when acid-reducing agents are coadministered. Pentagastrin and famotidine pretreatments were used to test two discovery compounds and distinct differences in their potential for pH-dependent absorption were observed. The model described herein can be used preclinically to screen out compounds, differentiate compounds, and support the assessment of various formulation- and prodrug-based strategies to mitigate the pH effect. Copyright © 2011 Wiley-Liss, Inc. and the American Pharmacists Association

A systematic review of methodology applied during preclinical anesthetic neurotoxicity studies: important issues and lessons relevant to the design of future clinical research.

PubMed

Disma, Nicola; Mondardini, Maria C; Terrando, Niccolò; Absalom, Anthony R; Bilotta, Federico

2016-01-01

Preclinical evidence suggests that anesthetic agents harm the developing brain thereby causing long-term neurocognitive impairments. It is not clear if these findings apply to humans, and retrospective epidemiological studies thus far have failed to show definitive evidence that anesthetic agents are harmful to the developing human brain. The aim of this systematic review was to summarize the preclinical studies published over the past decade, with a focus on methodological issues, to facilitate the comparison between different preclinical studies and inform better design of future trials. The literature search identified 941 articles related to the topic of neurotoxicity. As the primary aim of this systematic review was to compare methodologies applied in animal studies to inform future trials, we excluded a priori all articles focused on putative mechanism of neurotoxicity and the neuroprotective agents. Forty-seven preclinical studies were finally included in this review. Methods used in these studies were highly heterogeneous-animals were exposed to anesthetic agents at different developmental stages, in various doses and in various combinations with other drugs, and overall showed diverse toxicity profiles. Physiological monitoring and maintenance of physiological homeostasis was variable and the use of cognitive tests was generally limited to assessment of specific brain areas, with restricted translational relevance to humans. Comparison between studies is thus complicated by this heterogeneous methodology and the relevance of the combined body of literature to humans remains uncertain. Future preclinical studies should use better standardized methodologies to facilitate transferability of findings from preclinical into clinical science. © 2015 John Wiley & Sons Ltd.

Quality Assurance in Biobanking for Pre-Clinical Research

PubMed Central

Simeon-Dubach, Daniel; Zeisberger, Steffen M.; Hoerstrup, Simon P.

2016-01-01

It is estimated that not less than USD 28 billion are spent each year in the USA alone on irreproducible pre-clinical research, which is not only a fundamental loss of investment and resources but also a strong inhibitor of efficiency for upstream processes regarding the translation towards clinical applications and therapies. The issues and cost of irreproducibility has mainly been published on pre-clinical research. In contrast to pre-clinical research, test material is often being transferred into humans in clinical research. To protect treated human subjects and guarantee a defined quality standard in the field of clinical research, the manufacturing and processing infrastructures have to strictly follow and adhere to certain (inter-)national quality standards. It is assumed and suggested by the authors that by an implementation of certain quality standards within the area of pre-clinical research, billions of USD might be saved and the translation phase of promising pre-clinical results towards clinical applications may substantially be improved. In this review, we discuss how an implementation of a quality assurance (QA) management system might positively improve sample quality and sustainability within pre-clinically focused biobank infrastructures. Biobanks are frequently positioned at the very beginning of the biomedical research value chain, and, since almost every research material has been stored in a biobank during the investigated life cycle, biobanking seems to be of substantial importance from this perspective. The role model of a QA-regulated biobank structure can be found in biobanks within the context of clinical research organizations such as in regenerative medicine clusters. PMID:27781023

JAK2 aberrations in childhood B-cell precursor acute lymphoblastic leukemia

PubMed Central

de Goffau-Nobel, Willemieke; Hoogkamer, Alex Q.; Boer, Judith M.; Boeree, Aurélie; van de Ven, Cesca; Koudijs, Marco J.; Besselink, Nicolle J.M.; de Groot-Kruseman, Hester A.; Zwaan, Christian Michel; Horstmann, Martin A.; Pieters, Rob; den Boer, Monique L.

2017-01-01

JAK2 abnormalities may serve as target for precision medicines in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In the current study we performed a screening for JAK2 mutations and translocations, analyzed the clinical outcome and studied the efficacy of two JAK inhibitors in primary BCP-ALL cells. Importantly, we identify a number of limitations of JAK inhibitor therapy. JAK2 mutations mainly occurred in the poor prognostic subtypes BCR-ABL1-like and non- BCR-ABL1-like B-other (negative for sentinel cytogenetic lesions). JAK2 translocations were restricted to BCR-ABL1-like cases. Momelotinib and ruxolitinib were cytotoxic in both JAK2 translocated and JAK2 mutated cells, although efficacy in JAK2 mutated cells highly depended on cytokine receptor activation by TSLP. However, our data also suggest that the effect of JAK inhibition may be compromised by mutations in alternative survival pathways and microenvironment-induced resistance. Furthermore, inhibitors induced accumulation of phosphorylated JAK2Y1007, which resulted in a profound re-activation of JAK2 signaling upon release of the inhibitors. This preclinical evidence implies that further optimization and evaluation of JAK inhibitor treatment is necessary prior to its clinical integration in pediatric BCP-ALL. PMID:29163799

A Medical Student-Run Child and Adolescent Psychiatry Clinic: One Institution's Experience.

PubMed

Murzl, Cassandra A; Durns, Tyler A; Mowrey, Lorin T; Tubbs, Andrew S; Boeve, Sally A

2017-10-01

This report examines the experience of one institution's development of the first student-run psychiatry clinic that serves both adult and pediatric populations. The clinic is held weekly with pre-clinical and clinical medical student volunteers under the supervision of board-certified adult and child psychiatrists. The development and evolution of the clinic over time are evaluated with particular attention to obstacles overcome. Medical student volunteers were surveyed retrospectively to evaluate their experience with patients with psychiatric illness, skill development, and interest in psychiatry. Since January 2016, the clinic has scheduled 90 patients, 32% of which were pediatric patients. Ninety-six medical students have volunteered, with roughly equal parts from all four medical school classes. Respondents to the experience survey showed marked improvement in their comfort working with patients with mental illness. Additionally, 40% "strongly agreed" or "agreed" that their experience influenced their interest in pursuing psychiatry as a career. This report describes a student-run psychiatry clinic with a dual mission of education and service, and the challenges associated with these sometimes competing goals. This clinic serves a vital need within our community and may be an example of the role that student-run clinics can have in fostering interdisciplinary care, psychiatric recruitment, and training for medical students.

Point-of-care CD4 testing to inform selection of antiretroviral medications in south african antenatal clinics: a cost-effectiveness analysis.

PubMed

Ciaranello, Andrea L; Myer, Landon; Kelly, Kathleen; Christensen, Sarah; Daskilewicz, Kristen; Doherty, Katie; Bekker, Linda-Gail; Hou, Taige; Wood, Robin; Francke, Jordan A; Wools-Kaloustian, Kara; Freedberg, Kenneth A; Walensky, Rochelle P

2015-01-01

Many prevention of mother-to-child HIV transmission (PMTCT) programs currently prioritize antiretroviral therapy (ART) for women with advanced HIV. Point-of-care (POC) CD4 assays may expedite the selection of three-drug ART instead of zidovudine, but are costlier than traditional laboratory assays. We used validated models of HIV infection to simulate pregnant, HIV-infected women (mean age 26 years, gestational age 26 weeks) in a general antenatal clinic in South Africa, and their infants. We examined two strategies for CD4 testing after HIV diagnosis: laboratory (test rate: 96%, result-return rate: 87%, cost: $14) and POC (test rate: 99%, result-return rate: 95%, cost: $26). We modeled South African PMTCT guidelines during the study period (WHO "Option A"): antenatal zidovudine (CD4 ≤350/μL) or ART (CD4>350/μL). Outcomes included MTCT risk at weaning (age 6 months), maternal and pediatric life expectancy (LE), maternal and pediatric lifetime healthcare costs (2013 USD), and cost-effectiveness ($/life-year saved). In the base case, laboratory led to projected MTCT risks of 5.7%, undiscounted pediatric LE of 53.2 years, and undiscounted PMTCT plus pediatric lifetime costs of $1,070/infant. POC led to lower modeled MTCT risk (5.3%), greater pediatric LE (53.4 years) and lower PMTCT plus pediatric lifetime costs ($1,040/infant). Maternal outcomes following laboratory were similar to POC (LE: 21.2 years; lifetime costs: $23,860/person). Compared to laboratory, POC improved clinical outcomes and reduced healthcare costs. In antenatal clinics implementing Option A, the higher initial cost of a one-time POC CD4 assay will be offset by cost-savings from prevention of pediatric HIV infection.

Use of Ancillary Tests When Determining Brain Death in Pediatric Patients in the United States.

PubMed

Lewis, Ariane; Adams, Nellie; Chopra, Arun; Kirschen, Matthew P

2017-10-01

Although pediatric brain death guidelines stipulate when ancillary testing should be used during brain death determination, little is known about the way these recommendations are implemented in clinical practice. We conducted a survey of pediatric intensivists and neurologists in the United States on the use of ancillary testing. Although most respondents noted they only performed an ancillary test if the clinical examination and apnea test could not be completed, 20% of 195 respondents performed an ancillary test for other reasons, including (1) to convince a family that objected to the brain death determination that a patient is truly dead (n = 21), (2) personal preference (n = 14), and (3) institutional requirement (n = 5). Our findings suggest that pediatricians use ancillary tests for a variety of reasons during brain death determination. Medical societies and governmental regulatory bodies must reinforce the need for homogeneity in practice.

Mouse Models Applied to the Research of Pharmacological Treatments in Asthma.

PubMed

Marqués-García, Fernando; Marcos-Vadillo, Elena

2016-01-01

Models developed for the study of asthma mechanisms can be used to investigate new compounds with pharmacological activity against this disease. The increasing number of compounds requires a preclinical evaluation before starting the application in humans. Preclinical evaluation in animal models reduces the number of clinical trials positively impacting in the cost and in safety. In this chapter, three protocols for the study of drugs are shown: a model to investigate corticoids as a classical treatment of asthma; a protocol to test the effects of retinoic acid (RA) on asthma; and a mouse model to test new therapies in asthma as monoclonal antibodies.

Human engineered heart tissue as a model system for drug testing.

PubMed

Eder, Alexandra; Vollert, Ingra; Hansen, Arne; Eschenhagen, Thomas

2016-01-15

Drug development is time- and cost-intensive and, despite extensive efforts, still hampered by the limited value of current preclinical test systems to predict side effects, including proarrhythmic and cardiotoxic effects in clinical practice. Part of the problem may be related to species-dependent differences in cardiomyocyte biology. Therefore, the event of readily available human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CM) has raised hopes that this human test bed could improve preclinical safety pharmacology as well as drug discovery approaches. However, hiPSC-CM are immature and exhibit peculiarities in terms of ion channel function, gene expression, structural organization and functional responses to drugs that limit their present usefulness. Current efforts are thus directed towards improving hiPSC-CM maturity and high-content readouts. Culturing hiPSC-CM as 3-dimensional engineered heart tissue (EHT) improves CM maturity and anisotropy and, in a 24-well format using silicone racks, enables automated, multiplexed high content readout of contractile function. This review summarizes the principal technology and focuses on advantages and disadvantages of this technology and its potential for preclinical drug screening. Copyright © 2015 Elsevier B.V. All rights reserved.

Targeting of hyperactivated mTOR signaling in high-risk acute lymphoblastic leukemia in a pre-clinical model.

PubMed

Hasan, Md Nabiul; Queudeville, Manon; Trentin, Luca; Eckhoff, Sarah Mirjam; Bronzini, Ilaria; Palmi, Chiara; Barth, Thomas; Cazzaniga, Giovanni; te Kronnie, Geertruy; Debatin, Klaus-Michael; Meyer, Lüder Hinrich

2015-01-30

Despite increasingly successful treatment of pediatric ALL, up to 20% of patients encounter relapse. By current biomarkers, the majority of relapse patients is initially not identified indicating the need for prognostic and therapeutic targets reflecting leukemia biology. We previously described that rapid engraftment of patient ALL cells transplanted onto NOD/SCID mice (short time to leukemia, TTLshort) is indicative of early patient relapse. Gene expression profiling identified genes coding for molecules involved in mTOR signaling to be associated with TTLshort/early relapse leukemia. Here, we now functionally address mTOR signaling activity in primograft ALL samples and evaluate mTOR pathway inhibition as novel treatment strategy for high-risk ALL ex vivo and in vivo. By analysis of S6-phosphorylation downstream of mTOR, increased mTOR activation was found in TTLshort/high-risk ALL, which was effectively abrogated by mTOR inhibitors resulting in decreased leukemia proliferation and growth. In a preclinical setting treating individual patient-derived ALL in vivo, mTOR inhibition alone, and even more pronounced together with conventional remission induction therapy, significantly delayed post-treatment leukemia reoccurrence in TTLshort/high-risk ALL. Thus, the TTLshort phenotype is functionally characterized by hyperactivated mTOR signaling and can effectively be targeted ex vivo and in vivo providing a novel therapeutic strategy for high-risk ALL.

Clinical Development of VEGF Signaling Pathway Inhibitors in Childhood Solid Tumors

PubMed Central

Yamashiro, Darrell J.; Fox, Elizabeth

2011-01-01

Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers. PMID:22042784

Preclinical experimental stress studies: protocols, assessment and comparison.

PubMed

Bali, Anjana; Jaggi, Amteshwar Singh

2015-01-05

Stress is a state of threatened homeostasis during which a variety of adaptive processes are activated to produce physiological and behavioral changes. Preclinical models are pivotal for understanding these physiological or pathophysiological changes in the body in response to stress. Furthermore, these models are also important for the development of novel pharmacological agents for stress management. The well described preclinical stress models include immobilization, restraint, electric foot shock and social isolation stress. Stress assessment in animals is done at the behavioral level using open field, social interaction, hole board test; at the biochemical level by measuring plasma corticosterone and ACTH; at the physiological level by measuring food intake, body weight, adrenal gland weight and gastric ulceration. Furthermore the comparison between different stressors including electric foot shock, immobilization and cold stressor is described in terms of intensity, hormonal release, protein changes in brain, adaptation and sleep pattern. This present review describes these preclinical stress protocols, and stress assessment at different levels. Copyright © 2014 Elsevier B.V. All rights reserved.

Translational Mouse Models of Autism: Advancing Toward Pharmacological Therapeutics

PubMed Central

Kazdoba, Tatiana M.; Leach, Prescott T.; Yang, Mu; Silverman, Jill L.; Solomon, Marjorie

2016-01-01

Animal models provide preclinical tools to investigate the causal role of genetic mutations and environmental factors in the etiology of autism spectrum disorder (ASD). Knockout and humanized knock-in mice, and more recently knockout rats, have been generated for many of the de novo single gene mutations and copy number variants (CNVs) detected in ASD and comorbid neurodevelopmental disorders. Mouse models incorporating genetic and environmental manipulations have been employed for preclinical testing of hypothesis-driven pharmacological targets, to begin to develop treatments for the diagnostic and associated symptoms of autism. In this review, we summarize rodent behavioral assays relevant to the core features of autism, preclinical and clinical evaluations of pharmacological interventions, and strategies to improve the translational value of rodent models of autism. PMID:27305922

The opportunistic screening of refractive errors in school-going children by pediatrician using enhanced Brückner test

PubMed Central

Jain, Piyush; Kothari, Mihir T; Gode, Vaibhav

2016-01-01

Aim: The aim of this study was to compare the results of enhanced Brückner test (EBT) performed by a pediatrician and an experienced pediatric ophthalmologist. Subjects and Methods: In this prospective double-masked cohort study, a pediatrician and a pediatric ophthalmologist performed the EBT in a classroom of a school in semi-dark lighting condition using a direct ophthalmoscope. The results of the test were compared using 2 × 2 Bayesian table and kappa statistics. The findings of the pediatric ophthalmologists were considered gold standard. Results: Two hundred and thirty-six eyes of 118 subjects, mean age 6.8 ± 0.5 years (range, 5.4–7.8 years), were examined. The time taken to complete this test was <10 s per subject. The ophthalmologist identified 59 eyes as ametropic (12 hyperopic and 47 myopic eyes) and 177 as emmetropic compared to 61 eyes as ametropic and 175 emmetropic by pediatrician. The prevalence of the test positive was 25.9%. The sensitivity of the pediatrician was 90.2%, specificity was 97.7%, predictive value of the positive test was 93.2%, and predictive value of the negative test was 96.6%. The clinical agreement (kappa) between the pediatric ophthalmologist and the pediatrician was 0.9. Conclusion: The results of the EBT performed by pediatrician were comparable to that of an experienced pediatric ophthalmologist. Opportunistic screening of refractive errors using EBT by a pediatrician can be an important approach in the detection of ametropia in children. PMID:27905334

Memory and Learning in Pediatric Bipolar Disorder.

ERIC Educational Resources Information Center

McClure, Erin B.; Treland, Julia E.; Snow, Joseph; Dickstein, Daniel P.; Towbin, Kenneth E.; Charney, Dennis S.; Pine, Daniel S.; Leibenluft, Ellen

2005-01-01

Objective: To test the hypothesis that patients with pediatric bipolar disorder (PBPD) would demonstrate impairment relative to diagnosis-free controls of comparable age, gender, and IQ on measures of memory functioning. Method: The authors administered a battery of verbal and visuospatial memory tests to 35 outpatients with PBPD and 20 healthy…

Are Prior Experience and Subspecialty Training Time Predictive of Pediatric Anesthesia Exit Exam Scores for Rotating CA-2 Residents?

PubMed

Nelson, Jonathon H; Deutsch, Nina; Cohen, Ira T; Reddy, Srijaya K

2017-01-01

Anesthesiology residency programs commonly have rotations at free-standing children's hospitals to provide and/or supplement their residents' training in pediatric anesthesia. Length and timing of these rotations differ from program to program as can their residents' existing medical knowledge and clinical skills. We predicted that residents with prior pediatric anesthesia experience, who rotate at our pediatric institution for two consecutive months, will score higher on an exit exam compared to residents without prior pediatric experience or those that only rotate for one month. A 50-question multiple choice test was created using pediatric questions released from The American Board of Anesthesiology (ABA) written examinations. The test was administered and proctored at the end of each rotation. Study participants came from three different programs: Program A offers prior pediatric anesthesia experience and a one month rotation; Program B - offers prior pediatric anesthesia experience and a two month rotation; and Program C - does not offer prior pediatric anesthesia experience but includes a two month rotation. The 2014-2015 cohort consisted of 26 rotating second-year clinical anesthesia (CA-2) residents. One resident's exam scores were excluded from this study due to protocol violation. Mean exam scores for Program A, B, and C were 70.5% ± 5.7, 64.2% ± 7.0, and 67.3% ± 4.3, respectively. There was no statistically significant difference in the exit exam scores among the three groups. Prior pediatric anesthesia experience or length of time for subspecialty rotation was not associated with any significant difference in exit exam scores for CA-2 residents.

A new paradigm for obtaining marketing approval for pediatric-sized prosthetic heart valves.

PubMed

Yoganathan, Ajit P; Fogel, Mark; Gamble, Susan; Morton, Michael; Schmidt, Paul; Secunda, Jeff; Vidmar, Sara; Del Nido, Pedro

2013-10-01

Congenital heart valve disease is one of the most common abnormalities in children. There are limited technological solutions available for treating children with congenital heart valve diseases. The aim of this study is to provide the details of the consensus reached in terms of pediatric definitions, design approach, in vitro testing, and clinical trials, which may be used as guidance for developing prosthetic heart valves for the pediatric indication. In stark contrast to the various designs of adult-sized replacement valves available in the market, there are no Food and Drug Administration (FDA)-approved prosthetic heart valves available for use in the pediatric population. There is a pressing need for FDA-approved pediatric valve devices in the United States. The pediatric patient population has been typically excluded from replacement heart valve trials for several reasons. In January 2010, heart valve manufacturers and pediatric clinicians collaborated with academicians and FDA staff in a workshop to suggest ways to successfully evaluate pediatric prosthetic valves and conduct pediatric clinical trials to provide acceptable heart valve replacement options for this patient population. Recommendations, derived from ISO 5840:2005 and the 2010 FDA Draft Replacement Heart Valve Guidance, are provided for hydrodynamic, durability, and fatigue testing. The article specifically addresses in vitro and premarket and postmarket approval clinical studies that should be considered by a heart valve manufacturer for obtaining regulatory approval of pediatric sizes of prosthetic heart valve designs that are already approved for adult clinical use. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

A drop in pediatric subject examination scores after curriculum changes that emphasize general pediatric topics.

PubMed

Potts, M J; Phelan, K W

1997-09-01

To determine whether emphasizing a limited number of general pediatric objectives and using a test based on them would improve student knowledge of the topic areas. Before-after trial. Community-based medical school. Third-year medical students on a required clerkship in pediatrics. Six core objectives: recognizing the seriously ill child, stabilizing such a child, fluid and electrolyte requirements and therapy, newborn care, well child care, and variability of normal vital signs in children based on their age were defined and a modified essay examination was constructed. The test was given to pediatric students close to the end of their clerkship. In study year 1, no warning was given about the examination and results did not affect student grades. In study year 2, passing all items was a requirement and failure required remedial oral examination of any missed items. All students completed the National Board of Medical Examiners pediatric subject examination. For 7 of 8 essay items, significant increases in numbers of students passing were seen in study year 2, but students scored 51 points lower on the National Board of Medical Examiners pediatric subject examination (P=.002). The decrease in scores was not seen in any other clerkship or among pediatric students from a different campus of the medical school. Emphasis on core objectives and an essay examination significantly improved students' knowledge of the defined topics but decreased the scores on the National Board of Medical Examiners subject examination. This may be attributable to a difference in content between the 2 tests. Faculty proposing new curriculum guidelines need to review student assessment methods to avoid such unexpected changes in scores.

The Current State of Pediatric Sports Medicine: A Workforce Analysis.

PubMed

Engelman, Glenn; Koutures, Chris; Provance, Aaron

2016-01-01

Pediatric sports medicine is an evolving pediatric subspecialty. No workforce data currently exists describing the current state of pediatric sports medicine. The goal of this survey is to contribute information to the practicing pediatric sports medicine specialist, employers and other stakeholders regarding the current state of pediatric sports medicine. The Workforce Survey was conducted by the American Academy of Pediatrics (AAP) Division of Workforce and Medical Education Policy (WMEP) and included a 44-item standard questionnaire online addressing training, clinical practice and demographic characteristics as well as the 24-item AAP Council on Sports Medicine and Fitness (COSMF) questionnaire. Descriptive statistics were used to summarize all survey responses. Bivariate relationships were tested for statistical significance using Chi square. 145 surveys were returned, which represented a 52.7% response rate for eligible COSMF members and board certified non-council responders. The most common site of employment among respondents was university-based clinics. The respondents board certified in sports medicine were significantly more likely to perform fracture management, casting and splinting, neuropsychological testing and injections compared to those not board certified in sports medicine. A large proportion of respondents held an academic/medical school appointment. Increases were noted in both patient volume and the complexity of the injuries the specialists were treating. This pediatric sports medicine workforce study provides previously unappreciated insight into practice arrangements, weekly duties, procedures, number of patients seen, referral patterns, and potential future trends of the pediatric sports medicine specialist.

Teaching pediatric laboratory medicine to pathology residents.

PubMed

Pysher, Theodore J; Bach, Philip R; Geaghan, Sharon M; Hamilton, Marilyn S; Laposata, Michael; Lockitch, Gillian; Brugnara, Carlo; Coffin, Cheryl M; Pasquali, Marzia; Rinaldo, Piero; Roberts, William L; Rutledge, Joe C; Ashwood, Edward R; Blaylock, Robert C; Campos, Joseph M; Goldsmith, Barbara; Jones, Patricia M; Lim, Megan; Meikle, A Wayne; Perkins, Sherrie L; Perry, Deborah A; Petti, Cathy A; Rogers, Beverly B; Steele, Paul E; Weiss, Ronald L; Woods, Gail

2006-07-01

Laboratory data are essential to the medical care of fetuses, infants, children, and adolescents. However, the performance and interpretation of laboratory tests on specimens from these patients, which may constitute a significant component of the workload in general hospitals and integrated health care systems as well as specialized perinatal or pediatric centers, present unique challenges to the clinical pathologist and the laboratory. Therefore, pathology residents should receive training in pediatric laboratory medicine. Children's Health Improvement through Laboratory Diagnostics, a group of pathologists and laboratory scientists with interest and expertise in pediatric laboratory medicine, convened a task force to develop a list of curriculum topics, key resources, and training experiences in pediatric laboratory medicine for trainees in anatomic and clinical pathology or straight clinical pathology residency programs and in pediatric pathology fellowship programs. Based on the experiences of 11 training programs, we have compiled a comprehensive list of pediatric topics in the areas of clinical chemistry, endocrinology, hematology, urinalysis, coagulation medicine, transfusion medicine, immunology, microbiology and virology, biochemical genetics, cytogenetics and molecular diagnostics, point of care testing, and laboratory management. This report also includes recommendations for training experiences and a list of key texts and other resources in pediatric laboratory medicine. Clinical pathologists should be trained to meet the laboratory medicine needs of pediatric patients and to assist the clinicians caring for these patients with the selection and interpretation of laboratory studies. This review helps program directors tailor their curricula to more effectively provide this training.

A low-cost touchscreen operant chamber using a Raspberry Pi™.

PubMed

O'Leary, James D; O'Leary, Olivia F; Cryan, John F; Nolan, Yvonne M

2018-03-08

The development of a touchscreen platform for rodent testing has allowed new methods for cognitive testing that have been back-translated from clinical assessment tools to preclinical animal models. This platform for cognitive assessment in animals is comparable to human neuropsychological tests such as those employed by the Cambridge Neuropsychological Test Automated Battery, and thus has several advantages compared to the standard maze apparatuses typically employed in rodent behavioral testing, such as the Morris water maze. These include improved translation of preclinical models, as well as high throughput and the automation of animal testing. However, these systems are relatively expensive, which can impede progress for researchers with limited resources. Here we describe a low-cost touchscreen operant chamber based on the single-board computer, Raspberry Pi TM , which is capable of performing tasks similar to those supported by current state-of-the-art systems. This system provides an affordable alternative for cognitive testing in a touchscreen operant paradigm for researchers with limited funding.

Pediatric Primary Care Providers' Relationships with Mental Health Care Providers: Survey Results

ERIC Educational Resources Information Center

Pidano, Anne E.; Honigfeld, Lisa; Bar-Halpern, Miri; Vivian, James E.

2014-01-01

Background: As many as 20 % of children have diagnosable mental health conditions and nearly all of them receive pediatric primary health care. However, most children with serious mental health concerns do not receive mental health services. This study tested hypotheses that pediatric primary care providers (PPCPs) in relationships with mental…

Vascular Access Procedures

MedlinePlus

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Elective penicillin skin testing in a pediatric outpatient setting.

PubMed

Jost, Barbara Capes; Wedner, H James; Bloomberg, Gordon R

2006-12-01

Adverse reactions associated with penicillin-type antibiotics are common in pediatric practice, leading to the subsequent unnecessary use of alternative antibiotics. IgE-mediated penicillin allergy represents only a fraction of these adverse reactions. To examine (1) the trend of penicillin skin test reactivity during a recent 10-year interval, (2) the relative distribution of specific reagents related to a positive skin test result, and (3) skin test reactivity as a function of reaction history. Penicillin testing using 3 reagents--benzylpenicilloyl polylysine, penicillin G, and sodium penicilloate (penicillin A)--was conducted in a prospective study of 359 consecutive patients referred to an outpatient pediatric allergy clinic between January 1, 1993, and May 31, 2003. We also retrospectively reviewed penicillin skin test results for 562 children previously tested between January 1, 1979, and December 31, 1992. Between 1993 and 2003, the prevalence of penicillin skin test sensitivity markedly declined. Of all the positive skin test results between 1979 and 2002, either penicillin G or sodium penicilloate or both identified 34%, with sodium penicilloate alone responsible for 8.5%. The rate of positive skin test reactions was not significantly different between patients with vs without a history of suggestive IgE-mediated reactions. A marked decline in penicillin skin test sensitivity in the pediatric age group is identified. The minor determinant reagents penicillin G and sodium penicilloate are both necessary for determining potential penicillin allergy. Relating history alone to potential penicillin sensitivity is unreliable in predicting the presence or absence of a positive skin test result.

The interplay between academic performance and quality of life among preclinical students.

PubMed

Shareef, Mohammad Abrar; AlAmodi, Abdulhadi A; Al-Khateeb, Abdulrahman A; Abudan, Zainab; Alkhani, Mohammed A; Zebian, Sanderlla I; Qannita, Ahmed S; Tabrizi, Mariam J

2015-10-31

The high academic performance of medical students greatly influences their professional competence in long term career. Meanwhile, medical students greatly demand procuring a good quality of life that can help them sustain their medical career. This study examines validity and reliability of the tool among preclinical students and testifies the influence of their scholastic performance along with gender and academic year on their quality of life. A cross sectional study was conducted by distributing World Health Organization Quality of Life, WHOQOL-BREF, survey among medical students of year one to three at Alfaisal University. For validity, item discriminate validity(IDV) and confirmatory factor analysis were measured and for reliability, Cronbach's α test and internal item consistency(IIC) were examined. The association of GPA, gender and academic year with all major domains was drawn using Pearson's correlation, independent samples t-test and one-way ANOVA, respectively. A total of 335 preclinical students have responded to this questionnaire. The construct has demonstrated an adequate validity and good reliability. The high academic performance of students positively correlated with physical (r = 0.23, p < 0.001), psychological health (r = 0.29, p < 0.001), social relations (r = 0.11, p = 0.03) and environment (r = 0.23, p < 0.001). Male student scored higher than female peers in physical and psychological health. This study has identified a direct relationship between the academic performance of preclinical students and their quality of life. The WHOQOL-BREF is a valid and reliable tool among preclinical students and the positive direction of high academic performance with greater QOL suggests that academic achievers procure higher satisfaction and poor achievers need a special attention for the improvement of their quality of life.

Office spirometry in primary care pediatrics: a pilot study.

PubMed

Zanconato, Stefania; Meneghelli, Giorgio; Braga, Raffaele; Zacchello, Franco; Baraldi, Eugenio

2005-12-01

The aim of this study was to investigate the validity of office spirometry in primary care pediatric practices. Ten primary care pediatricians undertook a spirometry training program that was led by 2 pediatric pulmonologists from the Pediatric Department of the University of Padova. After the pediatricians' training, children with asthma or persistent cough underwent a spirometric test in the pediatrician's office and at a pulmonary function (PF) laboratory, in the same day in random order. Both spirometric tests were performed with a portable turbine flow sensor spirometer. We assessed the quality of the spirometric tests and compared a range of PF parameters obtained in the pediatricians' offices and in the PF laboratory according to the Bland and Altman method. A total of 109 children (mean age: 10.4 years; range: 6-15) were included in the study. Eighty-five (78%) of the spirometric tests that were performed in the pediatricians' offices met all of the acceptability and reproducibility criteria. The 24 unacceptable test results were attributable largely to a slow start and failure to satisfy end-of-test criteria. Only the 85 acceptable spirometric tests were considered for analysis. The agreement between the spirometric tests that were performed in the pediatrician's office and in the PF laboratory was good for the key parameters (forced vital capacity, forced expiratory volume in 1 second, and forced expiratory flow between 25% and 75%). The repeatability coefficient was 0.26 L for forced expiratory volume in 1 second (83 of 85 values fall within this range), 0.30 L for forced vital capacity (81 values fall within this range), and 0.58 L/s for forced expiratory flow between 25% and 75% (82 values fall within this range). In 79% of cases, the primary care pediatricians interpreted the spirometric tests correctly. It seems justifiable to perform spirometry in pediatric primary care, but an integrated approach involving both the primary care pediatrician and certified pediatric respiratory medicine centers is recommended because effective training and quality assurance are vital prerequisites for successful spirometry.

Theory of mind and empathy in preclinical and clinical Huntington’s disease

PubMed Central

Adjeroud, Najia; Besnard, Jérémy; Massioui, Nicole El; Verny, Christophe; Prudean, Adriana; Scherer, Clarisse; Gohier, Bénédicte; Bonneau, Dominique

2016-01-01

We investigated cognitive and affective Theory of Mind (ToM) and empathy in patients with premanifest and manifest Huntington’s disease (HD). The relationship between ToM performance and executive skills was also examined. Sixteen preclinical and 23 clinical HD patients, and 39 healthy subjects divided into 2 control groups were given a French adaptation of the Yoni test (Shamay-Tsoory, S.G., Aharon-Peretz, J. (2007). Dissociable prefrontal networks for cognitive and affective theory of mind: a lesion study. Neuropsychologia, 45(3), 3054–67) that examines first- and second-order cognitive and affective ToM processing in separate conditions with a physical control condition. Participants were also given questionnaires of empathy and cognitive tests which mainly assessed executive functions (inhibition and mental flexibility). Clinical HD patients made significantly more errors than their controls in the first- and second-order cognitive and affective ToM conditions of the Yoni task, but exhibited no empathy deficits. However, there was no evidence that ToM impairment was related to cognitive deficits in these patients. Preclinical HD patients were unimpaired in ToM tasks and empathy measures compared with their controls. Our results are consistent with the idea that impaired affective and cognitive mentalizing emerges with the clinical manifestation of HD, but is not necessarily part of the preclinical stage. Furthermore, these impairments appear independent of executive dysfunction and empathy. PMID:26211015

Comparison of pediatric radiation dose and vessel visibility on angiographic systems using piglets as a surrogate: antiscatter grid removal vs. lower detector air kerma settings with a grid — a preclinical investigation

PubMed Central

Racadio, John M.; Abruzzo, Todd A.; Johnson, Neil D.; Patel, Manish N.; Kukreja, Kamlesh U.; den Hartog, Mark. J. H.; Hoornaert, Bart P.A.; Nachabe, Rami A.

2015-01-01

The purpose of this study was to reduce pediatric doses while maintaining or improving image quality scores without removing the grid from X‐ray beam. This study was approved by the Institutional Animal Care and Use Committee. Three piglets (5, 14, and 20 kg) were imaged using six different selectable detector air kerma (Kair) per frame values (100%, 70%, 50%, 35%, 25%, 17.5%) with and without the grid. Number of distal branches visualized with diagnostic confidence relative to the injected vessel defined image quality score. Five pediatric interventional radiologists evaluated all images. Image quality score and piglet Kair were statistically compared using analysis of variance and receiver operating curve analysis to define the preferred dose setting and use of grid for a visibility of 2nd and 3rd order vessel branches. Grid removal reduced both dose to subject and imaging quality by 26%. Third order branches could only be visualized with the grid present; 100% detector Kair was required for smallest pig, while 70% detector Kair was adequate for the two larger pigs. Second order branches could be visualized with grid at 17.5% detector Kair for all three pig sizes. Without the grid, 50%, 35%, and 35% detector Kair were required for smallest to largest pig, respectively. Grid removal reduces both dose and image quality score. Image quality scores can be maintained with less dose to subject with the grid in the beam as opposed to removed. Smaller anatomy requires more dose to the detector to achieve the same image quality score. PACS numbers: 87.53.Bn, 87.57.N‐, 87.57.cj, 87.59.cf, 87.59.Dj PMID:26699297

CD22ΔE12 as a molecular target for corrective repair using a RNA trans-splicing strategy: Anti-leukemic activity of a rationally designed RNA trans-splicing molecule

PubMed Central

Uckun, Fatih M.; Qazi, Sanjive; Ma, Hong; Reaman, Gregory H.; Mitchell, Lloyd G.

2015-01-01

Our recent studies have demonstrated that the CD22 exon 12 deletion (CD22ΔE12) is a characteristic genetic defect of therapy-refractory clones in pediatric B-precursor acute lymphoblastic leukemia (BPL) and implicated the CD22ΔE12 genetic defect in the aggressive biology of relapsed or therapy-refractory pediatric BPL. The purpose of the present study was to further evaluate the biologic significance of the CD22ΔE12 molecular lesion and determine if it could serve as a molecular target for corrective repair using RNA trans-splicing therapy. We show that both pediatric and adult B-lineage lymphoid malignancies are characterized by a very high incidence of the CD22ΔE12 genetic defect. We provide experimental evidence that the correction of the CD22ΔE12 genetic defect in human CD22ΔE12+ BPL cells using a rationally designed CD22 RNA trans-splicing molecule (RTM) caused a pronounced reduction of their clonogenicity. The RTM-mediated correction replaced the downstream mutation-rich segment of Intron 12 and remaining segments of the mutant CD22 pre-mRNA with wildtype CD22 Exons 10-14, thereby preventing the generation of the cis-spliced aberrant CD22ΔE12 product. The anti-leukemic activity of this RTM against BPL xenograft clones derived from CD22ΔE12+ leukemia patients provides the preclinical proof-of-concept that correcting the CD22ΔE12 defect with rationally designed CD22 RTMs may provide the foundation for therapeutic innovations that are needed for successful treatment of high-risk and relapsed BPL patients. PMID:25567759

Magnetic Resonance (MR) Defecography

MedlinePlus

... have a personal story about radiology? Share your patient story here Pediatric Content Some imaging tests and treatments have special pediatric considerations. The teddy bear denotes child-specific content. Related ...

Marijuana Use in Epilepsy: The Myth and the Reality.

PubMed

Detyniecki, Kamil; Hirsch, Lawrence

2015-10-01

Marijuana has been utilized as a medicinal plant to treat a variety of conditions for nearly five millennia. Over the past few years, there has been an unprecedented interest in using cannabis extracts to treat epilepsy, spurred on by a few refractory pediatric cases featured in the media that had an almost miraculous response to cannabidiol-enriched marijuana extracts. This review attempts to answer the most important questions a clinician may have regarding the use of marijuana in epilepsy. First, we review the preclinical and human evidences for the anticonvulsant properties of the different cannabinoids, mainly tetrahydrocannabinol (THC) and cannabidiol (CBD). Then, we explore the safety data from animal and human studies. Lastly, we attempt to reconcile the controversy regarding physicians' and patients' opinions about whether the available evidence is sufficient to recommend the use of marijuana to treat epilepsy.

The Pediatric Test of Brain Injury: Development and Interpretation

ERIC Educational Resources Information Center

Hotz, Gillian A.; Helm-Estabrooks, Nancy; Nelson, Nickola Wolf; Plante, Elena

2009-01-01

The Pediatric Test of Brain Injury (PTBI) is designed to assess neurocognitive, language, and literacy abilities that are relevant to the school curriculum of children and adolescents recovering from brain injury. The PTBI is intended to help clinicians establish baseline levels of cognitive-linguistic abilities in the acute stages of recovery,…

Radiology in Medical Education: A Pediatric Radiology Elective as a Template for Other Radiology Courses.

PubMed

Hilmes, Melissa A; Hyatt, Eddie; Penrod, Cody H; Fleming, Amy E; Singh, Sudha P

2016-03-01

Traditionally, the pediatric radiology elective for medical students and pediatric residents constituted a morning teaching session focused mainly on radiography and fluoroscopy. A more structured elective was desired to broaden the exposure to more imaging modalities, create a more uniform educational experience, and include assessment tools. In 2012, an introductory e-mail and formal syllabus, including required reading assignments, were sent to participants before the start date. A rotating weekly schedule was expanded to include cross-sectional imaging (ultrasound, CT, MR) and nuclear medicine. The schedule could accommodate specific goals of the pediatric resident or medical student, as requested. Starting in 2013, an online pre-test and post-test were developed, as well as an online end-of-rotation survey specific to the pediatric radiology elective. Taking the Image Gently pledge was required. A scavenger hunt tool, cue cards, and electronic modules were added. Pre-test and post-test scores, averaged over 2 years, showed improvement in radiology knowledge, with scores increasing by 27% for medical students and 21% for pediatric residents. Surveys at the end of the elective were overwhelmingly positive, with constructive criticism and complimentary comments. We have successfully created an elective experience in radiology that dedicates time to education while preserving the workflow of radiologists. We have developed tools to provide a customized experience with many self-directed learning opportunities. Our tools and techniques are easily translatable to a general or adult radiology elective. Copyright © 2016 American College of Radiology. Published by Elsevier Inc. All rights reserved.

Improving Translation from Preclinical Studies to Clinical Trials in Acute Kidney Injury.

PubMed

Fiorentino, Marco; Kellum, John A

2018-05-23

Several cellular and molecular targets and mechanisms have been investigated in preclinical studies of acute kidney injury (AKI), but translation in successful clinical studies has failed to date. This article reviews many issues that have limited this and the potential future perspectives in AKI prevention and treatment. Preclinical models of AKI should closely mimic the complexity of human AKI, considering the importance of several comorbidities in determining the clinical course and outcomes in the human disease. Moreover, studies should test novel interventions in models where AKI is already established, instead of focusing only at primary prevention. AKI definitions and endpoints in animal studies should be similar to those applied in clinical studies; in particular, AKI biomarkers should be implemented to guide patient selection for clinical trials and monitor intervention efficacy. In this scenario, cell-cycle arrest biomarkers have been widely investigated as AKI predictors in both preclinical and clinical studies and they serve as useful tools for future interventional studies. A better understanding of human AKI through a large collection of biological samples and kidney biopsies and omics applications, and an iterative relationship between preclinical and clinical studies are critical steps to improve future preclinical models and clinical trials. Finally, given the great variability in clinical manifestation of AKI, a strong collaboration between research centers and industry is recommended. Key messages: Several methodological issues have hampered the translation of basic research findings in clinical studies, and overcoming these obstacles is necessary to achieve success. © 2018 S. Karger AG, Basel.

Assessment of the knowledge and attitudes regarding HIV/AIDS among pre-clinical medical students in Israel

PubMed Central

2014-01-01

Background Today’s medical students are the future physicians of people living with HIV/AIDS (PLWHA). It is therefore essential that medical students possess the appropriate knowledge and attitudes regarding PLWHA. This study aims to evaluate knowledge and attitudes of pre-clinical Israeli medical students and to assess whether their knowledge and attitudes change throughout their pre-clinical studies. Methods A cross-sectional study was conducted among all pre-clinical medical students from the four medical schools in Israel during the academic year of 2010/2011 (a total of 1,470 students). A self-administered questionnaire was distributed. The questionnaire sought student responses pertaining to knowledge of HIV transmission and non-transmission routes, basic knowledge of HIV/AIDS treatment and attitudes towards HIV/AIDS. Results The study’s response rate was 62.24 percent. Knowledge among pre-clinical medical students was generally high and showed a statistically significant improvement as students progressed through their pre-clinical studies. However, there were some misconceptions, mostly regarding HIV transmission via breastfeeding and knowledge of HIV prevention after exposure to the virus. Students’ attitudes were found to include stigmatizing notions. Furthermore, the majority of medical students correlated HIV with shame and fear. In addition, students’ attitudes toward HIV testing and providing confidential medical information were contradictory to health laws, protocols and guidelines. Overall, no positive changes in students’ attitudes were observed during the pre-clinical years of medical school. Conclusion The knowledge of pre-clinical medical students in Israel is generally high, although there are some knowledge inadequacies that require more emphasis in the curricula of the medical schools. Contrary to HIV-related knowledge, medical students’ attitudes are unaffected by their progression through medical school. Therefore, medical schools in Israel should modify their curricula to include teaching methods aimed at improving HIV-related attitudes and adherence to medical professionalism. PMID:24650351

Differences in sex distribution, anatomic location and MR imaging appearance of pediatric compared to adult chordomas.

PubMed

Sebro, Ronnie; DeLaney, Thomas; Hornicek, Francis; Schwab, Joseph; Choy, Edwin; Nielsen, G Petur; Rosenthal, Daniel I

2016-09-08

Chordomas are rare malignancies that primarily affect adults, but also rarely affect pediatric patients. We compared the imaging appearance, demographic and anatomic distributions of adult and pediatric chordomas in a large cohort. We performed a retrospective review of medical records of 220 subjects with histologically confirmed chordomas of the axial skeleton and pre-treatment magnetic resonance imaging studies. Age, sex, type of chordoma (conventional, chondroid or dedifferentiated), the anatomic location of the chordoma, as well as whether the lesion was primarily extra-osseous were recorded. Pediatric subjects were less than 21 years at the time of diagnosis. Binomial two-sample tests of proportions and Fisher's exact tests were used to compare proportions between the pediatric and adult subjects. Fifty six pediatric subjects (58.9 % female) and 164 adult subjects (42.1 % female) were identified. The proportion of female subjects with chordomas was significantly higher in the pediatric cohort compared to the adult cohort (P = 0.04). Most chordomas occur in Caucasians, however African-Americans were more represented in the pediatric cohort than in the adult cohort (P = 0.01). 69.6 % (39/56) of the pediatric chordomas involved the clivus/skull base and cervical spine compared to 29.3 % (48/164) of the adult chordomas (P = 1.99 × 10(-7)). Only 1.8 % (1/56) of the pediatric chordomas was in the sacrococcygeal region compared to 36.0 % (59/164) of the adult chordomas (P = 2.55 × 10(-8)). In cases where pre-treatment imaging was available, 93.8 % (16/17) of pediatric chordomas were predominantly extra-osseous compared to 76.7 % (46/60) of adult chordomas (P = 0.17). Pediatric chordomas more often affect females and occur most frequently at the craniocervical junction with decrease in incidence distally in the spine, whereas adult chordomas most frequently involve the craniocervical and sacrococcygeal regions.

Evaluation of Pediatric Questions on the Orthopaedic In-Training Examination-An Update.

PubMed

Murphy, Robert F; Nunez, Leah; Barfield, William R; Mooney, James F

2017-09-01

Pediatric orthopaedics is tested frequently on the Orthopaedic In-Training Examination (OITE). The most recent data on the pediatrics section of the OITE were generated from content 10 years old. The purpose of this study is to assess the pediatric orthopaedic questions on the 2011 to 2014 OITE, and to compare question categories and cognitive taxonomy with previous data. Four years (2011 to 2014) of OITE questions, answers, and references were reviewed. The number of pediatric questions per year was recorded, as well as presence of a clinical photo or imaging modality. Each question was categorized and assigned a cognitive taxonomy level. Categories included: knowledge; knowledge-treatment modalities; diagnosis; diagnosis/recognition of associated conditions; diagnosis/further studies; and diagnosis/treatment. Cognitive taxonomy levels included: simple recall, interpretation of data, and advanced problem-solving. The 3 most commonly covered topics were upper extremity trauma (17.4%), scoliosis (10.1%), and developmental dysplasia of the hip (5.7%). Compared with previous data, the percentage of pediatric questions was constant (13% vs. 14%). Categorically, the more recent OITE examinations contained significantly fewer questions testing simple knowledge (19% vs. 39%, P=0.0047), and significantly more questions testing knowledge of treatment modalities (17% vs. 9%, P=0.016) and diagnosis with associated conditions (19% vs. 9%, P=0.0034). Regarding cognitive taxonomy, there was a significant increase in the average number of questions that required advanced problem-solving (57% vs. 46%, P=0.048). Significantly more questions utilized clinical photographs and imaging studies (62% vs. 48%, P=0.012). The most common reference materials provided to support correct responses included Lovell and Winter's Pediatric Orthopaedics (25.7%) and the Journal of Pediatric Orthopaedics (23.4%). Although the percentage of pediatric questions on the OITE has remained essentially constant, the percentage of questions requiring advanced problem-solving or interpretation of images has increased significantly in the past 10 years. Knowledge of question type and content may be helpful for those involved in resident education and in the development of didactic pediatric orthopaedic curricula. Level IV.

Pediatric sample inclusion in an opt-out biorepository linking DNA to de-identified medical records: Pediatric BioVU

PubMed Central

McGregor, Tracy L.; Van Driest, Sara L.; Brothers, Kyle B.; Bowton, Erica A.; Muglia, Louis J.; Roden, Dan M.

2013-01-01

The Vanderbilt DNA repository, BioVU, links DNA from leftover clinical blood samples to de-identified electronic medical records. After initiating adult sample collection, pediatric extension required consideration of ethical concerns specific to pediatrics and implementation of specialized DNA extraction methods. In the first year of pediatric sample collection, over 11,000 samples were included from individuals younger than 18 years. We compared the pediatric BioVU cohort to the overall Vanderbilt University Medical Center pediatric population and found similar demographic characteristics; however, the BioVU cohort has higher rates of select diseases, medication exposures, and laboratory testing, demonstrating enriched representation of severe or chronic disease. This unbalanced sample accumulation may accelerate research of some cohorts, but also may limit study of relatively benign conditions and the accrual of unaffected and unbiased control samples. BioVU represents a feasible model for pediatric DNA biobanking but involves both ethical and practical considerations specific to the pediatric population. PMID:23281421

Preclinical Assessment of CD171-Directed CAR T-cell Adoptive Therapy for Childhood Neuroblastoma: CE7 Epitope Target Safety and Product Manufacturing Feasibility.

PubMed

Künkele, Annette; Taraseviciute, Agne; Finn, Laura S; Johnson, Adam J; Berger, Carolina; Finney, Olivia; Chang, Cindy A; Rolczynski, Lisa S; Brown, Christopher; Mgebroff, Stephanie; Berger, Michael; Park, Julie R; Jensen, Michael C

2017-01-15

The identification and vetting of cell surface tumor-restricted epitopes for chimeric antigen receptor (CAR)-redirected T-cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas and, specifically, on the glycosylation-dependent tumor-specific epitope recognized by the CE7 monoclonal antibody. CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays. The safety of targeting the CE7 epitope of CD171 with CE7-CAR T cells was evaluated in a preclinical rhesus macaque trial on the basis of CD171 homology and CE7 cross reactivity. The feasibility of generating bioactive CAR T cells from heavily pretreated pediatric patients with recurrent/refractory disease was assessed. CD171 is uniformly and abundantly expressed by neuroblastoma tumor specimens obtained at diagnoses and relapse independent of patient clinical risk group. CD171 expression in normal tissues is similar in humans and rhesus macaques. Infusion of up to 1 × 10 8 /kg CE7-CAR + CTLs in rhesus macaques revealed no signs of specific on-target off-tumor toxicity. Manufacturing of lentivirally transduced CD4 + and CD8 + CE7-CAR T-cell products under GMP was successful in 4 out of 5 consecutively enrolled neuroblastoma patients in a phase I study. All four CE7-CAR T-cell products demonstrated in vitro and in vivo antitumor activity. Our preclinical assessment of the CE7 epitope on CD171 supports its utility and safety as a CAR T-cell target for neuroblastoma immunotherapy. Clin Cancer Res; 23(2); 466-77. ©2016 AACR. ©2016 American Association for Cancer Research.

Importance of murine study design for testing toxicity of retroviral vectors in support of phase I trials.

PubMed

Will, Elke; Bailey, Jeff; Schuesler, Todd; Modlich, Ute; Balcik, Brenden; Burzynski, Ben; Witte, David; Layh-Schmitt, Gerlinde; Rudolph, Cornelia; Schlegelberger, Brigitte; von Kalle, Christof; Baum, Christopher; Sorrentino, Brian P; Wagner, Lars M; Kelly, Patrick; Reeves, Lilith; Williams, David A

2007-04-01

Although retroviral vectors are one of the most widely used vehicles for gene transfer, there is no uniformly accepted pre-clinical model defined to assess their safety, in particular their risk related to insertional mutagenesis. In the murine pre-clinical study presented here, 40 test and 10 control mice were transplanted with ex vivo manipulated bone marrow cells to assess the long-term effects of the transduction of hematopoietic cells with the retroviral vector MSCV-MGMT(P140K)wc. Test mice had significant gene marking 8-12 months post-transplantation with an average of 0.93 vector copies per cell and 41.5% of peripheral blood cells expressing the transgene MGMT(P140K), thus confirming persistent vector expression. Unexpectedly, six test mice developed malignant lymphoma. No vector was detected in the tumor cells of five animals with malignancies, indicating that the malignancies were not caused by insertional mutagenesis or MGMT(P140K) expression. Mice from a concurrent study with a different transgene also revealed additional cases of vector-negative lymphomas of host origin. We conclude that the background tumor formation in this mouse model complicates safety determination of retroviral vectors and propose an improved study design that we predict will increase the relevance and accuracy of interpretation of pre-clinical mouse studies.

Translation and cultural adaptation of the Pediatric Eosinophilic Esophagitis Symptom Score (PEESS v2.0).

PubMed

Santos, Maria Fernanda Oliveira; Barros, Cristina Palmer; Silva, Carlos Henrique Martins da; Paro, Helena Borges Martins da Silva

2017-11-04

To translate and culturally adapt the Pediatric Eosinophilic Esophagitis Symptom Score (version 2.0), a tool used to assess pediatric eosinophilic esophagitis symptoms reported by patients and/or their parents/caregivers. The Pediatric Eosinophilic Esophagitis Symptom Score was translated through the following stages: initial translation, back-translation, and consensus of independent reviewers through the Delphi technique. The pre-final version of the Pediatric Eosinophilic Esophagitis Symptom Score was applied to five 8-to-18-year-old patients and to ten parents of two-to-18-year-old patients from an outpatient pediatric gastroenterology service (pre-test). During the translation process, no translations presenting with difficult consensus in the review process or grammar inconsistencies were observed. During the pre-test, difficulties in comprehension of some unconventional terms, e.g., "náusea", were observed. Adverbs of frequency, such as "quase nunca" were also identified as being of difficult understanding by patients and parents, and the substitution by the term "raramente" was suggested. Such difficulties may be inherent to the pediatric age group. Age 8 years or above should be considered adequate for the self-reporting of symptoms. The study presents the Brazilian version of the Pediatric Eosinophilic Esophagitis Symptom Score, which is adapted to the Brazilian culture. This version may be introduced as a clinical and research tool for the assessment of patients with esophagic disease symptoms. The Pediatric Eosinophilic Esophagitis Symptom Score is a breakthrough in the evaluation of symptoms of pediatric eosinophilic esophagitis, since it reinforces the importance of self-reporting by patients who experience this disease. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Evaluation of an audience response system in a preclinical operative dentistry course.

PubMed

Elashvili, Ana; Denehy, Gerald E; Dawson, Deborah V; Cunningham, Marsha A

2008-11-01

Student performance was compared on written and psychomotor skill tests of freshman dental students receiving conventional lectures versus the same lectures containing interactive components using TurningPoint, a wireless audience response system (ARS). The research design was a controlled crossover study with seventy-seven freshman dental students conducted in a preclinical operative dentistry course. Two randomized groups alternated the two study lectures, one with ARS and the other without ARS. Student knowledge retention was measured through written examination using immediate posttest, as well as questions on the unit and final examinations. Psychomotor skill tests were given on both lecture topics. Statistically significant differences indicating superiority of ARS were identified for performance on the immediate posttest and psychomotor skill test only for the lecture "Principles of Dental Bonding." The other examinations/skill testing showed no significant difference. These results indicate that ARS is a promising teaching tool for dental education.

A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke

PubMed Central

Maysami, Samaneh; Wong, Raymond; Pradillo, Jesus M; Denes, Adam; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J

2015-01-01

Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials. PMID:26661169

Medications Development for the Treatment of Alcohol Use Disorder: Insights into the Predictive Value of Animal and Human Laboratory Models

PubMed Central

Yardley, Megan M.; Ray, Lara A.

2016-01-01

Development of effective treatments for alcohol use disorder (AUD) represents an important public health goal. This review provides a summary of completed preclinical and clinical studies testing pharmacotherapies for treatment of AUD. We discuss opportunities for improving the translation from preclinical findings to clinical trial outcomes, focusing on the validity and predictive value of animal and human laboratory models of AUD. Specifically, while preclinical studies of medications development have offered important insights into the neurobiology of the disorder and alcohol's molecular targets, limitations include the lack of standardized methods and streamlined processes whereby animal studies can readily inform human studies. Behavioral pharmacology studies provide a less expensive and valuable opportunity to assess the feasibility of a pharmacotherapy prior to initiating larger scale clinical trials by providing insights into the mechanism of the drug, which can then inform recruitment, analyses, and assessments. Summary tables are provided to illustrate the wide range of preclinical, human laboratory, and clinical studies of medications development for alcoholism. Taken together, this review highlights the challenges associated with animal paradigms, human laboratory studies and clinical trials with the overarching goal of advancing treatment development and highlighting opportunities to bridge the gap between preclinical and clinical research. PMID:26833803

A comparative analysis of acute-phase proteins as inflammatory biomarkers in preclinical toxicology studies: implications for preclinical to clinical translation.

PubMed

Watterson, Claire; Lanevschi, Anne; Horner, Judith; Louden, Calvert

2009-01-01

Recently, in early clinical development, a few biologics and small molecules intended as antitumor or anti-inflammatory agents have caused a severe adverse pro-inflammatory systemic reaction also known as systemic inflammatory response syndrome (SIRS). This toxicity could result from expected pharmacological effects of a therapeutic antibody and/or from interaction with antigens expressed on cells/tissues other than the intended target. Clinical monitoring of SIRS is challenging because of the narrow diagnostic window to institute a successful intervening therapeutic strategy prior to acute circulatory collapse. Furthermore, for these classes of therapeutic agents, studies in animals have low predictive ability to identify potential human hazards. In vitro screens with human cells, though promising, need further development. Therefore, identification of improved preclinical diagnostic markers of SIRS will enable clinicians to select applicable markers for clinical testing and avoid potentially catastrophic events. There is limited preclinical toxicology data describing the interspecies performance of acute-phase proteins because the response time, type, and duration of major acute-phase proteins vary significantly between species. This review will attempt to address this intellectual gap, as well as the use and applicability of acute-phase proteins as preclinical to clinical translational biomarkers of SIRS.

Decreased body mass index in the preclinical stage of autosomal dominant Alzheimer's disease.

PubMed

Müller, Stephan; Preische, Oliver; Sohrabi, Hamid R; Gräber, Susanne; Jucker, Mathias; Dietzsch, Janko; Ringman, John M; Martins, Ralph N; McDade, Eric; Schofield, Peter R; Ghetti, Bernardino; Rossor, Martin; Graff-Radford, Neill R; Levin, Johannes; Galasko, Douglas; Quaid, Kimberly A; Salloway, Stephen; Xiong, Chengjie; Benzinger, Tammie; Buckles, Virginia; Masters, Colin L; Sperling, Reisa; Bateman, Randall J; Morris, John C; Laske, Christoph

2017-04-27

The relationship between body-mass index (BMI) and Alzheimer´s disease (AD) has been extensively investigated. However, BMI alterations in preclinical individuals with autosomal dominant AD (ADAD) have not yet been investigated. We analyzed cross-sectional data from 230 asymptomatic members of families with ADAD participating in the Dominantly Inherited Alzheimer Network (DIAN) study including 120 preclinical mutation carriers (MCs) and 110 asymptomatic non-carriers (NCs). Differences in BMI and their relation with cerebral amyloid load and episodic memory as a function of estimated years to symptom onset (EYO) were analyzed. Preclinical MCs showed significantly lower BMIs compared to NCs, starting 11.2 years before expected symptom onset. However, the BMI curves begun to diverge already at 17.8 years before expected symptom onset. Lower BMI in preclinical MCs was significantly associated with less years before estimated symptom onset, higher global Aβ brain burden, and with lower delayed total recall scores in the logical memory test. The study provides cross-sectional evidence that weight loss starts one to two decades before expected symptom onset of ADAD. Our findings point toward a link between the pathophysiology of ADAD and disturbance of weight control mechanisms. Longitudinal follow-up studies are warranted to investigate BMI changes over time.

The Development of a Pediatric Inpatient Experience of Care Measure: Child HCAHPS®

PubMed Central

Toomey, Sara L.; Zaslavsky, Alan M.; Elliott, Marc N.; Gallagher, Patricia M.; Fowler, Floyd J.; Klein, David J.; Shulman, Shanna; Ratner, Jessica; McGovern, Caitriona; LeBlanc, Jessica L.; Schuster, Mark A.

2016-01-01

CMS uses Adult HCAHPS® scores for public reporting and pay-for-performance for most U.S. hospitals, but no publicly available standardized survey of inpatient experience of care exists for pediatrics. To fill the gap, CMS/AHRQ commissioned the development of the Consumer Assessment of Healthcare Providers and Systems Hospital Survey – Child Version (Child HCAHPS), a survey of parents/guardians of pediatric patients (<18 years old) who were recently hospitalized. This Special Article describes the development of Child HCAHPS, which included an extensive review of the literature and quality measures, expert interviews, focus groups, cognitive testing, pilot testing of the draft survey, a national field test with 69 hospitals in 34 states, psychometric analysis, and end-user testing of the final survey. We conducted extensive validity and reliability testing to determine which items would be included in the final survey instrument and to develop composite measures. We analyzed national field test data from 17,727 surveys collected from 11/12-1/14 from parents of recently hospitalized children. The final Child HCAHPS instrument has 62 items, including 39 patient experience items, 10 screeners, 12 demographic/descriptive items, and 1 open-ended item. The 39 experience items are categorized based on testing into 18 composite and single-item measures. Our composite and single-item measures demonstrated good to excellent hospital-level reliability at 300 responses per hospital. Child HCAHPS was developed to be a publicly available standardized survey of pediatric inpatient experience of care. It can be used to benchmark pediatric inpatient experience across hospitals and assist in efforts to improve the quality of inpatient care. PMID:26195542

Allergy Testing in Children With Low-Risk Penicillin Allergy Symptoms.

PubMed

Vyles, David; Adams, Juan; Chiu, Asriani; Simpson, Pippa; Nimmer, Mark; Brousseau, David C

2017-08-01

Penicillin allergy is commonly reported in the pediatric emergency department (ED). True penicillin allergy is rare, yet the diagnosis results from the denial of first-line antibiotics. We hypothesize that all children presenting to the pediatric ED with symptoms deemed to be low-risk for immunoglobulin E-mediated hypersensitivity will return negative results for true penicillin allergy. Parents of children aged 4 to 18 years old presenting to the pediatric ED with a history of parent-reported penicillin allergy completed an allergy questionnaire. A prespecified 100 children categorized as low-risk on the basis of reported symptoms completed penicillin allergy testing by using a standard 3-tier testing process. The percent of children with negative allergy testing results was calculated with a 95% confidence interval. Five hundred ninety-seven parents completed the questionnaire describing their child's reported allergy symptoms. Three hundred two (51%) children had low-risk symptoms and were eligible for testing. Of those, 100 children were tested for penicillin allergy. The median (interquartile range) age at testing was 9 years (5-12). The median (interquartile range) age at allergy diagnosis was 1 year (9 months-3 years). Rash (97 [97%]) and itching (63 [63%]) were the most commonly reported allergy symptoms. Overall, 100 children (100%; 95% confidence interval 96.4%-100%) were found to have negative results for penicillin allergy and had their labeled penicillin allergy removed from their medical record. All children categorized as low-risk by our penicillin allergy questionnaire were found to have negative results for true penicillin allergy. The utilization of this questionnaire in the pediatric ED may facilitate increased use of first-line penicillin antibiotics. Copyright © 2017 by the American Academy of Pediatrics.

Accelerating access to quality TB care for pediatric TB cases through better diagnostic strategy in four major cities of India.

PubMed

Raizada, Neeraj; Khaparde, Sunil D; Salhotra, Virender Singh; Rao, Raghuram; Kalra, Aakshi; Swaminathan, Soumya; Khanna, Ashwani; Chopra, Kamal Kishore; Hanif, M; Singh, Varinder; Umadevi, K R; Nair, Sreenivas Achuthan; Huddart, Sophie; Prakash, C H Surya; Mall, Shalini; Singh, Pooja; Saha, B K; Denkinger, Claudia M; Boehme, Catharina; Sarin, Sanjay

2018-01-01

Diagnosis of TB in children is challenging, and is largely based on positive history of contact with a TB case, clinical and radiological findings, often without microbiological confirmation. Diagnostic efforts are also undermined by challenges in specimen collection and the limited availability of high sensitivity, rapid diagnostic tests that can be applied with a quick turnaround time. The current project was undertaken in four major cities of India to address TB diagnostic challenges in pediatric population, by offering free of cost Xpert testing to pediatric presumptive TB cases, thereby paving the way for better TB care. A high throughput lab was established in each of the four project cities, and linked to various health care providers across the city through rapid specimen transportation and electronic reporting linkages. Free Xpert testing was offered to all pediatric (0-14 years) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities. The current project enrolled 42,238 pediatric presumptive TB cases from April, 2014 to June, 2016. A total of 3,340 (7.91%, CI 7.65-8.17) bacteriologically confirmed TB cases were detected, of which 295 (8.83%, CI 7.9-9.86) were rifampicin-resistant. The level of rifampicin resistance in the project cohort was high. Overall Xpert yielded a high proportion of valid results and TB detection rates were more than three-fold higher than smear microscopy. The project provided same-day testing and early availability of results led to rapid treatment initiation and success rates and very low rates of treatment failure and loss to follow-up. The current project demonstrated the feasibility of rolling out rapid and upfront Xpert testing for pediatric presumptive TB cases through a single Xpert lab per city in an efficient manner. Rapid turnaround testing time facilitated prompt and appropriate treatment initiation. These results suggest that the upfront Xpert assay is a promising solution to address TB diagnosis in children. The high levels of rifampicin resistance detected in presumptive pediatric TB patients tested under the project are a major cause of concern from a public health perspective which underscores the need to further prioritize upfront Xpert access to this vulnerable population.

Accelerating access to quality TB care for pediatric TB cases through better diagnostic strategy in four major cities of India

PubMed Central

Raizada, Neeraj; Khaparde, Sunil D.; Salhotra, Virender Singh; Rao, Raghuram; Kalra, Aakshi; Swaminathan, Soumya; Khanna, Ashwani; Chopra, Kamal Kishore; Hanif, M.; Singh, Varinder; Umadevi, K. R.; Nair, Sreenivas Achuthan; Huddart, Sophie; Prakash, C. H. Surya; Mall, Shalini; Singh, Pooja; Saha, B. K.; Denkinger, Claudia M.; Boehme, Catharina

2018-01-01

Background Diagnosis of TB in children is challenging, and is largely based on positive history of contact with a TB case, clinical and radiological findings, often without microbiological confirmation. Diagnostic efforts are also undermined by challenges in specimen collection and the limited availability of high sensitivity, rapid diagnostic tests that can be applied with a quick turnaround time. The current project was undertaken in four major cities of India to address TB diagnostic challenges in pediatric population, by offering free of cost Xpert testing to pediatric presumptive TB cases, thereby paving the way for better TB care. Methods A high throughput lab was established in each of the four project cities, and linked to various health care providers across the city through rapid specimen transportation and electronic reporting linkages. Free Xpert testing was offered to all pediatric (0–14 years) presumptive TB cases (both pulmonary and extra-pulmonary) seeking care at public and private health facilities. Results The current project enrolled 42,238 pediatric presumptive TB cases from April, 2014 to June, 2016. A total of 3,340 (7.91%, CI 7.65–8.17) bacteriologically confirmed TB cases were detected, of which 295 (8.83%, CI 7.9–9.86) were rifampicin-resistant. The level of rifampicin resistance in the project cohort was high. Overall Xpert yielded a high proportion of valid results and TB detection rates were more than three-fold higher than smear microscopy. The project provided same-day testing and early availability of results led to rapid treatment initiation and success rates and very low rates of treatment failure and loss to follow-up. Conclusion The current project demonstrated the feasibility of rolling out rapid and upfront Xpert testing for pediatric presumptive TB cases through a single Xpert lab per city in an efficient manner. Rapid turnaround testing time facilitated prompt and appropriate treatment initiation. These results suggest that the upfront Xpert assay is a promising solution to address TB diagnosis in children. The high levels of rifampicin resistance detected in presumptive pediatric TB patients tested under the project are a major cause of concern from a public health perspective which underscores the need to further prioritize upfront Xpert access to this vulnerable population. PMID:29489887

Diagnostic Yield of Routine Enteropathogenic Stool Tests in Pediatric Ulcerative Colitis.

PubMed

Ihekweazu, Faith D; Ajjarapu, Avanthi; Kellermayer, Richard

2015-01-01

It can be important to exclude infectious etiologies prior to adjusting immunosuppressive therapy in patients with ulcerative colitis (UC) exacerbation. We sought to determine the diagnostic yield of routine infectious stool studies in pediatric UC patients. We conducted a retrospective review of 152 pediatric UC patients at Texas Children's Hospital between January 2003 and December 2009. The patient records were followed through July 2014. The number and type of infectious stool studies performed and the results of those were collected. Three hundred fifty-four diagnostic stool tests were conducted for Clostridium difficile; 13.6% were positive. Two hundred twenty stool bacterial cultures were performed, and 1.8% were positive, all growing non-typhoid Salmonella. One of 13 (7.7%) Adenovirus PCR tests was positive. Two of 152 examinations (1.3%) for Ova and Parasites were positive. No stool tests for viral culture, viral particles, Yersinia or Rotavirus were positive. Clostridium difficile infection is common in pediatric UC, and routine screening during flares is strongly recommended. Other bacterial and parasitic infections routinely tested for are uncommon, but Salmonella may be a potentially important attribute to disease exacerbations in select patients. In patients without co-morbid conditions, the utility of performing non-specific fecal viral tests is questionable. © 2015 by the Association of Clinical Scientists, Inc.

Regression-based pediatric norms for the brief visuospatial memory test: revised and the symbol digit modalities test.

PubMed

Smerbeck, A M; Parrish, J; Yeh, E A; Hoogs, M; Krupp, Lauren B; Weinstock-Guttman, B; Benedict, R H B

2011-04-01

The Brief Visuospatial Memory Test - Revised (BVMTR) and the Symbol Digit Modalities Test (SDMT) oral-only administration are known to be sensitive to cerebral disease in adult samples, but pediatric norms are not available. A demographically balanced sample of healthy control children (N = 92) ages 6-17 was tested with the BVMTR and SDMT. Multiple regression analysis (MRA) was used to develop demographically controlled normative equations. This analysis provided equations that were then used to construct demographically adjusted z-scores for the BVMTR Trial 1, Trial 2, Trial 3, Total Learning, and Delayed Recall indices, as well as the SDMT total correct score. To demonstrate the utility of this approach, a comparison group of children with acute disseminated encephalomyelitis (ADEM) or multiple sclerosis (MS) were also assessed. We find that these visual processing tests discriminate neurological patients from controls. As the tests are validated in adult multiple sclerosis, they are likely to be useful in monitoring pediatric onset multiple sclerosis patients as they transition into adulthood.

MOON-test - determination of motor performance in the pediatric oncology.

PubMed

Götte, M; Kesting, S; Albrecht, C; Worth, A; Bös, K; Boos, J

2013-05-01

Pediatric cancer patients suffer from various negative consequences due to the disease, the medical therapy and the inactivity during the intensive treatment. Only few studies have systematically identified the adverse effects of cancer on motor performance in childhood. To determine the motor performance of pediatric cancer patients, a motor performance test was developed which is applicable for this specific patient group. Eight test items with reference values for healthy children were merged to the MOON-test (test for motor performance in the oncology). MOON was tested for feasibility and acceptance in 33 patients aged 4-18 years. Feasibility was confirmed for children with different types of cancer (hematological malignancies and solid tumors) and with amputation, endoprosthesis, during aplasia as well as reduced general condition. Furthermore the patients showed a broad acceptance. Based on the study findings, the use of MOON-test as a standardized motor performance diagnostic tool in clinical routine of oncological acute clinics as well as rehabilitation clinics can be recommended.· © Georg Thieme Verlag KG Stuttgart · New York.

[The role of biotechnology in pharmaceutical drug design].

PubMed

Gaisser, Sibylle; Nusser, Michael

2010-01-01

Biotechnological methods have become an important tool in pharmaceutical drug research and development. Today approximately 15 % of drug revenues are derived from biopharmaceuticals. The most relevant indications are oncology, metabolic disorders and disorders of the musculoskeletal system. For the future it can be expected that the relevance of biopharmaceuticals will further increase. Currently, the share of substances in preclinical testing that rely on biotechnology is more than 25 % of all substances in preclinical testing. Products for the treatment of cancer, metabolic disorders and infectious diseases are most important. New therapeutic approaches such as RNA interference only play a minor role in current commercial drug research and development with 1.5 % of all biological preclinical substances. Investments in sustainable high technology such as biotechnology are of vital importance for a highly developed country like Germany because of its lack of raw materials. Biotechnology helps the pharmaceutical industry to develop new products, new processes, methods and services and to improve existing ones. Thus, international competitiveness can be strengthened, new jobs can be created and existing jobs preserved.

Preclinical Testing of a Translocator Protein Ligand for the Treatment of Amyotrophic Lateral Sclerosis

DTIC Science & Technology

2017-03-01

Accessed October 26, 2015]. Barneoud, P. et al., 1997. Quantitative motor assessment in FALS mice: a longitudinal study . Neuroreport, 8, pp.2861–2865...cell study , we found that PK acts directly on motor neurons to prevent their death, not via the astrocytes. Then, we evidenced that PK protects not...in TSPO content may protect motor neurons against ALS. Second, in our preclinical study in ALS mice, we have determined that the best route to

SOFIA®RSV: prospective laboratory evaluation and implementation of a rapid diagnostic test in a pediatric emergency ward.

PubMed

Tran, Léa C; Tournus, Céline; Dina, Julia; Morello, Rémy; Brouard, Jacques; Vabret, Astrid

2017-06-26

Respiratory syncytial virus (RSV) is responsible for severe respiratory infections and higher costs in medical care. The two aims of this work were to assess the performances of SOFIA ® RSV tests in "real-life-laboratory" conditions (study 1) and implemented at point-of-care testing in a pediatric emergency department (ED, study 2), during two consecutive winter seasons. In study 1, fresh nasopharyngeal swabs from patients of all ages were sampled in 1.5 ml of Universal virological Transport Medium (UTM) and prospectively tested using SOFIA ® RSV tests. In study 2, conducted in a pediatric ED, nasopharyngeal swabs were placed in 3 ml of UTM. All SOFIA ® RSV tests were confirmed by molecular testing, considered as reference method. The epidemiological and clinical features of tested patients, as well as the care of these patients after obtaining quick results were evaluated. The sensitivities of SOFIA ® RSV in infants (aged under 24 months) performed in the laboratory and in the pediatric ED were respectively 95% (95% CI: 86.8-98.1) and 74.8% (95% CI: 68.0-80.9) compared to PCR. In study 1, the sensitivity among children (from 2 to 15 years old) and adults (above 15 years old) dropped to 45% (95% CI: 23.1-68.5) and 59% (95% CI: 32.9-81.6), respectively. In study 2, there were some differences in bed-management of SOFIA ® RSV positive compared to SOFIA ® RSV negative infants. SOFIA ® RSV tests performed in the laboratory and in the pediatric ED show high and satisfactory sensitivities among young children under 24 months, which supports its robustness and reliability. However, the impact of these tests on patient care at point-of-care cannot be clearly assessed when considering the limits of the study 2 design.

Transcriptional Responses Reveal Similarities Between Preclinical Rat Liver Testing Systems.

PubMed

Liu, Zhichao; Delavan, Brian; Roberts, Ruth; Tong, Weida

2018-01-01

Toxicogenomics (TGx) is an important tool to gain an enhanced understanding of toxicity at the molecular level. Previously, we developed a pair ranking (PRank) method to assess in vitro to in vivo extrapolation (IVIVE) using toxicogenomic datasets from the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) database. With this method, we investiagted three important questions that were not addressed in our previous study: (1) is a 1-day in vivo short-term assay able to replace the 28-day standard and expensive toxicological assay? (2) are some biological processes more conservative across different preclinical testing systems than others? and (3) do these preclinical testing systems have the similar resolution in differentiating drugs by their therapeutic uses? For question 1, a high similarity was noted (PRank score = 0.90), indicating the potential utility of shorter term in vivo studies to predict outcome in longer term and more expensive in vivo model systems. There was a moderate similarity between rat primary hepatocytes and in vivo repeat-dose studies (PRank score = 0.71) but a low similarity (PRank score = 0.56) between rat primary hepatocytes and in vivo single dose studies. To address question 2, we limited the analysis to gene sets relevant to specific toxicogenomic pathways and we found that pathways such as lipid metabolism were consistently over-represented in all three assay systems. For question 3, all three preclinical assay systems could distinguish compounds from different therapeutic categories. This suggests that any noted differences in assay systems was biological process-dependent and furthermore that all three systems have utility in assessing drug responses within a certain drug class. In conclusion, this comparison of three commonly used rat TGx systems provides useful information in utility and application of TGx assays.

Atomoxetine for hoarding disorder: A pre-clinical and clinical investigation.

PubMed

Grassi, Giacomo; Micheli, Laura; Di Cesare Mannelli, Lorenzo; Compagno, Elisa; Righi, Lorenzo; Ghelardini, Carla; Pallanti, Stefano

2016-12-01

Despite several studies suggested that inattention and impulsivity-compulsivity could represent two core dimensions of hoarding disorder (HD), only a small case series study investigated the effectiveness of attention-deficit-hyperactivity-disorder (ADHD) medications in HD. The aim of the present study was to target attentional and inhibitory control networks in HD patients through the ADHD medication atomoxetine, moving from a preclinical investigation on an animal model of compulsive-like behavior (marble burying test) to a clinical investigation on both medicated and unmedicated patients with a primary diagnosis of HD without ADHD. Our preclinical investigation showed that acute administration of atomoxetine significantly reduced the compulsive-like behaviours of mice in the marble burying test without affecting neither locomotor activity and coordination nor exploration behaviours. When compared, atomoxetine and fluoxetine showed similar effects on the marble burying test. However, fluoxetine impaired both locomotor and exploratory activity. In our clinical investigation 12 patients were enrolled and 11 patients completed an open trial with atomoxetine at flexible dose (40-80 mg) for 12 weeks. At the endpoint the mean UCLA Hoarding Severity Scale score decreased by 41.3% for the whole group (p = 0003). Six patients were classified as full responders (mean symptom reduction of 57.2%) and three patients as partial responders (mean symptom reduction of 27.3%). Inattentive and impulsivity symptoms showed a significant mean score reduction of 18.5% from baseline to the endpoint (F (1,9) = 20.9, p = 0.0013). Hoarding symptoms improvement was correlated to reduction of patients' disability and increased in their global functioning. These preclinical and clinical data suggest that atomoxetine may be effective for HD and therefore should be considered for future controlled trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

Specificity and Sensitivity Ratios of the Pediatric Language Acquisition Screening Tool for Early Referral-Revised.

ERIC Educational Resources Information Center

Sherman, Tracy; Shulman, Brian B.

1999-01-01

This study examined test characteristics of the Pediatric Language Acquisition Screening Tool for Early Referral-Revised (PLASTER-R), a set of developmental questionnaires for children 3 to 60 months of age. The PLASTER-R was moderately to highly successful in identifying children within normal limits for language development. Test-retest…

Evaluating the Appropriateness of a New Computer-Administered Measure of Adaptive Function for Children and Youth with Autism Spectrum Disorders

ERIC Educational Resources Information Center

Coster, Wendy J.; Kramer, Jessica M.; Tian, Feng; Dooley, Meghan; Liljenquist, Kendra; Kao, Ying-Chia; Ni, Pengsheng

2016-01-01

The Pediatric Evaluation of Disability Inventory-Computer Adaptive Test is an alternative method for describing the adaptive function of children and youth with disabilities using a computer-administered assessment. This study evaluated the performance of the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test with a national…

Hip contact forces in asymptomatic total hip replacement patients differ from normal healthy individuals: Implications for preclinical testing.

PubMed

Li, Junyan; Redmond, Anthony C; Jin, Zhongmin; Fisher, John; Stone, Martin H; Stewart, Todd D

2014-08-01

Preclinical durability testing of hip replacement implants is standardised by ISO-14242-1 (2002) which is based on historical inverse dynamics analysis using data obtained from a small sample of normal healthy individuals. It has not been established whether loading cycles derived from normal healthy individuals are representative of loading cycles occurring in patients following total hip replacement. Hip joint kinematics and hip contact forces derived from multibody modelling of forces during normal walking were obtained for 15 asymptomatic total hip replacement patients and compared to 38 normal healthy individuals and to the ISO standard for pre-clinical testing. Hip kinematics in the total hip replacement patients were comparable to the ISO data and the hip contact force in the normal healthy group was also comparable to the ISO cycles. Hip contact forces derived from the asymptomatic total hip replacement patients were comparable for the first part of the stance period but exhibited 30% lower peak loads at toe-off. Although the ISO standard provides a representative kinematic cycle, the findings call into question whether the hip joint contact forces in the ISO standard are representative of those occurring in the joint following total hip replacement. Copyright © 2014. Published by Elsevier Ltd.

Problem-based learning versus a traditional educational methodology: a comparison of preclinical and clinical periodontics performance.

PubMed

Rich, Sandra K; Keim, Robert G; Shuler, Charles F

2005-06-01

To evaluate efficacy of a problem-based learning (PBL) pedagogy in preclinical and clinical teaching, test scores of 234 undergraduate dental students from the conventionally taught classes of 2003 and 2004 were compared with scores of 274 dental students from the PBL classes of 2005 and 2006. Although the groups' means were close together, t-test analysis of scores revealed that PBL students performed significantly better than traditional (TRAD) students on midterm (p=.0001) and final (p=.015) examinations taken on student partner/mock patients. ANOVA comparing the classes with each other showed significant differences for the midterm and final, but not for the clinical examination. Further multiple comparison tests (Tukey HSD) for the midterm and final revealed that differences specifically reflected superior performance of PBL classes against one of the TRAD classes (2004). There was no difference in performance between PBL (n=134) and TRAD (n=233) students on examinations taken with actual clinical patients who were undergoing nonsurgical periodontal treatment. Over a two-year period, PBL students rated their program instructors at a mean of 4.41 on a Likert-type scale of 1 (not helpful) to 5 (outstanding). The program provides a PBL model for teaching preclinical and clinical skills supported by a four-year evaluation of manual skills outcomes.

Predicting the clinical performance of dental students with a manual dexterity test

PubMed Central

Lugassy, Diva; Levanon, Yafi; Pilo, Raphael; Shelly, Asaf; Rosen, Gal; Meirowitz, Avi

2018-01-01

Dentists must be skilled when using dental mirrors. Working with mirrors requires spatial perception, bimanual coordination, perceptual learning and fine motor skills. Many studies have attempted to determine the predictors of manual skills among pre-clinical students, but consensus has yet to be reached. We hypothesized that valid and reliable occupational therapy test performance regarding indirect vision would differ between dental students and junior dentists and would explain the variance in manual skill performance in pre-clinical courses. To test this hypothesis, we applied the Purdue Pegboard test and O’Connor Tweezer Dexterity test under different conditions of direct and indirect vision. We administered these tests to students in phantom-head academic courses in 2015 and 2016 and to junior dentists. Students performed the tests at three time points: before phantom training (T0), at the end of the training (T1) and in the middle of the following year of study (T2). Dentists performed the same tests twice at 1st and 2nd trials one week apart. The results showed that indirect tasks were significantly more difficult to perform for both groups. These dexterity tests were sensitive enough to detect students’ improvement after phantom training. The dentists’ performances were significantly better than those of students at T0, specifically with regard to the use of tweezers under direct and indirect vision (the O’Connor test). A regression analysis showed that students’ manual grades obtained at the beginning of the phantom course, their performance on the Purdue test using both hands, and their performance on the O’Connor test under indirect vision predicted phantom course success in 80% of cases. The O’Connor test under indirect vision is the most informative means of monitoring and predicting the manual skills required in the pre-clinical year of dentistry studies. PMID:29518127

Pediatric Anthropometry

NASA Astrophysics Data System (ADS)

Klinich, Kathleen D.; Reed, Matthew P.

Anthropometry is the measurement of human size, shape, and physical capabilities. Most pediatric anthropometry data are gathered to describe child growth patterns, but data on body size, mass distribution, range of motion, and posture are used to develop crash test dummies and computational models of child occupants. Pediatric anthropometry data are also used to determine child restraint dimensions, so they will accommodate the applicable population of child occupants.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Y; Fullerton, G; Goins, B

Purpose: In our previous study a preclinical multi-modality quality assurance (QA) phantom that contains five tumor-simulating test objects with 2, 4, 7, 10 and 14 mm diameters was developed for accurate tumor size measurement by researchers during cancer drug development and testing. This study analyzed the errors during tumor volume measurement from preclinical magnetic resonance (MR), micro-computed tomography (micro- CT) and ultrasound (US) images acquired in a rodent tumor model using the preclinical multi-modality QA phantom. Methods: Using preclinical 7-Tesla MR, US and micro-CT scanners, images were acquired of subcutaneous SCC4 tumor xenografts in nude rats (3–4 rats per group;more » 5 groups) along with the QA phantom using the same imaging protocols. After tumors were excised, in-air micro-CT imaging was performed to determine reference tumor volume. Volumes measured for the rat tumors and phantom test objects were calculated using formula V = (π/6)*a*b*c where a, b and c are the maximum diameters in three perpendicular dimensions determined by the three imaging modalities. Then linear regression analysis was performed to compare image-based tumor volumes with the reference tumor volume and known test object volume for the rats and the phantom respectively. Results: The slopes of regression lines for in-vivo tumor volumes measured by three imaging modalities were 1.021, 1.101 and 0.862 for MRI, micro-CT and US respectively. For phantom, the slopes were 0.9485, 0.9971 and 0.9734 for MRI, micro-CT and US respectively. Conclusion: For both animal and phantom studies, random and systematic errors were observed. Random errors were observer-dependent and systematic errors were mainly due to selected imaging protocols and/or measurement method. In the animal study, there were additional systematic errors attributed to ellipsoidal assumption for tumor shape. The systematic errors measured using the QA phantom need to be taken into account to reduce measurement errors during the animal study.« less

An immunologic model for rapid vaccine assessment -- a clinical trial in a test tube.

PubMed

Higbee, Russell G; Byers, Anthony M; Dhir, Vipra; Drake, Donald; Fahlenkamp, Heather G; Gangur, Jyoti; Kachurin, Anatoly; Kachurina, Olga; Leistritz, Del; Ma, Yifan; Mehta, Riyaz; Mishkin, Eric; Moser, Janice; Mosquera, Luis; Nguyen, Mike; Parkhill, Robert; Pawar, Santosh; Poisson, Louis; Sanchez-Schmitz, Guzman; Schanen, Brian; Singh, Inderpal; Song, Haifeng; Tapia, Tenekua; Warren, William; Wittman, Vaughan

2009-09-01

While the duration and size of human clinical trials may be difficult to reduce, there are several parameters in pre-clinical vaccine development that may be possible to further optimise. By increasing the accuracy of the models used for pre-clinical vaccine testing, it should be possible to increase the probability that any particular vaccine candidate will be successful in human trials. In addition, an improved model will allow the collection of increasingly more-informative data in pre-clinical tests, thus aiding the rational design and formulation of candidates entered into clinical evaluation. An acceleration and increase in sophistication of pre-clinical vaccine development will thus require the advent of more physiologically-accurate models of the human immune system, coupled with substantial advances in the mechanistic understanding of vaccine efficacy, achieved by using this model. We believe the best viable option available is to use human cells and/or tissues in a functional in vitro model of human physiology. Not only will this more accurately model human diseases, it will also eliminate any ethical, moral and scientific issues involved with use of live humans and animals. An in vitro model, termed "MIMIC" (Modular IMmune In vitro Construct), was designed and developed to reflect the human immune system in a well-based format. The MIMIC System is a laboratory-based methodology that replicates the human immune system response. It is highly automated, and can be used to simulate a clinical trial for a diverse population, without putting human subjects at risk. The MIMIC System uses the circulating immune cells of individual donors to recapitulate each individual human immune response by maintaining the autonomy of the donor. Thus, an in vitro test system has been created that is functionally equivalent to the donor's own immune system and is designed to respond in a similar manner to the in vivo response. 2009 FRAME.

Eunice Kennedy Shriver National Institute of Child Health and Human Development Pediatric Formulation Initiative: selected reports from working groups.

PubMed

Giacoia, George P; Taylor-Zapata, Perdita; Mattison, Donald

2008-11-01

The Pediatric Formulation Initiative (PFI) is a project of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The PFI was established to address the issue of the lack of appropriate formulations in children and to use this activity as a means to improve pediatric formulations, as mandated by the Best Pharmaceuticals for Children Act of 2002 and 2007. The PFI began in 2005 with the formation of 3 working groups-Scientific, Economics, and Taste and Flavor. These groups began the process of identifying issues, gathering needed information, and considering possible ways to overcome barriers to the development of pediatric drug formulations. The purpose of this supplement was to provide details of the working groups' activities through presentation of full-length articles. Also presented is an article that discusses the 2007 European Union (EU) regulation on medicinal products for pediatric use. Information for this article was gathered from the proceedings of a PFI workshop, sponsored by the NICHD, that was held in Bethesda, Maryland, on December 6 and 7, 2005, as well as postworkshop discussions of the different working groups. The increased awareness that the majority of medications used today have not been labeled for use in children, and have not been tested to define safety, efficacy, and appropriate dosing, has led to the passage of legislation in the United States and in the EU to create incentives to stimulate the testing of drugs in this special population. It is imperative that the problems associated with the compounding and use of extemporaneous formulations as described in this supplement be addressed. Regulatory barriers to the availability of commercially developed pediatric formulations in different countries will need to be minimized or removed. New drug delivery systems will need to be tested and made available to pediatric patients. Further research in the mediators of bitter taste and study of taste blockers, as well as newer methods for taste testing in pediatrics, should be encouraged. An overarching goal for the future is addressing the economic barriers to develop appropriate pediatric dosage forms for drugs with limited market penetration. The lack of appropriate formulations is part of a larger problem that includes limited development and manufacture of medicines tailored for pediatric patients (particularly those affected by neglected diseases), insufficient investment in drug trials, and limited research on drug disposition in various pediatric populations worldwide. The solution to these issues will require alignment of vision and commitment as a global priority of policy makers, regulators, scientists, pharmaceutical sponsors, academic institutions, governments, and research foundations.

Patient-derived xenografts as preclinical neuroblastoma models.

PubMed

Braekeveldt, Noémie; Bexell, Daniel

2018-05-01

The prognosis for children with high-risk neuroblastoma is often poor and survivors can suffer from severe side effects. Predictive preclinical models and novel therapeutic strategies for high-risk disease are therefore a clinical imperative. However, conventional cancer cell line-derived xenografts can deviate substantially from patient tumors in terms of their molecular and phenotypic features. Patient-derived xenografts (PDXs) recapitulate many biologically and clinically relevant features of human cancers. Importantly, PDXs can closely parallel clinical features and outcome and serve as excellent models for biomarker and preclinical drug development. Here, we review progress in and applications of neuroblastoma PDX models. Neuroblastoma orthotopic PDXs share the molecular characteristics, neuroblastoma markers, invasive properties and tumor stroma of aggressive patient tumors and retain spontaneous metastatic capacity to distant organs including bone marrow. The recent identification of genomic changes in relapsed neuroblastomas opens up opportunities to target treatment-resistant tumors in well-characterized neuroblastoma PDXs. We highlight and discuss the features and various sources of neuroblastoma PDXs, methodological considerations when establishing neuroblastoma PDXs, in vitro 3D models, current limitations of PDX models and their application to preclinical drug testing.

Pediatric residents' learning styles and temperaments and their relationships to standardized test scores.

PubMed

Tuli, Sanjeev Y; Thompson, Lindsay A; Saliba, Heidi; Black, Erik W; Ryan, Kathleen A; Kelly, Maria N; Novak, Maureen; Mellott, Jane; Tuli, Sonal S

2011-12-01

Board certification is an important professional qualification and a prerequisite for credentialing, and the Accreditation Council for Graduate Medical Education (ACGME) assesses board certification rates as a component of residency program effectiveness. To date, research has shown that preresidency measures, including National Board of Medical Examiners scores, Alpha Omega Alpha Honor Medical Society membership, or medical school grades poorly predict postresidency board examination scores. However, learning styles and temperament have been identified as factors that 5 affect test-taking performance. The purpose of this study is to characterize the learning styles and temperaments of pediatric residents and to evaluate their relationships to yearly in-service and postresidency board examination scores. This cross-sectional study analyzed the learning styles and temperaments of current and past pediatric residents by administration of 3 validated tools: the Kolb Learning Style Inventory, the Keirsey Temperament Sorter, and the Felder-Silverman Learning Style test. These results were compared with known, normative, general and medical population data and evaluated for correlation to in-service examination and postresidency board examination scores. The predominant learning style for pediatric residents was converging 44% (33 of 75 residents) and the predominant temperament was guardian 61% (34 of 56 residents). The learning style and temperament distribution of the residents was significantly different from published population data (P  =  .002 and .04, respectively). Learning styles, with one exception, were found to be unrelated to standardized test scores. The predominant learning style and temperament of pediatric residents is significantly different than that of the populations of general and medical trainees. However, learning styles and temperament do not predict outcomes on standardized in-service and board examinations in pediatric residents.

Pediatric Residents' Learning Styles and Temperaments and Their Relationships to Standardized Test Scores

PubMed Central

Tuli, Sanjeev Y.; Thompson, Lindsay A.; Saliba, Heidi; Black, Erik W.; Ryan, Kathleen A.; Kelly, Maria N.; Novak, Maureen; Mellott, Jane; Tuli, Sonal S.

2011-01-01

Background Board certification is an important professional qualification and a prerequisite for credentialing, and the Accreditation Council for Graduate Medical Education (ACGME) assesses board certification rates as a component of residency program effectiveness. To date, research has shown that preresidency measures, including National Board of Medical Examiners scores, Alpha Omega Alpha Honor Medical Society membership, or medical school grades poorly predict postresidency board examination scores. However, learning styles and temperament have been identified as factors that 5 affect test-taking performance. The purpose of this study is to characterize the learning styles and temperaments of pediatric residents and to evaluate their relationships to yearly in-service and postresidency board examination scores. Methods This cross-sectional study analyzed the learning styles and temperaments of current and past pediatric residents by administration of 3 validated tools: the Kolb Learning Style Inventory, the Keirsey Temperament Sorter, and the Felder-Silverman Learning Style test. These results were compared with known, normative, general and medical population data and evaluated for correlation to in-service examination and postresidency board examination scores. Results The predominant learning style for pediatric residents was converging 44% (33 of 75 residents) and the predominant temperament was guardian 61% (34 of 56 residents). The learning style and temperament distribution of the residents was significantly different from published population data (P  =  .002 and .04, respectively). Learning styles, with one exception, were found to be unrelated to standardized test scores. Conclusions The predominant learning style and temperament of pediatric residents is significantly different than that of the populations of general and medical trainees. However, learning styles and temperament do not predict outcomes on standardized in-service and board examinations in pediatric residents. PMID:23205211

Crosscheck Principle in Pediatric Audiology Today: A 40-Year Perspective

PubMed Central

2016-01-01

The crosscheck principle is just as important in pediatric audiology as it was when first described 40 years ago. That is, no auditory test result should be accepted and used in the diagnosis of hearing loss until it is confirmed or crosschecked by one or more independent measures. Exclusive reliance on only one or two tests, even objective auditory measures, may result in a auditory diagnosis that is not clear or perhaps incorrect. On the other hand, close and careful analysis of findings for a test battery consisting of objective procedures and behavioral tests whenever feasible usually leads to prompt and accurate diagnosis of auditory dysfunction. This paper provides a concise review of the crosscheck principle from its introduction to its clinical application today. The review concludes with a description of a modern test battery for pediatric hearing assessment that supplements traditional behavioral tests with a variety of independent objective procedures including aural immittance measures, otoacoustic emissions, and auditory evoked responses. PMID:27626077

Crosscheck Principle in Pediatric Audiology Today: A 40-Year Perspective.

PubMed

Hall, James W

2016-09-01

The crosscheck principle is just as important in pediatric audiology as it was when first described 40 years ago. That is, no auditory test result should be accepted and used in the diagnosis of hearing loss until it is confirmed or crosschecked by one or more independent measures. Exclusive reliance on only one or two tests, even objective auditory measures, may result in a auditory diagnosis that is not clear or perhaps incorrect. On the other hand, close and careful analysis of findings for a test battery consisting of objective procedures and behavioral tests whenever feasible usually leads to prompt and accurate diagnosis of auditory dysfunction. This paper provides a concise review of the crosscheck principle from its introduction to its clinical application today. The review concludes with a description of a modern test battery for pediatric hearing assessment that supplements traditional behavioral tests with a variety of independent objective procedures including aural immittance measures, otoacoustic emissions, and auditory evoked responses.

Pediatric Asthma

MedlinePlus

... Asthma (Pediatric) Find a Doctor Appointments & Questions Patient Education & Support Visiting Us Tests & Procedures Ways to Give National Jewish Health ... Programs Health Information Doctors & Departments Clinical Research & ... Training Contact Us Make a Donation Make an Appointment Patient Portal ...

Home blood sugar testing

MedlinePlus

... Groot LJ, de Kretser DM, et al, eds. Endocrinology: Adult and Pediatric . 7th ed. Philadelphia, PA: Elsevier ... Groot LJ, de Kretser DM, et al, eds. Endocrinology: Adult and Pediatric . 7th ed. Philadelphia, PA: Elsevier ...

Novel Roles of Amyloid-Beta Protein Precursor Metabolites in Fragile X Syndrome and Autism

PubMed Central

Westmark, Cara J.; Sokol, Deborah K.; Maloney, Bryan; Lahiri, Debomoy K.

2017-01-01

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is associated with up to 5% of autism cases. Several promising drugs are in preclinical testing for FXS; however, bench-to-bedside plans for the clinic are severely limited due to lack of validated biomarkers and outcome measures. Published work from our laboratories has demonstrated altered levels of amyloid-beta (Aβ) protein precursor (APP) and its metabolites in FXS and idiopathic autism. Westmark and colleagues have focused on β-secretase (amyloidogenic) processing and the accumulation of Aβ peptides in adult FXS models while Lahiri and Sokol have studied α-secretase (nonamyloidogenic or anabolic) processing and altered levels of sAPPα and Aβ in pediatric autism and FXS. Thus, our groups have hypothesized a pivotal role for these Alzheimer’s disease (AD)-related proteins in the neurodevelopmental disorders of FXS and autism. In this review, we discuss the contribution of APP metabolites to FXS and autism pathogenesis as well as the potential use of these metabolites as blood-based biomarkers and therapeutic targets. Our future focus is to identify key underlying mechanisms through which APP metabolites contribute to FXS and autism condition-to-disease pathology. Positive outcomes will support utilizing APP metabolites as blood-based biomarkers in clinical trials as well as testing drugs that modulate APP processing as potential disease therapeutics. Our studies to understand the role of APP metabolites in developmental conditions such as FXS and autism are a quantum leap for the neuroscience field, which has traditionally restricted any role of APP to AD and aging. PMID:27573877

The prevalence and consequences of burnout on a group of preclinical dental students.

PubMed

Atalayin, Cigdem; Balkis, Murat; Tezel, Huseyin; Onal, Banu; Kayrak, Gul

2015-01-01

The aim of this study is to investigate the prevalence of burnout among a group of Turkish preclinical dental students, to compare the level of burnout and to determine the consequences in structural equation model. Preclinical dental students (n = 329, 50.5% of females and 49.5% of males) aged between 18 and 24 took part in the study. Maslach burnout inventory student version, academic satisfaction scale, and personal information sheet were used to gather data. Pearson correlation analyses, t-test, and one-way ANOVA were used for statistical analysis. The proposed theoretical model was tested via observed variable path analysis using maximum likelihood parameter estimation with AMOS 7.0. About 22.3% of students had high level of emotional exhaustion, 16.7% of students had high level of cynicism, and 17.9% of students suffered from high level of reduced academic efficacy. While the students attending the first grade reported higher level of reduced academic efficacy, the students in the third grade reported higher level of emotional exhaustion. Academic workload played an important role in the development of burnout. As consequences of burnout, students with high levels of burnout intended to change their current major and did not to plan to continue to postgraduate education. Students with high level of burnout reported less level of academic satisfaction and academic achievement. Creating awareness on the burnout of dental students from the preclinical period may be useful for prevention and more compatible dental education environment.

Theory of mind and empathy in preclinical and clinical Huntington's disease.

PubMed

Adjeroud, Najia; Besnard, Jérémy; El Massioui, Nicole; Verny, Christophe; Prudean, Adriana; Scherer, Clarisse; Gohier, Bénédicte; Bonneau, Dominique; Allain, Philippe

2016-01-01

We investigated cognitive and affective Theory of Mind (ToM) and empathy in patients with premanifest and manifest Huntington's disease (HD). The relationship between ToM performance and executive skills was also examined. Sixteen preclinical and 23 clinical HD patients, and 39 healthy subjects divided into 2 control groups were given a French adaptation of the Yoni test (Shamay-Tsoory, S.G., Aharon-Peretz, J. (2007). Dissociable prefrontal networks for cognitive and affective theory of mind: a lesion study. Neuropsychologia, 45(3), 3054-67) that examines first- and second-order cognitive and affective ToM processing in separate conditions with a physical control condition. Participants were also given questionnaires of empathy and cognitive tests which mainly assessed executive functions (inhibition and mental flexibility). Clinical HD patients made significantly more errors than their controls in the first- and second-order cognitive and affective ToM conditions of the Yoni task, but exhibited no empathy deficits. However, there was no evidence that ToM impairment was related to cognitive deficits in these patients. Preclinical HD patients were unimpaired in ToM tasks and empathy measures compared with their controls. Our results are consistent with the idea that impaired affective and cognitive mentalizing emerges with the clinical manifestation of HD, but is not necessarily part of the preclinical stage. Furthermore, these impairments appear independent of executive dysfunction and empathy. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Pharmacotherapy in the Management of Pediatric Obesity.

PubMed

Kelly, Aaron S; Fox, Claudia K

2017-08-01

This review provides a rationale for the use of pharmacotherapy in pediatric weight management, summarizes results of some of the key pediatric clinical trials of approved and "off-label" obesity medications, introduces new options in the pediatric pipeline, and offers a glimpse into the future of pediatric obesity medicine. Despite the need for adjunctive treatments to enhance the outcomes of lifestyle modification therapy among youth with obesity, none of the obesity medications evaluated to date have been shown to meaningfully reduce BMI or cardiometabolic risk factors. Promising medications recently approved for the treatment of obesity in adults will soon be tested in pediatric trials, offering hope that new therapeutic options will soon be available. As new medications are approved to treat pediatric obesity, it will be important to evaluate the safety and efficacy of combination pharmacotherapy and investigate predictors of response. Application of precision medicine approaches to the field of pediatric obesity management will improve the long-term outlook for the tens of millions of youth afflicted with this serious and recalcitrant disease.

Deficits in social cognition and response flexibility in pediatric bipolar disorder.

PubMed

McClure, Erin B; Treland, Julia E; Snow, Joseph; Schmajuk, Mariana; Dickstein, Daniel P; Towbin, Kenneth E; Charney, Dennis S; Pine, Daniel S; Leibenluft, Ellen

2005-09-01

Little is known about neuropsychological and social-cognitive function in patients with pediatric bipolar disorder. Identification of specific deficits and strengths that characterize pediatric bipolar disorder would facilitate advances in diagnosis, treatment, and research on pathophysiology. The purpose of this study was to test the hypothesis that youths with bipolar disorder would perform more poorly than matched healthy comparison subjects on measures of social cognition, motor inhibition, and response flexibility. Forty outpatients with pediatric bipolar disorder and 22 comparison subjects (no differences in age, gender, and IQ) completed measures of social cognition (the pragmatic judgment subtest of the Comprehensive Assessment of Spoken Language, facial expression recognition subtests of the Diagnostic Analysis of Nonverbal Accuracy Scale, the oral expression subtest of the Test of Language Competence), inhibition and response flexibility (stop and stop-change tasks), and motor inhibition (continuous performance tasks). Pediatric bipolar disorder patients performed more poorly than comparison subjects on social-cognitive measures (pragmatic judgment of language, facial expression recognition) and on a task requiring response flexibility. These deficits were present in euthymic patients. Differences between patients and comparison subjects could not be attributed to comorbid attention deficit hyperactivity disorder. Findings of impaired social cognition and response flexibility in youths with pediatric bipolar disorder suggest continuity between pediatric bipolar disorder and adult bipolar disorder. These findings provide a foundation for neurocognitive research designed to identify the neural mechanisms underlying these deficits.

A comprehensive review of noninvasive liver fibrosis tests in pediatric nonalcoholic Fatty liver disease.

PubMed

Mansoor, Sana; Collyer, Elizabeth; Alkhouri, Naim

2015-06-01

Nonalcoholic fatty liver disease (NAFLD) and its spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and fibrosis have been increasing in the pediatric population. The presence and severity of fibrosis in patients with NAFLD are important prognostic factors for the risk of disease progression to cirrhosis. The gold standard for staging liver fibrosis is a liver biopsy. However, given the risks of this procedure, especially in the pediatric population, the development of noninvasive markers to diagnose and monitor progression of NAFLD is desirable. This paper will review recently developed noninvasive methods for diagnosing liver fibrosis in children with NAFLD. These include simple fibrosis scores, advanced biochemical markers, and radiologic imaging studies. Simple fibrosis scores use readily available laboratory tests; available one include AST/ALT ratio, AST to platelet ratio index (APRI), fibrosis (FIB)-4 index, NAFLD fibrosis score (NFS), pediatric NAFLD fibrosis index (PNFI), and pediatric NALFD fibrosis score (PNFS). Advanced biochemical markers include biomarkers of hepatocyte cell death such as cytokeratin 18 fragment levels, and markers of extracellular matrix turnover such as the Enhanced Liver Fibrosis (ELF) test and hyaluronic acid. Radiologic imaging studies estimate liver stiffness as a surrogate for liver fibrosis; these include transient elastography (TE), magnetic resonance elastography (MRE), and acoustic radiation force impulse imaging (ARFI).

Pediatric Predispositional Genetic Risk Communication: Potential Utility for Prevention and Control of Melanoma Risk as an Exemplar.

PubMed

Wu, Yelena P; Mays, Darren; Kohlmann, Wendy; Tercyak, Kenneth P

2017-10-01

Predispositional genetic testing among minor children is intensely debated due to the potential benefits and harms of providing this type of genetic information to children and their families. Existing guidelines on pediatric genetic testing state that predispositional testing could be appropriate for minors if preventive services exist that mitigate children's risk for or severity of the health condition in question. We use the example of hereditary melanoma to illustrate the rationale for and potential application of genetic risk communication for an adult-onset cancer to a pediatric population where childhood behaviors may reduce risk of disease later in life. We draw from the adult melanoma genetic risk communication and pediatric health behavior change literatures to suggest ways in which genetic test reporting and complementary education could be delivered to children who carry a hereditary risk for melanoma and their families in order to foster children's engagement in melanoma preventive behaviors. Genetic discoveries will continue to yield new opportunities to provide predispositional genetic risk information to unaffected individuals, including children, and could be delivered within programs that provide personalized and translational approaches to cancer prevention.

Evaluation of the hybrid III and Q-series pediatric ATD upper neck loads as compared to pediatric volunteers in low-speed frontal crashes.

PubMed

Seacrist, Thomas; Mathews, Emily A; Balasubramanian, Sriram; Maltese, Matthew R; Arbogast, Kristy B

2013-11-01

Debate exists in the automotive community regarding the validity of the pediatric ATD neck response and corresponding neck loads. Previous research has shown that the pediatric ATDs exhibit hyper-flexion and chin-to-chest contact resulting in overestimations of neck loads and neck injury criteria. Our previous work comparing the kinematics of the Hybrid III and Q-series 6 and 10-year-old ATDs to pediatric volunteers in low-speed frontal sled tests revealed decreased ATD cervical and thoracic spine excursions. These kinematic differences may contribute to the overestimation of upper neck loads by the ATD. The current study compared upper neck loads of the Hybrid III and Q-series 6 and 10-year-old ATDs against size-matched male pediatric volunteers in low-speed frontal sled tests. A 3-D near-infrared target tracking system quantified the position of markers on the ATD and pediatric volunteers (head top, nasion, bilateral external auditory meatus). Shear force (F x ), axial force (F z ), bending moment (M y ), and head angular acceleration ([Formula: see text]) were calculated about the upper neck using standard equations of motion. In general, the ATDs underestimated axial force and overestimated bending moment compared to the human volunteers. The Hybrid III 6, Q6, and Q10 exhibited reduced head angular acceleration and modest increases in upper neck shear compared to the pediatric volunteers. The reduction in axial force and bending moment has important implications for neck injury predictions as both are used when calculating N ij . These analyses provide insight into the biofidelity of the pediatric ATD upper neck loads in low-speed crash environments.

Mechanical Circulatory Support of the Critically Ill Child Awaiting Heart Transplantation

PubMed Central

Gazit, Avihu Z; Gandhi, Sanjiv K; C Canter, Charles

2010-01-01

The majority of children awaiting heart transplantation require inotropic support, mechanical ventilation, and/or extracorporeal membrane oxygenation (ECMO) support. Unfortunately, due to the limited pool of organs, many of these children do not survive to transplant. Mechanical circulatory support of the failing heart in pediatrics is a new and rapidly developing field world-wide. It is utilized in children with acute congestive heart failure associated with congenital heart disease, cardiomyopathy, and myocarditis, both as a bridge to transplantation and as a bridge to myocardial recovery. The current arsenal of mechanical assist devices available for children is limited to ECMO, intra-aortic balloon counterpulsation, centrifugal pump ventricular assist devices, the DeBakey ventricular assist device Child; the Thoratec ventricular assist device; and the Berlin Heart. In the spring of 2004, five contracts were awarded by the National Heart, Lung and Blood Institute to support preclinical development for a range of pediatric ventricular assist devices and similar circulatory support systems. The support of early development efforts provided by this program is expected to yield several devices that will be ready for clinical trials within the next few years. Our work reviews the current international experience with mechanical circulatory support in children and summarizes our own experience since 2005 with the Berlin Heart, comparing the indications for use, length of support, and outcome between these modalities. PMID:21286278

Preclinical Evaluation of Engineered Oncolytic Herpes Simplex Virus for the Treatment of Neuroblastoma

PubMed Central

Gillory, Lauren A.; Megison, Michael L.; Stewart, Jerry E.; Mroczek-Musulman, Elizabeth; Nabers, Hugh C.; Waters, Alicia M.; Kelly, Virginia; Coleman, Jennifer M.; Markert, James M.; Gillespie, G. Yancey; Friedman, Gregory K.; Beierle, Elizabeth A.

2013-01-01

Despite intensive research efforts and therapeutic advances over the last few decades, the pediatric neural crest tumor, neuroblastoma, continues to be responsible for over 15% of pediatric cancer deaths. Novel therapeutic options are needed for this tumor. Recently, investigators have shown that mice with syngeneic murine gliomas treated with an engineered, neuroattenuated oncolytic herpes simplex virus-1 (oHSV), M002, had a significant increase in survival. M002 has deletions in both copies of the γ134.5 gene, enabling replication in tumor cells but precluding infection of normal neural cells. We hypothesized that M002 would also be effective in the neural crest tumor, neuroblastoma. We showed that M002 infected, replicated, and decreased survival in neuroblastoma cell lines. In addition, we showed that in murine xenografts, treatment with M002 significantly decreased tumor growth, and that this effect was augmented with the addition of ionizing radiation. Importantly, survival could be increased by subsequent doses of radiation without re-dosing of the virus. Finally, these studies showed that the primary entry protein for oHSV, CD111 was expressed by numerous neuroblastoma cell lines and was also present in human neuroblastoma specimens. We concluded that M002 effectively targeted neuroblastoma and that this oHSV may have potential for use in children with unresponsive or relapsed neuroblastoma. PMID:24130898

Using screen-based simulation to improve performance during pediatric resuscitation.

PubMed

Biese, Kevin J; Moro-Sutherland, Donna; Furberg, Robert D; Downing, Brian; Glickman, Larry; Murphy, Alison; Jackson, Cheryl L; Snyder, Graham; Hobgood, Cherri

2009-12-01

To assess the ability of a screen-based simulation-training program to improve emergency medicine and pediatric resident performance in critical pediatric resuscitation knowledge, confidence, and skills. A pre-post, interventional design was used. Three measures of performance were created and assessed before and after intervention: a written pre-course knowledge examination, a self-efficacy confidence score, and a skills-based high-fidelity simulation code scenario. For the high-fidelity skills assessment, independent physician raters recorded and reviewed subject performance. The intervention consisted of eight screen-based pediatric resuscitation scenarios that subjects had 4 weeks to complete. Upon completion of the scenarios, all three measures were repeated. For the confidence assessment, summary pre- and post-test summary confidence scores were compared using a t-test, and for the skills assessment, pre-scores were compared with post-test measures for each individual using McNemar's chi-square test for paired samples. Twenty-six of 35 (71.3%) enrolled subjects completed the institutional review board-approved study. Increases were observed in written test scores, confidence, and some critical interventions in high-fidelity simulation. The mean improvement in cumulative confidence scores for all residents was 10.1 (SD +/-4.9; range 0-19; p < 0.001), with no resident feeling less confident after the intervention. Although overall performance in simulated codes did not change significantly, with average scores of 6.65 (+/-1.76) to 7.04 (+/-1.37) out of 9 possible points (p = 0.58), improvement was seen in the administering of appropriate amounts of IV fluids (59-89%, p = 0.03). In this study, improvements in resident knowledge, confidence, and performance of certain skills in simulated pediatric cardiac arrest scenarios suggest that screen-based simulations may be an effective way to enhance resuscitation skills of pediatric providers. These results should be confirmed using a randomized design with an appropriate control group. (c) 2009 by the Society for Academic Emergency Medicine.

Molecular and clinical implementations of ovarian cancer mouse avatar models.

PubMed

Zayed, Amira A; Mandrekar, Sumithra J; Haluska, Paul

2015-09-01

Innovation in oncology drug development has been hindered by lack of preclinical models that reliably predict clinical activity of novel therapies in cancer patients. Increasing desire for individualize treatment of patients with cancer has led to an increase in the use of patient-derived xenografts (PDX) engrafted into immune-compromised mice for preclinical modeling. Large numbers of tumor-specific PDX models have been established and proved to be powerful tools in pre-clinical testing. A subset of PDXs, referred to as Avatars, establish tumors in an orthotopic and treatment naïve fashion that may represent the most clinical relevant model of individual human cancers. This review will discuss ovarian cancer (OC) PDX models demonstrating the opportunities and limitations of these models in cancer drug development, and describe concepts of clinical trials design in Avatar guided therapy.

Quality improvement utilizing in-situ simulation for a dual-hospital pediatric code response team.

PubMed

Yager, Phoebe; Collins, Corey; Blais, Carlene; O'Connor, Kathy; Donovan, Patricia; Martinez, Maureen; Cummings, Brian; Hartnick, Christopher; Noviski, Natan

2016-09-01

Given the rarity of in-hospital pediatric emergency events, identification of gaps and inefficiencies in the code response can be difficult. In-situ, simulation-based medical education programs can identify unrecognized systems-based challenges. We hypothesized that developing an in-situ, simulation-based pediatric emergency response program would identify latent inefficiencies in a complex, dual-hospital pediatric code response system and allow rapid intervention testing to improve performance before implementation at an institutional level. Pediatric leadership from two hospitals with a shared pediatric code response team employed the Institute for Healthcare Improvement's (IHI) Breakthrough Model for Collaborative Improvement to design a program consisting of Plan-Do-Study-Act cycles occurring in a simulated environment. The objectives of the program were to 1) identify inefficiencies in our pediatric code response; 2) correlate to current workflow; 3) employ an iterative process to test quality improvement interventions in a safe environment; and 4) measure performance before actual implementation at the institutional level. Twelve dual-hospital, in-situ, simulated, pediatric emergencies occurred over one year. The initial simulated event allowed identification of inefficiencies including delayed provider response, delayed initiation of cardiopulmonary resuscitation (CPR), and delayed vascular access. These gaps were linked to process issues including unreliable code pager activation, slow elevator response, and lack of responder familiarity with layout and contents of code cart. From first to last simulation with multiple simulated process improvements, code response time for secondary providers coming from the second hospital decreased from 29 to 7 min, time to CPR initiation decreased from 90 to 15 s, and vascular access obtainment decreased from 15 to 3 min. Some of these simulated process improvements were adopted into the institutional response while others continue to be trended over time for evidence that observed changes represent a true new state of control. Utilizing the IHI's Breakthrough Model, we developed a simulation-based program to 1) successfully identify gaps and inefficiencies in a complex, dual-hospital, pediatric code response system and 2) provide an environment in which to safely test quality improvement interventions before institutional dissemination. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Tensile failure properties of the perinatal, neonatal, and pediatric cadaveric cervical spine.

PubMed

Luck, Jason F; Nightingale, Roger W; Song, Yin; Kait, Jason R; Loyd, Andre M; Myers, Barry S; Bass, Cameron R Dale

2013-01-01

Biomechanical tensile testing of perinatal, neonatal, and pediatric cadaveric cervical spines to failure. To assess the tensile failure properties of the cervical spine from birth to adulthood. Pediatric cervical spine biomechanical studies have been few due to the limited availability of pediatric cadavers. Therefore, scaled data based on human adult and juvenile animal studies have been used to augment the limited pediatric cadaver data. Despite these efforts, substantial uncertainty remains in our understanding of pediatric cervical spine biomechanics. A total of 24 cadaveric osteoligamentous head-neck complexes, 20 weeks gestation to 18 years, were sectioned into segments (occiput-C2 [O-C2], C4-C5, and C6-C7) and tested in tension to determine axial stiffness, displacement at failure, and load-to-failure. Tensile stiffness-to-failure (N/mm) increased by age (O-C2: 23-fold, neonate: 22 ± 7, 18 yr: 504; C4-C5: 7-fold, neonate: 71 ± 14, 18 yr: 509; C6-C7: 7-fold, neonate: 64 ± 17, 18 yr: 456). Load-to-failure (N) increased by age (O-C2: 13-fold, neonate: 228 ± 40, 18 yr: 2888; C4-C5: 9-fold, neonate: 207 ± 63, 18 yr: 1831; C6-C7: 10-fold, neonate: 174 ± 41, 18 yr: 1720). Normalized displacement at failure (mm/mm) decreased by age (O-C2: 6-fold, neonate: 0.34 ± 0.076, 18 yr: 0.059; C4-C5: 3-fold, neonate: 0.092 ± 0.015, 18 yr: 0.035; C6-C7: 2-fold, neonate: 0.088 ± 0.019, 18 yr: 0.037). Cervical spine tensile stiffness-to-failure and load-to-failure increased nonlinearly, whereas normalized displacement at failure decreased nonlinearly, from birth to adulthood. Pronounced ligamentous laxity observed at younger ages in the O-C2 segment quantitatively supports the prevalence of spinal cord injury without radiographic abnormality in the pediatric population. This study provides important and previously unavailable data for validating pediatric cervical spine models, for evaluating current scaling techniques and animal surrogate models, and for the development of more biofidelic pediatric crash test dummies.

[Staged oncological screening with TG test].

PubMed

Bakhlaev, I E; Ageenko, A I; Rolik, I S

2006-01-01

The authors present their analysis of screening methods used for early diagnostics of cancer of various localization and for detection of high-risk individuals. They offer a program of step-by-step screening that makes it possible to cover more population with prophylactic examination and to reduce the need for special examination methods. TG-test is a universal and the most informative blastomatous process indicator at any stage, including the preclinical one. The practical screening results double the revealing rate of oncopathology and allow for three-fold reduction in the diagnostic costs compared with standard methods of cancer diagnostics. The medical efficiency of the oncological screening is high; in one third of the examined patients a tumor is diagnosed at the preclinical stage.

Evaluation of pediatric upper extremity peripheral nerve injuries.

PubMed

Ho, Emily S

2015-01-01

The evaluation of motor and sensory function of the upper extremity after a peripheral nerve injury is critical to diagnose the location and extent of nerve injury as well as document functional recovery in children. The purpose of this paper is to describe an approach to the evaluation of the pediatric upper extremity peripheral nerve injuries through a critical review of currently used tests of sensory and motor function. Outcome studies on pediatric upper extremity peripheral nerve injuries in the Medline database were reviewed. The evaluation of the outcome in children less than 10 years of age with an upper extremity peripheral nerve injury includes careful observation of preferred prehension patterns, examination of muscle atrophy and sudomotor function, provocative tests, manual muscle testing and tests of sensory threshold and tactile gnosis. The evaluation of outcome in children with upper extremity peripheral nerve injuries warrants a unique approach. Copyright © 2015 Hanley & Belfus. Published by Elsevier Inc. All rights reserved.

C-Type Natriuretic Peptide Analog as Therapy for Achondroplasia.

PubMed

Legeai-Mallet, Laurence

2016-01-01

Fibroblast growth factor receptor 3 (FGFR3) is an important regulator of bone formation. Gain-of-function mutations in the FGFR3 gene result in chondrodysplasias which include achondroplasia (ACH), the most common form of dwarfism, in which skull, appendicular and axial skeletons are affected. The skeletal phenotype of patients with ACH showed defective proliferation and differentiation of the chondrocytes in the growth plate cartilage. Both endochondral and membranous ossification processes are disrupted during development. At cellular level, Fgfr3 mutations induce increased phosphorylation of the tyrosine kinase receptor FGFR3, which correlate with an enhanced activation of its downstream signaling pathways. Potential therapeutic strategies have emerged for ACH. Several preclinical studies have been conducted such as the C-type natriuretic peptide (CNP) analog (BMN111), intermittent parathyroid hormone injections, soluble FGFR3 therapy, and meclozine and statin treatments. Among the putative targets to antagonize FGFR3 signaling, CNP (or BMN111) is one of the most promising strategies. BMN111 acts as a key regulator of longitudinal bone growth by downregulating the mitogen-activated protein kinase pathway, which is activated as a result of a FGFR3 gain-of-function mutation. Preclinical studies showed that BMN111 treatment led to a large improvement in skeletal parameters in Fgfr3Y367C/+ mice mimicking ACH. In 2014, a clinical trial (phase 2) of BMN111 in pediatric patients with ACH has started. This first clinical trial marks the first big step towards real treatment for these patients. © 2016 S. Karger AG, Basel.

Urine testing and urinary tract infections in febrile infants seen in office settings: the Pediatric Research in Office Settings' Febrile Infant Study.

PubMed

Newman, Thomas B; Bernzweig, Jane A; Takayama, John I; Finch, Stacia A; Wasserman, Richard C; Pantell, Robert H

2002-01-01

To determine the predictors and results of urine testing of young febrile infants seen in office settings. Prospective cohort study. Offices of 573 pediatric practitioners from 219 practices in the American Academy of Pediatrics Pediatric Research in Office Settings' research network. A total of 3066 infants 3 months or younger with temperatures of 38 degrees C or higher were evaluated and treated according to the judgment of their practitioners. Urine testing results, early and late urinary tract infections (UTIs), and UTIs with bacteremia. Fifty-four percent of the infants initially had urine tested, of whom 10% had a UTI. The height of the fever was associated with urine testing and a UTI among those tested (adjusted odds ratio per degree Celsius, 2.2 for both). Younger age, ill appearance, and lack of a fever source were associated with urine testing but not with a UTI, whereas lack of circumcision (adjusted odds ratio, 11.6), female sex (adjusted odds ratio, 5.4), and longer duration of fever (adjusted odds ratio, 1.8 for fever lasting > or = 24 hours) were not associated with urine testing but were associated with a UTI. Bacteremia accompanied the UTI in 10% of the patients, including 17% of those younger than 1 month. Among 807 infants not initially tested or treated with antibiotics, only 2 had a subsequent documented UTI; both did well. Practitioners order urine tests selectively, focusing on younger and more ill-appearing infants and on those without an apparent fever source. Such selective urine testing, with close follow-up, was associated with few late UTIs in this large study. Urine testing should focus particularly on uncircumcised boys, girls, the youngest and sickest infants, and those with persistent fever.

Altered structural brain changes and neurocognitive performance in pediatric HIV.

PubMed

Yadav, Santosh K; Gupta, Rakesh K; Garg, Ravindra K; Venkatesh, Vimala; Gupta, Pradeep K; Singh, Alok K; Hashem, Sheema; Al-Sulaiti, Asma; Kaura, Deepak; Wang, Ena; Marincola, Francesco M; Haris, Mohammad

2017-01-01

Pediatric HIV patients often suffer with neurodevelopmental delay and subsequently cognitive impairment. While tissue injury in cortical and subcortical regions in the brain of adult HIV patients has been well reported there is sparse knowledge about these changes in perinatally HIV infected pediatric patients. We analyzed cortical thickness, subcortical volume, structural connectivity, and neurocognitive functions in pediatric HIV patients and compared with those of pediatric healthy controls. With informed consent, 34 perinatally infected pediatric HIV patients and 32 age and gender matched pediatric healthy controls underwent neurocognitive assessment and brain magnetic resonance imaging (MRI) on a 3 T clinical scanner. Altered cortical thickness, subcortical volumes, and abnormal neuropsychological test scores were observed in pediatric HIV patients. The structural network connectivity analysis depicted lower connection strengths, lower clustering coefficients, and higher path length in pediatric HIV patients than healthy controls. The network betweenness and network hubs in cortico-limbic regions were distorted in pediatric HIV patients. The findings suggest that altered cortical and subcortical structures and regional brain connectivity in pediatric HIV patients may contribute to deficits in their neurocognitive functions. Further, longitudinal studies are required for better understanding of the effect of HIV pathogenesis on brain structural changes throughout the brain development process under standard ART treatment.

Transfusion-related immunomodulation: review of the literature and implications for pediatric critical illness.

PubMed

Muszynski, Jennifer A; Spinella, Philip C; Cholette, Jill M; Acker, Jason P; Hall, Mark W; Juffermans, Nicole P; Kelly, Daniel P; Blumberg, Neil; Nicol, Kathleen; Liedel, Jennifer; Doctor, Allan; Remy, Kenneth E; Tucci, Marisa; Lacroix, Jacques; Norris, Philip J

2017-01-01

Transfusion-related immunomodulation (TRIM) in the intensive care unit (ICU) is difficult to define and likely represents a complicated set of physiologic responses to transfusion, including both proinflammatory and immunosuppressive effects. Similarly, the immunologic response to critical illness in both adults and children is highly complex and is characterized by both acute inflammation and acquired immune suppression. How transfusion may contribute to or perpetuate these phenotypes in the ICU is poorly understood, despite the fact that transfusion is common in critically ill patients. Both hyperinflammation and severe immune suppression are associated with poor outcomes from critical illness, underscoring the need to understand potential immunologic consequences of blood product transfusion. In this review we outline the dynamic immunologic response to critical illness, provide clinical evidence in support of immunomodulatory effects of blood product transfusion, review preclinical and translational studies to date of TRIM, and provide insight into future research directions. © 2016 AABB.

Hypoxia as a therapy for mitochondrial disease.

PubMed

Jain, Isha H; Zazzeron, Luca; Goli, Rahul; Alexa, Kristen; Schatzman-Bone, Stephanie; Dhillon, Harveen; Goldberger, Olga; Peng, Jun; Shalem, Ophir; Sanjana, Neville E; Zhang, Feng; Goessling, Wolfram; Zapol, Warren M; Mootha, Vamsi K

2016-04-01

Defects in the mitochondrial respiratory chain (RC) underlie a spectrum of human conditions, ranging from devastating inborn errors of metabolism to aging. We performed a genome-wide Cas9-mediated screen to identify factors that are protective during RC inhibition. Our results highlight the hypoxia response, an endogenous program evolved to adapt to limited oxygen availability. Genetic or small-molecule activation of the hypoxia response is protective against mitochondrial toxicity in cultured cells and zebrafish models. Chronic hypoxia leads to a marked improvement in survival, body weight, body temperature, behavior, neuropathology, and disease biomarkers in a genetic mouse model of Leigh syndrome, the most common pediatric manifestation of mitochondrial disease. Further preclinical studies are required to assess whether hypoxic exposure can be developed into a safe and effective treatment for human diseases associated with mitochondrial dysfunction. Copyright © 2016, American Association for the Advancement of Science.

Clinical correlations of dry eye syndrome and allergic conjunctivitis in Korean children.

PubMed

Kim, Tae Hyung; Moon, Nam Ju

2013-01-01

Clinical patterns in pediatric patients with dry eye syndrome and allergic conjunctivitis were investigated. Children aged 6 to 15 years with dry eye symptoms were included. Slit-lamp examinations including tear film break-up time, Schirmer's test, and fluorescent staining were performed, and subjective symptoms were investigated. Patients with allergic conjunctivitis were subjected to skin prick tests. Tear film break-up time was shorter and the number of symptoms related to dry eyes was higher in pediatric patients with allergic conjunctivitis than in those without allergic conjunctivitis. Patients with allergic conjunctivitis who had higher numbers of positive allergens on the skin prick test also had shorter tear film break-up time. Because pediatric patients with dry eye syndrome tend to complain less about their symptoms than adult patients, dry eye syndrome is commonly overlooked. This study showed that dry eyes tended to be more severe with the presence of allergic conjunctivitis; the more allergens present, the more severe the dry eyes. More attention should be paid to the treatment of pediatric patients with dry eyes accompanied by allergies. Copyright 2013, SLACK Incorporated.

Obtaining genetic testing in pediatric epilepsy.

PubMed

Ream, Margie A; Patel, Anup D

2015-10-01

The steps from patient evaluation to genetic diagnosis remain complicated. We discuss some of the genetic testing methods available along with their general advantages and disadvantages. We briefly review common pediatric epilepsy syndromes with strong genetic association and provide a potentially useful algorithm for genetic testing in drug-resistant epilepsy. We performed an extensive literature review of available information as it pertains to genetic testing and genetics in pediatric epilepsy. If a genetic disorder is suspected as the cause of epilepsy, based on drug resistance, family history, or clinical phenotype, timely diagnosis may reduce overall cost, limit the diagnostic odyssey that can bring much anxiety to families, improve prognostic accuracy, and lead to targeted therapy. Interpretation of complicated results should be performed only in collaboration with geneticists and genetic counselors, unless the ordering neurologist has a strong background in and understanding of genetics. Genetic testing can play an important role in the care provided to patients with epilepsy. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

The value of the UK Clinical Aptitude Test in predicting pre-clinical performance: a prospective cohort study at Nottingham Medical School.

PubMed

Yates, Janet; James, David

2010-07-28

The UK Clinical Aptitude Test (UKCAT) was introduced in 2006 as an additional tool for the selection of medical students. It tests mental ability in four distinct domains (Quantitative Reasoning, Verbal Reasoning, Abstract Reasoning, and Decision Analysis), and the results are available to students and admissions panels in advance of the selection process. As yet the predictive validity of the test against course performance is largely unknown.The study objective was to determine whether UKCAT scores predict performance during the first two years of the 5-year undergraduate medical course at Nottingham. We studied a single cohort of students, who entered Nottingham Medical School in October 2007 and had taken the UKCAT. We used linear regression analysis to identify independent predictors of marks for different parts of the 2-year preclinical course. Data were available for 204/260 (78%) of the entry cohort. The UKCAT total score had little predictive value. Quantitative Reasoning was a significant independent predictor of course marks in Theme A ('The Cell'), (p = 0.005), and Verbal Reasoning predicted Theme C ('The Community') (p < 0.001), but otherwise the effects were slight or non-existent. This limited study from a single entry cohort at one medical school suggests that the predictive value of the UKCAT, particularly the total score, is low. Section scores may predict success in specific types of course assessment.The ultimate test of validity will not be available for some years, when current cohorts of students graduate. However, if this test of mental ability does not predict preclinical performance, it is arguably less likely to predict the outcome in the clinical years. Further research from medical schools with different types of curriculum and assessment is needed, with longitudinal studies throughout the course.

Correlation of the Pediatric Volitional Questionnaire with the Test of Playfulness in a Virtual Environment: The Power of Engagement

ERIC Educational Resources Information Center

Reid, Denise

2005-01-01

The Pediatric Volitional Questionnaire (PVQ) was used along with the Test of Playfulness (TOP) to assess 16 children with cerebral palsy who took part in a study of virtual reality play intervention. Both observational measures are designed to assess children as they are engaged in occupations in one or more environments. Virtual reality offers an…

Improving Healthcare in Pediatric Oncology: Development and Testing of Multiple Indicators to Evaluate a Hub-And-Spoke Model.

PubMed

Zucchetti, Giulia; Bertorello, Nicoletta; Angelastro, Angela; Gianino, Paola; Bona, Gianni; Barbara, Affif; Besenzon, Luigi; Brach Del Prever, Adalberto; Pesce, Fernando; Nangeroni, Marco; Fagioli, Franca

2017-06-01

Purpose The hub-and-spoke is a new innovation model in healthcare that has been adopted in some countries to manage rare pathologies. We developed a set of indicators to assess current quality practices of the hub-and-spoke model adopted in the Interregional Pediatric Oncology Network in Northwest Italy and to promote patient, family, and professional healthcare empowerment. Methods Literature and evidence-based clinical guidelines were reviewed and multiprofessional team workshops were carried out to highlight some important issues on healthcare in pediatric oncology and to translate them into a set of multiple indicators. For each indicator, specific questions were formulated and tested through a series of questionnaires completed by 80 healthcare professionals and 50 pediatric patients and their parents. Results The results highlighted a positive perception of healthcare delivered by the hub-and-spoke model (M HP = 156, M Pat = 93, M Par = 104). Based on the participants' suggestions, some quality improvements have been implemented. Conclusions This study represents the first attempt to examine this new model of pediatric oncology care through the active involvement of patients, families, and healthcare professionals. Suggestions for adopting a hub-and-spoke model in pediatric oncology in other regions and countries are also highlighted.

In search of antiepileptogenic treatments for post-traumatic epilepsy.

PubMed

Saletti, Patricia G; Ali, Idrish; Casillas-Espinosa, Pablo M; Semple, Bridgette D; Lisgaras, Christos; Moshé, Solomon L; Galanopoulou, Aristea S

2018-06-21

Post-traumatic epilepsy (PTE) occurs in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the existing preclinical studies test efficacy towards pathologies of functional recovery after TBI, while a few studies are emerging testing the effects towards induced or spontaneous seizures. Here we review the existing preclinical trials testing new candidate treatments for TBI sequelae and PTE, and discuss future directions for efforts aiming at developing antiepileptogenic and disease-modifying treatments. Copyright © 2018. Published by Elsevier Inc.

Preclinical dose number and its application in understanding drug absorption risk and formulation design for preclinical species.

PubMed

Wuelfing, W Peter; Daublain, Pierre; Kesisoglou, Filippos; Templeton, Allen; McGregor, Caroline

2015-04-06

In the drug discovery setting, the ability to rapidly identify drug absorption risk in preclinical species at high doses from easily measured physical properties is desired. This is due to the large number of molecules being evaluated and their high attrition rate, which make resource-intensive in vitro and in silico evaluation unattractive. High-dose in vivo data from rat, dog, and monkey are analyzed here, using a preclinical dose number (PDo) concept based on the dose number described by Amidon and other authors (Pharm. Res., 1993, 10, 264-270). PDo, as described in this article, is simply calculated as dose (mg/kg) divided by compound solubility in FaSSIF (mg/mL) and approximates the volume of biorelevant media per kilogram of animal that would be needed to fully dissolve the dose. High PDo values were found to be predictive of difficulty in achieving drug exposure (AUC)-dose proportionality in in vivo studies, as could be expected; however, this work analyzes a large data set (>900 data points) and provides quantitative guidance to identify drug absorption risk in preclinical species based on a single solubility measurement commonly carried out in drug discovery. Above the PDo values defined, >50% of all in vivo studies exhibited poor AUC-dose proportionality in rat, dog, and monkey, and these values can be utilized as general guidelines in discovery and early development to rapidly assess risk of solubility-limited absorption for a given compound. A preclinical dose number generated by biorelevant dilutions of formulated compounds (formulated PDo) was also evaluated and defines solubility targets predictive of suitable AUC-dose proportionality in formulation development efforts. Application of these guidelines can serve to efficiently identify compounds in discovery that are likely to present extreme challenges with respect to solubility-limited absorption in preclinical species as well as reduce the testing of poor formulations in vivo, which is a key ethical and resource matter.

MR-CBCT image-guided system for radiotherapy of orthotopic rat prostate tumors.

PubMed

Chiu, Tsuicheng D; Arai, Tatsuya J; Campbell Iii, James; Jiang, Steve B; Mason, Ralph P; Stojadinovic, Strahinja

2018-01-01

Multi-modality image-guided radiotherapy is the standard of care in contemporary cancer management; however, it is not common in preclinical settings due to both hardware and software limitations. Soft tissue lesions, such as orthotopic prostate tumors, are difficult to identify using cone beam computed tomography (CBCT) imaging alone. In this study, we characterized a research magnetic resonance (MR) scanner for preclinical studies and created a protocol for combined MR-CBCT image-guided small animal radiotherapy. Two in-house dual-modality, MR and CBCT compatible, phantoms were designed and manufactured using 3D printing technology. The phantoms were used for quality assurance tests and to facilitate end-to-end testing for combined preclinical MR and CBCT based treatment planning. MR and CBCT images of the phantoms were acquired utilizing a Varian 4.7 T scanner and XRad-225Cx irradiator, respectively. The geometry distortion was assessed by comparing MR images to phantom blueprints and CBCT. The corrected MR scans were co-registered with CBCT and subsequently used for treatment planning. The fidelity of 3D printed phantoms compared to the blueprint design yielded favorable agreement as verified with the CBCT measurements. The geometric distortion, which varied between -5% and 11% throughout the scanning volume, was substantially reduced to within 0.4% after correction. The distortion free MR images were co-registered with the corresponding CBCT images and imported into a commercial treatment planning software SmART Plan. The planning target volume (PTV) was on average 19% smaller when contoured on the corrected MR-CBCT images relative to raw images without distortion correction. An MR-CBCT based preclinical workflow was successfully designed and implemented for small animal radiotherapy. Combined MR-CBCT image-guided radiotherapy for preclinical research potentially delivers enhanced relevance to human radiotherapy for various disease sites. This novel protocol is wide-ranging and not limited to the orthotopic prostate tumor study presented in the study.

Continuing Medical Education for Air Medical Providers: The Successes and Challenges.

PubMed

Miller, Jenna O; Thammasitboon, Satid; Hsu, Deborah C; Shah, Manish I; Minard, Charles G; Graf, Jeanine M

2016-02-01

Research has shown that patients transported by nonpediatric teams have higher rates of morbidity and mortality. There is currently a paucity of pediatric standardized ongoing medical education for emergency medical service providers, thus we aimed to develop a model curriculum to increase their knowledge regarding pediatric respiratory distress and failure. The curriculum was based on the Kolb Learning Cycle to optimize learning. Target learners were flight nurses (registered nurse) and emergency medical technicians of a private helicopter emergency transport team. The topics included were pediatric stridor, wheezing, and respiratory failure. Online modules were developed for continued spaced education. Knowledge gained from the interventions was measured by precurricular and postcurricular testing and compared with paired t tests. A linear mixed regression model was used to investigate covariates of interest. Sixty-two learners attended the workshop. Fifty-nine learners completed both precurricular and postcurricular testing. The mean increase between pretest and posttest scores was 12.1% (95% confidence interval, 9.4, 14.8; P < 0.001). Type of licensure (private emergency medical technician vs registered nurse) and number of years experience had no association with the level of knowledge gained. Learners who had greater than 1 year of pediatric transport experience scored higher on their pretests. There was no significant retention shown by those who participated in spaced education. The curriculum was associated with a short term increased knowledge regarding pediatric respiratory distress and failure for emergency helicopter transport providers and could be used as an alternative model to develop standardized ongoing medical education in pediatrics. Further work is needed to achieve knowledge retention in this learner population.

A study protocol testing the implementation, efficacy, and cost effectiveness of the ezParent program in pediatric primary care

PubMed Central

Schoeny, Michael; Risser, Heather; Johnson, Tricia

2016-01-01

Introduction Up to 20% of children demonstrate behavior problems that interfere with relationship development and academic achievement. Parent participation in behavioral parent training programs has been shown to decrease child problem behaviors and promote positive parent-child relationships. However, attendance and parent involvement in face-to-face parent training remain low. Testing the implementation, efficacy, and cost of alternative delivery models is needed to (a) increase the reach and sustainability of parent training interventions and (b) address the barriers to parent participation and implementation of such programs, specifically in primary health care settings. The purpose of this paper is to describe the study protocol evaluating the implementation, efficacy, and cost-effectiveness of delivering the tablet-based ezParent program in pediatric primary care sites. Methods The implementation of the ezParent in four pediatric primary care sites will be evaluated using a descriptive design and cost-effectiveness analysis. The efficacy of the ezParent will be tested using a randomized controlled trial design with 312 parents of 2 to 5 year old children from pediatric primary care settings. Data on parenting and child behavior outcomes will be obtained from all participants at baseline, and 3, 6, and 12 months post baseline. Discussion Integrating and evaluating the implementation of the ezParent in pediatric primary care is an innovative opportunity to promote positive parenting with potential for universal access to the preschool population and for low cost by building on existing infrastructure in pediatric primary care. PMID:27592122

In-Hospital Quality-of-Care Measures for Pediatric Sepsis Syndrome.

PubMed

Odetola, Folafoluwa O; Freed, Gary; Shevrin, Caroline; Madden, Brian; McCormick, Julie; Dombkowski, Kevin

2017-07-24

Sepsis syndrome, comprising sepsis, severe sepsis, and septic shock, is a leading cause of child mortality and morbidity, for which the delivery of time-sensitive care leads to improved survival. We aimed to describe the development and testing of quality measures for in-hospital care of pediatric sepsis syndrome. Seven measures of quality of care for children hospitalized with sepsis syndrome were developed by using an iterative process including literature review, development of concepts and candidate measures, and selection of measures for feasibility and importance by 2 panels of experts. The measures were tested for reliability and validity among children 0 to 18 years of age hospitalized with sepsis syndrome from January 1, 2012, to June 30, 2013. Of 27 hospitals, 59% had no protocol for the identification and treatment of pediatric sepsis syndrome. Blood culture was performed in only 70% of patients with pediatric sepsis syndrome. Antibiotics were administered within 1 hour of diagnosis in 70% of patients with pediatric severe sepsis or septic shock, and timely fluid resuscitation was performed in 50% of patients with severe sepsis or septic shock. Documentation of heart rate during fluid resuscitation of children with severe sepsis or septic shock was observed in 18% of cases. Two measures could not be rigorously tested for validity and reliability given the rarity of septic shock and were deemed infeasible. This multisite study to develop and validate measures of the quality of hospital care of children with sepsis syndrome highlights the existence of important gaps in delivery of care. Copyright © 2017 by the American Academy of Pediatrics.

An overview of bilastine metabolism during preclinical investigations.

PubMed

Lucero, María Luisa; Gonzalo, Ana; Mumford, Rory; Betanzos, Mónica; Alejandro, Ana

2012-06-01

Knowledge of the biotransformation of oral H₁ antihistamines is clinically important because it can define their pharmacokinetic profile through possible effects on absorption (i.e., first-pass metabolism) and elimination. Further, clinically significant interactions with inhibitors of cytochrome P450 (CYP) have previously been reported for drugs of this therapeutic group, such as terfenadine and astemizole, indicating the possibility of drug-drug interactions involving agents that share the same metabolic pathway. The aim of this article was to review the preclinical testing of a new antihistamine (i.e., bilastine) in terms of its biotransformation in various animal species, including humans, and to evaluate its potential for possible drug-drug interactions involving the CYP system. A wide array of preclinical experiments were reviewed, all of which demonstrated that bilastine undergoes minimal metabolism in all species tested to date, including humans. Further, bilastine did not interact significantly, either as an inhibitor or inducer, with the CYP enzyme system, suggesting a low propensity for involvement in drug-drug interactions. These characteristics demonstrate the potential for bilastine to be a good choice for allergic patients receiving treatment for other concomitant diseases, including those with renal or hepatic dysfunction.

Single vs. combination immunotherapeutic strategies for glioma

PubMed Central

Chandran, Mayuri; Candolfi, Marianela; Shah, Diana; Mineharu, Yohei; Yadav, Vivek; Koschmann, Carl; Asad, Antonela S.; Lowenstein, Pedro R.; Castro, Maria G.

2017-01-01

Introduction Malignant gliomas are highly invasive tumors, associated with a dismal survival rate despite standard of care, which includes surgical resection, radiotherapy and chemotherapy with temozolomide (TMZ). Precision immunotherapies or combinations of immunotherapies that target unique tumor-specific featuresmay substantially improve upon existing treatments. Areas covered Clinical trials of single immunotherapies have shown therapeutic potential in high-grade glioma patients, and emerging preclinical studies indicate that combinations of immunotherapies may be more effective than monotherapies. In this review we discuss emerging combinations of immunotherapies and compare efficacy of single vs. combined therapies tested in preclinical brain tumor models. Expert opinion Malignant gliomas are characterized by a number of factors which may limit the success of single immunotherapies including inter-tumor and intra-tumor heterogeneity, intrinsic resistance to traditional therapies, immunosuppression, and immune selection for tumor cells with low antigenicity. Combination of therapies which target multiple aspects of tumor physiology are likely to be more effective than single therapies. While we describe a limited number of combination immunotherapies which are currently being tested in preclinical and clinical studies, the field is expanding at an astounding rate, and endless combinations remain open for exploration. PMID:28286975

Effect of Two Preclinical Curricula on NMBE Part I Examination Performance.

ERIC Educational Resources Information Center

Farquhar, Lynda J.; And Others

1986-01-01

Comparison of medical students' performance on the National Board of Medical Examiners test, Part I, indicates that the replacement of scheduled instructional time (i.e., lecture-based instruction) with a guided problem-solving program was not detrimental to test scores. (MSE)

Utilizing an Orally Dissolving Strip for Pharmacological and Toxicological Studies: A Simple and Humane Alternative to Oral Gavage for Animals

PubMed Central

Lieu, Dustin; Asatryan, Liana; Davies, Daryl L.

2016-01-01

Prior to testing novel therapeutics in humans, short and long term preclinical (i.e., animal), repetitive pharmacological and toxicological testing is required. In most cases, the preferred route of administration is via oral delivery. At the present time, oral delivery is mostly accomplished using an oral gavage procedure, in part, because it can achieve consistent and precise dosing in the animal model. Although this method is well established it does have complications that can result in a high rate of animal attrition. To this end, the procedure introduced here describes an alternative to the oral gavage method in which the desired drug is incorporated into a tastant, orally dissolving strip (ODS) that can simply be presented to the test animal where it is then rapidly taken up with minimal manipulation of the test subject. Herein, we demonstrate that preclinical, oral drug delivery using the ODS method represents a safe, convenient, and humane alternative to oral gavage. PMID:27078261

Amyloid and tau signatures of brain metabolic decline in preclinical Alzheimer's disease.

PubMed

Pascoal, Tharick A; Mathotaarachchi, Sulantha; Shin, Monica; Park, Ah Yeon; Mohades, Sara; Benedet, Andrea L; Kang, Min Su; Massarweh, Gassan; Soucy, Jean-Paul; Gauthier, Serge; Rosa-Neto, Pedro

2018-06-01

We aimed to determine the amyloid (Aβ) and tau biomarker levels associated with imminent Alzheimer's disease (AD) - related metabolic decline in cognitively normal individuals. A threshold analysis was performed in 120 cognitively normal elderly individuals by modelling 2-year declines in brain glucose metabolism measured with [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) as a function of [ 18 F]florbetapir Aβ positron emission tomography (PET) and cerebrospinal fluid phosphorylated tau biomarker thresholds. Additionally, using a novel voxel-wise analytical framework, we determined the sample sizes needed to test an estimated 25% drugeffect with 80% of power on changes in FDG uptake over 2 years at every brain voxel. The combination of [ 18 F]florbetapir standardized uptake value ratios and phosphorylated-tau levels more than one standard deviation higher than their respective thresholds for biomarker abnormality was the best predictor of metabolic decline in individuals with preclinical AD. We also found that a clinical trial using these thresholds would require as few as 100 individuals to test a 25% drug effect on AD-related metabolic decline over 2 years. These results highlight the new concept that combined Aβ and tau thresholds can predict imminent neurodegeneration as an alternative framework with a high statistical power for testing the effect of disease-modifying therapies on [ 18 F]FDG uptake decline over a typical 2-year clinical trial period in individuals with preclinical AD.

Bifidobacterium longum 1714 as a translational psychobiotic: modulation of stress, electrophysiology and neurocognition in healthy volunteers.

PubMed

Allen, A P; Hutch, W; Borre, Y E; Kennedy, P J; Temko, A; Boylan, G; Murphy, E; Cryan, J F; Dinan, T G; Clarke, G

2016-11-01

The emerging concept of psychobiotics-live microorganisms with a potential mental health benefit-represents a novel approach for the management of stress-related conditions. The majority of studies have focused on animal models. Recent preclinical studies have identified the B. longum 1714 strain as a putative psychobiotic with an impact on stress-related behaviors, physiology and cognitive performance. Whether such preclinical effects could be translated to healthy human volunteers remains unknown. We tested whether psychobiotic consumption could affect the stress response, cognition and brain activity patterns. In a within-participants design, healthy volunteers (N=22) completed cognitive assessments, resting electroencephalography and were exposed to a socially evaluated cold pressor test at baseline, post-placebo and post-psychobiotic. Increases in cortisol output and subjective anxiety in response to the socially evaluated cold pressor test were attenuated. Furthermore, daily reported stress was reduced by psychobiotic consumption. We also observed subtle improvements in hippocampus-dependent visuospatial memory performance, as well as enhanced frontal midline electroencephalographic mobility following psychobiotic consumption. These subtle but clear benefits are in line with the predicted impact from preclinical screening platforms. Our results indicate that consumption of B. longum 1714 is associated with reduced stress and improved memory. Further studies are warranted to evaluate the benefits of this putative psychobiotic in relevant stress-related conditions and to unravel the mechanisms underlying such effects.

Improvement of Skills in Cardiopulmonary Resuscitation of Pediatric Residents by Recorded Video Feedbacks.

PubMed

Anantasit, Nattachai; Vaewpanich, Jarin; Kuptanon, Teeradej; Kamalaporn, Haruitai; Khositseth, Anant

2016-11-01

To evaluate the pediatric residents' cardiopulmonary resuscitation (CPR) skills, and their improvements after recorded video feedbacks. Pediatric residents from a university hospital were enrolled. The authors surveyed the level of pediatric resuscitation skill confidence by a questionnaire. Eight psychomotor skills were evaluated individually, including airway, bag-mask ventilation, pulse check, prompt starting and technique of chest compression, high quality CPR, tracheal intubation, intraosseous, and defibrillation. The mock code skills were also evaluated as a team using a high-fidelity mannequin simulator. All the participants attended a concise Pediatric Advanced Life Support (PALS) lecture, and received video-recorded feedback for one hour. They were re-evaluated 6 wk later in the same manner. Thirty-eight residents were enrolled. All the participants had a moderate to high level of confidence in their CPR skills. Over 50 % of participants had passed psychomotor skills, except the bag-mask ventilation and intraosseous skills. There was poor correlation between their confidence and passing the psychomotor skills test. After course feedback, the percentage of high quality CPR skill in the second course test was significantly improved (46 % to 92 %, p = 0.008). The pediatric resuscitation course should still remain in the pediatric resident curriculum and should be re-evaluated frequently. Video-recorded feedback on the pitfalls during individual CPR skills and mock code case scenarios could improve short-term psychomotor CPR skills and lead to higher quality CPR performance.

Common data elements for preclinical epilepsy research: Standards for data collection and reporting. A TASK3 report of the AES/ILAE Translational Task Force of the ILAE.

PubMed

Harte-Hargrove, Lauren C; French, Jacqueline A; Pitkänen, Asla; Galanopoulou, Aristea S; Whittemore, Vicky; Scharfman, Helen E

2017-11-01

The major objective of preclinical translational epilepsy research is to advance laboratory findings toward clinical application by testing potential treatments in animal models of seizures and epilepsy. Recently there has been a focus on the failure of preclinical discoveries to translate reliably, or even to be reproduced in different laboratories. One potential cause is a lack of standardization in preclinical data collection. The resulting difficulties in comparing data across studies have led to high cost and missed opportunity, which in turn impede clinical trials and advances in medical care. Preclinical epilepsy research has successfully brought numerous antiseizure treatments into the clinical practice, yet the unmet clinical needs have prompted the reconsideration of research strategies to optimize epilepsy therapy development. In the field of clinical epilepsy there have been successful steps to improve such problems, such as generation of common data elements (CDEs) and case report forms (CRFs and standards of data collection and reporting) by a team of leaders in the field. Therefore, the Translational Task Force was appointed by the International League Against Epilepsy (ILAE) and the American Epilepsy Society (AES), in partnership with the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institutes of Health (NIH) to define CDEs for animal epilepsy research studies and prepare guidelines for data collection and experimental procedures. If adopted, the preclinical CDEs could facilitate collaborative epilepsy research, comparisons of data across different laboratories, and promote rigor, transparency, and impact, particularly in therapy development. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Preclinical diagnosis of Alzheimer’s disease: Prevention or prediction?

PubMed Central

Nitrini, Ricardo

2010-01-01

The diagnosis of Alzheimer’s disease (AD) for cases with dementia may be too late to allow effective treatment. Criteria for diagnosis of preclinical AD suggested by the Alzheimer’s Association include the use of molecular and structural biomarkers. Preclinical diagnosis will enable testing of new drugs and forms of treatment toward achieving successful preventive treatment. But what are the advantages for the individual? To know that someone who is cognitively normal is probably going to develop AD’s dementia when there is no effective preventive treatment is definitely not good news. A research method whereby volunteers are assigned to receive treatment or placebo without knowing whether they are in the control or at-risk arm of a trial would overcome this potential problem. If these new criteria are used wisely they may represent a relevant milestone in the search for a definitive treatment for AD. PMID:29213696

The Potential of Adaptive Design in Animal Studies.

PubMed

Majid, Arshad; Bae, Ok-Nam; Redgrave, Jessica; Teare, Dawn; Ali, Ali; Zemke, Daniel

2015-10-12

Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research.

The Potential of Adaptive Design in Animal Studies

PubMed Central

Majid, Arshad; Bae, Ok-Nam; Redgrave, Jessica; Teare, Dawn; Ali, Ali; Zemke, Daniel

2015-01-01

Clinical trials are the backbone of medical research, and are often the last step in the development of new therapies for use in patients. Prior to human testing, however, preclinical studies using animal subjects are usually performed in order to provide initial data on the safety and effectiveness of prospective treatments. These studies can be costly and time consuming, and may also raise concerns about the ethical treatment of animals when potentially harmful procedures are involved. Adaptive design is a process by which the methods used in a study may be altered while it is being conducted in response to preliminary data or other new information. Adaptive design has been shown to be useful in reducing the time and costs associated with clinical trials, and may provide similar benefits in preclinical animal studies. The purpose of this review is to summarize various aspects of adaptive design and evaluate its potential for use in preclinical research. PMID:26473839

What factors promote resilience and protect against burnout in first-year pediatric and medicine-pediatric residents?

PubMed

Olson, Kayloni; Kemper, Kathi J; Mahan, John D

2015-07-01

Burnout has high costs for pediatricians and their patients. There is increasing interest in educational interventions to promote resilience and minimize burnout among pediatric trainees. This study tested a conceptual model of factors that might promote resilience and protect against burnout, and which could serve as targets for addressing burnout in pediatric residents. Questionnaires were administered in a cross-sectional survey of (n = 45) first-year pediatric and medicine-pediatric residents. A minority (40%) of residents met one or more criteria for burnout. Physician empathy and emotional intelligence were not significantly correlated with burnout or resilience. Self-compassion and mindfulness were positively associated with resilience and inversely associated with burnout. Thus many residents in this sample endorsed burnout; mindfulness and self-compassion were associated with resilience and may promote resilience and protect against burnout in these trainees. Future studies should explore the impact of training in mindfulness and self-compassion in pediatric trainees. © The Author(s) 2015.

Transcranial Magnetic and Direct Current Stimulation in Children.

PubMed

Hameed, Mustafa Q; Dhamne, Sameer C; Gersner, Roman; Kaye, Harper L; Oberman, Lindsay M; Pascual-Leone, Alvaro; Rotenberg, Alexander

2017-02-01

Promising results in adult neurologic and psychiatric disorders are driving active research into transcranial brain stimulation techniques, particularly transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), in childhood and adolescent syndromes. TMS has realistic utility as an experimental tool tested in a range of pediatric neuropathologies such as perinatal stroke, depression, Tourette syndrome, and autism spectrum disorder (ASD). tDCS has also been tested as a treatment for a number of pediatric neurologic conditions, including ASD, attention-deficit/hyperactivity disorder, epilepsy, and cerebral palsy. Here, we complement recent reviews with an update of published TMS and tDCS results in children, and discuss developmental neuroscience considerations that should inform pediatric transcranial stimulation.

Transcranial Magnetic and Direct Current Stimulation in Children

PubMed Central

Hameed, Mustafa Q.; Dhamne, Sameer C.; Gersner, Roman; Kaye, Harper L.; Oberman, Lindsay M.; Pascual-Leone, Alvaro

2018-01-01

Promising results in adult neurologic and psychiatric disorders are driving active research into transcranial brain stimulation techniques, particularly transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), in childhood and adolescent syndromes. TMS has realistic utility as an experimental tool tested in a range of pediatric neuropathologies such as perinatal stroke, depression, Tourette syndrome, and autism spectrum disorder (ASD). tDCS has also been tested as a treatment for a number of pediatric neurologic conditions, including ASD, attention-deficit/hyperactivity disorder, epilepsy, and cerebral palsy. Here, we complement recent reviews with an update of published TMS and tDCS results in children, and discuss developmental neuroscience considerations that should inform pediatric transcranial stimulation. PMID:28229395

Assessing pediatrics residents' mathematical skills for prescribing medication: a need for improved training.

PubMed

Glover, Mark L; Sussmane, Jeffrey B

2002-10-01

To evaluate residents' skills in performing basic mathematical calculations used for prescribing medications to pediatric patients. In 2001, a test of ten questions on basic calculations was given to first-, second-, and third-year residents at Miami Children's Hospital in Florida. Four additional questions were included to obtain the residents' levels of training, specific pediatrics intensive care unit (PICU) experience, and whether or not they routinely double-checked doses and adjusted them for each patient's weight. The test was anonymous and calculators were permitted. The overall score and the score for each resident class were calculated. Twenty-one residents participated. The overall average test score and the mean test score of each resident class was less than 70%. Second-year residents had the highest mean test scores, although there was no significant difference between the classes of residents (p =.745) or relationship between the residents' PICU experiences and their exam scores (p =.766). There was no significant difference between residents' levels of training and whether they double-checked their calculations (p =.633) or considered each patient's weight relative to the dose prescribed (p =.869). Seven residents committed tenfold dosing errors, and one resident committed a 1,000-fold dosing error. Pediatrics residents need to receive additional education in performing the calculations needed to prescribe medications. In addition, residents should be required to demonstrate these necessary mathematical skills before they are allowed to prescribe medications.

Pediatric surgical capacity building - a pathway to improving access to pediatric surgical care in Haiti.

PubMed

Kaseje, Neema; Jenny, Hillary; Jeudy, Andre Patrick; MacLee, Jean Louis; Meara, John G; Ford, Henri R

2018-02-01

Lack of human resources is a major barrier to accessing pediatric surgical care globally. Our aim was to establish a model for pediatric surgical training of general surgery residents in a resource constrained region. A pediatric surgical program with a pediatric surgical rotation for general surgery residents in a tertiary hospital in Haiti in 2015 was established. We conducted twice daily patient rounds, ran an outpatient clinic, and provided emergent and elective pediatric surgical care, with tasks progressively given to residents until they could run clinic and perform the most common elective and emergent procedures. We conducted baseline and post-intervention knowledge exams and dedicated 1 day a week to teaching and research activities. We measured the following outcomes: number of residents that completed the rotation, mean pre and post intervention test scores, patient volume in clinic and operating room, postoperative outcomes, resident ability to perform most common elective and emergent procedures, and resident participation in research. Nine out of 9 residents completed the rotation; 987 patients were seen in outpatient clinic, and 564 procedures were performed in children <15years old. There was a 50% increase in volume of pediatric cases and a 100% increase in procedures performed in children <4years old. Postoperative outcomes were: 0% mortality for elective cases and 18% mortality for emergent cases, 3% complication rate for elective cases and 6% complication rate for emergent cases. Outcomes did not change with increased responsibility given to residents. All senior residents (n=4) could perform the most common elective and emergent procedures without changes in mortality and complication rates. Increases in mean pre and post intervention test scores were 12% (PGY1), 24% (PGY2), and 10% (PGY3). 75% of senior residents participated in research activities as first or second authors. Establishing a program in pediatric surgery with capacity building of general surgery residents for pediatric surgical care provision is feasible in a resource constrained setting without negative effects on patient outcomes. This model can be applied in other resource constrained settings to increase human resources for global pediatric surgical care provision. III. Copyright © 2017 Elsevier Inc. All rights reserved.

The Australian Medical Schools Assessment Collaboration: benchmarking the preclinical performance of medical students.

PubMed

O'Mara, Deborah A; Canny, Ben J; Rothnie, Imogene P; Wilson, Ian G; Barnard, John; Davies, Llewelyn

2015-02-02

To report the level of participation of medical schools in the Australian Medical Schools Assessment Collaboration (AMSAC); and to measure differences in student performance related to medical school characteristics and implementation methods. Retrospective analysis of data using the Rasch statistical model to correct for missing data and variability in item difficulty. Linear model analysis of variance was used to assess differences in student performance. 6401 preclinical students from 13 medical schools that participated in AMSAC from 2011 to 2013. Rasch estimates of preclinical basic and clinical science knowledge. Representation of Australian medical schools and students in AMSAC more than doubled between 2009 and 2013. In 2013 it included 12 of 19 medical schools and 68% of medical students. Graduate-entry students scored higher than students entering straight from school. Students at large schools scored higher than students at small schools. Although the significance level was high (P < 0.001), the main effect sizes were small (4.5% and 2.3%, respectively). The time allowed per multiple choice question was not significantly associated with student performance. The effect on performance of multiple assessments compared with the test items as part of a single end-of-year examination was negligible. The variables investigated explain only 12% of the total variation in student performance. An increasing number of medical schools are participating in AMSAC to monitor student performance in preclinical sciences against an external benchmark. Medical school characteristics account for only a small part of overall variation in student performance. Student performance was not affected by the different methods of administering test items.

The prevalence and consequences of burnout on a group of preclinical dental students

PubMed Central

Atalayin, Cigdem; Balkis, Murat; Tezel, Huseyin; Onal, Banu; Kayrak, Gul

2015-01-01

Objective: The aim of this study is to investigate the prevalence of burnout among a group of Turkish preclinical dental students, to compare the level of burnout and to determine the consequences in structural equation model. Materials and Methods: Preclinical dental students (n = 329, 50.5% of females and 49.5% of males) aged between 18 and 24 took part in the study. Maslach burnout inventory student version, academic satisfaction scale, and personal information sheet were used to gather data. Pearson correlation analyses, t-test, and one-way ANOVA were used for statistical analysis. The proposed theoretical model was tested via observed variable path analysis using maximum likelihood parameter estimation with AMOS 7.0. Results: About 22.3% of students had high level of emotional exhaustion, 16.7% of students had high level of cynicism, and 17.9% of students suffered from high level of reduced academic efficacy. While the students attending the first grade reported higher level of reduced academic efficacy, the students in the third grade reported higher level of emotional exhaustion. Academic workload played an important role in the development of burnout. As consequences of burnout, students with high levels of burnout intended to change their current major and did not to plan to continue to postgraduate education. Students with high level of burnout reported less level of academic satisfaction and academic achievement. Conclusions: Creating awareness on the burnout of dental students from the preclinical period may be useful for prevention and more compatible dental education environment. PMID:26430363

Collaborative learning in pre-clinical dental hygiene education.

PubMed

Mueller-Joseph, Laura J; Nappo-Dattoma, Luisa

2013-04-01

Dental hygiene education continues to move beyond mastery of content material and skill development to learning concepts that promote critical-thinking and problem-solving skills. The purpose of this research was to evaluate the effectiveness of collaborative learning and determine the growth in intellectual development of 54 first-year dental hygiene students. The control group used traditional pre-clinical teaching and the experimental group used collaborative pedagogy for instrument introduction. All students were subjected to a post-test evaluating their ability to apply the principles of instrumentation. Intellectual development was determined using pre- and post-tests based on the Perry Scheme of Intellectual Development. Student attitudes were assessed using daily Classroom Assessment Activities and an end-of-semester departmental course evaluation. Findings indicated no significant difference between collaborative learning and traditional learning in achieving pre-clinical competence as evidenced by the students' ability to apply the principles of instrumentation. Advancement in intellectual development did not differ significantly between groups. Value added benefits of a collaborative learning environment as identified by the evaluation of student attitudes included decreased student reliance on authority, recognition of peers as legitimate sources of learning and increased self-confidence. A significant difference in student responses to daily classroom assessments was evident on the 5 days a collaborative learning environment was employed. Dental hygiene students involved in a pre-clinical collaborative learning environment are more responsible for their own learning and tend to have a more positive attitude toward the subject matter. Future studies evaluating collaborative learning in clinical dental hygiene education need to investigate the cost/benefit ratio of the value added outcomes of collaborative learning.

Large animal models for vaccine development and testing.

PubMed

Gerdts, Volker; Wilson, Heather L; Meurens, Francois; van Drunen Littel-van den Hurk, Sylvia; Wilson, Don; Walker, Stewart; Wheler, Colette; Townsend, Hugh; Potter, Andrew A

2015-01-01

The development of human vaccines continues to rely on the use of animals for research. Regulatory authorities require novel vaccine candidates to undergo preclinical assessment in animal models before being permitted to enter the clinical phase in human subjects. Substantial progress has been made in recent years in reducing and replacing the number of animals used for preclinical vaccine research through the use of bioinformatics and computational biology to design new vaccine candidates. However, the ultimate goal of a new vaccine is to instruct the immune system to elicit an effective immune response against the pathogen of interest, and no alternatives to live animal use currently exist for evaluation of this response. Studies identifying the mechanisms of immune protection; determining the optimal route and formulation of vaccines; establishing the duration and onset of immunity, as well as the safety and efficacy of new vaccines, must be performed in a living system. Importantly, no single animal model provides all the information required for advancing a new vaccine through the preclinical stage, and research over the last two decades has highlighted that large animals more accurately predict vaccine outcome in humans than do other models. Here we review the advantages and disadvantages of large animal models for human vaccine development and demonstrate that much of the success in bringing a new vaccine to market depends on choosing the most appropriate animal model for preclinical testing. © The Author 2015. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Strategies for bringing drug delivery tools into discovery.

PubMed

Kwong, Elizabeth; Higgins, John; Templeton, Allen C

2011-06-30

The past decade has yielded a significant body of literature discussing approaches for development and discovery collaboration in the pharmaceutical industry. As a result, collaborations between discovery groups and development scientists have increased considerably. The productivity of pharma companies to deliver new drugs to the market, however, has not increased and development costs continue to rise. Inability to predict clinical and toxicological response underlies the high attrition rate of leads at every step of drug development. A partial solution to this high attrition rate could be provided by better preclinical pharmacokinetics measurements that inform PD response based on key pathways that drive disease progression and therapeutic response. A critical link between these key pharmacology, pharmacokinetics and toxicology studies is the formulation. The challenges in pre-clinical formulation development include limited availability of compounds, rapid turn-around requirements and the frequent un-optimized physical properties of the lead compounds. Despite these challenges, this paper illustrates some successes resulting from close collaboration between formulation scientists and discovery teams. This close collaboration has resulted in development of formulations that meet biopharmaceutical needs from early stage preclinical in vivo model development through toxicity testing and development risk assessment of pre-clinical drug candidates. Published by Elsevier B.V.

NIA-AA Staging of Preclinical Alzheimer Disease: Discordance and Concordance of CSF and Imaging Biomarkers

PubMed Central

Vos, Stephanie J. B.; Gordon, Brian A.; Su, Yi; Visser, Pieter Jelle; Holtzman, David M.; Morris, John C.; Fagan, Anne M.; Benzinger, Tammie L. S.

2016-01-01

The National Institute of Aging and Alzheimer’s Association (NIA-AA) criteria for Alzheimer disease (AD) treat neuroimaging and cerebrospinal fluid (CSF) markers of AD pathology as if they would be interchangeable. We tested this assumption in 212 cognitively normal participants who have both neuroimaging and CSF measures of β-amyloid (CSF Aβ1-42 and PET imaging with Pittsburgh Compound B) and neuronal injury (CSF t-tau and p-tau and structural MRI) with longitudinal clinical follow-up. Participants were classified in preclinical AD Stage 1 (β-amyloidosis) or preclinical AD Stage 2+ (β-amyloidosis and neuronal injury) using the NIA-AA criteria, or in the normal or suspected non-Alzheimer pathophysiology group (SNAP; neuronal injury without β-amyloidosis). At baseline, 21% of participants had preclinical AD based on CSF and 28% based upon neuroimaging. Between modalities, staging was concordant in only 47% of participants. Disagreement resulted from low concordance between biomarkers of neuronal injury. Still, individuals in Stage 2+ using either criterion had an increased risk for clinical decline. This highlights the heterogeneity of the definition of neuronal injury, and has important implications for clinical trials utilizing biomarkers for enrollment or as surrogate endpoint measures. PMID:27318129

Ethical issues in pediatric genetic testing and screening.

PubMed

Botkin, Jeffrey R

2016-12-01

Developments in genetic test technologies enable a detailed analysis of the genomes of individuals across the range of human development from embryos to adults with increased precision and lower cost. These powerful technologies raise a number of ethical issues in pediatrics, primarily because of the frequent lack of clinical utility of genetic information, the generation of secondary results and questions over the proper scope of parental authority for testing. Several professional organizations in the fields of genetics and pediatrics have published new guidance on the ethical, legal, and policy issues relevant to genetic testing in children. The roles of predictive testing for adult-onset conditions, the management of secondary findings and the role of informed consent for newborn screening remain controversial. However, research and experience are not demonstrating serious adverse psychosocial impacts from genetic testing and screening in children. The use of these technologies is expanding with the notion that the personal utility of test results, rather than clinical utility, may be sufficient to justify testing. The use of microarray and genome sequencing technologies is expanding in the care of children. More deference to parental decision-making is evolving in contexts wherein information and counseling can be made readily available.

Preclinical Testing of an Oncolytic Parvovirus in Ewing Sarcoma: Protoparvovirus H-1 Induces Apoptosis and Lytic Infection In Vitro but Fails to Improve Survival In Vivo.

PubMed

Lacroix, Jeannine; Kis, Zoltán; Josupeit, Rafael; Schlund, Franziska; Stroh-Dege, Alexandra; Frank-Stöhr, Monika; Leuchs, Barbara; Schlehofer, Jörg R; Rommelaere, Jean; Dinsart, Christiane

2018-06-03

About 70% of all Ewing sarcoma (EWS) patients are diagnosed under the age of 20 years. Over the last decades little progress has been made towards finding effective treatment approaches for primarily metastasized or refractory Ewing sarcoma in young patients. Here, in the context of the search for novel therapeutic options, the potential of oncolytic protoparvovirus H-1 (H-1PV) to treat Ewing sarcoma was evaluated, its safety having been proven previously tested in adult cancer patients and its oncolytic efficacy demonstrated on osteosarcoma cell cultures. The effects of viral infection were tested in vitro on four human Ewing sarcoma cell lines. Notably evaluated were effects of the virus on the cell cycle and its replication efficiency. Within 24 h after infection, the synthesis of viral proteins was induced. Efficient H-1PV replication was confirmed in all four Ewing sarcoma cell lines. The cytotoxicity of the virus was determined on the basis of cytopathic effects, cell viability, and cell lysis. These in vitro experiments revealed efficient killing of Ewing sarcoma cells by H-1PV at a multiplicity of infection between 0.1 and 5 plaque forming units (PFU)/cell. In two of the four tested cell lines, significant induction of apoptosis by H-1PV was observed. H-1PV thus meets all the in vitro criteria for a virus to be oncolytic towards Ewing sarcoma. In the first xenograft experiments, however, although an antiproliferative effect of intratumoral H-1PV injection was observed, no significant improvement of animal survival was noted. Future projects aiming to validate parvovirotherapy for the treatment of pediatric Ewing sarcoma should focus on combinatorial treatments and will require the use of patient-derived xenografts and immunocompetent syngeneic animal models.

Identification of Candida parapsilosis Sensu Lato in Pediatric Patients and Antifungal Susceptibility Testing

PubMed Central

Dudiuk, Catiana; Fernández, Mariana; Rojas, Florencia; Alegre, Liliana; Córdoba, Susana; Garcia-Effron, Guillermo; Giusiano, Gustavo

2017-01-01

ABSTRACT A total of 59 Candida parapsilosis sensu stricto and 1 Candida orthopsilosis recovered from catheters and blood cultures of pediatric patients from the northeastern region of Argentina were studied. Susceptibility to azoles, amphotericin B, and echinocandins was tested by the broth microdilution method. According to CLSI clinical breakpoints, >91% of the strains were azole susceptible, whereas 15% showed high amphotericin B MICs. PMID:28483957

Management of natural health products in pediatrics: a provider-focused quality improvement project.

PubMed

Gutierrez, Emily; Silbert-Flagg, JoAnne; Vohra, Sunita

2015-01-01

The use of natural health products by pediatric patients is common, yet health care providers often do not provide management guidance. The purpose of this project was to improve management of natural health products by pediatric nurse practitioners. Pediatric nurse practitioners from large metropolitan city were recruited (n = 32). A paired pretest-posttest design was used. Study participants were engaged to improve knowledge of natural health products, and a management toolkit was created and tested. Mean knowledge scores increased from 59.19 to 76.3 (p < .01). Management practices improved with regard to patient guidance (p < .01) and resource utilization (p < .01). Assessments of product use (p = .51) and drug/herb interactions (p = .35) were not significant. This investigation is the first known study to improve knowledge and management of natural health products in pediatric clinical practice. Copyright © 2015 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.

Graded Exercise Testing in a Pediatric Weight Management Center: The DeVos Protocol.

PubMed

Eisenmann, Joey C; Guseman, Emily Hill; Morrison, Kyle; Tucker, Jared; Smith, Lucie; Stratbucker, William

2015-12-01

In this article, we describe a protocol used to test the functional capacity of the obese pediatric patient and describe the peak oxygen consumption (VO2peak) of patients seeking treatment at a pediatric weight management center. One hundred eleven (mean age, 12.5 ± 3.0 years) patients performed a multistage exercise test on a treadmill, of which 90 (81%) met end-test criteria and provided valid VO2peak data. Peak VO2 was expressed: (1) in absolute terms (L·min(-1)); (2) as the ratio of the volume of oxygen consumed per minute relative to total body mass (mL·kg(-1)·min(-1)); and (3) as the ratio of the volume of oxygen consumed per minute relative to fat-free mass (mL·FFM·kg(-1)·min(-1)). Mean BMI z-score was 2.4 ± 0.3 and the mean percent body fat was 36.5 ± 9.7%. Absolute VO2peak (L·min(-1)) was significantly different between sexes; however, relative values were similar between sexes. Mean VO2peak was 25.7 ± 4.8 mL·kg(-1)·min(-1) with a range of 13.5-36.7 mL·kg(-1)·min(-1). Obese youth seeking treatment at a stage 3 pediatric weight management center exhibit low VO2peak. The protocol outlined here should serve as a model for similar programs interested in the submaximal and peak responses to exercise in obese pediatric patients.

Pediatric training and practice of Canadian chiropractic and naturopathic doctors: a 2004-2014 comparative study.

PubMed

Porcino, Antony; Solomonian, Leslie; Zylich, Stephen; Gluvic, Brian; Doucet, Chantal; Vohra, Sunita

2017-12-01

To assess chiropractic (DC) and naturopathic doctors' (ND) knowledge, attitudes, and behaviour with respect to the pediatric patients in their practice. Cross-sectional surveys were developed in collaboration with DC and ND educators. Surveys were sent to randomly selected DCs and NDs in Ontario, Canada in 2004, and a national online survey was conducted in 2014. Data were analyzed using descriptive statistics, t-tests, non-parametric tests, and linear regression. Response rates for DCs were n = 172 (34%) in 2004, n = 553 (15.5%) in 2014, and for NDs, n = 171 (36%) in 2004, n = 162 (7%) in 2014. In 2014, 366 (78.4%) of DCs and 83 (61%) of NDs saw one or more pediatric patients per week. Pediatric training was rated as inadequate by most respondents in both 2004 and 2014, with most respondents (n = 643, 89.9%) seeking post-graduate training by 2014. Respondents' comfort in treating children and youth is based on experience and post-graduate training. Both DCs and NDs that see children and youth in their practices address a broad array of pediatric health concerns, from well child care and preventative health, to mild and serious illness. Although the response rate in 2014 is low, the concerns identified a decade earlier remain. The majority of responding DCs and NDs see infants, children, and youth for a variety of health conditions and issues, but self-assess their undergraduate pediatric training as inadequate. We encourage augmented pediatric educational content be included as core curriculum for DCs and NDs and suggest collaboration with institutions/organizations with expertise in pediatric education to facilitate curriculum development, especially in areas that affect patient safety.

Variations in management of common inpatient pediatric illnesses: hospitalists and community pediatricians.

PubMed

Conway, Patrick H; Edwards, Sarah; Stucky, Erin R; Chiang, Vincent W; Ottolini, Mary C; Landrigan, Christopher P

2006-08-01

The goal was to test the hypothesis that pediatric hospitalists use evidence-based therapies and tests more consistently in the care of inpatients and use therapies and tests of unproven benefit less often, compared with community pediatricians. A national survey was administered to hospitalists and a random sample of community pediatricians. Hospitalists and community pediatricians reported their frequency of use of diagnostic tests and therapies, on 5-point Likert scales (ranging from never to almost always), for common inpatient pediatric illnesses. Responses were compared in univariate and multivariable logistic regression analyses controlling for gender, race, years out of residency, days spent attending per year, hospital practice type, and completion of fellowship/postgraduate training. Two hundred thirteen pediatric hospitalists and 352 community pediatricians responded. In multivariable regression analyses, hospitalists were significantly more likely to report often or almost always using the following evidence-based therapies for asthma: albuterol and ipratropium in the first 24 hours of hospitalization. After the first urinary tract infection, hospitalists were more likely to report obtaining the recommended renal ultrasound and voiding cystourethrogram. Hospitalists were significantly more likely than community pediatricians to report rarely or never using the following therapies of unproven benefit: levalbuterol, inhaled steroid therapy, and oral steroid therapy for bronchiolitis; stool culture and rotavirus testing for gastroenteritis; and ipratropium after 24 hours of hospitalization for asthma. Overall, in comparison with community pediatricians, hospitalists reported greater adherence to evidence-based therapies and tests in the care of hospitalized patients and less use of therapies and tests of unproven benefit.

Coagulopathy and transfusion therapy in pediatric liver transplantation

PubMed Central

Nacoti, Mirco; Corbella, Davide; Fazzi, Francesco; Rapido, Francesca; Bonanomi, Ezio

2016-01-01

Bleeding and coagulopathy are critical issues complicating pediatric liver transplantation and contributing to morbidity and mortality in the cirrhotic child. The complexity of coagulopathy in the pediatric patient is illustrated by the interaction between three basic models. The first model, “developmental hemostasis”, demonstrates how a different balance between pro- and anticoagulation factors leads to a normal hemostatic capacity in the pediatric patient at various ages. The second, the “cell based model of coagulation”, takes into account the interaction between plasma proteins and cells. In the last, the concept of “rebalanced coagulation” highlights how the reduction of both pro- and anticoagulation factors leads to a normal, although unstable, coagulation profile. This new concept has led to the development of novel techniques used to analyze the coagulation capacity of whole blood for all patients. For example, viscoelastic methodologies are increasingly used on adult patients to test hemostatic capacity and to guide transfusion protocols. However, results are often confounding or have limited impact on morbidity and mortality. Moreover, data from pediatric patients remain inadequate. In addition, several interventions have been proposed to limit blood loss during transplantation, including the use of antifibrinolytic drugs and surgical techniques, such as the piggyback and lowering the central venous pressure during the hepatic dissection phase. The rationale for the use of these interventions is quite solid and has led to their incorporation into clinical practice; yet few of them have been rigorously tested in adults, let alone in children. Finally, the postoperative period in pediatric cohorts of patients has been characterized by an enhanced risk of hepatic vessel thrombosis. Thrombosis in fact remains the primary cause of early graft failure and re-transplantation within the first 30 d following surgery, and it occurs despite prolongation of standard coagulation assays. Data, however, are currently lacking regarding the use of anti-aggregation/anticoagulation therapies and how to best monitor for thrombosis in the early postoperative period in pediatric patients. Therefore, further studies are necessary to elucidate the interaction between the development of the coagulation system and cirrhosis in children. Moreover, strategies to optimize blood transfusion and anticoagulation must be tested specifically in pediatric patients. In conclusion, data from the adult world can be translated with difficulty into the pediatric field as indication for transplantation, baseline pathologies and levels of pro- and anticoagulation factors are not comparable between the two populations. PMID:26877606

Is adiponectin a marker of preclinical atherosclerosis in kidney transplantation?

PubMed

Cañas, Laura; Bayés, Beatriz; Granada, Maria L; Ibernon, Meritxell; Porrini, Esteban; Benítez, Rosa; Díaz, Juan M; Lauzurica, Ricardo; Moreso, Francesc; Torres, Armando; Lampreabe, Ildefonso; Serra, Assumpta; Romero, Ramon

2012-01-01

The aim of this study was to analyze the relationship between pre-transplant adiponectin (pre-ADP), abnormalities in glucose homeostasis (AGH) at three months post-transplantation, and preclinical atherosclerosis in non-diabetic patients prior to kidney transplantation (KT). We carried out a multicenter study in 157 non-diabetic KT patients (66.5% men; age: 50±13 yr). Pre-ADP levels were analyzed using radioimmunoassay. Carotid ultrasound was performed to determine carotid intima-media thickness (c-IMT). Oral glucose tolerance test was carried out to classify patients according ADA criteria. Of the patients, 52.8% had AGH. Median pre-ADP was 19.5 (14-27) μg/mL. An inverse correlation was found between ADP and HOMA index (r=-0.432; p<0.001). Median c-IMT was 0.6 (0.48-0.71) mm. Significant inverse correlation existed between ADP and c-IMT on both sides (p<0.05). Patients with c-IMT >0.6 mm had more AGH (p=0.012) and lower ADP levels (p=0.02). We performed a logistic regression analysis using preclinical atherosclerosis (c-IMT ≥0.6 mm) as dependent variable and sex, age, BMI, ADP, AGH, and HOMA index as independent variables of altered c-IMT. Age, pre-ADP, and AGH were independent risk factors for elevated c-IMT. Patients with AGH have a greater presence of preclinical atherosclerosis. ADP has an inverse relationship with AGH and is an independent marker of preclinical atherosclerosis. © 2011 John Wiley & Sons A/S.

Sex differences in mechanical allodynia: how can it be preclinically quantified and analyzed?

PubMed Central

Nicotra, Lauren; Tuke, Jonathan; Grace, Peter M.; Rolan, Paul E.; Hutchinson, Mark R.

2014-01-01

Translating promising preclinical drug discoveries to successful clinical trials remains a significant hurdle in pain research. Although animal models have significantly contributed to understanding chronic pain pathophysiology, the majority of research has focused on male rodents using testing procedures that produce sex difference data that do not align well with comparable clinical experiences. Additionally, the use of animal pain models presents ongoing ethical challenges demanding continuing refinement of preclinical methods. To this end, this study sought to test a quantitative allodynia assessment technique and associated statistical analysis in a modified graded nerve injury pain model with the aim to further examine sex differences in allodynia. Graded allodynia was established in male and female Sprague Dawley rats by altering the number of sutures placed around the sciatic nerve and quantified by the von Frey test. Linear mixed effects modeling regressed response on each fixed effect (sex, oestrus cycle, pain treatment). On comparison with other common von Frey assessment techniques, utilizing lower threshold filaments than those ordinarily tested, at 1 s intervals, appropriately and successfully investigated female mechanical allodynia, revealing significant sex and oestrus cycle difference across the graded allodynia that other common behavioral methods were unable to detect. Utilizing this different von Frey approach and graded allodynia model, a single suture inflicting less allodynia was sufficient to demonstrate exaggerated female mechanical allodynia throughout the phases of dioestrus and pro-oestrus. Refining the von Frey testing method, statistical analysis technique and the use of a graded model of chronic pain, allowed for examination of the influences on female mechanical nociception that other von Frey methods cannot provide. PMID:24592221

Nondestructive microimaging during preclinical pin-on-plate testing of novel materials for arthroplasty.

PubMed

Teeter, Matthew G; Langohr, G Daniel G; Medley, John B; Holdsworth, David W

2014-02-01

The purpose of this study was to determine the ability of micro-computed tomography to quantify wear in preclinical pin-on-plate testing of materials for use in joint arthroplasty. Wear testing of CoCr pins articulating against six polyetheretherketone plates was performed using a pin-on-plate apparatus over 2 million cycles. Change in volume due to wear was quantified with gravimetric analysis and with micro-computed tomography, and the volumes were compared. Separately, the volume of polyetheretherketone pin-on-plate specimens that had been soaking in fluid for 52 weeks was quantified with both gravimetric analysis and micro-computed tomography, and repeated after drying. The volume change with micro-computed tomography was compared to the mass change with gravimetric analysis. The mean wear volume measured was 8.02 ± 6.38 mm(3) with gravimetric analysis and 6.76 ± 5.38 mm(3) with micro-computed tomography (p = 0.06). Micro-computed tomography volume measurements did not show a statistically significant change with drying for either the plates (p = 0.60) or the pins (p = 0.09), yet drying had a significant effect on the gravimetric mass measurements for both the plates (p = 0.03) and the pins (p = 0.04). Micro-computed tomography provided accurate measurements of wear in polyetheretherketone pin-on-plate test specimens, and no statistically significant change was caused by fluid uptake. Micro-computed tomography quantifies wear depth and wear volume, mapped to the specific location of damage on the specimen, and is also capable of examining subsurface density as well as cracking. Its noncontact, nondestructive nature makes it ideal for preclinical testing of materials, in which further additional analysis techniques may be utilized.

PopED lite: An optimal design software for preclinical pharmacokinetic and pharmacodynamic studies.

PubMed

Aoki, Yasunori; Sundqvist, Monika; Hooker, Andrew C; Gennemark, Peter

2016-04-01

Optimal experimental design approaches are seldom used in preclinical drug discovery. The objective is to develop an optimal design software tool specifically designed for preclinical applications in order to increase the efficiency of drug discovery in vivo studies. Several realistic experimental design case studies were collected and many preclinical experimental teams were consulted to determine the design goal of the software tool. The tool obtains an optimized experimental design by solving a constrained optimization problem, where each experimental design is evaluated using some function of the Fisher Information Matrix. The software was implemented in C++ using the Qt framework to assure a responsive user-software interaction through a rich graphical user interface, and at the same time, achieving the desired computational speed. In addition, a discrete global optimization algorithm was developed and implemented. The software design goals were simplicity, speed and intuition. Based on these design goals, we have developed the publicly available software PopED lite (http://www.bluetree.me/PopED_lite). Optimization computation was on average, over 14 test problems, 30 times faster in PopED lite compared to an already existing optimal design software tool. PopED lite is now used in real drug discovery projects and a few of these case studies are presented in this paper. PopED lite is designed to be simple, fast and intuitive. Simple, to give many users access to basic optimal design calculations. Fast, to fit a short design-execution cycle and allow interactive experimental design (test one design, discuss proposed design, test another design, etc). Intuitive, so that the input to and output from the software tool can easily be understood by users without knowledge of the theory of optimal design. In this way, PopED lite is highly useful in practice and complements existing tools. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Diagnostic potential of nested PCR, galactomannan EIA, and beta-D-glucan for invasive aspergillosis in pediatric patients.

PubMed

Badiee, Parisa; Alborzi, Abdolvahab; Karimi, Mahammad; Pourabbas, Bahman; Haddadi, Pedram; Mardaneh, Jalal; Moieni, Mahsa

2012-04-13

Limited specific data and investigations are available for invasive aspergillosis (IA) in pediatric patients. We evaluated the diagnostic potential of three noninvasive tests including the Platelia Aspergillus EIA kit for using galactomannan antigen, (1,3)-β-D-glucan Detection Reagent Kit, and nested-PCR for Aspergillus DNA in sera. We evaluated the diagnostic potential of three noninvasive tests including EIA for galactomannan antigen  (Platelia Aspergillus), nested  PCR assay for Aspergillus DNA and test for (1→3)-β-D-glucan (Glucatell assay Kit). All pediatric patients treated at the hematology/oncology unit who were at increased risk of developing invasive aspergillosis were enrolled. Clinical samples were examined for Aspergillus infections by mycological methods. Serial blood samples were collected twice weekly and evaluated by noninvasive tests. We analyzed 230 consecutive blood samples from 62 pediatric patients. The incidence rate of invasive aspergillosis in the patients was found to be 27.4%, and the etiologic agents were Aspergillus flavus, Aspergillus fumigatus, and Aspergillus spp.  The sensitivity, specificity, positive and negative predictive values, and likelihood ratios for positive and negative results of galactomannan in patients with proven and probable IA were 90%, 92%, 81.8%, 96%, 11.25, and 0.1; for beta-D-glucan they were 50%, 46%, 26%, 70.6%, 0.9, 0.9; and for nested-PCR they were 80%, 96.2%, 88.9%, 92.6%, 21, and 0.2, respectively. The conventional methods are not able to detect IA, due to the lack of valid and proper sampling. Galactomannan and nested-PCR tests in serum, with enough accuracy and reliability, can serve as noninvasive methods for the detection of IA in pediatric patients. However, the beta-D-glucan test cannot serve as an efficient diagnostic tool in those with hematologic disorders. 

Relationships among age, gender, anthropometric characteristics, and dynamic balance in children 5 to 12 years old.

PubMed

Butz, Sarah M; Sweeney, Jane K; Roberts, Pamela L; Rauh, Mitchell J

2015-01-01

To examine relationships among age, gender, anthropometrics, and dynamic balance. Height, weight, and arm and foot length were measured in 160 children with typical development aged 5 to 12 years. Dynamic balance was assessed using the Timed Up and Go (TUG) test, Pediatric Reach Test (PRT), and Pediatric Balance Scale (PBS). Moderate to good positive relationships (r = 0.61 and r = 0.56) were found between increasing age and PRT and PBS scores. A fair negative relationship (r = -0.49) was observed between age and TUG test. No significant gender-by-age group difference was observed. Age had the strongest influence on TUG and PBS scores; arm length had the strongest influence on PRT scores. Dynamic balance ability is directly related to chronological age. Age and arm length have the strongest relationships with balance scores. These findings may assist pediatric therapists in selecting dynamic balance tests according to age rather than specific diagnosis.

Assessment of processing speed in children with mild TBI: a "first look" at the validity of pediatric ImPACT.

PubMed

Newman, Julie B; Reesman, Jennifer H; Vaughan, Christopher G; Gioia, Gerard A

2013-01-01

Deficit in the speed of cognitive processing is a commonly identified neuropsychological change in children recovering from a mild TBI. However, there are few validated child assessment instruments that allow for serial assessment over the course of recovery in this population. Pediatric ImPACT is a novel measure that purports to assess cognitive speed, learning, and efficiency in this population. The current study sought to validate the use of this new measure by comparing it to traditional paper and pencil measures of processing speed. One hundred and sixty-four children (71% male) age 5-12 with mild TBI evaluated in an outpatient concussion clinic were administered Pediatric ImPACT and other neuropsychological test measures as part of a flexible test battery. Performance on the Response Speed Composite of Pediatric ImPACT was more strongly associated with other measures of cognitive processing speed, than with measures of immediate/working memory and learning/memory in this sample of injured children. There is preliminary support for convergent and discriminant validity of Pediatric ImPACT as a measure for use in post-concussion evaluations of processing speed in children.

Development of an Electronic Pediatric All-Cause Harm Measurement Tool Using a Modified Delphi Method.

PubMed

Stockwell, David Christopher; Bisarya, Hema; Classen, David C; Kirkendall, Eric S; Lachman, Peter I; Matlow, Anne G; Tham, Eric; Hyman, Dan; Lehman, Samuel M; Searles, Elizabeth; Muething, Stephen E; Sharek, Paul J

2016-12-01

To have impact on reducing harm in pediatric inpatients, an efficient and reliable process for harm detection is needed. This work describes the first step toward the development of a pediatric all-cause harm measurement tool by recognized experts in the field. An international group of leaders in pediatric patient safety and informatics were charged with developing a comprehensive pediatric inpatient all-cause harm measurement tool using a modified Delphi technique. The process was conducted in 5 distinct steps: (1) literature review of triggers (elements from a medical record that assist in identifying patient harm) for inclusion; (2) translation of triggers to likely associated harm, improving the ability for expert prioritization; (3) 2 applications of a modified Delphi selection approach with consensus criteria using severity and frequency of harm as well as detectability of the associated trigger as criteria to rate each trigger and associated harm; (4) developing specific trigger logic and relevant values when applicable; and (5) final vetting of the entire trigger list for pilot testing. Literature and expert panel review identified 108 triggers and associated harms suitable for consideration (steps 1 and 2). This list was pared to 64 triggers and their associated harms after the first of the 2 independent expert reviews. The second independent expert review led to further refinement of the trigger package, resulting in 46 items for inclusion (step 3). Adding in specific trigger logic expanded the list. Final review and voting resulted in a list of 51 triggers (steps 4 and 5). Application of a modified Delphi method on an expert-constructed list of 108 triggers, focusing on severity and frequency of harms as well as detectability of triggers in an electronic medical record, resulted in a final list of 51 pediatric triggers. Pilot testing this list of pediatric triggers to identify all-cause harm for pediatric inpatients is the next step to establish the appropriateness of each trigger for inclusion in a global pediatric safety measurement tool.

Effects of dimethylaminoethanol pyroglutamate (DMAE p-Glu) against memory deficits induced by scopolamine: evidence from preclinical and clinical studies.

PubMed

Blin, Olivier; Audebert, Christine; Pitel, Séverine; Kaladjian, Arthur; Casse-Perrot, Catherine; Zaim, Mohammed; Micallef, Joelle; Tisne-Versailles, Jacky; Sokoloff, Pierre; Chopin, Philippe; Marien, Marc

2009-12-01

Dimethylaminoethanol pyroglutamate (DMAE p-Glu) is a compound resulting from the reaction between dimethylaminoethanol (an indirect precursor of acetylcholine) and pyroglutamic acid (a cyclic derivative of glutamic acid having procholinergic properties and promnesic effects in both animals and man). The present study undertook preclinical and clinical evaluations to test a potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit. In preclinical study, DMAE p-Glu was studied in rats by intracerebral microdialysis in conscious freely moving animals, on performance of rats in the Morris water maze test of spatial memory, and on the deficit in passive avoidance behavior induced by scopolamine. The clinical study examined the effect of DMAE p-Glu on cognitive deficits induced by an intravenous injection of scopolamine in healthy young male subjects. In rat experiments, DMAE p-Glu increased the extracellular levels of choline and acetylcholine in the medial prefrontal cortex, as assessed by intracerebral microdialysis, improved performance in a test of spatial memory, and reduced scopolamine-induced memory deficit in passive avoidance behavior. Clinical study results show that scopolamine induced a memory deficit and that DMAE p-Glu produced a significant positive effect on scores in the Buschke test, as well as a slight but significant difference on choice reaction time. These results indicate that DMAE p-Glu reduces the deleterious effect of scopolamine on long-term memory in healthy volunteers and suggest that DMAE p-Glu might be effective in reducing memory deficits in patients with cognitive impairment.

Measuring drug absorption improves interpretation of behavioral responses in a larval zebrafish locomotor assay for predicting seizure liability.

PubMed

Cassar, Steven; Breidenbach, Laura; Olson, Amanda; Huang, Xin; Britton, Heather; Woody, Clarissa; Sancheti, Pankajkumar; Stolarik, DeAnne; Wicke, Karsten; Hempel, Katja; LeRoy, Bruce

2017-11-01

Unanticipated effects on the central nervous system are a concern during new drug development. A larval zebrafish locomotor assay can reveal seizure liability of experimental molecules before testing in mammals. Relative absorption of compounds by larvae is lacking in prior reports of such assays; having those data may be valuable for interpreting seizure liability assay performance. Twenty-eight reference drugs were tested at multiple dose levels in fish water and analyzed by a blinded investigator. Responses of larval zebrafish were quantified during a 30min dosing period. Predictive metrics were calculated by comparing fish activity to mammalian seizure liability for each drug. Drug level analysis was performed to calculate concentrations in dose solutions and larvae. Fifteen drug candidates with neuronal targets, some having preclinical convulsion findings in mammals, were tested similarly. The assay has good predictive value of established mammalian responses for reference drugs. Analysis of drug absorption by larval fish revealed a positive correlation between hyperactive behavior and pro-convulsive drug absorption. False negative results were associated with significantly lower compound absorption compared to true negative, or true positive results. The predictive value for preclinical toxicology findings was inferior to that suggested by reference drugs. Disproportionately low exposures in larvae giving false negative results demonstrate that drug exposure analysis can help interpret results. Due to the rigorous testing commonly performed in preclinical toxicology, predicting convulsions in those studies may be more difficult than predicting effects from marketed drugs. Copyright © 2017 Elsevier Inc. All rights reserved.

Preclinical evaluation of implantable cardioverter-defibrillator developed for magnetic resonance imaging use.

PubMed

Gold, Michael R; Kanal, Emanuel; Schwitter, Juerg; Sommer, Torsten; Yoon, Hyun; Ellingson, Michael; Landborg, Lynn; Bratten, Tara

2015-03-01

Many patients with an implantable cardioverter-defibrillator (ICD) have indications for magnetic resonance imaging (MRI). However, MRI is generally contraindicated in ICD patients because of potential risks from hazardous interactions between the MRI and ICD system. The purpose of this study was to use preclinical computer modeling, animal studies, and bench and scanner testing to demonstrate the safety of an ICD system developed for 1.5-T whole-body MRI. MRI hazards were assessed and mitigated using multiple approaches: design decisions to increase safety and reliability, modeling and simulation to quantify clinical MRI exposure levels, animal studies to quantify the physiologic effects of MRI exposure, and bench testing to evaluate safety margin. Modeling estimated the incidence of a chronic change in pacing capture threshold >0.5 V and 1.0 V to be less than 1 in 160,000 and less than 1 in 1,000,000 cases, respectively. Modeling also estimated the incidence of unintended cardiac stimulation to occur in less than 1 in 1,000,000 cases. Animal studies demonstrated no delay in ventricular fibrillation detection and no reduction in ventricular fibrillation amplitude at clinical MRI exposure levels, even with multiple exposures. Bench and scanner testing demonstrated performance and safety against all other MRI-induced hazards. A preclinical strategy that includes comprehensive computer modeling, animal studies, and bench and scanner testing predicts that an ICD system developed for the magnetic resonance environment is safe and poses very low risks when exposed to 1.5-T normal operating mode whole-body MRI. Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Closing the delivery gaps in pediatric HIV care in Togo, West Africa: using the care delivery value chain framework to direct quality improvement.

PubMed

Fiori, Kevin; Schechter, Jennifer; Dey, Monica; Braganza, Sandra; Rhatigan, Joseph; Houndenou, Spero; Gbeleou, Christophe; Palerbo, Emmanuel; Tchangani, Elfamozo; Lopez, Andrew; Bensen, Emily; Hirschhorn, Lisa R

2016-03-01

Providing quality care for all children living with HIV/AIDS remains a global challenge and requires the development of new healthcare delivery strategies. The care delivery value chain (CDVC) is a framework that maps activities required to provide effective and responsive care for a patient with a particular disease across the continuum of care. By mapping activities along a value chain, the CDVC enables managers to better allocate resources, improve communication, and coordinate activities. We report on the successful application of the CDVC as a strategy to optimize care delivery and inform quality improvement (QI) efforts with the overall aim of improving care for Pediatric HIV patients in Togo, West Africa. Over the course of 12 months, 13 distinct QI activities in Pediatric HIV/AIDS care delivery were monitored, and 11 of those activities met or exceeded established targets. Examples included: increase in infants receiving routine polymerase chain reaction testing at 2 months (39-95%), increase in HIV exposed children receiving confirmatory HIV testing at 18 months (67-100%), and increase in patients receiving initial CD4 testing within 3 months of HIV diagnosis (67-100%). The CDVC was an effective approach for evaluating existing systems and prioritizing gaps in delivery for QI over the full cycle of Pediatric HIV/AIDS care in three specific ways: (1) facilitating the first comprehensive mapping of Pediatric HIV/AIDS services, (2) identifying gaps in available services, and (3) catalyzing the creation of a responsive QI plan. The CDVC provided a framework to drive meaningful, strategic action to improve Pediatric HIV care in Togo.

The Symbol Digit Modalities Test is an effective cognitive screen in pediatric onset multiple sclerosis (MS).

PubMed

Charvet, Leigh E; Beekman, Rachel; Amadiume, Nneka; Belman, Anita L; Krupp, Lauren B

2014-06-15

To evaluate the Symbol Digit Modalities Test (SDMT) as a tool for identifying pediatric-onset MS patients at risk for cognitive impairment. The SDMT is a brief measure of cognitive processing speed that is often used in adult MS patients. Approximately one-third of pediatric-onset MS patients have cognitive impairment and there is a need for an effective screening instrument. Seventy (70) consecutive outpatients with pediatric-onset MS underwent clinical evaluations including the SDMT and were compared to those with other pediatric neurological diagnoses (OND, n=40) and healthy controls (HC, n=32). A subset of the MS group and all healthy controls completed neuropsychological evaluation within one year of SDMT administration. The MS group performed worse on the SDMT compared to the HC group (p=0.02). Thirty-seven percent (37%) of the MS, 20% of the OND, and 9% of HC groups scored in the impaired range. For MS participants who underwent neuropsychological testing (n=31), the SDMT showed 77% sensitivity and 81% specificity for detecting neuropsychological impairment when administered within one year and reached 100% sensitivity when the interval was under two months (n=17). Overall, older age and increased disability predicted poorer SDMT performance (age r=-0.26, p=0.03) and the Expanded Disability Status Scale score or EDSS (r=-0.47, p<0.001), while a history of optic neuritis predicted better performance (p=0.04). Optical coherence tomography measures were not related to SDMT performance. In this preliminary study, the SDMT was an effective brief screen for detecting cognitive impairment in pediatric-onset MS. Copyright © 2014 Elsevier B.V. All rights reserved.

Autism training in pediatric residency: evaluation of a case-based curriculum.

PubMed

Major, Nili E; Peacock, Georgina; Ruben, Wendy; Thomas, Jana; Weitzman, Carol C

2013-05-01

Despite recent studies indicating the high prevalence of autism spectrum disorders (ASDs), there has been little focus on improving ASD education during pediatric residency training. The objective of this study was to evaluate a new curriculum developed in partnership with the Centers for Disease Control and Prevention and the Maternal and Child Health Bureau about ASDs. "Autism Case Training (ACT): A Developmental-Behavioral Pediatrics Curriculum" consists of 7 case-based teaching modules. Modules were facilitated by faculty at 26 pediatric residency programs and data were obtained on 114 residents. Pre- and post-test data revealed significant short-term improvements in residents' knowledge and self-assessed competence regarding ASDs. Findings suggest that the ACT curriculum is effective in enhancing training about ASDs in pediatric residency programs.

Comparative analysis of semantic localization accuracies between adult and pediatric DICOM CT images

NASA Astrophysics Data System (ADS)

Robertson, Duncan; Pathak, Sayan D.; Criminisi, Antonio; White, Steve; Haynor, David; Chen, Oliver; Siddiqui, Khan

2012-02-01

Existing literature describes a variety of techniques for semantic annotation of DICOM CT images, i.e. the automatic detection and localization of anatomical structures. Semantic annotation facilitates enhanced image navigation, linkage of DICOM image content and non-image clinical data, content-based image retrieval, and image registration. A key challenge for semantic annotation algorithms is inter-patient variability. However, while the algorithms described in published literature have been shown to cope adequately with the variability in test sets comprising adult CT scans, the problem presented by the even greater variability in pediatric anatomy has received very little attention. Most existing semantic annotation algorithms can only be extended to work on scans of both adult and pediatric patients by adapting parameters heuristically in light of patient size. In contrast, our approach, which uses random regression forests ('RRF'), learns an implicit model of scale variation automatically using training data. In consequence, anatomical structures can be localized accurately in both adult and pediatric CT studies without the need for parameter adaptation or additional information about patient scale. We show how the RRF algorithm is able to learn scale invariance from a combined training set containing a mixture of pediatric and adult scans. Resulting localization accuracy for both adult and pediatric data remains comparable with that obtained using RRFs trained and tested using only adult data.

The Assay Guidance Manual: Quantitative Biology and Pharmacology in Preclinical Drug Discovery.

PubMed

Coussens, Nathan P; Sittampalam, G Sitta; Guha, Rajarshi; Brimacombe, Kyle; Grossman, Abigail; Chung, Thomas D Y; Weidner, Jeffrey R; Riss, Terry; Trask, O Joseph; Auld, Douglas; Dahlin, Jayme L; Devanaryan, Viswanath; Foley, Timothy L; McGee, James; Kahl, Steven D; Kales, Stephen C; Arkin, Michelle; Baell, Jonathan; Bejcek, Bruce; Gal-Edd, Neely; Glicksman, Marcie; Haas, Joseph V; Iversen, Philip W; Hoeppner, Marilu; Lathrop, Stacy; Sayers, Eric; Liu, Hanguan; Trawick, Bart; McVey, Julie; Lemmon, Vance P; Li, Zhuyin; McManus, Owen; Minor, Lisa; Napper, Andrew; Wildey, Mary Jo; Pacifici, Robert; Chin, William W; Xia, Menghang; Xu, Xin; Lal-Nag, Madhu; Hall, Matthew D; Michael, Sam; Inglese, James; Simeonov, Anton; Austin, Christopher P

2018-06-07

The Assay Guidance Manual (AGM) is an eBook of best-practices for the design, development, and implementation of robust assays for early drug discovery. Initiated by pharmaceutical company scientists, the manual provides guidance for designing a "testing funnel" of assays to identify genuine hits using high-throughput screening (HTS) and advancing them through pre-clinical development. Combined with a workshop/tutorial component, the overall goal of the AGM is to provide a valuable resource for training translational scientists. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Identification of Candida parapsilosis Sensu Lato in Pediatric Patients and Antifungal Susceptibility Testing.

PubMed

Cattana, Maria Emilia; Dudiuk, Catiana; Fernández, Mariana; Rojas, Florencia; Alegre, Liliana; Córdoba, Susana; Garcia-Effron, Guillermo; Giusiano, Gustavo

2017-07-01

A total of 59 Candida parapsilosis sensu stricto and 1 Candida orthopsilosis recovered from catheters and blood cultures of pediatric patients from the northeastern region of Argentina were studied. Susceptibility to azoles, amphotericin B, and echinocandins was tested by the broth microdilution method. According to CLSI clinical breakpoints, >91% of the strains were azole susceptible, whereas 15% showed high amphotericin B MICs. Copyright © 2017 American Society for Microbiology.

Clinical Outcome Assessments: Use of Normative Data in a Pediatric Rare Disease.

PubMed

Phillips, Dawn; Leiro, Beth

2018-05-01

Pediatric rare diseases present unique challenges in clinical trial design and in selection of clinical outcome assessments (COAs) used to support claims in medical product labeling. COAs that discriminate level of function relative to a normative sample are particularly important in the pediatric rare disease setting because the literature is often void of natural history data. Pediatric rare disease clinical trials will often include a wide age distribution. Gross and fine motor skills, communication, cognition, and independence in activities of daily living vary by age, and it may be difficult to distinguish between treatment effect and change due to developmental maturation. Asfotase alfa was granted breakthrough therapy designation and subsequently approved for the treatment of hypophosphatasia (HPP; a genetic metabolic musculoskeletal disorder) and is used in this discussion to illustrate COA selection in a pediatric rare disease. Multiple COAs with normative data in HPP clinical trials for asfotase alfa are presented. The assessment instruments included the Bayley Scales of Infant and Toddler Development-Third Edition, the Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, the Childhood Health Assessment Questionnaire, the Pediatric Outcomes Data Collection Instrument, handheld dynamometry, the 6-minute walk test, and the Modified Performance-Oriented Mobility Assessment-Gait scale. Multiple end points were required to adequately capture the impact of asfotase alfa treatment on the multiple systems affected in HPP. These data illustrate the importance of using multiple COAs that provide normative data and to use COAs early in the drug development process for rare pediatric disease. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Rising utilization of inpatient pediatric asthma pathways.

PubMed

Kaiser, Sunitha V; Rodean, Jonathan; Bekmezian, Arpi; Hall, Matt; Shah, Samir S; Mahant, Sanjay; Parikh, Kavita; Morse, Rustin; Puls, Henry; Cabana, Michael D

2018-02-01

Clinical pathways are detailed care plans that operationalize evidence-based guidelines into an accessible format for health providers. Their goal is to link evidence to practice to optimize patient outcomes and delivery efficiency. It is unknown to what extent inpatient pediatric asthma pathways are being utilized nationally. (1) Describe inpatient pediatric asthma pathway design and implementation across a large hospital network. (2) Compare characteristics of hospitals with and without pathways. We conducted a descriptive, cross-sectional, survey study of hospitals in the Pediatric Research in Inpatient Settings Network (75% children's hospitals, 25% community hospitals). Our survey determined if each hospital used a pathway and pathway characteristics (e.g. pathway elements, implementation methods). Hospitals with and without pathways were compared using Chi-square tests (categorical variables) and Student's t-tests (continuous variables). Surveys were distributed to 3-5 potential participants from each hospital and 302 (74%) participants responded, representing 86% (106/123) of surveyed hospitals. From 2005-2015, the proportion of hospitals utilizing inpatient asthma pathways increased from 27% to 86%. We found variation in pathway elements, implementation strategies, electronic medical record integration, and compliance monitoring across hospitals. Hospitals with pathways had larger inpatient pediatric programs [mean 12.1 versus 6.1 full-time equivalents, p = 0.04] and were more commonly free-standing children's hospitals (52% versus 23%, p = 0.05). From 2005-2015, there was a dramatic rise in implementation of inpatient pediatric asthma pathways. We found variation in many aspects of pathway design and implementation. Future studies should determine optimal implementation strategies to better support hospital-level efforts in improving pediatric asthma care and outcomes.

Validity Evidence for a Serious Game to Assess Performance on Critical Pediatric Emergency Medicine Scenarios.

PubMed

Gerard, James M; Scalzo, Anthony J; Borgman, Matthew A; Watson, Christopher M; Byrnes, Chelsie E; Chang, Todd P; Auerbach, Marc; Kessler, David O; Feldman, Brian L; Payne, Brian S; Nibras, Sohail; Chokshi, Riti K; Lopreiato, Joseph O

2018-06-01

We developed a first-person serious game, PediatricSim, to teach and assess performances on seven critical pediatric scenarios (anaphylaxis, bronchiolitis, diabetic ketoacidosis, respiratory failure, seizure, septic shock, and supraventricular tachycardia). In the game, players are placed in the role of a code leader and direct patient management by selecting from various assessment and treatment options. The objective of this study was to obtain supportive validity evidence for the PediatricSim game scores. Game content was developed by 11 subject matter experts and followed the American Heart Association's 2011 Pediatric Advanced Life Support Provider Manual and other authoritative references. Sixty subjects with three different levels of experience were enrolled to play the game. Before game play, subjects completed a 40-item written pretest of knowledge. Game scores were compared between subject groups using scoring rubrics developed for the scenarios. Validity evidence was established and interpreted according to Messick's framework. Content validity was supported by a game development process that involved expert experience, focused literature review, and pilot testing. Subjects rated the game favorably for engagement, realism, and educational value. Interrater agreement on game scoring was excellent (intraclass correlation coefficient = 0.91, 95% confidence interval = 0.89-0.9). Game scores were higher for attendings followed by residents then medical students (Pc < 0.01) with large effect sizes (1.6-4.4) for each comparison. There was a very strong, positive correlation between game and written test scores (r = 0.84, P < 0.01). These findings contribute validity evidence for PediatricSim game scores to assess knowledge of pediatric emergency medicine resuscitation.

Patient Health Communication Mediating Effects Between Gastrointestinal Symptoms and Gastrointestinal Worry in Pediatric Inflammatory Bowel Disease.

PubMed

Varni, James W; Shulman, Robert J; Self, Mariella M; Saeed, Shehzad A; Patel, Ashish S; Nurko, Samuel; Neigut, Deborah A; Saps, Miguel; Zacur, George M; Dark, Chelsea V; Bendo, Cristiane B; Pohl, John F

2017-05-01

To investigate the effects of patient health communication regarding their inflammatory bowel disease (IBD) to their health care providers and significant others in their daily life as a mediator in the relationship between gastrointestinal symptoms and gastrointestinal worry in pediatric patients. The Pediatric Quality of Life Inventory Gastrointestinal Symptoms, Gastrointestinal Worry, and Communication Scales, and Pediatric Quality of Life Inventory 4.0 Generic Core Scales were completed in a 9-site study by 252 pediatric patients with IBD. Gastrointestinal Symptoms Scales measuring stomach pain, constipation, or diarrhea and patient communication were tested for bivariate and multivariate linear associations with Gastrointestinal Worry Scales specific to patient worry about stomach pain or bowel movements. Mediational analyses were conducted to test the hypothesized mediating effects of patient health communication as an intervening variable in the relationship between gastrointestinal symptoms and gastrointestinal worry. The predictive effects of gastrointestinal symptoms on gastrointestinal worry were mediated in part by patient health communication with health care providers/significant others in their daily life. In predictive models using multiple regression analyses, the full conceptual model of demographic variables, gastrointestinal symptoms (stomach pain, constipation, or diarrhea), and patient communication significantly accounted for 46, 43, and 54 percent of the variance in gastrointestinal worry (all Ps < 0.001), respectively, reflecting large effect sizes. Patient health communication explains in part the effects of gastrointestinal symptoms on gastrointestinal worry in pediatric patients with IBD. Supporting patient disease-specific communication to their health care providers and significant others may improve health-related quality of life for pediatric patients with IBD.

Improving Pediatric Preparedness in Critical Access Hospital Emergency Departments: Impact of a Longitudinal In Situ Simulation Program.

PubMed

Katznelson, Jessica H; Wang, Jiangxia; Stevens, Martha W; Mills, William A

2018-01-01

Critical access hospitals (CAH) see few pediatric patients. Many of these hospitals do not have access to physicians with pediatric training. We sought to evaluate the impact of an in situ pediatric simulation program in the CAH emergency department setting on care team performance during resuscitation scenarios. Five CAHs conducted 6 high-fidelity pediatric simulations over a 12-month period. Team performance was evaluated using a validated 35-item checklist representing commonly expected resuscitation team interventions. Checklists were scored by assigning zero point for "yes" and 1 point for "no". A lower final score meant more items on the list had been completed. The Kruskal-Wallis rank test was used to assess for differences in average scores among institutions. A linear mixed effects model with a random institution intercept was used to examine trends in average scores over time. P < 0.05 was considered significant. The Kruskal-Wallis rank test showed no difference in average scores among institutions. (P = 0.90). Checklist scores showed a significant downward trend over time, with a scenario-to-scenario decrease of 0.022 (P < 0.01). One hundred percent of providers surveyed in the last month stated they would benefit from ongoing scenarios. Regularly scheduled pediatric simulations in the CAH emergency department setting improved team performance over time on expected resuscitation tasks. The program was accepted by providers. Implementation of simulation-based training programs can help address concerns regarding pediatric preparedness in the CAH setting. A future project will look at the impact of the program on patient care and safety.

Management of pediatric central nervous system emergencies: a review for general radiologists.

PubMed

Rebollo Polo, M

2016-05-01

To review the most common and most important diseases and disorders of the central nervous system (CNS) in pediatric emergencies, discussing the indications for different imaging tests in each context. In pediatric patients, acute neurologic symptoms (seizures, deteriorating level of consciousness, focal neurologic deficits, etc.) can appear in diverse clinical situations (trauma, child abuse, meningoencephalitis, ischemia…). It is important to decide on the most appropriate neuroimaging diagnostic algorithm for each situation and age group, as well as to know the signs of the most typical lesions that help us in the etiological differential diagnosis. Pediatric patients' increased vulnerability to ionizing radiation and the possible need for sedation in studies that require more time are factors that should be taken into account when indicating an imaging test. It is essential to weigh the risks and benefits for the patient and to avoid unnecessary studies. Copyright © 2016 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

High-risk medical devices, children and the FDA: regulatory challenges facing pediatric mechanical circulatory support devices.

PubMed

Almond, Christopher S D; Chen, Eric A; Berman, Michael R; Less, Joanne R; Baldwin, J Timothy; Linde-Feucht, Sarah R; Hoke, Tracey R; Pearson, Gail D; Jenkins, Kathy; Duncan, Brian W; Zuckerman, Bram D

2007-01-01

Pediatric mechanical circulatory support is a critical unmet need in the United States. Infant- and child-sized ventricular assist devices are currently being developed largely through federal contracts and grants through the National Heart, Lung, and Blood Institute (NHLBI). Human testing and marketing of high-risk devices for children raises epidemiologic and regulatory issues that will need to be addressed. Leaders from the US Food and Drug Administration (FDA), NHLBI, academic pediatric community, and industry convened in January 2006 for the first FDA Workshop on the Regulatory Process for Pediatric Mechanical Circulatory Support Devices. The purpose was to provide the pediatric community with an overview of the federal regulatory process for high-risk medical devices and to review the challenges specific to the development and regulation of pediatric mechanical circulatory support devices. Pediatric mechanical circulatory support present significant epidemiologic, logistic, and financial challenges to industry, federal regulators, and the pediatric community. Early interactions with the FDA, shared appreciation of challenges, and careful planning will be critical to avoid unnecessary delays in making potentially life-saving devices available for children. Collaborative efforts to address these challenges are warranted.

Critical assessment of pediatric neurosurgery patient/parent educational information obtained via the Internet.

PubMed

Garcia, Michael; Daugherty, Christopher; Ben Khallouq, Bertha; Maugans, Todd

2018-05-01

OBJECTIVE The Internet is used frequently by patients and family members to acquire information about pediatric neurosurgical conditions. The sources, nature, accuracy, and usefulness of this information have not been examined recently. The authors analyzed the results from searches of 10 common pediatric neurosurgical terms using a novel scoring test to assess the value of the educational information obtained. METHODS Google and Bing searches were performed for 10 common pediatric neurosurgical topics (concussion, craniosynostosis, hydrocephalus, pediatric brain tumor, pediatric Chiari malformation, pediatric epilepsy surgery, pediatric neurosurgery, plagiocephaly, spina bifida, and tethered spinal cord). The first 10 "hits" obtained with each search engine were analyzed using the Currency, Relevance, Authority, Accuracy, and Purpose (CRAAP) test, which assigns a numerical score in each of 5 domains. Agreement between results was assessed for 1) concurrent searches with Google and Bing; 2) Google searches over time (6 months apart); 3) Google searches using mobile and PC platforms concurrently; and 4) searches using privacy settings. Readability was assessed with an online analytical tool. RESULTS Google and Bing searches yielded information with similar CRAAP scores (mean 72% and 75%, respectively), but with frequently differing results (58% concordance/matching results). There was a high level of agreement (72% concordance) over time for Google searches and also between searches using general and privacy settings (92% concordance). Government sources scored the best in both CRAAP score and readability. Hospitals and universities were the most prevalent sources, but these sources had the lowest CRAAP scores, due in part to an abundance of self-marketing. The CRAAP scores for mobile and desktop platforms did not differ significantly (p = 0.49). CONCLUSIONS Google and Bing searches yielded useful educational information, using either mobile or PC platforms. Most information was relevant and accurate; however, the depth and breadth of information was variable. Search results over a 6-month period were moderately stable. Pediatric neurosurgery practices and neurosurgical professional organization websites were inferior (less current, less accurate, less authoritative, and less purposeful) to governmental and encyclopedia-type resources such as Wikipedia. This presents an opportunity for pediatric neurosurgeons to participate in the creation of better online patient/parent educational material.

Discovery and identification of potential biomarkers of pediatric Acute Lymphoblastic Leukemia

PubMed Central

Shi, Linan; Zhang, Jun; Wu, Peng; Feng, Kai; Li, Jing; Xie, Zhensheng; Xue, Peng; Cai, Tanxi; Cui, Ziyou; Chen, Xiulan; Hou, Junjie; Zhang, Jianzhong; Yang, Fuquan

2009-01-01

Background Acute lymphoblastic leukemia (ALL) is a common form of cancer in children. Currently, bone marrow biopsy is used for diagnosis. Noninvasive biomarkers for the early diagnosis of pediatric ALL are urgently needed. The aim of this study was to discover potential protein biomarkers for pediatric ALL. Methods Ninety-four pediatric ALL patients and 84 controls were randomly divided into a "training" set (45 ALL patients, 34 healthy controls) and a test set (49 ALL patients, 30 healthy controls and 30 pediatric acute myeloid leukemia (AML) patients). Serum proteomic profiles were measured using surface-enhanced laser desorption/ionization-time-of-flight mass spectroscopy (SELDI-TOF-MS). A classification model was established by Biomarker Pattern Software (BPS). Candidate protein biomarkers were purified by HPLC, identified by LC-MS/MS and validated using ProteinChip immunoassays. Results A total of 7 protein peaks (9290 m/z, 7769 m/z, 15110 m/z, 7564 m/z, 4469 m/z, 8937 m/z, 8137 m/z) were found with differential expression levels in the sera of pediatric ALL patients and controls using SELDI-TOF-MS and then analyzed by BPS to construct a classification model in the "training" set. The sensitivity and specificity of the model were found to be 91.8%, and 90.0%, respectively, in the test set. Two candidate protein peaks (7769 and 9290 m/z) were found to be down-regulated in ALL patients, where these were identified as platelet factor 4 (PF4) and pro-platelet basic protein precursor (PBP). Two other candidate protein peaks (8137 and 8937 m/z) were found up-regulated in the sera of ALL patients, and these were identified as fragments of the complement component 3a (C3a). Conclusion Platelet factor (PF4), connective tissue activating peptide III (CTAP-III) and two fragments of C3a may be potential protein biomarkers of pediatric ALL and used to distinguish pediatric ALL patients from healthy controls and pediatric AML patients. Further studies with additional populations or using pre-diagnostic sera are needed to confirm the importance of these findings as diagnostic markers of pediatric ALL. PMID:19291297

Job Satisfaction and Relocation Desire among Pediatric Dentists in Puerto Rico.

PubMed

Arévalo, Oscar; Saman, Daniel M; Tabares, Miguel; Hernández, Ana; Sanders-Ward, Rebecca

2015-12-01

To determine the levels of satisfaction, license status, and desire to relocate of pediatric dentists in Puerto Rico. Pediatric dentists in Puerto Rico were surveyed via telephone interviews. Data were collected through a 34-item questionnaire that explored satisfaction as related to income, continuing education, professional goals, and participation in the Mi Salud program. Frequencies, chi-square analysis, and Fisher's exact 2-tailed t-test were utilized to determine the relationships between satisfaction and the demographics of the pediatric dentists. Sixty pediatric dentists participated in our survey-77% of the total number of pediatric dentists practicing in Puerto Rico. Overall, 65% of the participating pediatric dentists expressed dissatisfaction. Male pediatric dentists were more dissatisfied than their female colleagues were. Most pediatric dentists participating in Mi Salud expressed dissatisfaction. When asked about whether or not they had considered migrating to the mainland, those who were dissatisfied were more likely to have considered that idea than were those who were satisfied. Overall, 57% of the pediatric dentists comprising our sample had considered relocating to the continental United States. In general, the pediatric dentists who participated in our study expressed dissatisfaction in most areas except when asked about their ability to reach professional goals. Determining the levels of satisfaction of health care providers is important in the maintaining of an adequate workforce. As current levels of dissatisfaction are high, it is important to determine what variables are related to satisfaction so that corrective measures can be taken to ensure that retention rates improve, thereby maintaining an adequate pediatric dental workforce.

Recapitulation of Tumor Heterogeneity and Molecular Signatures in a 3D Brain Cancer Model with Decreased Sensitivity to Histone Deacetylase Inhibition

PubMed Central

Smith, Stuart J.; Wilson, Martin; Ward, Jennifer H.; Rahman, Cheryl V.; Peet, Andrew C.; Macarthur, Donald C.; Rose, Felicity R. A. J.; Grundy, Richard G.; Rahman, Ruman

2012-01-01

Introduction Physiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS). Methods CNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat. Results Macroscopic RCCS aggregates recapitulated the heterogeneous morphology of brain tumors with a distinct proliferating rim, necrotic core and oxygen tension gradient. Gene expression and microRNA analyses revealed significant differences with 3D expression intermediate to 2D cultures and primary brain tumors. Metabolic profiling revealed differential profiles, with an increase in tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a drug testing tool, we determined the efficacy of Vorinostat against aggregates of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced sensitivity when assaying in 3D culture conditions compared to classical 2D drug screen approaches. Conclusions Our comprehensive characterization demonstrates that 3D RCCS culture of high grade brain tumor cells has profound effects on the genetic, epigenetic and metabolic profiles of cultured cells, with these cells residing as an intermediate phenotype between that of 2D cultures and primary tumors. There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS partially re-capitulates tissue specific features, allowing drug testing in a more relevant ex vivo system. PMID:23272238

Quantiferon-Cytomegalovirus assay: A potentially useful tool in the evaluation of CMV-specific CD8+ T-cell reconstitution in pediatric hematopoietic stem cell transplant patients.

PubMed

Paouri, Bilio; Soldatou, Alexandra; Petrakou, Eftihia; Theodosaki, Maria; Tsentidis, Charalampos; Kaisari, Katerina; Oikonomopoulou, Christina; Matsas, Minos; Goussetis, Eugenios

2018-05-18

Pediatric HSCT recipients are at high risk for CMV reactivation due to their immature immune system and therapy following transplantation. Reconstitution of CMV-specific T-cell immunity is associated with control and protection against CMV. The clinical utility of monitoring CMV-specific CMI to predict CMV viremia in pediatric HSCT patients using the Quantiferon-CMV (QIAGEN ® ) test was investigated prospectively. Thirty-seven pediatric allogeneic HSCT recipients were enrolled from 3/2010-6/2012. CMV viremia was detected via weekly real-time PCR. The Quantiferon-CMV test was conducted pretransplant, early after transplantation, 30, 90, 180, 270, and 360 days post-transplantation. The incidence of CMV viremia was 51% (19/37) with half of the episodes within ≤30 days post-transplant. Fifteen patients showed CMV-specific immunity (average of 82 days). The cumulative incidence of CMV reactivation in patients who developed CMV-specific immunity was lower than those who did not (15% vs 53%; P = .023). The ROC statistical analysis showed that the AUC was 0.725 in predicting viremia, for Quantiferon-CMV test. In this cohort, the Quantiferon-CMV assay was a valuable method for identifying pediatric HSCT patients at high risk for CMV viremia, suggesting potential clinical utility to individualize patient's management post-transplant. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pediatric Dentistry in Primary Healthcare: Creation, Development, and Evaluation of a Distance Education Course.

PubMed

Bavaresco, Caren Serra; Bragança, Silvana Gonçalves; D'Avila, Otávio Pereira; Umpierre, Roberto; Harzheim, Erno; Rodrigues, Jonas Almeida

2018-01-02

Oral health in childhood is a major problem for global public health. In Brazil, the prevalence of childhood tooth decay varies from 12% to 46%. Dental care treatment in Brazil is almost the exclusive responsibility of primary healthcare (PHC). Therefore, it is essential these professionals are prepared to conduct restorative, endodontic, and exodontic treatments and preventive care in children. Children make up a large proportion of the population in territories requiring advanced dental care provided by PHC in Brazil. To care for these patients, it is necessary to have both manual dexterity and technical knowledge of pediatric dentistry. Accordingly, this study aimed to develop a distance course on pediatric dentistry. A pretest questionnaire consisting of 15 questions was used to assess initial dental knowledge of participants. After completion of a five-module course, participants retook the same initial dental knowledge questionnaire (post-test). Descriptive statistic and paired t test, one-way analysis of variance, and Pearson and Spearman correlation were used, and a significance level of 5% was set. The majority of participants completing the five-module course were women who earned specialty degrees beyond undergraduate studies and currently worked in PHC (>5 years). Participant performance on the dental knowledge questionnaire after completion of the five-module course improved pre- to post-test. These data suggest that completion of a distance course on pediatric dentistry can be an effective tool for improving knowledge of pediatric dentistry in PHC professionals.

TU-EF-210-01: HIFU, Drug Delivery, and Immunotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ferrara, K.

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

TU-EF-210-04: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farahani, K.

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

TU-EF-210-03: Real-Time Ablation Monitoring and Lesion Quantification Using Harmonic Motion Imaging

DOE Office of Scientific and Technical Information (OSTI.GOV)

Konofagou, E.

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

TU-EF-210-00: Therapeutic Strategies and Image Guidance

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

TU-EF-210-02: MRg Hyperthermia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chopra, R.

2015-06-15

The use of therapeutic ultrasound to provide targeted therapy is an active research area that has a broad application scope. The invited talks in this session will address currently implemented strategies and protocols for both hyperthermia and ablation applications using therapeutic ultrasound. The role of both ultrasound and MRI in the monitoring and assessment of these therapies will be explored in both pre-clinical and clinical applications. Katherine Ferrara: High Intensity Focused Ultrasound, Drug Delivery, and Immunotherapy Rajiv Chopra: Translating Localized Doxorubicin Delivery to Pediatric Oncology using MRI-guided HIFU Elisa Konofagou: Real-time Ablation Monitoring and Lesion Quantification using Harmonic Motion Imagingmore » Keyvan Farahani: AAPM Task Groups in Interventional Ultrasound Imaging and Therapy Learning Objectives: Understand the role of ultrasound in localized drug delivery and the effects of immunotherapy when used in conjunction with ultrasound therapy. Understand potential targeted drug delivery clinical applications including pediatric oncology. Understand the technical requirements for performing targeted drug delivery. Understand how radiation-force approaches can be used to both monitor and assess high intensity focused ultrasound ablation therapy. Understand the role of AAPM task groups in ultrasound imaging and therapies. Chopra: Funding from Cancer Prevention and Research Initiative of Texas (CPRIT), Award R1308 Evelyn and M.R. Hudson Foundation; Research Support from Research Contract with Philips Healthcare; COI are Co-founder of FUS Instruments Inc Ferrara: Supported by NIH, UCDavis and California (CIRM and BHCE) Farahani: In-kind research support from Philips Healthcare.« less

The Neurotensin NTS1 Receptor Agonist PD149163 Produces Antidepressant-Like Effects in the Forced Swim Test: Further Support for Neurotensin as a Novel Pharmacologic Strategy for Antidepressant Drugs.

PubMed

Carey, Lawrence M; Rice, Remington J; Prus, Adam J

2017-08-01

Preclinical Research Neurotensin is a nonbrain penetrant neuropeptide neurotransmitter that alters dopaminergic and serotonergic neurotransmission. Previous animal behavioral studies have demonstrated that intra-ventral tegmental administration of neurotensin and system administration of the selective neurotensin NTS 1 receptor agonist, PD149163 produce antidepressant-like effects in a forced swim test and a differential reinforcement of low rate task, respectively. The present study sought to expand upon these past findings by assessing systemic administration of PD149163 in a forced swim test, a primary antidepressant preclinical screening model, in mice. The tricyclic antidepressant drug imipramine was tested for comparison, and both compounds were also assessed in an open field test. Both PD149163 and imipramine reduced time spent immobile, an antidepressant-like effect, in the forced swim test. The highest dose of each compound significantly reduced locomotor activity. These findings provide further evidence for the putative antidepressant effects for PD149163 and suggest that NTS 1 receptor activation may be a novel pharmacologic strategy for antidepressant drug development. Drug Dev Res 78 : 196-202, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Pediatric Thoracic Trauma: Recognition and Management.

PubMed

Reynolds, Stacy L

2018-05-01

Thoracic injuries account for less than one-tenth of all pediatric trauma-related injuries but comprise 14% of pediatric trauma-related deaths. Thoracic trauma includes injuries to the lungs, heart, aorta and great vessels, esophagus, tracheobronchial tree, and structures of the chest wall. Children have unique anatomic features that change the patterns of observed injury compared with adults. This review article outlines the clinical presentation, diagnostic testing, and management principles required to successfully manage injured children with thoracic trauma. Copyright © 2018 Elsevier Inc. All rights reserved.

Establishment of a patient-derived orthotopic osteosarcoma mouse model.

PubMed

Blattmann, Claudia; Thiemann, Markus; Stenzinger, Albrecht; Roth, Eva K; Dittmar, Anne; Witt, Hendrik; Lehner, Burkhard; Renker, Eva; Jugold, Manfred; Eichwald, Viktoria; Weichert, Wilko; Huber, Peter E; Kulozik, Andreas E

2015-04-30

Osteosarcoma (OS) is the most common pediatric primary malignant bone tumor. As the prognosis for patients following standard treatment did not improve for almost three decades, functional preclinical models that closely reflect important clinical cancer characteristics are urgently needed to develop and evaluate new treatment strategies. The objective of this study was to establish an orthotopic xenotransplanted mouse model using patient-derived tumor tissue. Fresh tumor tissue from an adolescent female patient with osteosarcoma after relapse was surgically xenografted into the right tibia of 6 immunodeficient BALB/c Nu/Nu mice as well as cultured into medium. Tumor growth was serially assessed by palpation and with magnetic resonance imaging (MRI). In parallel, a primary cell line of the same tumor was established. Histology and high-resolution array-based comparative genomic hybridization (aCGH) were used to investigate both phenotypic and genotypic characteristics of different passages of human xenografts and the cell line compared to the tissue of origin. A primary OS cell line and a primary patient-derived orthotopic xenotranplanted mouse model were established. MRI analyses and histopathology demonstrated an identical architecture in the primary tumor and in the xenografts. Array-CGH analyses of the cell line and all xenografts showed highly comparable patterns of genomic progression. So far, three further primary patient-derived orthotopic xenotranplanted mouse models could be established. We report the first orthotopic OS mouse model generated by transplantation of tumor fragments directly harvested from the patient. This model represents the morphologic and genomic identity of the primary tumor and provides a preclinical platform to evaluate new treatment strategies in OS.

In utero therapy for congenital disorders using amniotic fluid stem cells

PubMed Central

Ramachandra, Durrgah L.; Shaw, Steven S. W.; Shangaris, Panicos; Loukogeorgakis, Stavros; Guillot, Pascale V.; Coppi, Paolo De; David, Anna L.

2014-01-01

Congenital diseases are responsible for over a third of all pediatric hospital admissions. Advances in prenatal screening and molecular diagnosis have allowed the detection of many life-threatening genetic diseases early in gestation. In utero transplantation (IUT) with stem cells could cure affected fetuses but so far in humans, successful IUT using allogeneic hematopoietic stem cells (HSCs), has been limited to fetuses with severe immunologic defects and more recently IUT with allogeneic mesenchymal stem cell transplantation, has improved phenotype in osteogenesis imperfecta. The options of preemptive treatment of congenital diseases in utero by stem cell or gene therapy changes the perspective of congenital diseases since it may avoid the need for postnatal treatment and reduce future costs. Amniotic fluid stem (AFS) cells have been isolated and characterized in human, mice, rodents, rabbit, and sheep and are a potential source of cells for therapeutic applications in disorders for treatment prenatally or postnatally. Gene transfer to the cells with long-term transgenic protein expression is feasible. Recently, pre-clinical autologous transplantation of transduced cells has been achieved in fetal sheep using minimally invasive ultrasound guided injection techniques. Clinically relevant levels of transgenic protein were expressed in the blood of transplanted lambs for at least 6 months. The cells have also demonstrated the potential of repair in a range of pre-clinical disease models such as neurological disorders, tracheal repair, bladder injury, and diaphragmatic hernia repair in neonates or adults. These results have been encouraging, and bring personalized tissue engineering for prenatal treatment of genetic disorders closer to the clinic. PMID:25566071

VIVA LA SALUD INFANTILE: Pediatric obesity treatment in an underserved Hispanic community

USDA-ARS?s Scientific Manuscript database

Pediatric obesity in the US disproportionately impacts minority populations who face socioeconomic and cultural barriers to weight management programs. The specific aim of this pilot study was to test the effectiveness of diet behavior modification or diet behavior modification plus structured aerob...

Assessment of Age-Related Differences in Functional Capacity Using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT)

PubMed Central

Atkins, A.S.; Stroescu, I.; Spagnola, N.B.; Davis, V.G.; Patterson, T.D.; Narasimhan, M.; Harvey, P.D.; Keefe, R.S.E.

2015-01-01

Clinical trials for primary prevention and early intervention in preclinical AD require measures of functional capacity with improved sensitivity to deficits in healthier, non-demented individuals. To this end, the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) was developed as a direct performance-based assessment of functional capacity that is sensitive to changes in function across multiple populations. Using a realistic virtual reality environment, the VRFCAT assesses a subject's ability to complete instrumental activities associated with a shopping trip. The present investigation represents an initial evaluation of the VRFCAT as a potential co-primary measure of functional capacity in healthy aging and preclinical MCI/AD by examining test-retest reliability and associations with cognitive performance in healthy young and older adults. The VRFCAT was compared and contrasted with the UPSA-2-VIM, a traditional performance-based assessment utilizing physical props. Results demonstrated strong age-related differences in performance on each VRFCAT outcome measure, including total completion time, total errors, and total forced progressions. VRFCAT performance showed strong correlations with cognitive performance across both age groups. VRFCAT Total Time demonstrated good test-retest reliability (ICC=.80 in young adults; ICC=.64 in older adults) and insignificant practice effects, indicating the measure is suitable for repeated testing in healthy populations. Taken together, these results provide preliminary support for the VRFCAT as a potential measure of functionally relevant change in primary prevention and preclinical AD/MCI trials. PMID:26618145

[Modeling the academic performance of medical students in basic sciences and pre-clinical courses: a longitudinal study].

PubMed

Zúñiga, Denisse; Mena, Beltrán; Oliva, Rose; Pedrals, Nuria; Padilla, Oslando; Bitran, Marcela

2009-10-01

The study of predictors of academic performance is relevant for medical education. Most studies of academic performance use global ratings as outcome measure, and do not evaluate the influence of the assessment methods. To model by multivariate analysis, the academic performance of medical considering, besides academic and demographic variables, the methods used to assess students' learning and their preferred modes of information processing. Two hundred seventy two students admitted to the medical school of the Pontificia Universidad Católica de Chile from 2000 to 2003. Six groups of variables were studied to model the students' performance in five basic science courses (Anatomy, Biology, Calculus, Chemistry and Physics) and two pre-clinical courses (Integrated Medical Clinic I and IT). The assessment methods examined were multiple choice question tests, Objective Structured Clinical Examination and tutor appraisal. The results of the university admission tests (high school grades, mathematics and biology tests), the assessment methods used, the curricular year and previous application to medical school, were predictors of academic performance. The information processing modes influenced academic performance, but only in interaction with other variables. Perception (abstract or concrete) interacted with the assessment methods, and information use (active or reflexive), with sex. The correlation between the real and predicted grades was 0.7. In addition to the academic results obtained prior to university entrance, the methods of assessment used in the university and the information processing modes influence the academic performance of medical students in basic and preclinical courses.

Rat animal model for preclinical testing of microparticle urethral bulking agents.

PubMed

Mann-Gow, Travis K; Blaivas, Jerry G; King, Benjamin J; El-Ghannam, Ahmed; Knabe, Christine; Lam, Michael K; Kida, Masatoshi; Sikavi, Cameron S; Plante, Mark K; Krhut, Jan; Zvara, Peter

2015-04-01

To develop an economic, practical and readily available animal model for preclinical testing of urethral bulking therapies, as well as to establish feasible experimental methods that allow for complete analysis of hard microparticle bulking agents. Alumina ceramic beads suspended in hyaluronic acid were injected into the proximal urethra of 15 female rats under an operating microscope. We assessed overall lower urinary tract function, bulking material intraurethral integrity and local host tissue response over time. Microphotographs were taken during injection and again 6 months postoperatively, before urethral harvest. Urinary flow rate and voiding frequency were assessed before and after injection. At 6 months, the urethra was removed and embedded in resin. Hard tissue sections were cut using a sawing microtome, and processed for histological analysis using scanning electron microscopy, light microscopy and immunohistochemistry. Microphotographs of the urethra showed complete volume retention of the bulking agent at 6 months. There was no significant difference between average urinary frequency and mean urinary flow rate at 1 and 3 months postinjection as compared with baseline. Scanning electron microscopy proved suitable for evaluation of microparticle size and integrity, as well as local tissue remodeling. Light microscopy and immunohistochemistry allowed for evaluation of an inflammatory host tissue reaction to the bulking agent. The microsurgical injection technique, in vivo physiology and novel hard tissue processing for histology, described in the present study, will allow for future comprehensive preclinical testing of urethral bulking therapy agents containing microparticles made of a hard material. © 2015 The Japanese Urological Association.

Assessment of clinical reasoning: A Script Concordance test designed for pre-clinical medical students.

PubMed

Humbert, Aloysius J; Johnson, Mary T; Miech, Edward; Friedberg, Fred; Grackin, Janice A; Seidman, Peggy A

2011-01-01

The Script Concordance test (SCT) measures clinical reasoning in the context of uncertainty by comparing the responses of examinees and expert clinicians. It uses the level of agreement with a panel of experts to assign credit for the examinee's answers. This study describes the development and validation of a SCT for pre-clinical medical students. Faculty from two US medical schools developed SCT items in the domains of anatomy, biochemistry, physiology, and histology. Scoring procedures utilized data from a panel of 30 expert physicians. Validation focused on internal reliability and the ability of the SCT to distinguish between different cohorts. The SCT was administered to an aggregate of 411 second-year and 70 fourth-year students from both schools. Internal consistency for the 75 test items was satisfactory (Cronbach's alpha = 0.73). The SCT successfully differentiated second- from fourth-year students and both student groups from the expert panel in a one-way analysis of variance (F(2,508) = 120.4; p < 0.0001). Mean scores for students from the two schools were not significantly different (p = 0.20). This SCT successfully differentiated pre-clinical medical students from fourth-year medical students and both cohorts of medical students from expert clinicians across different institutions and geographic areas. The SCT shows promise as an easy-to-administer measure of "problem-solving" performance in competency evaluation even in the beginning years of medical education.

Feasibility of Primary Tumor Culture Models and Preclinical Prediction Assays for Head and Neck Cancer: A Narrative Review

PubMed Central

Dohmen, Amy J. C.; Swartz, Justin E.; Van Den Brekel, Michiel W. M.; Willems, Stefan M.; Spijker, René; Neefjes, Jacques; Zuur, Charlotte L.

2015-01-01

Primary human tumor culture models allow for individualized drug sensitivity testing and are therefore a promising technique to achieve personalized treatment for cancer patients. This would especially be of interest for patients with advanced stage head and neck cancer. They are extensively treated with surgery, usually in combination with high-dose cisplatin chemoradiation. However, adding cisplatin to radiotherapy is associated with an increase in severe acute toxicity, while conferring only a minor overall survival benefit. Hence, there is a strong need for a preclinical model to identify patients that will respond to the intended treatment regimen and to test novel drugs. One of such models is the technique of culturing primary human tumor tissue. This review discusses the feasibility and success rate of existing primary head and neck tumor culturing techniques and their corresponding chemo- and radiosensitivity assays. A comprehensive literature search was performed and success factors for culturing in vitro are debated, together with the actual value of these models as preclinical prediction assay for individual patients. With this review, we aim to fill a gap in the understanding of primary culture models from head and neck tumors, with potential importance for other tumor types as well. PMID:26343729

Nanobiotechnology-based delivery strategies: New frontiers in brain tumor targeted therapies.

PubMed

Mangraviti, Antonella; Gullotti, David; Tyler, Betty; Brem, Henry

2016-10-28

Despite recent technological advancements and promising preclinical experiments, brain tumor patients are still met with limited treatment options. Some of the barriers to clinical improvements include the systemic toxicity of cytotoxic compounds, the impedance of the blood brain barrier (BBB), and the lack of therapeutic agents that can selectively target the intracranial tumor environment. To overcome such barriers, a number of chemotherapeutic agents and nucleic acid-based therapies are rapidly being synthesized and tested as new brain tumor-targeted delivery strategies. Novel carriers include liposomal and polymeric nanoparticles, wafers, microchips, microparticle-based nanoplatforms and cells-based vectors. Strong preclinical results suggest that these nanotechnologies are set to transform the therapeutic paradigm for brain tumor treatment. In addition to new tumoricidal agents, parallel work is also being conducted on the BBB front. Preclinical testing of chemical and physical modulation strategies is yielding improved intracranial concentrations. New diagnostic and therapeutic imaging techniques, such as high-intensity focused ultrasound and MRI-guided focused ultrasound, are being used to modulate the BBB in a more precise and non-invasive manner. This review details some of the tremendous advances that are being explored in current brain tumor targeted therapies, including local implant development, nanobiotechnology-based delivery strategies, and techniques of BBB manipulation. Copyright © 2016 Elsevier B.V. All rights reserved.

The NOTCH3 score: a pre-clinical CADASIL biomarker in a novel human genomic NOTCH3 transgenic mouse model with early progressive vascular NOTCH3 accumulation.

PubMed

Rutten, Julie W; Klever, Roselin R; Hegeman, Ingrid M; Poole, Dana S; Dauwerse, Hans G; Broos, Ludo A M; Breukel, Cor; Aartsma-Rus, Annemieke M; Verbeek, J Sjef; van der Weerd, Louise; van Duinen, Sjoerd G; van den Maagdenberg, Arn M J M; Lesnik Oberstein, Saskia A J

2015-12-29

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic NOTCH3 protein accumulation in the small- to medium sized arterioles. The accumulation is systemic but most pronounced in the brain vasculature where it leads to clinical symptoms of recurrent stroke and dementia. There is no therapy for CADASIL, and therapeutic development is hampered by a lack of feasible clinical outcome measures and biomarkers, both in mouse models and in CADASIL patients. To facilitate pre-clinical therapeutic interventions for CADASIL, we aimed to develop a novel, translational CADASIL mouse model. We generated transgenic mice in which we overexpressed the full length human NOTCH3 gene from a genomic construct with the archetypal c.544C > T, p.Arg182Cys mutation. The four mutant strains we generated have respective human NOTCH3 RNA expression levels of 100, 150, 200 and 350 % relative to endogenous mouse Notch3 RNA expression. Immunohistochemistry on brain sections shows characteristic vascular human NOTCH3 accumulation in all four mutant strains, with human NOTCH3 RNA expression levels correlating with age at onset and progression of NOTCH3 accumulation. This finding was the basis for developing the 'NOTCH3 score', a quantitative measure for the NOTCH3 accumulation load. This score proved to be a robust and sensitive method to assess the progression of NOTCH3 accumulation, and a feasible biomarker for pre-clinical therapeutic testing. This novel, translational CADASIL mouse model is a suitable model for pre-clinical testing of therapeutic strategies aimed at delaying or reversing NOTCH3 accumulation, using the NOTCH3 score as a biomarker.

Reducing blood testing in pediatric patients after heart surgery: a quality improvement project.

PubMed

Delgado-Corcoran, Claudia; Bodily, Stephanie; Frank, Deborah U; Witte, Madolin K; Castillo, Ramon; Bratton, Susan L

2014-10-01

To safely optimize blood testing and costs for pediatric cardiac surgical patients without adversely impacting patient outcomes. This is a quality improvement cohort project with pre- and postintervention groups. University-affiliated pediatric cardiac ICU in a tertiary care children's hospital. All patients were surgical patients for whom Risk Adjustment for Congenital Heart Surgery categories allowed for stratification by complexity. The preintervention group was treated in 2010 and the postintervention group in 2011. Laboratory ordering processes were analyzed, and practice changed to limit standing blood test orders and requires individualized ordering. Three hundred nineteen patients were studied in 2010 and 345 in 2011. Groups were similar in median age, weight, length of stay (ICU length of stay), and Risk Adjustment for Congenital Heart Surgery category. There was a reduction in the total blood tests per patient (24 vs 38; p < 0.0001) and length of stay adjusted tests per patient-day (10.4 vs 14.4; p = 0.0001) in the postintervention group. The largest test reductions were blood gases and single electrolytes. Adverse outcomes, such as extubation failure (6.4% vs 5.6%), central catheter-associated bloodstream infection (2.2 vs 1.5), and hospital mortality (0.6% vs 0.6%), were not significantly different between the groups. Cost analysis demonstrated an overall laboratory cost savings of 32%. In addition, the volume of packed RBC transfusions was also significantly decreased in the postintervention group among the most complex patients (Risk Adjustment for Congenital Heart Surgery, 6). Blood testing rates were safely decreased in postoperative pediatric cardiac patients by changing laboratory ordering practices. In addition, packed RBC transfusion was decreased among the most complex patients.

Human Xenografts Are Not Rejected in a Naturally Occurring Immunodeficient Porcine Line: A Human Tumor Model in Pigs

PubMed Central

Basel, Matthew T.; Balivada, Sivasai; Beck, Amanda P.; Kerrigan, Maureen A.; Pyle, Marla M.; Dekkers, Jack C.M.; Wyatt, Carol R.; Rowland, Robert R.R.; Anderson, David E.; Bossmann, Stefan H.

2012-01-01

Abstract Animal models for cancer therapy are invaluable for preclinical testing of potential cancer treatments; however, therapies tested in such models often fail to translate into clinical settings. Therefore, a better preclinical model for cancer treatment testing is needed. Here we demonstrate that an immunodeficient line of pigs can host and support the growth of xenografted human tumors and has the potential to be an effective animal model for cancer therapy. Wild-type and immunodeficient pigs were injected subcutaneously in the left ear with human melanoma cells (A375SM cells) and in the right ear with human pancreatic carcinoma cells (PANC-1). All immunodeficient pigs developed tumors that were verified by histology and immunohistochemistry. Nonaffected littermates did not develop tumors. Immunodeficient pigs, which do not reject xenografted human tumors, have the potential to become an extremely useful animal model for cancer therapy because of their similarity in size, anatomy, and physiology to humans. PMID:23514746

Fully Implantable Deep Brain Stimulation System with Wireless Power Transmission for Long-term Use in Rodent Models of Parkinson's Disease.

PubMed

Heo, Man Seung; Moon, Hyun Seok; Kim, Hee Chan; Park, Hyung Woo; Lim, Young Hoon; Paek, Sun Ha

2015-03-01

The purpose of this study to develop new deep-brain stimulation system for long-term use in animals, in order to develop a variety of neural prostheses. Our system has two distinguished features, which are the fully implanted system having wearable wireless power transfer and ability to change the parameter of stimulus parameter. It is useful for obtaining a variety of data from a long-term experiment. To validate our system, we performed pre-clinical test in Parkinson's disease-rat models for 4 weeks. Through the in vivo test, we observed the possibility of not only long-term implantation and stability, but also free movement of animals. We confirmed that the electrical stimulation neither caused any side effect nor damaged the electrodes. We proved possibility of our system to conduct the long-term pre-clinical test in variety of parameter, which is available for development of neural prostheses.

Animal testing is still the best way to find new treatments for patients.

PubMed

Garattini, Silvio; Grignaschi, Giuliano

2017-04-01

Experimental research proceeds by hypotheses formulated on the basis of previous or new knowledge and then tested. If they are accepted, they serve as the basis for further hypotheses, and if they are rejected new hypotheses can be developed. In other words, when we are at the frontiers of knowledge the path is forged by "trial and error". When a trial shows a hypothesis is wrong, this is a step toward making fewer errors. This process also applies to drug development. There is no magic formula at present to predict - at the pre-clinical level - the therapeutic value of a drug for people with a disease. However, pre-clinical studies are needed in order to formulate hypotheses that justify clinical trials. Without these preliminary studies in vitro and in vivo in selected animal species it would be unethical to test still unproven chemicals in humans. Copyright © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Stress Reduction through Audio Distraction in Anxious Pediatric Dental Patients: An Adjunctive Clinical Study.

PubMed

Singh, Divya; Samadi, Firoza; Jaiswal, Jn; Tripathi, Abhay Mani

2014-01-01

The purpose of the present study was to evaluate the eff-cacy of 'audio distraction' in anxious pediatric dental patients. Sixty children were randomly selected and equally divided into two groups of thirty each. The first group was control group (group A) and the second group was music group (group B). The dental procedure employed was extraction for both the groups. The children included in music group were allowed to hear audio presentation throughout the treatment procedure. Anxiety was measured by using Venham's picture test, pulse rate, blood pressure and oxygen saturation. 'Audio distraction' was found efficacious in alleviating anxiety of pediatric dental patients. 'Audio distraction' did decrease the anxiety in pediatric patients to a significant extent. How to cite this article: Singh D, Samadi F, Jaiswal JN, Tripathi AM. Stress Reduction through Audio Distraction in Anxious Pediatric Dental Patients: An Adjunctive Clinical Study. Int J Clin Pediatr Dent 2014;7(3):149-152.

Enhancing pediatric clinical competency with high-fidelity simulation.

PubMed

Birkhoff, Susan D; Donner, Carol

2010-09-01

In today's tertiary pediatric hospital setting, the increased complexity of patient care demands seamless coordination and collaboration among multidisciplinary team members. In an effort to enhance patient safety, clinical competence, and teamwork, simulation-based learning has become increasingly integrated into pediatric clinical practice as an innovative educational strategy. The simulated setting provides a risk-free environment where learners can incorporate cognitive, psychomotor, and affective skill acquisition without fear of harming patients. One pediatric university hospital in Southeastern Pennsylvania has enhanced the traditional American Heart Association (AHA) Pediatric Advanced Life Support (PALS) course by integrating high-fidelity simulation into skill acquisition, while still functioning within the guidelines and framework of the AHA educational standards. However, very little research with reliable standardized testing methods has been done to measure the effect of simulation-based learning. This article discusses the AHA guidelines for PALS, evaluation of PALS and nursing clinical competencies, communication among a multidisciplinary team, advantages and disadvantages of simulation, incorporation of high-fidelity simulation into pediatric practice, and suggestions for future practice. Copyright 2010, SLACK Incorporated.

Expression of glypican-3 is highly associated with pediatric hepatoblastoma: a systemic analysis.

PubMed

Xiong, Xiao-Li; Qin, Huan; Yan, Su-Qi; Zhou, Li-Shan; Chen, Peng; Zhao, Dong- Chi

2015-01-01

Glypican-3 (GPC3) is reported to be an oncofetal protein that is a useful diagnostic immunomarker for hepatoblastoma. However, the results are not inclusive. This study systemically investigated the association between expression of GPC3 and pediatric hepatoblastoma. Clinical studies evaluating the association were identified using a predefined search strategy. GPC3 immunohistochemistry was applied in the pathological diagnosis of hepatoblastoma using the monoclonal antibodies with formalin-fixed and paraffin-embedded specimens. Positive predictive rates for the association between expression of GPC3 and pediatric hepatoblastoma were calculated. Specimens from four clinical studies which including 134 patients with pediatric hepatoblastoma tested by GPC3 immunohistochemistry were considered eligible for inclusion. Systemic analysis showed that, in all patients, pooled positive predictive rate of the association between expression of GPC3 and pediatric hepatoblastoma was 95.5% (128/134). This systemic analysis suggests that the expression of glypican-3 is highly associated with the diagnosis of pediatric hepatoblastoma.

In vitro assessment of skin irritation potential of surfactant-based formulations by using a 3-D skin reconstructed tissue model and cytokine response.

PubMed

Walters, Russel M; Gandolfi, Lisa; Mack, M Catherine; Fevola, Michael; Martin, Katharine; Hamilton, Mathew T; Hilberer, Allison; Barnes, Nicole; Wilt, Nathan; Nash, Jennifer R; Raabe, Hans A; Costin, Gertrude-Emilia

2016-12-01

The personal care industry is focused on developing safe, more efficacious, and increasingly milder products, that are routinely undergoing preclinical and clinical testing before becoming available for consumer use on skin. In vitro systems based on skin reconstructed equivalents are now established for the preclinical assessment of product irritation potential and as alternative testing methods to the classic Draize rabbit skin irritation test. We have used the 3-D EpiDerm™ model system to evaluate tissue viability and primary cytokine interleukin-1α release as a way to evaluate the potential dermal irritation of 224 non-ionic, amphoteric and/or anionic surfactant-containing formulations, or individual raw materials. As part of our testing programme, two representative benchmark materials with known clinical skin irritation potential were qualified through repeated testing, for use as references for the skin irritation evaluation of formulations containing new surfactant ingredients. We have established a correlation between the in vitro screening approach and clinical testing, and are continually expanding our database to enhance this correlation. This testing programme integrates the efforts of global manufacturers of personal care products that focus on the development of increasingly milder formulations to be applied to the skin, without the use of animal testing. 2016 FRAME.

Antibiotic Resistance in Pediatric Urinary Tract Infections.

PubMed

Stultz, Jeremy S; Doern, Christopher D; Godbout, Emily

2016-12-01

Urinary tract infections (UTIs) are a common problem in pediatric patients. Resistance to common antibiotic agents appears to be increasing over time, although resistance rates may vary based on geographic region or country. Prior antibiotic exposure is a pertinent risk factor for acquiring resistant organisms during a first UTI and recurrent UTI. Judicious prescribing of antibiotics for common pediatric conditions is needed to prevent additional resistance from occurring. Complex pediatric patients with histories of hospitalizations, prior antibiotic exposure, and recurrent UTIs are also at high risk for acquiring UTIs due to extended spectrum beta-lactamase-producing organisms. Data regarding the impact of in vitro antibiotic susceptibility testing interpretation on UTI treatment outcomes is lacking.

NIA-AA staging of preclinical Alzheimer disease: discordance and concordance of CSF and imaging biomarkers.

PubMed

Vos, Stephanie J B; Gordon, Brian A; Su, Yi; Visser, Pieter Jelle; Holtzman, David M; Morris, John C; Fagan, Anne M; Benzinger, Tammie L S

2016-08-01

The National Institute of Aging and Alzheimer's Association (NIA-AA) criteria for Alzheimer disease (AD) treat neuroimaging and cerebrospinal fluid (CSF) markers of AD pathology as if they would be interchangeable. We tested this assumption in 212 cognitively normal participants who have both neuroimaging and CSF measures of β-amyloid (CSF Aβ1-42 and positron emission tomography imaging with Pittsburgh Compound B) and neuronal injury (CSF t-tau and p-tau and structural magnetic resonance imaging) with longitudinal clinical follow-up. Participants were classified in preclinical AD stage 1 (β-amyloidosis) or preclinical AD stage 2+ (β-amyloidosis and neuronal injury) using the NIA-AA criteria, or in the normal or suspected non-Alzheimer disease pathophysiology group (neuronal injury without β-amyloidosis). At baseline, 21% of participants had preclinical AD based on CSF and 28% based on neuroimaging. Between modalities, staging was concordant in only 47% of participants. Disagreement resulted from low concordance between biomarkers of neuronal injury. Still, individuals in stage 2+ using either criterion had an increased risk for clinical decline. This highlights the heterogeneity of the definition of neuronal injury and has important implications for clinical trials using biomarkers for enrollment or as surrogate end point measures. Copyright © 2016 Elsevier Inc. All rights reserved.

Teaching methods and surgical training in North American graduate periodontics programs: exploring the landscape.

PubMed

Ghiabi, Edmond; Taylor, K Lynn

2010-06-01

This project aimed at documenting the surgical training curricula offered by North American graduate periodontics programs. A survey consisting of questions on teaching methods employed and the content of the surgical training program was mailed to directors of all fifty-eight graduate periodontics programs in Canada and the United States. The chi-square test was used to assess whether the residents' clinical experience was significantly (P<0.05) influenced by having a) a structured preclinical program or b) another dental residency program in the institution. Thirty-four programs (59 percent) responded to the survey. Twenty-six programs (76 percent of respondents) reported offering a structured preclinical component. Traditional teaching methods such as slides, live demonstration, DVD/CD, and animal cadavers were the most common teaching methods used, whereas online courses, computer simulation, and various surgical mannequins were least commonly used. The most commonly performed surgical procedures were conventional flaps, periodontal plastic procedures, hard tissue grafts, and implants. Furthermore, residents in programs offering a structured preclinical component performed significantly more procedures (P=0.012) using lasers than those in programs not offering a structured preclinical program. Devising new and innovative teaching methods is a clear avenue for future development in North American graduate periodontics programs.

Aptitude, Achievement and Competence in Medicine: A Latent Variable Path Model

ERIC Educational Resources Information Center

Collin, V. Terri; Violato, Claudio; Hecker, Kent

2009-01-01

To develop and test a latent variable path model of general achievement, aptitude for medicine and competence in medicine employing data from the Medical College Admission Test (MCAT), pre-medical undergraduate grade point average (UGPA) and demographic characteristics for competence in pre-clinical and measures of competence (United States…

Bioengineered humanized livers as better three-dimensional drug testing model system.

PubMed

Vishwakarma, Sandeep Kumar; Bardia, Avinash; Lakkireddy, Chandrakala; Nagarapu, Raju; Habeeb, Md Aejaz; Khan, Aleem Ahmed

2018-01-27

To develop appropriate humanized three-dimensional ex-vivo model system for drug testing. Bioengineered humanized livers were developed in this study using human hepatic stem cells repopulation within the acellularized liver scaffolds which mimics with the natural organ anatomy and physiology. Six cytochrome P-450 probes were used to enable efficient identification of drug metabolism in bioengineered humanized livers. The drug metabolism study in bioengineered livers was evaluated to identify the absorption, distribution, metabolism, excretion and toxicity responses. The bioengineered humanized livers showed cellular and molecular characteristics of human livers. The bioengineered liver showed three-dimensional natural architecture with intact vasculature and extra-cellular matrix. Human hepatic cells were engrafted similar to the human liver. Drug metabolism studies provided a suitable platform alternative to available ex-vivo and in vivo models for identifying cellular and molecular dynamics of pharmacological drugs. The present study paves a way towards the development of suitable humanized preclinical model systems for pharmacological testing. This approach may reduce the cost and time duration of preclinical drug testing and further overcomes on the anatomical and physiological variations in xenogeneic systems.

Confounding Brain Stem Function During Pediatric Brain Death Determination: Two Case Reports.

PubMed

Hansen, Gregory; Joffe, Ari R

2017-06-01

A patient who has been declared brain dead is considered to be both legally and clinically dead. However, we report 2 pediatric cases in which the patients demonstrated clinical signs of brain stem function that are not recognized or tested in current Canadian or US guidelines.

Pediatric clinical trial studies antibody treatment for various types of solid tumors | Center for Cancer Research

Cancer.gov

A clinical trial for pediatric patients will test the safety and efficacy of enoblituzumab in solid tumors that express a specific protein, including neuroblastoma, rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, Wilms tumor, or desmoplastic small round cell tumor. Read more... 

Clinical Applications of Gastrointestinal Manometry in Children

PubMed Central

2014-01-01

Manometry is a noninvasive diagnostic tool for identifying motility dysfunction of the gastrointestinal tract. Despite the great technical advances in monitoring motility, performance of the study in pediatric patients has several limitations that should be considered during the procedure and interpretation of the test results. This article reviews the clinical applications of conventional esophageal and anorectal manometries in children by describing a technique for performing the test. This review will develop the uniformity required for the methods of performance, the parameters for measurement, and interpretation of test results that could be applied in pediatric clinical practice. PMID:24749084

Multivariate Protein Signatures of Pre-Clinical Alzheimer's Disease in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Plasma Proteome Dataset

PubMed Central

Johnstone, Daniel; Milward, Elizabeth A.; Berretta, Regina; Moscato, Pablo

2012-01-01

Background Recent Alzheimer's disease (AD) research has focused on finding biomarkers to identify disease at the pre-clinical stage of mild cognitive impairment (MCI), allowing treatment to be initiated before irreversible damage occurs. Many studies have examined brain imaging or cerebrospinal fluid but there is also growing interest in blood biomarkers. The Alzheimer's Disease Neuroimaging Initiative (ADNI) has generated data on 190 plasma analytes in 566 individuals with MCI, AD or normal cognition. We conducted independent analyses of this dataset to identify plasma protein signatures predicting pre-clinical AD. Methods and Findings We focused on identifying signatures that discriminate cognitively normal controls (n = 54) from individuals with MCI who subsequently progress to AD (n = 163). Based on p value, apolipoprotein E (APOE) showed the strongest difference between these groups (p = 2.3×10−13). We applied a multivariate approach based on combinatorial optimization ((α,β)-k Feature Set Selection), which retains information about individual participants and maintains the context of interrelationships between different analytes, to identify the optimal set of analytes (signature) to discriminate these two groups. We identified 11-analyte signatures achieving values of sensitivity and specificity between 65% and 86% for both MCI and AD groups, depending on whether APOE was included and other factors. Classification accuracy was improved by considering “meta-features,” representing the difference in relative abundance of two analytes, with an 8-meta-feature signature consistently achieving sensitivity and specificity both over 85%. Generating signatures based on longitudinal rather than cross-sectional data further improved classification accuracy, returning sensitivities and specificities of approximately 90%. Conclusions Applying these novel analysis approaches to the powerful and well-characterized ADNI dataset has identified sets of plasma biomarkers for pre-clinical AD. While studies of independent test sets are required to validate the signatures, these analyses provide a starting point for developing a cost-effective and minimally invasive test capable of diagnosing AD in its pre-clinical stages. PMID:22485168

Preclinical assessment of a new recombinant ADAMTS-13 drug product (BAX930) for the treatment of thrombotic thrombocytopenic purpura.

PubMed

Kopić, A; Benamara, K; Piskernik, C; Plaimauer, B; Horling, F; Höbarth, G; Ruthsatz, T; Dietrich, B; Muchitsch, E-M; Scheiflinger, F; Turecek, M; Höllriegl, W

2016-07-01

Essentials ADAMTS-13-deficiency is a cause of thrombotic thrombocytopenic purpura (TTP). Preclinical safety of recombinant human ADAMTS-13 (BAX930) was shown in animal models. Preclinical efficacy of BAX930 was shown in a mouse model of TTP. BAX930 showed advantageous efficacy over fresh frozen plasma, the current standard of care. Click to hear Dr Cataland and Prof. Lämmle present a seminar on Thrombotic Thrombocytopenic Purpura (TTP): new Insights in Pathogenesis and Treatment Modalities. Background Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder characterized by microthrombosis in small blood vessels of the body, resulting in a low platelet count. Baxalta has developed a new recombinant ADAMTS-13 (rADAMTS-13) product (BAX930) for on-demand and prophylactic treatment of patients with hereditary TTP (hTTP). Objectives To evaluate the pharmacokinetics, efficacy and safety of BAX930 in different species, by use of an extensive preclinical program. Methods The prophylactic and therapeutic efficacies of BAX930 were tested in a previously established TTP mouse model. Pharmacokinetics were evaluated after single intravenous bolus injection in mice and rats, and after repeated dosing in cynomolgus monkeys. Toxicity was assessed in rats and monkeys, safety pharmacology in monkeys, and local tolerance in rabbits. Results BAX930 was shown to be efficacious, as demonstrated by a stabilized platelet count in ADAMTS-13 knockout mice that were thrombocytopenic when treated. Prophylactic efficacy was dose-dependent and comparable with that achieved by treatment with fresh frozen plasma, the mainstay of hTTP treatment. Therapeutic efficacy was treatment interval-dependent. Safety pharmacology evaluation did not show any deleterious effects of BAX930 on cardiovascular and respiratory functions in monkeys. The compound's pharmacokinetics were similar and dose-proportional in mice, rats, and monkeys. BAX930 was well tolerated in rats, monkeys, and rabbits, even at the highest doses tested. Conclusions These results demonstrate that BAX930 has a favorable preclinical profile, and support the clinical development of rADAMTS-13 for the treatment of hTTP. © 2016 International Society on Thrombosis and Haemostasis.

Progress of the National Pediatric Free Antiretroviral Therapy program in China.

PubMed

Zhao, Yan; Sun, Xin; He, Yun; Tang, Zhirong; Peng, Guoping; Liu, Aiwen; Qiao, Xiaochun; Li, Huiqin; Chen, Zhiqiang; Dou, Zhihui; Ma, Ye; Liu, Zhongfu; Zhang, Fujie

2010-10-01

In 2003, the Chinese Government initiated a free antiretroviral therapy (ART) program focusing on adult AIDS patients. Pediatric antiretroviral (ARV) formulations were yet unavailable. It was not until July 2005, with the initiation of a two-stage program implemented by the Chinese Ministry of Health, that pediatric formulations became accessible in China. Initially, the pediatric ART program was piloted in six provinces with the highest incidences of pediatric HIV/AIDS. The pilot stage allowed the Chinese Center for Disease Control and Prevention (CCDC) to finalize entry criteria, treatment regimen, and patient monitoring and follow-up procedures. The second stage commenced at the end of 2006 when the program was scaled-up nationally. In order to guarantee treatment of pediatric patients, extensive training in the selection of appropriate ARV drug regimen and dosage was provided to doctors, often through on-site collaboration with domestic and international experts. The CCDC simultaneously established a pediatric ARV management system and a pediatric ART information system. CD4 count and other laboratory tests are being routinely performed on these pediatric patients. By the end of June 2009, 1529 pediatric patients had received ARV under the national program. However, challenges remain. Firstly, many children infected with HIV/AIDS live in rural areas where the treatment quality is hindered by the limited number of medical facilities and skilled medical workers. Secondly, much of the pediatric ARV drug supply depends on donation. An effort needs to be made by the Chinese Government to establish China's own drug procurement and supply system.

Development of a Pediatric Adverse Events Terminology.

PubMed

Gipson, Debbie S; Kirkendall, Eric S; Gumbs-Petty, Brenda; Quinn, Theresa; Steen, A; Hicks, Amanda; McMahon, Ann; Nicholas, Savian; Zhao-Wong, Anna; Taylor-Zapata, Perdita; Turner, Mark; Herreshoff, Emily; Jones, Charlotte; Davis, Jonathan M; Haber, Margaret; Hirschfeld, Steven

2017-01-01

In 2009, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Pediatric Terminology Harmonization Initiative to establish a core library of terms to facilitate the acquisition and sharing of knowledge between pediatric clinical research, practice, and safety reporting. A coalition of partners established a Pediatric Terminology Adverse Event Working Group in 2013 to develop a specific terminology relevant to international pediatric adverse event (AE) reporting. Pediatric specialists with backgrounds in clinical care, research, safety reporting, or informatics, supported by biomedical terminology experts from the National Cancer Institute's Enterprise Vocabulary Services participated. The multinational group developed a working definition of AEs and reviewed concepts (terms, synonyms, and definitions) from 16 pediatric clinical domains. The resulting AE terminology contains >1000 pediatric diseases, disorders, or clinical findings. The terms were tested for proof of concept use in 2 different settings: hospital readmissions and the NICU. The advantages of the AE terminology include ease of adoption due to integration with well-established and internationally accepted biomedical terminologies, a uniquely temporal focus on pediatric health and disease from conception through adolescence, and terms that could be used in both well- and underresourced environments. The AE terminology is available for use without restriction through the National Cancer Institute's Enterprise Vocabulary Services and is fully compatible with, and represented in, the Medical Dictionary for Regulatory Activities. The terminology is intended to mature with use, user feedback, and optimization. Copyright © 2017 by the American Academy of Pediatrics.

Reproducibility in science: improving the standard for basic and preclinical research.

PubMed

Begley, C Glenn; Ioannidis, John P A

2015-01-02

Medical and scientific advances are predicated on new knowledge that is robust and reliable and that serves as a solid foundation on which further advances can be built. In biomedical research, we are in the midst of a revolution with the generation of new data and scientific publications at a previously unprecedented rate. However, unfortunately, there is compelling evidence that the majority of these discoveries will not stand the test of time. To a large extent, this reproducibility crisis in basic and preclinical research may be as a result of failure to adhere to good scientific practice and the desperation to publish or perish. This is a multifaceted, multistakeholder problem. No single party is solely responsible, and no single solution will suffice. Here we review the reproducibility problems in basic and preclinical biomedical research, highlight some of the complexities, and discuss potential solutions that may help improve research quality and reproducibility. © 2015 American Heart Association, Inc.

Subjective memory complaints in preclinical autosomal dominant Alzheimer disease.

PubMed

Norton, Daniel J; Amariglio, Rebecca; Protas, Hillary; Chen, Kewei; Aguirre-Acevedo, Daniel C; Pulsifer, Brendan; Castrillon, Gabriel; Tirado, Victoria; Munoz, Claudia; Tariot, Pierre; Langbaum, Jessica B; Reiman, Eric M; Lopera, Francisco; Sperling, Reisa A; Quiroz, Yakeel T

2017-10-03

To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Self-reported SMC were greater in carriers than noncarriers ( p = 0.02). Study partner-based SMC did not differ between groups ( p = 0.21), but in carriers increased with age ( r = 0.66, p < 0.001) and decreased with hippocampal volume ( r = -0.35, p = 0.08). Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset. © 2017 American Academy of Neurology.

Analysis of an In-Service Examination for Core Pediatric Craniofacial Surgery Knowledge.

PubMed

Silvestre, Jason; Chang, Benjamin; Taylor, Jesse A

2016-01-01

Little is known about designing an effective residency curriculum for pediatric craniofacial surgery. This study elucidates the pediatric craniofacial curriculum of the Plastic Surgery In-Service Training Examination (PSITE) to facilitate knowledge acquisition during residency. Approximately, 6 consecutive PSITEs were reviewed for pediatric craniofacial questions (2010-2015). Subjects were categorized according to topics on the American Board of Plastic Surgery written board examination. Questions were categorized using an educational taxonomy model. Answer references were categorized by source and publication lag. Of 1174 PSITE questions, 147 tested pediatric craniofacial topics (12.5%). Questions appeared predominately in the Craniomaxillofacial section (83.0%, p < 0.001). The annual representation was stable more than 6 years (range: 10.2%-14.4%, p = 0.842). Question taxonomy favored interpretation (45.6%) and decision-making (40.8%) over recall (13.6%, p < 0.001) skills, and 41 questions had an associated image (27.9%) and most were photographic (76.7%, p < 0.001). The most frequently tested categories on the American Board of Plastic Surgery written examination content outline were craniofacial anomalies (23.5%), benign and malignant tumors (17.6%), and cleft lip and palate (12.5%). Overall, 80 unique journals were cited 304 times with a mean publication lag of 9.4 ± 10.9 years. Plastic and Reconstructive Surgery (34.5%) was the most cited journal (p < 0.001). These data may assist in designating core knowledge competency in pediatric craniofacial surgery for plastic surgery residents. A further understanding of PSITE utility for core knowledge competency in pediatric craniofacial surgery would be the focus of future work. Copyright © 2016 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.

The presence of urinary nitrites is a significant predictor of pediatric urinary tract infection susceptibility to first- and third-generation cephalosporins.

PubMed

Weisz, Dany; Seabrook, Jamie A; Lim, Rodrick K

2010-07-01

Previous studies in adults have refuted the use of nitrites as a predictor of bacterial resistance to both trimethoprim-sulfamethoxazole and cephalosporins. Some centers now consider first-line outpatient therapy with an oral third-generation cephalosporin appropriate for young children. The objective of this study was to determine if nitrite-negative pediatric urinary tract infections (UTIs) were more likely than nitrite-positive UTIs to be resistant to cephalosporins. This may enable physicians to adjust antimicrobial therapy before patients leave the Emergency Department (ED) to avoid the complications of ineffectively treated pediatric UTIs. A retrospective chart review examined, over a 9-month period, 173 pediatric patients who were diagnosed with a clinical UTI in the ED and who also had a positive urine culture and a recorded dipstick at the time of visit. The chi-squared test and Fisher's exact test were used to compare nitrite-negative vs. nitrite-positive UTIs for resistance to third-generation cephalosporins and other empiric antimicrobials. For third-generation cephalosporins, 1.4% of nitrite-positive UTIs were resistant, whereas 14.4% of nitrite-negative UTIs were resistant (95% confidence interval [CI] -0.22 to -0.05). For first-generation cephalosporins, 8.4% were resistant in the nitrite-positive group, compared to 22.2% in the nitrite-negative group (95% CI -0.24 to -0.03). The absence of urinary nitrites is a significant indicator for potential resistance to cephalosporins in pediatric UTIs. Due to low levels of pediatric UTI resistance, cephalosporins continue to represent useful empiric therapy in the general pediatric population. However, in high-risk patients, physicians may opt to alter their empiric choice of antibiotic based on the presence of urinary nitrites. Copyright 2010 Elsevier Inc. All rights reserved.

Feasibility of the music therapy assessment tool for awareness in disorders of consciousness (MATADOC) for use with pediatric populations.

PubMed

Magee, Wendy L; Ghetti, Claire M; Moyer, Alvin

2015-01-01

Measuring responsiveness to gain accurate diagnosis in populations with disorders of consciousness (DOC) is of central concern because these patients have such complex clinical presentations. Due to the uncertainty of accuracy for both behavioral and neurophysiological measures in DOC, combined assessment approaches are recommended. A number of standardized behavioral measures can be used with adults with DOC with minor to moderate reservations relating to the measures' psychometric properties and clinical applicability. However, no measures have been standardized for use with pediatric DOC populations. When adapting adult measures for children, confounding factors include developmental considerations for language-based items included in all DOC measures. Given the lack of pediatric DOC measures, there is a pressing need for measures that are sensitive to the complex clinical presentations typical of DOC and that can accommodate the developmental levels of pediatric populations. The music therapy assessment tool for awareness in disorders of consciousness (MATADOC) is a music-based measure that has been standardized for adults with DOC. Given its emphasis on non-language based sensory stimuli, it is well-suited to pediatric populations spanning developmental stages. In a pre-pilot exploratory study, we examined the clinical utility of this measure and explored trends for test-retest and inter-rater agreement as well as its performance against external reference standards. In several cases, MATADOC items in the visual and auditory domains produced outcomes suggestive of higher level functioning when compared to outcomes provided by other DOC measures. Preliminary findings suggest that the MATADOC provides a useful protocol and measure for behavioral assessment and clinical treatment planning with pediatric DOC. Further research with a larger sample is warranted to test a version of the MATADOC that is refined to meet developmental needs of pediatric DOC populations.

Feasibility of the music therapy assessment tool for awareness in disorders of consciousness (MATADOC) for use with pediatric populations

PubMed Central

Magee, Wendy L.; Ghetti, Claire M.; Moyer, Alvin

2015-01-01

Measuring responsiveness to gain accurate diagnosis in populations with disorders of consciousness (DOC) is of central concern because these patients have such complex clinical presentations. Due to the uncertainty of accuracy for both behavioral and neurophysiological measures in DOC, combined assessment approaches are recommended. A number of standardized behavioral measures can be used with adults with DOC with minor to moderate reservations relating to the measures’ psychometric properties and clinical applicability. However, no measures have been standardized for use with pediatric DOC populations. When adapting adult measures for children, confounding factors include developmental considerations for language-based items included in all DOC measures. Given the lack of pediatric DOC measures, there is a pressing need for measures that are sensitive to the complex clinical presentations typical of DOC and that can accommodate the developmental levels of pediatric populations. The music therapy assessment tool for awareness in disorders of consciousness (MATADOC) is a music-based measure that has been standardized for adults with DOC. Given its emphasis on non-language based sensory stimuli, it is well-suited to pediatric populations spanning developmental stages. In a pre-pilot exploratory study, we examined the clinical utility of this measure and explored trends for test-retest and inter-rater agreement as well as its performance against external reference standards. In several cases, MATADOC items in the visual and auditory domains produced outcomes suggestive of higher level functioning when compared to outcomes provided by other DOC measures. Preliminary findings suggest that the MATADOC provides a useful protocol and measure for behavioral assessment and clinical treatment planning with pediatric DOC. Further research with a larger sample is warranted to test a version of the MATADOC that is refined to meet developmental needs of pediatric DOC populations. PMID:26074850

Comparability of the Patient-Reported Outcomes Measurement Information System Pediatric short form symptom measures across culture: examination between Chinese and American children with cancer.

PubMed

Liu, Yanyan; Yuan, Changrong; Wang, Jichuan; Brown, Jeanne Geiger; Zhou, Fen; Zhao, Xiufang; Shen, Min; Hinds, Pamela S

2016-10-01

Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric forms measure symptoms and function of pediatric patients experiencing chronic disease by using the same measures. Comparability is one of the most important purposes of the PROMIS initiative. This study aimed to test the factorial structures of four symptom measures (i.e., Anxiety, Depression, Fatigue, and Pain Interference) in the original English and the Chinese versions and examine the measurement invariance of the measures across two cultures. Four PROMIS Pediatric measures were used to assess symptoms, respectively, in Chinese (n = 232) and American (n = 200) children and adolescents (8-17 years old) in treatment for cancer or in survivorship. The categorical confirmatory factor analysis (CCFA) model was used to examine factorial structures, and multigroup CCFA was applied to test measurement invariance of these measures between the Chinese and American samples. The CCFA models of the four PROMIS Pediatric symptom measures fit the data well for both the Chinese and American children and adolescents. Minor partial measurement invariance was identified. Factor means and factor variances of the four PROMIS measures were not significantly different between the two populations. Our results provide evidence that the four PROMIS Pediatric symptom measures have valid factorial structures and a statistical property of measurement invariance across American and Chinese children and adolescents with cancer. This means that the items of these measures were interpreted in a conceptually similar manner by two groups. They could be readily used for meaningful cross-cultural comparisons involving pediatric oncology patients in these two countries.

Optimization of a miniature Maglev ventricular assist device for pediatric circulatory support.

PubMed

Zhang, Juntao; Koert, Andrew; Gellman, Barry; Gempp, Thomas M; Dasse, Kurt A; Gilbert, Richard J; Griffith, Bartley P; Wu, Zhongjun J

2007-01-01

A miniature Maglev blood pump based on magnetically levitated bearingless technology is being developed and optimized for pediatric patients. We performed impeller optimization by characterizing the hemodynamic and hemocompatibility performances using a combined computational and experimental approach. Both three-dimensional flow features and hemolytic characteristics were analyzed using computational fluid dynamics (CFD) modeling. Hydraulic pump performances and hemolysis levels of three different impeller designs were quantified and compared numerically. Two pump prototypes were constructed from the two impeller designs and experimentally tested. Comparison of CFD predictions with experimental results showed good agreement. The optimized impeller remarkably increased overall pump hydraulic output by more than 50% over the initial design. The CFD simulation demonstrated a clean and streamlined flow field in the main flow path. The numerical results by hemolysis model indicated no significant high shear stress regions. Through the use of CFD analysis and bench-top testing, the small pediatric pump was optimized to achieve a low level of blood damage and improved hydraulic performance and efficiency. The Maglev pediatric blood pump is innovative due to its small size, very low priming volume, excellent hemodynamic and hematologic performance, and elimination of seal-related and bearing-related failures due to adoption of magnetically levitated bearingless motor technology, making it ideal for pediatric applications.

Formulation design of oral pediatric Acetazolamide suspension: dose uniformity and physico-chemical stability study.

PubMed

Santoveña, Ana; Suárez-González, Javier; Martín-Rodríguez, Cristina; Fariña, José B

2017-03-01

The formulation of an active pharmaceutical ingredient (API) as oral solution or suspension in pediatrics is a habitual practice, due to the non-existence of many commercialized medicines in pediatric doses. It is also the simplest way to prepare and administer them to this vulnerable population. The design of a formulation that assures the dose and the system stability depends on the physico-chemical properties of the API. In this study, we formulate a class IV API, Acetazolamide (AZM) as suspension for oral administration to pediatric population. The suspension must comply attributes of quality, safety and efficacy for this route of administration. We use simple compounding procedures, as well as fewer pure excipients, as recommended for children. Mass and uniformity content assays and physical and chemical stability studies were performed. To quantify the API an UPLC method was used. We verified the physico-chemical stability of the suspensions and that they passed the mass test of the European Pharmacopeia (EP), but not the dose uniformity test. This reveals that AZM must be formulated as liquid forms with a more complex system of excipients (not usually indicated in pediatrics), or otherwise solid forms capable of assuring uniformity of mass and dose for every dosage unit.

The effect of a curfew on pediatric out-of-hospital EMS responses.

PubMed

Weiss, S J; Couk, J; Nobile, M; Ernst, A A; Johnson, W

1998-01-01

The purpose of a curfew is to decrease the amount of crime inflicted on minors during the late hours of the night. On June 1, 1994, a city curfew was instituted in New Orleans, requiring all persons 17 years of age or younger to be off the streets from 9 PM to 6 AM Sunday through Thursday, and from 11 PM to 6 AM on Friday and Saturday. This study evaluated the effect of the curfew on emergency medical services (EMS) transports for patients who were 17 years old or younger (pediatric). Data from all pediatric transports were included from the months before (5/94) and after (6/94) the institution of the curfew, and from the same two months one year earlier (5/93 and 6/93). A chi-square test was used to evaluate comparisons. The city EMS transports 48,000 patients per year in a one-tiered system (paramedic only) that acts as the sole provider of emergency EMS transport in the city. Approximately 10% of all transports are pediatric, and 40% of the pediatric transports are for trauma. A total of 1,642 transports were found that fit the inclusion criteria. In May 1993, there were 415 total pediatric transports; 234 were pediatric trauma. In June 1993, there were 406 total pediatric transports; 250 were pediatric trauma. In May 1994, there were 447 total pediatric runs; 243 were pediatric trauma. During the postcurfew month, June 1994, there were a significant decrease in pediatric transports to 370 (p < 0.01) and a significant decrease in pediatric trauma transport to 189 (p < 0.01). The institution of a curfew may lead to a drop in pediatric EMS runs during curfew hours. Another value of the curfew may be in the secondary effects of the curfew in preventing childhood injury during noncurfew hours.

[Preclinical study of noopept toxicity].

PubMed

Kovalenko, L P; Smol'nikova, N M; Alekseeva, S V; Nemova, E P; Sorokina, A V; Miramedova, M G; Kurapova, S P; Sidorina, E I; Kulakova, A V; Daugel'-Dauge, N O

2002-01-01

Within the framework of a preclinical investigation, the new nootrope drug noopept (N-phenyl-acetyl-L-propyl-glycine ethylate) was tested for chronic toxicity upon peroral administration in a dose of 10 or 100 mg/kg over 6 months in both male and female rabbits. The results of observations showed that noopept administered in this dose range induced no irreversible pathologic changes in the organs and systems studied and exhibited no allergenic, immunotoxic, and mutagen activity. The drug affected neither the generative function nor the antenatal or postnatal progeny development. Noopept produced a dose-dependent suppression of inflammation reaction to concanavalin A and stimulated the cellular and humoral immune response in mice.

T-cell receptor gene therapy: critical parameters for clinical success.

PubMed

Linnemann, Carsten; Schumacher, Ton N M; Bendle, Gavin M

2011-09-01

T-cell receptor (TCR) gene therapy aims to induce immune reactivity against tumors by introducing genes encoding a tumor-reactive TCR into patient T cells. This approach has been extensively tested in preclinical mouse models, and initial clinical trials have demonstrated the feasibility and potential of TCR gene therapy as a cancer treatment. However, data obtained from preclinical and clinical studies suggest that both the therapeutic efficacy and the safety of TCR gene therapy can be and needs to be further enhanced. This review highlights those strategies that can be followed to develop TCR gene therapy into a clinically relevant treatment option for cancer patients.

Management of Leigh syndrome: Current status and new insights.

PubMed

Chen, L; Cui, Y; Jiang, D; Ma, C Y; Tse, H-F; Hwu, W-L; Lian, Q

2018-06-01

Leigh syndrome (LS) is an inherited mitochondrial encephalopathy associated with gene mutations of oxidative phosphorylation pathway that result in early disability and death in affected young children. Currently, LS is incurable and unresponsive to many treatments, although some case reports indicate that supplements can improve the condition. Many novel therapies are being continuously tested in pre-clinical studies. In this review, we summarize the genetic basis of LS, current treatment, pre-clinical studies in animal models and the management of other mitochondrial diseases. Future therapeutical strategies and challenges are also discussed. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Laboratory animals as surrogate models of human obesity

PubMed Central

Nilsson, Cecilia; Raun, Kirsten; Yan, Fei-fei; Larsen, Marianne O; Tang-Christensen, Mads

2012-01-01

Obesity and obesity-related metabolic diseases represent a growing socioeconomic problem throughout the world. Great emphasis has been put on establishing treatments for this condition, including pharmacological intervention. However, there are many obstacles and pitfalls in the development process from pre-clinical research to the pharmacy counter, and there is no certainty that what has been observed pre-clinically will translate into an improvement in human health. Hence, it is important to test potential new drugs in a valid translational model early in their development. In the current mini-review, a number of monogenetic and polygenic models of obesity will be discussed in view of their translational character. PMID:22301857

Animal Testing

NASA Astrophysics Data System (ADS)

Moretto, Johnny; Chauffert, Bruno; Bouyer, Florence

The development of a new anticancer drug is a long, complex and multistep process which is supervised by regulatory authorities from the different countries all around the world [1]. Application of a new drug for admission to the market is supported by preclinical and clinical data, both including the determination of pharmacodynamics, toxicity, antitumour activity, therapeutic index, etc. As preclinical studies are associated with high cost, optimization of animal experiments is crucial for the overall development of a new anticancer agent. Moreover, in vivo efficacy studies remain a determinant panel for advancement of agents to human trials and thus, require cautious design and interpretation from experimental and ethical point of views.

Test de Evaluacion de Conocimientos Medicos-CIIPME (Test of Evaluation of Medical Knowledge-CIIPME). Publication No. 42.

ERIC Educational Resources Information Center

Alfici, C.; And Others

The purpose of this research is to build a test for the evaluation of the knowledge needed by medical students before entering clinical courses in medical school. The criterion for this was provided by teachers in both the pre-clinical and clinical subjects. The Pilot instrument consisted of 335 items that covered 8 sections. Each one of these…

Retention of knowledge and skills in pediatric basic life support amongst pediatricians.

PubMed

Binkhorst, Mathijs; Coopmans, Michelle; Draaisma, Jos M T; Bot, Petra; Hogeveen, Marije

2018-05-07

Retention of resuscitation skills is usually assessed at a predefined moment, which enables participants to prepare themselves, possibly introducing bias. In this multicenter study, we evaluated the retention of knowledge and skills in pediatric basic life support (PBLS) amongst 58 pediatricians and pediatric residents with an unannounced examination. Practical PBLS skills were assessed with a validated scoring instrument, theoretical knowledge with a 10-item multiple-choice test (MCQ). Participants self-assessed their PBLS capabilities using five-point Likert scales. Background data were collected with a questionnaire. Of our participants, 21% passed the practical PBLS exam: 29% failed on compressions/ventilations, 31% on other parts of the algorithm, 19% on both. Sixty-nine percent passed the theoretical test. Participants who more recently completed a PBLS course performed significantly better on the MCQ (p = 0.03). This association was less clear-cut for performance on the practical exam (p = 0.11). Older, attending pediatricians with more years of experience in pediatrics performed less well than their younger colleagues (p < 0.05). Fifty-one percent of the participants considered themselves competent in PBLS. No correlation was found between self-assessed PBLS capabilities and actual performance on the practical exam (p = 0.25). Retention of PBLS skills appears to be poor amongst pediatricians and residents, whereas PBLS knowledge is retained somewhat better. What is Known: • Pediatricians and pediatric residents are not always competent in pediatric basic life support (PBLS) in daily practice. Poor retention of skills supposedly accounts for this incompetence. Without regular exposure, resuscitation skills usually deteriorate within 3 to 6 months after training. • Examination of resuscitation skills usually takes place after training. Also, in most studies evaluating retention of skills, participants are tested at a predefined moment. Inasmuch as participants are able to prepare themselves, these assessments do not reflect the ad hoc resuscitation capabilities of pediatricians and residents. What is New: • In this study, pediatricians and pediatric residents had to complete an unannounced PBLS exam at variable time intervals from last certification. Retention of PBLS skills was rather poor (pass rate 21%). • The PBLS skills of older, attending pediatricians with many working years in pediatrics appeared to be inferior to those of their younger colleagues.

Development and Preliminary Face and Content Validation of the “Which Health Approaches and Treatments Are You Using?” (WHAT) Questionnaires Assessing Complementary and Alternative Medicine Use in Pediatric Rheumatology

PubMed Central

Toupin April, Karine; Stinson, Jennifer; Boon, Heather; Duffy, Ciarán M.; Huber, Adam M.; Gibbon, Michele; Descarreaux, Martin; Spiegel, Lynn; Vohra, Sunita; Tugwell, Peter

2016-01-01

Objective Complementary and alternative medicine (CAM) is commonly used by children with juvenile idiopathic arthritis (JIA), yet no validated questionnaires assess that use. The objective of this study was to develop child self- and parent proxy-report questionnaires assessing CAM use and to determine the face and content validity of the “Which Health Approaches and Treatments are you using?” (WHAT) questionnaires in pediatric rheumatology. Methods A sequential phased mixed methods approach was used to develop the questionnaires. A Delphi Survey of 126 experts followed by an interdisciplinary consensus conference of 14 stakeholders in CAM, general pediatrics and pediatric rheumatology was held to develop consensus on the content of the questionnaires using a nominal group technique. To determine face and content validity of the questionnaires, two groups, including (a) a purposive sample of 22 children with JIA 8 to 18 years and their parents from the Children’s Hospital of Eastern Ontario and the Hospital for Sick Children, and (b) 21 Canadian pediatric rheumatology experts, participated in interviews. Participants were independently asked about the goal, understandability and comprehensiveness of the WHAT questionnaires, as well as the relevance of items. Results Consensus was reached on 17 items of the WHAT questionnaires. The domains found to be relevant were child’s CAM use, factors associated with CAM use, perceived impact of CAM use, and communication about CAM. A total of 15 items in the parent proxy-report questionnaire and 13 items in the child report questionnaire showed adequate content validity. Conclusions Consensus was reached by experts on the content of a pediatric CAM questionnaire. Face and content validity testing and modifications made to the WHAT questionnaires have helped ensure adequate preliminary validity for use in pediatric rheumatology. This constitutes the basis for further testing of these questionnaires in pediatric rheumatology and for adaptation to other chronic diseases. PMID:26964088

Development and Preliminary Face and Content Validation of the "Which Health Approaches and Treatments Are You Using?" (WHAT) Questionnaires Assessing Complementary and Alternative Medicine Use in Pediatric Rheumatology.

PubMed

Toupin April, Karine; Stinson, Jennifer; Boon, Heather; Duffy, Ciarán M; Huber, Adam M; Gibbon, Michele; Descarreaux, Martin; Spiegel, Lynn; Vohra, Sunita; Tugwell, Peter

2016-01-01

Complementary and alternative medicine (CAM) is commonly used by children with juvenile idiopathic arthritis (JIA), yet no validated questionnaires assess that use. The objective of this study was to develop child self- and parent proxy-report questionnaires assessing CAM use and to determine the face and content validity of the "Which Health Approaches and Treatments are you using?" (WHAT) questionnaires in pediatric rheumatology. A sequential phased mixed methods approach was used to develop the questionnaires. A Delphi Survey of 126 experts followed by an interdisciplinary consensus conference of 14 stakeholders in CAM, general pediatrics and pediatric rheumatology was held to develop consensus on the content of the questionnaires using a nominal group technique. To determine face and content validity of the questionnaires, two groups, including (a) a purposive sample of 22 children with JIA 8 to 18 years and their parents from the Children's Hospital of Eastern Ontario and the Hospital for Sick Children, and (b) 21 Canadian pediatric rheumatology experts, participated in interviews. Participants were independently asked about the goal, understandability and comprehensiveness of the WHAT questionnaires, as well as the relevance of items. Consensus was reached on 17 items of the WHAT questionnaires. The domains found to be relevant were child's CAM use, factors associated with CAM use, perceived impact of CAM use, and communication about CAM. A total of 15 items in the parent proxy-report questionnaire and 13 items in the child report questionnaire showed adequate content validity. Consensus was reached by experts on the content of a pediatric CAM questionnaire. Face and content validity testing and modifications made to the WHAT questionnaires have helped ensure adequate preliminary validity for use in pediatric rheumatology. This constitutes the basis for further testing of these questionnaires in pediatric rheumatology and for adaptation to other chronic diseases.

Graded aerobic treadmill testing in pediatric sports-related concussion: safety, clinical use, and patient outcomes.

PubMed

Cordingley, Dean; Girardin, Richard; Reimer, Karen; Ritchie, Lesley; Leiter, Jeff; Russell, Kelly; Ellis, Michael J

2016-12-01

OBJECTIVE The objectives of this study were 2-fold: 1) to evaluate the safety, tolerability, and clinical use of graded aerobic treadmill testing in pediatric patients with sports-related concussion (SRC), and 2) to evaluate the clinical outcomes of treatment with a submaximal aerobic exercise program in patients with physiological post-concussion disorder (PCD). METHODS The authors conducted a retrospective chart review of pediatric patients (age < 20 years) with SRC who were referred to a multidisciplinary pediatric concussion program and underwent graded aerobic treadmill testing between October 9, 2014, and February 11, 2016. Clinical assessments were carried out by a single neurosurgeon and included clinical history taking, physical examination, and recording specific patient-reported concussion-related symptoms using the Post-Concussion Symptom Scale (PCSS). Graded aerobic treadmill testing using a modified Balke protocol for incremental increases in intensity was used as a diagnostic tool to assess physiological recovery, classify post-concussion syndrome (PCS) subtype, and reassess patients following treatment. Patients with a symptom-limited threshold on treadmill testing (physiological PCD) were treated with an individually tailored submaximal exercise prescription and multidisciplinary targeted therapies. RESULTS One hundred six patients (mean age 15.1 years, range 11-19 years) with SRC underwent a total of 141 treadmill tests. There were no serious complications related to treadmill testing in this study. Overall, 138 (97.9%) of 141 tests were well tolerated and contributed valuable clinical information. Treadmill testing confirmed physiological recovery in 63 (96.9%) of 65 patients tested, allowing successful return to play in 61 (93.8%). Treadmill testing was used to diagnose physiological PCD in 58 patients and cervicogenic PCD in 1 patient. Of the 41 patients with physiological PCD who had complete follow-up and were treated with tailored submaximal exercise prescription, 37 (90.2%) were classified as clinically improved and 33 (80.5%) successfully returned to sporting activities. Patients who did not respond or experienced an incomplete response to submaximal aerobic exercise treatment included 7 patients with migraine headaches and 1 patient with a postinjury psychiatric disorder. CONCLUSIONS Graded aerobic treadmill testing is a safe, tolerable, and clinically valuable tool that can assist in the evaluation and management of pediatric SRC. Future research is needed to confirm the clinical value of this tool in return-to-play decision making. Studies are also needed to understand the pathophysiology of physiological PCD and the effects of targeted treatment.

A computer model of the pediatric circulatory system for testing pediatric assist devices.

PubMed

Giridharan, Guruprasad A; Koenig, Steven C; Mitchell, Michael; Gartner, Mark; Pantalos, George M

2007-01-01

Lumped parameter computer models of the pediatric circulatory systems for 1- and 4-year-olds were developed to predict hemodynamic responses to mechanical circulatory support devices. Model parameters, including resistance, compliance and volume, were adjusted to match hemodynamic pressure and flow waveforms, pressure-volume loops, percent systole, and heart rate of pediatric patients (n = 6) with normal ventricles. Left ventricular failure was modeled by adjusting the time-varying compliance curve of the left heart to produce aortic pressures and cardiac outputs consistent with those observed clinically. Models of pediatric continuous flow (CF) and pulsatile flow (PF) ventricular assist devices (VAD) and intraaortic balloon pump (IABP) were developed and integrated into the heart failure pediatric circulatory system models. Computer simulations were conducted to predict acute hemodynamic responses to PF and CF VAD operating at 50%, 75% and 100% support and 2.5 and 5 ml IABP operating at 1:1 and 1:2 support modes. The computer model of the pediatric circulation matched the human pediatric hemodynamic waveform morphology to within 90% and cardiac function parameters with 95% accuracy. The computer model predicted PF VAD and IABP restore aortic pressure pulsatility and variation in end-systolic and end-diastolic volume, but diminish with increasing CF VAD support.

Choosing Wisely: the American College of Rheumatology's Top 5 for pediatric rheumatology.

PubMed

Rouster-Stevens, Kelly A; Ardoin, Stacy P; Cooper, Ashley M; Becker, Mara L; Dragone, Leonard L; Huttenlocher, Anna; Jones, Karla B; Kolba, Karen S; Moorthy, L Nandini; Nigrovic, Peter A; Stinson, Jennifer N; Ferguson, Polly J

2014-05-01

To create a pediatric rheumatology Top 5 list as part of the American Board of Internal Medicine Foundation's Choosing Wisely campaign. Delphi surveys of a core group of representative pediatric rheumatology providers from across North America generated candidate Top 5 items. Items with high content agreement and perceived to be of prevalent use and of high impact were included in a survey of all American College of Rheumatology (ACR) members who identified themselves as providing care to pediatric patients. Items with the highest ratings were subjected to literature review and further evaluation. A total of 121 candidate items were proposed in the initial Delphi survey and were reduced to 28 items in subsequent surveys. These 28 items were sent to 1,198 rheumatology providers who care for pediatric patients, and 397 (33%) responded. Based upon survey data and literature review, the Top 5 items were identified. These items focused on testing for antinuclear antibodies, autoantibody panels, Lyme disease, methotrexate toxicity monitoring, and use of routine radiographs. The ACR pediatric rheumatology Top 5 is one of the first pediatric subspecialty-specific Choosing Wisely Top 5 lists and provides an opportunity for patients and providers to discuss appropriate use of health care in pediatric rheumatology. Copyright © 2014 by the American College of Rheumatology.

Pediatrics Residents' Confidence and Performance Following a Longitudinal Quality Improvement Curriculum.

PubMed

Courtlandt, Cheryl; Noonan, Laura; Koricke, Maureen Walsh; Zeskind, Philip Sanford; Mabus, Sarah; Feld, Leonard

2016-02-01

Quality improvement (QI) training is an integral part of residents' education. Understanding the educational value of a QI curriculum facilitates understanding of its impact. The purpose of this study was to evaluate the effects of a longitudinal QI curriculum on pediatrics residents' confidence and competence in the acquisition and application of QI knowledge and skills. Three successive cohorts of pediatrics residents (N = 36) participated in a longitudinal curriculum designed to increase resident confidence in QI knowledge and skills. Key components were a succession of progressive experiential projects, QI coaching, and resident team membership culminating in leadership of the project. Residents completed precurricular and postcurricular surveys and demonstrated QI competence by performance on the pediatric QI assessment scenario. Residents participating in the Center for Advancing Pediatric Excellence QI curriculum showed significant increases in pre-post measures of confidence in QI knowledge and skills. Coaching and team leadership were ranked by resident participants as having the most educational value among curriculum components. A pediatric QI assessment scenario, which correlated with resident-perceived confidence in acquisition of QI skills but not QI knowledge, is a tool available to test pediatrics residents' QI knowledge. A 3-year longitudinal, multimodal, experiential QI curriculum increased pediatrics residents' confidence in QI knowledge and skills, was feasible with faculty support, and was well-accepted by residents.

Preclinical Alzheimer's Disease: Implications for Refinement of the Concept.

PubMed

Vos, Stephanie J B; Visser, Pieter Jelle

2018-05-23

Increasing interest in clinical trials and clinical research settings to identify Alzheimer's disease (AD) in the earliest stages of the disease has led to the concept of preclinical AD. Individuals with preclinical AD have AD pathology without clinical symptoms yet. Accumulating evidence has shown that biomarkers can identify preclinical AD and that preclinical AD is associated with a poor clinical outcome. Little is known yet about the role of vascular and lifestyle risk factors in the development of preclinical AD. In order to better understand preclinical AD pathology and clinical progression rates, there is a need to refine the concept of preclinical AD. This will be of great value for advancements in future research, clinical trials, and eventually clinical practice.

PCR examination of bronchoalveolar lavage samples is a useful tool in pre-clinical diagnosis of ovine pulmonary adenocarcinoma (Jaagsiekte).

PubMed

Voigt, K; Brügmann, M; Huber, K; Dewar, P; Cousens, C; Hall, M; Sharp, J M; Ganter, M

2007-12-01

Ovine pulmonary adenocarcinoma (OPA) is a contagious lung tumour of sheep caused by Jaagsiekte sheep retrovirus (JSRV). The disease is a particular problem in flocks in many parts of the world. The aim of the study was to assess screening methods for individual animals as a prelude to future eradication trials. Results of histological examination were used as the standard to evaluate the relative sensitivity and specificity of an established heminested polymerase chain reaction (PCR) test for JSRV proviral DNA from blood and bronchoalveolar lavage (BAL) samples. PCR results from tissue samples are included as control data. PCR testing of blood samples was found to have an estimated sensitivity of only 10% (95% confidence interval (CI) 3-20) while the sensitivity of the PCR test on BAL samples was 89% (CI 79-96) in comparison to the results of histological examination. We conclude that PCR testing of BAL samples is an effective confirmatory test for sheep with suspected clinical OPA. It is also a useful tool for the pre-clinical identification of individual infected sheep within an infected flock and therefore may prove beneficial in future control or eradication programmes.

RSV antibody test

MedlinePlus

Respiratory syncytial virus antibody test; RSV serology; Bronchiolitis - RSV test ... Crowe JE. Respiratory syncytial virus. In: Kliegman RM, Stanton BF, St. Geme JW, Schor NF, eds. Nelson Textbook of Pediatrics . 20th ...

Epidemiology of pediatric skin diseases in the mid-western Anatolian region of Turkey.

PubMed

Kacar, Seval Dogruk; Ozuguz, Pinar; Polat, Serap; Manav, Vildan; Bukulmez, Aysegul; Karaca, Semsettin

2014-10-01

The field of pediatric dermatology has gained importance with the increment of pediatric patients and the discrepancy of their skin diseases with the adult versions. We aimed to describe frequency and distribution of pediatric skin diseases, and the diagnostic procedures and treatments prescribed. Cross-sectional epidemiological study. We collected data about diagnostic patterns, diagnostic methods and treatment modalities in pediatric dermatology outpatient clinic visits over 18 months. Infectious diseases (27.9%) and among them viral warts (17.5%) were the most prevalent diagnoses, followed by acne-acneiform diseases (19.9%) and allergic diseases (14.5%). Among the diagnostic tests histopathology was required in 5.2%, usually to diagnose inflammatory and tumoral lesions. Topical treatments (49.3%) were followed by systemic treatments (32.4%) in majority of cases. Viral warts were among the most common dermatoses, and preventive measures for HPV transmission should become important part of public health efforts in children.

Design and evaluation of a disaster preparedness logistics tool.

PubMed

Neches, Robert; Ryutov, Tatyana; Kichkaylo, Tatiana; Burke, Rita V; Claudius, Ilene A; Upperman, Jeffrey S

2009-01-01

The purpose of this article is to describe the development and testing of the Pediatric Emergency Decision Support System (PEDSS), a dynamic tool for pediatric victim disaster planning. This is a descriptive article outlining an innovative automated approach to pediatric decision support and disaster planning. Disaster Resource Centers and umbrella hospitals in Los Angeles County. The authors use a model set of hypothetical patients for our pediatric disaster planning approach. The authors developed the PEDSS software to accomplish two goals: (a) core that supports user interaction and data management requirements (e.g., accessing demographic information about a healthcare facility's catchment area) and (b) set of modules each addressing a critical disaster preparation issue. The authors believe the PEDSS tool will help hospital disaster response personnel produce and maintain disaster response plans that apply best practice pediatric recommendations to their particular local conditions and requirements.

Prehospital Care for the Adult and Pediatric Seizure Patient: Current Evidence-based Recommendations.

PubMed

Silverman, Eric C; Sporer, Karl A; Lemieux, Justin M; Brown, John F; Koenig, Kristi L; Gausche-Hill, Marianne; Rudnick, Eric M; Salvucci, Angelo A; Gilbert, Greg H

2017-04-01

We sought to develop evidence-based recommendations for the prehospital evaluation and treatment of adult and pediatric patients with a seizure and to compare these recommendations against the current protocol used by the 33 emergency medical services (EMS) agencies in California. We performed a review of the evidence in the prehospital treatment of patients with a seizure, and then compared the seizure protocols of each of the 33 EMS agencies for consistency with these recommendations. We analyzed the type and route of medication administered, number of additional rescue doses permitted, and requirements for glucose testing prior to medication. The treatment for eclampsia and seizures in pediatric patients were analyzed separately. Protocols across EMS Agencies in California varied widely. We identified multiple drugs, dosages, routes of administration, re-dosing instructions, and requirement for blood glucose testing prior to medication delivery. Blood glucose testing prior to benzodiazepine administration is required by 61% (20/33) of agencies for adult patients and 76% (25/33) for pediatric patients. All agencies have protocols for giving intramuscular benzodiazepines and 76% (25/33) have protocols for intranasal benzodiazepines. Intramuscular midazolam dosages ranged from 2 to 10 mg per single adult dose, 2 to 8 mg per single pediatric dose, and 0.1 to 0.2 mg/kg as a weight-based dose. Intranasal midazolam dosages ranged from 2 to 10 mg per single adult or pediatric dose, and 0.1 to 0.2 mg/kg as a weight-based dose. Intravenous/intrasosseous midazolam dosages ranged from 1 to 6 mg per single adult dose, 1 to 5 mg per single pediatric dose, and 0.05 to 0.1 mg/kg as a weight-based dose. Eclampsia is specifically addressed by 85% (28/33) of agencies. Forty-two percent (14/33) have a protocol for administering magnesium sulfate, with intravenous dosages ranging from 2 to 6 mg, and 58% (19/33) allow benzodiazepines to be administered. Protocols for a patient with a seizure, including eclampsia and febrile seizures, vary widely across California. These recommendations for the prehospital diagnosis and treatment of seizures may be useful for EMS medical directors tasked with creating and revising these protocols.

Effects of Within-Talker Variability on Speech Intelligibility in Mandarin-Speaking Adult and Pediatric Cochlear Implant Patients

PubMed Central

Su, Qiaotong; Galvin, John J.; Zhang, Guoping; Li, Yongxin

2016-01-01

Cochlear implant (CI) speech performance is typically evaluated using well-enunciated speech produced at a normal rate by a single talker. CI users often have greater difficulty with variations in speech production encountered in everyday listening. Within a single talker, speaking rate, amplitude, duration, and voice pitch information may be quite variable, depending on the production context. The coarse spectral resolution afforded by the CI limits perception of voice pitch, which is an important cue for speech prosody and for tonal languages such as Mandarin Chinese. In this study, sentence recognition from the Mandarin speech perception database was measured in adult and pediatric Mandarin-speaking CI listeners for a variety of speaking styles: voiced speech produced at slow, normal, and fast speaking rates; whispered speech; voiced emotional speech; and voiced shouted speech. Recognition of Mandarin Hearing in Noise Test sentences was also measured. Results showed that performance was significantly poorer with whispered speech relative to the other speaking styles and that performance was significantly better with slow speech than with fast or emotional speech. Results also showed that adult and pediatric performance was significantly poorer with Mandarin Hearing in Noise Test than with Mandarin speech perception sentences at the normal rate. The results suggest that adult and pediatric Mandarin-speaking CI patients are highly susceptible to whispered speech, due to the lack of lexically important voice pitch cues and perhaps other qualities associated with whispered speech. The results also suggest that test materials may contribute to differences in performance observed between adult and pediatric CI users. PMID:27363714

Online education improves pediatric residents' understanding of atopic dermatitis.

PubMed

Craddock, Megan F; Blondin, Heather M; Youssef, Molly J; Tollefson, Megha M; Hill, Lauren F; Hanson, Janice L; Bruckner, Anna L

2018-01-01

Pediatricians manage skin conditions such as atopic dermatitis (AD) but report that their dermatologic training is inadequate. Online modules may enhance medical education when sufficient didactic or clinical teaching experiences are lacking. We assessed whether an online module about AD improved pediatric residents' knowledge and changed their clinical management of AD. Target and control cohorts of pediatric residents from two institutions were recruited. Target subjects took a 30-question test about AD early in their residency, reviewed the online module, and repeated the test 6 months and 1 year later. The control subjects, who had 1 year of clinical experience but had not reviewed the online module, also took the test. The mean percentage of correct answers was calculated and compared using two-sided, two-sample independent t tests and repeated-measures analysis of variance. For a subset of participants, clinical documentation from AD encounters was reviewed and 13 practice behaviors were compared using the Fisher exact test. Twenty-five subjects in the target cohort and 29 subjects in the control cohort completed the study. The target cohort improved from 18.0 ± 3.2 to 23.4 ± 3.4 correctly answered questions over 1 year (P < .001). This final value was greater than that of the control cohort (20.7 ± 4.5; P = .01). Meaningful differences in practice behaviors were not seen. Pediatric residents who reviewed an online module about AD demonstrated statistically significant improvement in disease-specific knowledge over time and had statistically significantly higher scores than controls. Online dermatology education may effectively supplement traditional clinical teaching. © 2017 Wiley Periodicals, Inc.

Intraventricular Delivery of Engineered Oncolytic Herpes Simplex Virotherapy to Treat Localized and Metastatic Pediatric Brain Tumors

DTIC Science & Technology

2016-08-01

medulloblastoma (MB) to oHSV. Patient derived MB xenograft D341-luc, which is luciferase enabled, was used for the experiment. Athymic nude mice received...ability of G207 and M002 to kill another patient-derived pediatric group Page 10 3 MB xenograft D425-luc. Additionally, we will begin to test...from pediatric MB xenografts D425 and D341 (no identifiable information will be accessible to the research team by any means) and in Trp53-/- Ptch

A novel semi-automatic snake robot for natural orifice transluminal endoscopic surgery: preclinical tests in animal and human cadaver models (with video).

PubMed

Son, Jaebum; Cho, Chang Nho; Kim, Kwang Gi; Chang, Tae Young; Jung, Hyunchul; Kim, Sung Chun; Kim, Min-Tae; Yang, Nari; Kim, Tae-Yun; Sohn, Dae Kyung

2015-06-01

Natural orifice transluminal endoscopic surgery (NOTES) is an emerging surgical technique. We aimed to design, create, and evaluate a new semi-automatic snake robot for NOTES. The snake robot employs the characteristics of both a manual endoscope and a multi-segment snake robot. This robot is inserted and retracted manually, like a classical endoscope, while its shape is controlled using embedded robot technology. The feasibility of a prototype robot for NOTES was evaluated in animals and human cadavers. The transverse stiffness and maneuverability of the snake robot appeared satisfactory. It could be advanced through the anus as far as the peritoneal cavity without any injury to adjacent organs. Preclinical tests showed that the device could navigate the peritoneal cavity. The snake robot has advantages of high transverse force and intuitive control. This new robot may be clinically superior to conventional tools for transanal NOTES.

The Affordable Care Act and health insurance exchanges: effects on the pediatric dental benefit.

PubMed

Orynich, C Ashley; Casamassimo, Paul S; Seale, N Sue; Reggiardo, Paul; Litch, C Scott

2015-01-01

To examine the relationship between state health insurance Exchange selection and pediatric dental benefit design, regulation and cost. Medical and dental plans were analyzed across three types of state health insurance Exchanges: State-based (SB), State-partnered (SP), and Federally-facilitated (FF). Cost-analysis was completed for 10,427 insurance plans, and health policy expert interviews were conducted. One-way ANOVA compared the cost-sharing structure of stand-alone dental plans (SADP). T-test statistics compared differences in average total monthly pediatric premium costs. No causal relationships were identified between Exchange selection and the pediatric dental benefit's design, regulation or cost. Pediatric medical and dental coverage offered through the embedded plan design exhibited comparable average total monthly premium costs to aggregate cost estimates for the separately purchased SADP and traditional medical plan (P=0.11). Plan designs and regulatory policies demonstrated greater correlation between the SP and FF Exchanges, as compared to the SB Exchange. Parameters defining the pediatric dental benefit are complex and vary across states. Each state Exchange was subject to barriers in improving the quality of the pediatric dental benefit due to a lack of defined, standardized policy parameters and further legislative maturation is required.

Pediatric Bipolar Disorder versus Severe Mood Dysregulation: Risk for Manic Episodes on Follow-Up

ERIC Educational Resources Information Center

Stringaris, Argyris; Baroni, Argelinda; Haimm, Caroline; Brotman, Melissa; Lowe, Catherine H.; Myers, Frances; Rustgi, Eileen; Wheeler, Wanda; Kayser, Reilly; Towbin, Kenneth; Leibenluft, Ellen

2010-01-01

Objective: An important question in pediatric bipolar research is whether marked nonepisodic irritability is a manifestation of bipolar disorder in youth. This study tests the hypothesis that youth with severe mood dysregulation (SMD), a category created for the purpose of studying children presenting with severe nonepisodic irritability, will be…

Types of pediatric diabetes mellitus defined by anti-islet autoimmunity and random C-peptide at diagnosis

USDA-ARS?s Scientific Manuscript database

The objective of this study was to test the hypothesis that anti-islet autoantibody expression and random serum C-peptide obtained at diagnosis define phenotypes of pediatric diabetes with distinct clinical features. We analyzed 607 children aged <19 yr consecutively diagnosed with diabetes after ex...

Commentary: pediatric eHealth interventions: common challenges during development, implementation, and dissemination.

PubMed

Wu, Yelena P; Steele, Ric G; Connelly, Mark A; Palermo, Tonya M; Ritterband, Lee M

2014-07-01

To provide an overview of common challenges that pediatric eHealth researchers may encounter when planning, developing, testing, and disseminating eHealth interventions along with proposed solutions for addressing these challenges. The article draws on the existing eHealth literature and the authors' collective experience in pediatric eHealth research. The challenges associated with eHealth interventions and their proposed solutions are multifaceted and cut across a number of areas from eHealth program development through dissemination. Collaboration with a range of individuals (e.g., multidisciplinary colleagues, commercial entities, primary stakeholders) is the key to eHealth intervention success. To ensure adequate resources for design, development, and planning for sustainability, a number of public and private sources of funding are available. A study design that addresses ethical concerns and security issues is critical to ensure scientific integrity and intervention dissemination. Table I summarizes key issues to consider during eHealth intervention development, testing, and dissemination. © The Author 2014. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Evaluation of a Test Battery to Assess Perception of Music in Children With Cochlear Implants.

PubMed

Roy, Alexis T; Scattergood-Keepper, Lindsay; Carver, Courtney; Jiradejvong, Patpong; Butler, Caty; Limb, Charles J

2014-06-01

A number of studies have investigated music perception in adult cochlear implant (CI) users. However, little is known about how pediatric CI users perceive and process music, in part because suitable methods for assessing music perception in this population are lacking. Therefore, we developed the Music in Children With Cochlear Implants (MCCI) battery to assess music perception in pediatric CI users younger than 9 years. To pilot test the MCCI on a group of pediatric CI users to determine its feasibility for measuring music perception and to compare performance of CI users with that of normal-hearing (NH) control participants. The pilot test was conducted in an academic tertiary care center. The MCCI evaluated rhythm, pitch, melody, harmony, and timbre perception. For each section, 10 pediatric CI users and 10 NH controls were presented with a pair of stimuli that possibly varied along a single musical element (eg, rhythm). Participants were required to indicate whether the stimuli in the pair were the same or different. Administration of the MCCI. Percentage correct on each section of the MCCI and the aggregate score of all sections by group. The MCCI provided a basic characterization of musical perceptual abilities. In the aggregate, NH controls significantly outperformed CI users in music perception (mean [SD] accuracy for CI users vs NH controls: rhythm, 73% [20%] vs 78% [20%]; pitch, 84% [12%] vs 91% [13%]; melody, 65% [16%] vs 75% [18%]; harmony, 74% [13%] vs 75% [14%]; and timbre, 80% [17%] vs 90% [12%]; repeated-measures analysis of variance, F1,17 = 9.3; P < .01). Despite obtaining lower accuracies than NH controls, however, the CI users achieved above-chance accuracy in all sections of the MCCI (1-sample t test, P < .01), including pitch-based sections that are traditionally difficult for CI users. These results suggest that CI users can make use of temporal and spectral cues to discriminate between musical stimuli, although not to the extent of their NH peers. The MCCI provided an efficient and user-friendly assessment of music perception in pediatric CI users. This test battery may serve as a valuable tool to evaluate music perceptual abilities of pediatric CI users and measure the effects of interventions.

Corrections of clinical chemistry test results in a laboratory information system.

PubMed

Wang, Sihe; Ho, Virginia

2004-08-01

The recently released reports by the Institute of Medicine, To Err Is Human and Patient Safety, have received national attention because of their focus on the problem of medical errors. Although a small number of studies have reported on errors in general clinical laboratories, there are, to our knowledge, no reported studies that focus on errors in pediatric clinical laboratory testing. To characterize the errors that have caused corrections to have to be made in pediatric clinical chemistry results in the laboratory information system, Misys. To provide initial data on the errors detected in pediatric clinical chemistry laboratories in order to improve patient safety in pediatric health care. All clinical chemistry staff members were informed of the study and were requested to report in writing when a correction was made in the laboratory information system, Misys. Errors were detected either by the clinicians (the results did not fit the patients' clinical conditions) or by the laboratory technologists (the results were double-checked, and the worksheets were carefully examined twice a day). No incident that was discovered before or during the final validation was included. On each Monday of the study, we generated a report from Misys that listed all of the corrections made during the previous week. We then categorized the corrections according to the types and stages of the incidents that led to the corrections. A total of 187 incidents were detected during the 10-month study, representing a 0.26% error detection rate per requisition. The distribution of the detected incidents included 31 (17%) preanalytic incidents, 46 (25%) analytic incidents, and 110 (59%) postanalytic incidents. The errors related to noninterfaced tests accounted for 50% of the total incidents and for 37% of the affected tests and orderable panels, while the noninterfaced tests and panels accounted for 17% of the total test volume in our laboratory. This pilot study provided the rate and categories of errors detected in a pediatric clinical chemistry laboratory based on the corrections of results in the laboratory information system. A direct interface of the instruments to the laboratory information system showed that it had favorable effects on reducing laboratory errors.

Ambulatory and home blood pressure monitoring in children and adolescents: diagnosis of hypertension and assessment of target-organ damage.

PubMed

Karpettas, Nikos; Nasothimiou, Efthimia; Kollias, Anastasios; Vazeou, Adriani; Stergiou, George S

2013-04-01

The prevalence of elevated blood pressure in children and adolescents is more common than previously believed and often represents the early onset of essential hypertension, particularly in adolescents. The definition of hypertension in children is based on distribution criteria and normalcy tables that provide blood pressure percentiles for each measurement method (office, ambulatory and home) according to the individual's age, gender and body size. Owing to the white coat and masked hypertension phenomena, ambulatory blood pressure monitoring is indispensable for the diagnosis of hypertension in children. Home blood pressure monitoring in children has been less well studied, and at present, treatment decisions should not be based solely on such measurements. Hypertension-induced preclinical target-organ damage (mainly echocardiographic left ventricular hypertrophy) is not uncommon in children and should be evaluated in all hypertensive children. Other indices of target-organ damage, such as carotid intima-media thickness, pulse wave velocity and microalbuminuria, remain under investigation in pediatric hypertension.

Beyond the VAD: Human Factors Engineering for Mechanically Assisted Circulation in the 21st Century.

PubMed

Throckmorton, Amy L; Patel-Raman, Sonna M; Fox, Carson S; Bass, Ellen J

2016-06-01

Thousands of ventricular assist devices (VADs) currently provide circulatory support to patients worldwide, and dozens of heart pump designs for adults and pediatric patients are under various stages of development in preparation for translation to clinical use. The successful bench-to-bedside development of a VAD involves a structured evaluation of possible system states, including human interaction with the device and auxiliary component usage in the hospital or home environment. In this study, we review the literature and present the current landscape of preclinical design and assessment, decision support tools and procedures, and patient-centered therapy. Gaps of knowledge are identified. The study findings support the need for more attention to user-centered design approaches for medical devices, such as mechanical circulatory assist systems, that specifically involve detailed qualitative and quantitative assessments of human-device interaction to mitigate risk and failure. Copyright © 2015 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.

Inflammatory stress and sarcomagenesis: a vicious interplay.

PubMed

Radons, Jürgen

2014-01-01

Chronic inflammation represents one of the hallmarks of cancer, but its role in sarcomagenesis has long been overlooked. Sarcomas are a rare and heterogeneous group of tumors of mesenchymal origin accounting for less than 1 % of cancers in adults but 21 % of cancers in the pediatric population. Sarcomas are associated with bad prognosis, and their management requires a multidisciplinary team approach. Several lines of evidence indicate that inflammation has been implicated in sarcomagenesis leading to the activation of the key transcription factors HIF-1, NF- κB, and STAT-3 involved in a complex inflammatory network. In the past years, an increasing number of new targets have been identified in the treatment of sarcomas leading to the development of new drugs that aim to interrupt the vicious connection between inflammation and sarcomagenesis. This article makes a brief overview of preclinical and clinical evidence of the molecular pathways involved in the inflammatory stress response in sarcomagenesis and the most targeted therapies.

Fundamentals in Biostatistics for Research in Pediatric Dentistry: Part I - Basic Concepts.

PubMed

Garrocho-Rangel, J A; Ruiz-Rodríguez, M S; Pozos-Guillén, A J

The purpose of this report was to provide the reader with some basic concepts in order to better understand the significance and reliability of the results of any article on Pediatric Dentistry. Currently, Pediatric Dentists need the best evidence available in the literature on which to base their diagnoses and treatment decisions for the children's oral care. Basic understanding of Biostatistics plays an important role during the entire Evidence-Based Dentistry (EBD) process. This report describes Biostatistics fundamentals in order to introduce the basic concepts used in statistics, such as summary measures, estimation, hypothesis testing, effect size, level of significance, p value, confidence intervals, etc., which are available to Pediatric Dentists interested in reading or designing original clinical or epidemiological studies.

Melatonin treatment of pediatric residents for adaptation to night shift work.

PubMed

Cavallo, Anita; Ris, M Douglas; Succop, Paul; Jaskiewicz, Julie

2005-01-01

Night float rotations are used in residency training programs to reduce residents' sleep deprivation. Night shift work, however, is accompanied by deleterious effects on sleep, mood, and attention. To test whether melatonin reduces the deleterious effects of night shift work on sleep, mood, and attention in pediatric residents during night float rotation. Double-blind, randomized, placebo-controlled crossover. Participants took melatonin (3 mg) or a placebo before bedtime in the morning after night shift; completed a sleep diary and an adverse-effects questionnaire daily; and completed the Profile of Mood States and the Conners Continuous Performance Test 3 times in each study week to test mood and attention, respectively. A university-affiliated, tertiary-care pediatric hospital. Healthy second-year pediatric residents working 2 night float rotations. Standardized measures of sleep, mood, and attention. Twenty-eight residents completed both treatments; 17 completed 1 treatment (10 placebo, 7 melatonin). There was not a statistically significant difference in measures of sleep, mood, and 5 of 6 measures of attention during melatonin and placebo treatment. One measure of attention, the number of omission errors, was significantly lower on melatonin (3.0 +/- 9.6) than on placebo (4.5 +/- 17.5) (z = -2.12, P = .03). The isolated finding of improvement of 1 single measure of attention in a test situation during melatonin treatment was not sufficiently robust to demonstrate a beneficial effect of melatonin in the dose used. Other strategies need to be considered to help residents in adaptation to night shift work.

Epilepsy: Transition from pediatric to adult care. Recommendations of the Ontario epilepsy implementation task force.

PubMed

Andrade, Danielle M; Bassett, Anne S; Bercovici, Eduard; Borlot, Felippe; Bui, Esther; Camfield, Peter; Clozza, Guida Quaglia; Cohen, Eyal; Gofine, Timothy; Graves, Lisa; Greenaway, Jon; Guttman, Beverly; Guttman-Slater, Maya; Hassan, Ayman; Henze, Megan; Kaufman, Miriam; Lawless, Bernard; Lee, Hannah; Lindzon, Lezlee; Lomax, Lysa Boissé; McAndrews, Mary Pat; Menna-Dack, Dolly; Minassian, Berge A; Mulligan, Janice; Nabbout, Rima; Nejm, Tracy; Secco, Mary; Sellers, Laurene; Shapiro, Michelle; Slegr, Marie; Smith, Rosie; Szatmari, Peter; Tao, Leeping; Vogt, Anastasia; Whiting, Sharon; Carter Snead, O

2017-09-01

The transition from a pediatric to adult health care system is challenging for many youths with epilepsy and their families. Recently, the Ministry of Health and Long-Term Care of the Province of Ontario, Canada, created a transition working group (TWG) to develop recommendations for the transition process for patients with epilepsy in the Province of Ontario. Herein we present an executive summary of this work. The TWG was composed of a multidisciplinary group of pediatric and adult epileptologists, psychiatrists, and family doctors from academia and from the community; neurologists from the community; nurses and social workers from pediatric and adult epilepsy programs; adolescent medicine physician specialists; a team of physicians, nurses, and social workers dedicated to patients with complex care needs; a lawyer; an occupational therapist; representatives from community epilepsy agencies; patients with epilepsy; parents of patients with epilepsy and severe intellectual disability; and project managers. Three main areas were addressed: (1) Diagnosis and Management of Seizures; 2) Mental Health and Psychosocial Needs; and 3) Financial, Community, and Legal Supports. Although there are no systematic studies on the outcomes of transition programs, the impressions of the TWG are as follows. Teenagers at risk of poor transition should be identified early. The care coordination between pediatric and adult neurologists and other specialists should begin before the actual transfer. The transition period is the ideal time to rethink the diagnosis and repeat diagnostic testing where indicated (particularly genetic testing, which now can uncover more etiologies than when patients were initially evaluated many years ago). Some screening tests should be repeated after the move to the adult system. The seven steps proposed herein may facilitate transition, thereby promoting uninterrupted and adequate care for youth with epilepsy leaving the pediatric system. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

A Multi-Institutional Simulation Boot Camp for Pediatric Cardiac Critical Care Nurse Practitioners.

PubMed

Brown, Kristen M; Mudd, Shawna S; Hunt, Elizabeth A; Perretta, Julianne S; Shilkofski, Nicole A; Diddle, J Wesley; Yurasek, Gregory; Bembea, Melania; Duval-Arnould, Jordan; Nelson McMillan, Kristen

2018-06-01

Assess the effect of a simulation "boot camp" on the ability of pediatric nurse practitioners to identify and treat a low cardiac output state in postoperative patients with congenital heart disease. Additionally, assess the pediatric nurse practitioners' confidence and satisfaction with simulation training. Prospective pre/post interventional pilot study. University simulation center. Thirty acute care pediatric nurse practitioners from 13 academic medical centers in North America. We conducted an expert opinion survey to guide curriculum development. The curriculum included didactic sessions, case studies, and high-fidelity simulation, based on high-complexity cases, congenital heart disease benchmark procedures, and a mix of lesion-specific postoperative complications. To cover multiple, high-complexity cases, we implemented Rapid Cycle Deliberate Practice method of teaching for selected simulation scenarios using an expert driven checklist. Knowledge was assessed with a pre-/posttest format (maximum score, 100%). A paired-sample t test showed a statistically significant increase in the posttest scores (mean [SD], pre test, 36.8% [14.3%] vs post test, 56.0% [15.8%]; p < 0.001). Time to recognize and treat an acute deterioration was evaluated through the use of selected high-fidelity simulation. Median time improved overall "time to task" across these scenarios. There was a significant increase in the proportion of clinically time-sensitive tasks completed within 5 minutes (pre, 60% [30/50] vs post, 86% [43/50]; p = 0.003] Confidence and satisfaction were evaluated with a validated tool ("Student Satisfaction and Self-Confidence in Learning"). Using a five-point Likert scale, the participants reported a high level of satisfaction (4.7 ± 0.30) and performance confidence (4.8 ± 0.31) with the simulation experience. Although simulation boot camps have been used effectively for training physicians and educating critical care providers, this was a novel approach to educating pediatric nurse practitioners from multiple academic centers. The course improved overall knowledge, and the pediatric nurse practitioners reported satisfaction and confidence in the simulation experience.

Examination of the safety of pediatric vaccine schedules in a non-human primate model: assessments of neurodevelopment, learning, and social behavior.

PubMed

Curtis, Britni; Liberato, Noelle; Rulien, Megan; Morrisroe, Kelly; Kenney, Caroline; Yutuc, Vernon; Ferrier, Clayton; Marti, C Nathan; Mandell, Dorothy; Burbacher, Thomas M; Sackett, Gene P; Hewitson, Laura

2015-06-01

In the 1990s, the mercury-based preservative thimerosal was used in most pediatric vaccines. Although there are currently only two thimerosal-containing vaccines (TCVs) recommended for pediatric use, parental perceptions that vaccines pose safety concerns are affecting vaccination rates, particularly in light of the much expanded and more complex schedule in place today. The objective of this study was to examine the safety of pediatric vaccine schedules in a non-human primate model. We administered vaccines to six groups of infant male rhesus macaques (n = 12-16/group) using a standardized thimerosal dose where appropriate. Study groups included the recommended 1990s Pediatric vaccine schedule, an accelerated 1990s Primate schedule with or without the measles-mumps-rubella (MMR) vaccine, the MMR vaccine only, and the expanded 2008 schedule. We administered saline injections to age-matched control animals (n = 16). Infant development was assessed from birth to 12 months of age by examining the acquisition of neonatal reflexes, the development of object concept permanence (OCP), computerized tests of discrimination learning, and infant social behavior. Data were analyzed using analysis of variance, multilevel modeling, and survival analyses, where appropriate. We observed no group differences in the acquisition of OCP. During discrimination learning, animals receiving TCVs had improved performance on reversal testing, although some of these same animals showed poorer performance in subsequent learning-set testing. Analysis of social and nonsocial behaviors identified few instances of negative behaviors across the entire infancy period. Although some group differences in specific behaviors were reported at 2 months of age, by 12 months all infants, irrespective of vaccination status, had developed the typical repertoire of macaque behaviors. This comprehensive 5-year case-control study, which closely examined the effects of pediatric vaccines on early primate development, provided no consistent evidence of neurodevelopmental deficits or aberrant behavior in vaccinated animals.

System Vaccinology for the Evaluation of Influenza Vaccine Safety by Multiplex Gene Detection of Novel Biomarkers in a Preclinical Study and Batch Release Test

PubMed Central

Mizukami, Takuo; Momose, Haruka; Kuramitsu, Madoka; Takizawa, Kazuya; Araki, Kumiko; Furuhata, Keiko; Ishii, Ken J.; Hamaguchi, Isao; Yamaguchi, Kazunari

2014-01-01

Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, β2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv) from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch-to-batch consistency and vaccine safety as an alternative to animal testing. PMID:25010690

The effectiveness of an e-learning program on pediatric medication safety for undergraduate students: a pretest-post-test intervention study.

PubMed

Lee, Tzu-Ying; Lin, Fang-Yi

2013-04-01

Safe medication management is a major competency taught in the nursing curriculum. However, administering pediatric medications is considered a common clinical stressor for Taiwanese students. A supplemental e-learning program that helps students fill the gap between basic nursing skills and pediatric knowledge on medication safety was developed. To evaluate the effectiveness of an e-learning program to increase pediatric medication management among students who take pediatric nursing courses. This intervention study used a historical comparison design. A university in Northern Taiwan. A total of 349 undergraduate nursing students who took pediatric nursing courses participated. Eighty students in the comparison group received regular pediatric courses, including the lectures and clinical practicum; 269 students in the intervention group received an e-learning program, in addition to the standard pediatric courses. Between February 2011 and July 2012 pediatric medication management, including pediatric medication knowledge and calculation ability, was measured at the beginning of the first class, at the completion of the lectures, and at the completion of the clinical practicum. The program was evaluated qualitatively and quantitatively. The intervention group had significantly higher pediatric medication management scores at completion of the lecture course and at the completion of the clinical practicum than the comparison group based on the first day of the lecture course, after adjusting for age, nursing program, and having graduated from a junior college in nursing. Overall, the students appreciated the program that included various teaching modalities content that related to the administration of medication. Using an e-learning program on pediatric medication management is an effective learning method in addition to sitting in a regular lecture course. The different emphases in each module, provided by experienced instructors, enabled the students to be more aware of their role in pediatric medication safety. Copyright © 2013 Elsevier Ltd. All rights reserved.

The design and pre-clinical evaluation of knee replacements for osteoarthritis.

PubMed

Walker, Peter S

2015-03-18

One of the concepts that Rik Huiskes promoted was that implants such as knee and hip replacements could be analyzed and optimized using numerical models such as finite element analysis, or by experimental testing, an area he called pre-clinical testing. The design itself could be formulated or improved by defining a specific goal or asking a key question. These propositions are examined in the light of almost five decades of experience with knee implants. Achieving the required laxity and stability, was achieved by attempting to reproduce anatomical values by suitable radii of curvature and selective ligament retention. Obtaining durable fixation was based on testing many configurations to obtain the most uniform stress distribution at the implant-bone interface. Achieving the best overall kinematics has yet to be fully solved due to the variations in activities and patients. These and many other factors have usually been addressed individually rather than as a composite, although as time has gone on, successful features have gradually been assimilated into most designs. But even a systematic approach has been flawed because some unrecognized response was not accounted for in the pre-clinical model, a limitation of models in general. In terms of the design process, so far no method has emerged for systematically reaching an optimal solution from all aspects, although this is possible in principle. Overall however, predictive numerical or physical models should be an essential element in the design of new or improved knee replacements, a part of the design process itself. Copyright © 2015. Published by Elsevier Ltd.

Perspectives on Canadian core fellowship training in pediatric anesthesia: a survey of graduate fellows.

PubMed

O'Leary, James D; Crawford, Mark W

2015-10-01

Educators in anesthesia have an obligation to ensure that fellowship programs are training anesthesiologists to meet the highest standards of performance in clinical and academic practice. The objective of this survey was to characterize the perspectives of graduates of Canadian core fellowship programs in pediatric anesthesia (during a ten-year period starting in 2003) on the adequacies and inadequacies of fellowship training. We conducted an electronic survey of graduates from eight departments of pediatric anesthesia in Canada who completed one-year core fellowship training in pediatric anesthesia from 2003 to 2013. A novel survey design was implemented, and the content and structure of the design were tested before distribution. Data were collected on respondents' demographics, details of training and practice settings, perceived self-efficacy in subspecialty practices, research experience, and perspectives on one-year core fellowship training in pediatric anesthesia. Descriptive statistics and 95% confidence intervals were determined. The survey was sent to 132 anesthesiologists who completed core fellowship training in pediatric anesthesia in Canada. Sixty-five (49%) completed and eligible surveys were received. Most of the anesthesiologists surveyed perceived that 12 months of core fellowship training are sufficient to acquire the knowledge and critical skills needed to practice pediatric anesthesia. Subspecialty areas most frequently perceived to require improved training included pediatric cardiac anesthesia, chronic pain medicine, and regional anesthesia. This survey reports perceived deficiencies in domains of pediatric anesthesia fellowship training. These findings should help guide the future development of core and advanced fellowship training programs in pediatric anesthesia.

Dehydration treatment practices among pediatrics-trained and non-pediatrics trained emergency physicians.

PubMed

Nunez, Jeranil; Liu, Deborah R; Nager, Alan L

2012-04-01

We sought to survey emergency physicians in the United States regarding the management of pediatric dehydration secondary to acute gastroenteritis. We hypothesized that responses from physicians with dedicated pediatric training (PT), that is, board certification in pediatrics or pediatric emergency medicine, would differ from responses of physicians with no dedicated pediatric training (non-PT). An anonymous survey was mailed to randomly selected members of the American College of Emergency Physicians and sent electronically to enrollees of Brown University pediatric emergency medicine listserv. The survey consisted of 17 multiple-choice questions based on a clinical scenario depicting a 2-year-old with acute gastroenteritis and moderate dehydration. Questions asked related to treatment preferences, practice setting, and training information. One thousand sixty-nine surveys were received: 997 surveys were used for data analysis, including 269 PT physicians and 721 non-PT physicians. Seventy-nine percent of PT physicians correctly classified the scenario patient as moderately dehydrated versus 71% of non-PT physicians (P = 0.063). Among those who correctly classified the patient, 121 PT physicians (58%) and 350 non-PT physicians (68%) would initially hydrate the patient with intravenous fluids. Pediatrics-trained physicians were more likely to initially choose oral or nasogastric hydration compared with non-PT physicians (P = 0.0127). Pediatrics-trained physicians were less likely to perform laboratory testing compared with the non-PT group (n = 92, 45%, vs n = 337, 66%; P < 0.0001). Contrary to established recommendations for the management of moderately dehydrated children, significantly more PT physicians, compared with non-PT physicians, follow established guidelines.

Spectacle prescription in children: Understanding practical approach of Indian ophthalmologists

PubMed Central

Monga, Sumit; Dave, Paaraj

2018-01-01

Purpose: The aim of this study is to survey the management approach, regarding spectacle prescription in children, among Indian ophthalmologists. Methods: A web-based, anonymous questionnaire (multiple choice questions dealing with practical aspects of pediatric refraction), was sent to available database of Indian ophthalmologists. The survey responses (depicted in %) were compared using the amount of pediatric clientele in one's practice (Group A: <25%, Group B: 25% or more). The responses were also analyzed in relation to the published concepts from literature. Results: Two hundred and ten ophthalmologists (2.74% response rate; 48% in Group A), from all over India, responded to the survey. There were wide discrepancies in the responses (both, in and among, Groups A and B; P > 0.05, Chi-square test), as to when and how much refractive error to prescribe in children, for a given situation. Conclusion: A wide gap exists between pediatric spectacle prescription patterns of Indian ophthalmologists, as compared to the recommended pediatric ophthalmology protocols. The management approach, for certain situations concerning the pediatric refraction, was better among those with higher pediatric clientele. PMID:29676306

MicroRNA-106b~25 cluster is upregulated in relapsed MLL-rearranged pediatric acute myeloid leukemia

PubMed Central

Verboon, Lonneke J.; Obulkasim, Askar; de Rooij, Jasmijn D.E.; Katsman, Jenny E.; Sonneveld, Edwin; Baruchel, André; Trka, Jan; Reinhardt, Dirk; Pieters, Rob; Cloos, Jacqueline; Kaspers, Gertjan J.L.; Klusmann, Jan-Henning; Zwaan, Christian Michel; Fornerod, Maarten; van den Heuvel-Eibrink, Marry M.

2016-01-01

The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia (MLL)-rearranged pediatric cohort. AML with MLL- rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL-rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL-rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7, was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL-rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL-rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL-rearrangements. PMID:27351222

Development of a Pediatric Adverse Events Terminology

PubMed Central

Gipson, Debbie S.; Kirkendall, Eric S.; Gumbs-Petty, Brenda; Quinn, Theresa; Steen, A.; Hicks, Amanda; McMahon, Ann; Nicholas, Savian; Zhao-Wong, Anna; Taylor-Zapata, Perdita; Turner, Mark; Herreshoff, Emily; Jones, Charlotte; Davis, Jonathan M.; Haber, Margaret; Hirschfeld, Steven

2017-01-01

In 2009, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) established the Pediatric Terminology Harmonization Initiative to establish a core library of terms to facilitate the acquisition and sharing of knowledge between pediatric clinical research, practice, and safety reporting. A coalition of partners established a Pediatric Terminology Adverse Event Working Group in 2013 to develop a specific terminology relevant to international pediatric adverse event (AE) reporting. Pediatric specialists with backgrounds in clinical care, research, safety reporting, or informatics, supported by biomedical terminology experts from the National Cancer Institute’s Enterprise Vocabulary Services participated. The multinational group developed a working definition of AEs and reviewed concepts (terms, synonyms, and definitions) from 16 pediatric clinical domains. The resulting AE terminology contains >1000 pediatric diseases, disorders, or clinical findings. The terms were tested for proof of concept use in 2 different settings: hospital readmissions and the NICU. The advantages of the AE terminology include ease of adoption due to integration with well-established and internationally accepted biomedical terminologies, a uniquely temporal focus on pediatric health and disease from conception through adolescence, and terms that could be used in both well- and underresourced environments. The AE terminology is available for use without restriction through the National Cancer Institute’s Enterprise Vocabulary Services and is fully compatible with, and represented in, the Medical Dictionary for Regulatory Activities. The terminology is intended to mature with use, user feedback, and optimization. PMID:28028203

Pediatric in vitro and in silico models of deposition via oral and nasal inhalation.

PubMed

Carrigy, Nicholas B; Ruzycki, Conor A; Golshahi, Laleh; Finlay, Warren H

2014-06-01

Respiratory tract deposition models provide a useful method for optimizing the design and administration of inhaled pharmaceutical aerosols, and can be useful for estimating exposure risks to inhaled particulate matter. As aerosol must first pass through the extrathoracic region prior to reaching the lungs, deposition in this region plays an important role in both cases. Compared to adults, much less extrathoracic deposition data are available with pediatric subjects. Recently, progress in magnetic resonance imaging and computed tomography scans to develop pediatric extrathoracic airway replicas has facilitated addressing this issue. Indeed, the use of realistic replicas for benchtop inhaler testing is now relatively common during the development and in vitro evaluation of pediatric respiratory drug delivery devices. Recently, in vitro empirical modeling studies using a moderate number of these realistic replicas have related airway geometry, particle size, fluid properties, and flow rate to extrathoracic deposition. Idealized geometries provide a standardized platform for inhaler testing and exposure risk assessment and have been designed to mimic average in vitro deposition in infants and children by replicating representative average geometrical dimensions. In silico mathematical models have used morphometric data and aerosol physics to illustrate the relative importance of different deposition mechanisms on respiratory tract deposition. Computational fluid dynamics simulations allow for the quantification of local deposition patterns and an in-depth examination of aerosol behavior in the respiratory tract. Recent studies have used both in vitro and in silico deposition measurements in realistic pediatric airway geometries to some success. This article reviews the current understanding of pediatric in vitro and in silico deposition modeling via oral and nasal inhalation.

Treatment with escitalopram but not desipramine decreases escape latency times in a learned helplessness model using juvenile rats.

PubMed

Reed, Abbey L; Anderson, Jeffrey C; Bylund, David B; Petty, Frederick; El Refaey, Hesham; Happe, H Kevin

2009-08-01

The pharmacological treatment of depression in children and adolescents is different from that of adults due to the lack of efficacy of certain antidepressants in the pediatric age group. Our current understanding of why these differences occur is very limited. To develop more effective treatments, a juvenile animal model of depression was tested to validate it as a possible model to specifically study pediatric depression. Procedures for use with juvenile rats at postnatal day (PND) 21 and 28 were adapted from the adult learned helplessness model in which, 24 h after exposure to inescapable stress, animals are unable to remove themselves from an easily escapable stressor. Rats were treated for 7 days with either the selective serotonin reuptake inhibitor escitalopram at 10 mg/kg or the tricyclic antidepressant desipramine at 3, 10, or 15 mg/kg to determine if treatment could decrease escape latency times. Escitalopram treatment was effective at decreasing escape latency times in all ages tested. Desipramine treatment did not decrease escape latency times for PND 21 rats, but did decrease times for PND 28 and adult animals. The learned helplessness model with PND 21 rats predicts the efficacy of escitalopram and the lack of efficacy of desipramine seen in the treatment of pediatric depression. These findings suggest that the use of PND 21 rats in a modified learned helplessness procedure may be a valuable model of human pediatric depression that can predict pediatric antidepressant efficacy and be used to study antidepressant mechanisms involved in pediatric depression.

Early Detection of Motor Dysfunction in the SOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis (ALS) Using Home Cage Running Wheels

PubMed Central

Bennett, Ellen J.; Mead, Richard J.; Azzouz, Mimoun; Shaw, Pamela J.; Grierson, Andrew J.

2014-01-01

The SOD1G93A mouse has been used since 1994 for preclinical testing in amyotrophic lateral sclerosis (ALS). Despite recent genetic advances in our understanding of ALS, transgenic mice expressing mutant SOD1 remain the best available, and most widely used, vertebrate model of the disease. We previously described an optimised and rapid approach for preclinical studies in the SOD1G93A mouse. Here we describe improvements to this approach using home cage running wheels to obtain daily measurements of motor function, with minimal intervention. We show that home cage running wheels detect reductions in motor function at a similar time to the rotarod test, and that the data obtained are less variable allowing the use of smaller groups of animals to obtain satisfactory results. This approach refines use of the SOD1G93A model, and reduces the number of animals undergoing procedures of substantial severity, two central principles of the 3Rs (replacement, reduction and refinement of animal use in research). The small group sizes and rapid timescales enable affordable large-scale therapeutic pre-screening in the SOD1G93A mouse, as well as rapid validation of published positive effects in a second laboratory, one of the major stumbling blocks in ALS preclinical therapy development. PMID:25268710

Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

PubMed

Dietrich, Barbara; Schiviz, Alexandra; Hoellriegl, Werner; Horling, Frank; Benamara, Karima; Rottensteiner, Hanspeter; Turecek, Peter L; Schwarz, Hans Peter; Scheiflinger, Friedrich; Muchitsch, Eva-Maria

2013-11-01

Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P ≤ 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans.

Tocotrienol vitamin E protects against preclinical canine ischemic stroke by inducing arteriogenesis.

PubMed

Rink, Cameron; Christoforidis, Greg; Khanna, Savita; Peterson, Laura; Patel, Yojan; Khanna, Suchin; Abduljalil, Amir; Irfanoglu, Okan; Machiraju, Raghu; Bergdall, Valerie K; Sen, Chandan K

2011-11-01

Vitamin E consists of tocopherols and tocotrienols, in which α-tocotrienol is the most potent neuroprotective form that is also effective in protecting against stroke in rodents. As neuroprotective agents alone are insufficient to protect against stroke, we sought to test the effects of tocotrienol on the cerebrovascular circulation during ischemic stroke using a preclinical model that enables fluoroscopy-guided angiography. Mongrel canines (mean weight=26.3±3.2 kg) were supplemented with tocotrienol-enriched (TE) supplement (200 mg b.i.d, n=11) or vehicle placebo (n=9) for 10 weeks before inducing transient middle cerebral artery (MCA) occlusion. Magnetic resonance imaging was performed 1 hour and 24 hours post reperfusion to assess stroke-induced lesion volume. Tocotrienol-enriched supplementation significantly attenuated ischemic stroke-induced lesion volume (P<0.005). Furthermore, TE prevented loss of white matter fiber tract connectivity after stroke as evident by probabilistic tractography. Post hoc analysis of cerebral angiograms during MCA occlusion revealed that TE-supplemented canines had improved cerebrovascular collateral circulation to the ischemic MCA territory (P<0.05). Tocotrienol-enriched supplementation induced arteriogenic tissue inhibitor of metalloprotease 1 and subsequently attenuated the activity of matrix metalloproteinase-2. Outcomes of the current preclinical trial set the stage for a clinical trial testing the effects of TE in patients who have suffered from transient ischemic attack and are therefore at a high risk for stroke.

Stress-based animal models of depression: Do we actually know what we are doing?

PubMed

Yin, Xin; Guven, Nuri; Dietis, Nikolas

2016-12-01

Depression is one of the leading causes of disability and a significant health-concern worldwide. Much of our current understanding on the pathogenesis of depression and the pharmacology of antidepressant drugs is based on pre-clinical models. Three of the most popular stress-based rodent models are the forced swimming test, the chronic mild stress paradigm and the learned helplessness model. Despite their recognizable advantages and limitations, they are associated with an immense variability due to the high number of design parameters that define them. Only few studies have reported how minor modifications of these parameters affect the model phenotype. Thus, the existing variability in how these models are used has been a strong barrier for drug development as well as benchmark and evaluation of these pre-clinical models of depression. It also has been the source of confusing variability in the experimental outcomes between research groups using the same models. In this review, we summarize the known variability in the experimental protocols, identify the main and relevant parameters for each model and describe the variable values using characteristic examples. Our view of depression and our efforts to discover novel and effective antidepressants is largely based on our detailed knowledge of these testing paradigms, and requires a sound understanding around the importance of individual parameters to optimize and improve these pre-clinical models. Copyright © 2016 Elsevier B.V. All rights reserved.

Preliminary study for small animal preclinical hadrontherapy facility

NASA Astrophysics Data System (ADS)

Russo, G.; Pisciotta, P.; Cirrone, G. A. P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G. I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M. C.; Cuttone, G.

2017-02-01

Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and gamma index test. This work represents the first step towards the realization of a preclinical hadrontherapy facility at INFN-LNS in Catania for the future in vivo studies.

Comparative effectiveness of hand scaling by undergraduate dental students following a two-week pre-clinical training course.

PubMed

Gartenmann, S J; Hofer, D; Wiedemeier, D; Sahrmann, P; Attin, T; Schmidlin, P R

2018-04-25

The Bologna reform resulted in a drastic restructuring of pre-clinical training courses at the University of Zurich. The aim of this study was to assess student pre-clinical scaling/root planning skills after just 8.5 hours of manual training. Three consecutive classes of dental students (n = 41; n = 34; n = 48) were tasked with removing lacquer concrement from the maxillary left canine on a typodont using Gracey and universal (Deppeler M23A) curettes. At baseline (prior to instruction), a timed 5-minute session of scaling/root planning was undertaken. The second scaling/root planning session was held immediately following training. Eight experienced dental hygienists and eight lay people served as positive and negative controls, using the same instruments and time limit, respectively. Instrumented teeth were collected, scanned and planimetrically analysed for the percentage of tooth surface cleaned. Statistical analyses were performed to assess the dental students' improvement after the training (Wilcoxon signed-rank test) and to compare it to that of laypeople and dental hygienists (Kruskal-Wallis rank sum test followed by Conover's post hoc test). At baseline, the dental students' mean scaling scores of the cleaned surfaces were not significantly different than those of laypeople (29.8%, 31.0%, 42% vs 27.9%). However, after 8.5 hours of manual training, the students' ability to clean the maxillary tooth improved significantly and they achieved mean removal values of 61.7%, 79.5% and 76% compared to the 67.4% (P < .001) of the experienced dental hygienists (Tables and ). There were no statistically significant differences between the scores achieved by students after training and those achieved by experienced dental hygienists. A shortened pre-clinical training time was sufficient for students to acquire the basic scaling/root planning skills needed in preparation for clinical training. Further research is needed to identify ways to help students consistently reach highest skill levels. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Transition from Longitudinal to Block Structure of Preclinical Courses: Outcomes and Experiences

PubMed Central

Marinović, Darko; Hren, Darko; Sambunjak, Dario; Rašić, Ivan; Škegro, Ivan; Marušić, Ana; Marušić, Matko

2009-01-01

Aim To evaluate the transition from a longitudinal to block/modular structure of preclinical courses in a medical school adapting to the process of higher education harmonization in Europe. Methods Average grades and the exam pass rates were compared for 11 preclinical courses before and after the transition from the longitudinal (academic years 1999/2000 to 2001/2002) to block/modular curriculum (academic years 2002/2003 to 2004/2005) at Zagreb University School of Medicine, Croatia. Attitudes of teachers toward the 2 curriculum structures were assessed by a semantic differential scale, and the experiences during the transition were explored in focus groups of students and teachers. Results With the introduction of the block/modular curriculum, average grades mostly increased, except in 3 major courses: Anatomy, Physiology, and Pathology. The proportion of students who passed the exams at first attempt decreased in most courses, but the proportion of students who successfully passed the exam by the end of the summer exam period increased. Teachers generally had more positive attitudes toward the longitudinal (median [C]±intequartile range [Q], 24 ± 16) than block/modular curriculum (C±Q, 38 ± 26) (P = 0.001, Wilcoxon signed rank test). The qualitative inquiry indicated that the dissatisfaction of students and teachers with the block/modular preclinical curriculum was caused by perceived hasty introduction of the reform under pressure and without much adaptation of the teaching program and materials, which reflected negatively on the learning processes and outcomes. Conclusion Any significant alteration in the temporal structure of preclinical courses should be paralleled by a change in the content and teaching methodology, and carefully planned and executed in order to achieve better academic outcomes. PMID:19839073

Preclinical evaluation of hydrogel sealed fluropassivated indigenous vascular prosthesis.

PubMed

Unnikrishnan, Madathipat; Umashankar, P R; Viswanathan, Sidharth; Savlania, Ajay; Joseph, Roy; Muraleedharan, C V; Agrawal, Vivek; Shenoy, Sachin J; Krishnan, Lissy K; Mohanan, P V; Sabareeswaran, A

2017-11-01

Polyethylene terephthalate (PET) graft, designed and developed at our institute for vascular reconstruction, is porous to promote optimal incorporation and neointima formation, requiring pre-clotting or biomodification by sealing the pores before implantation. The objective of this study was to characterize, test and perform preclinical evaluation of hydrogel (alginate dialdehyde cross-linked gelatin) sealed fluoropassivated PET vascular prosthesis in pig model, so as to avoid pre-clotting, for its safety and efficacy before employing the indigenous and less expensive graft for clinical use. Hydrogel sealed, fluoropassivated PET vascular prosthesis were tested for haemocompatibility and toxicity followed by small animal toxicology tests and in vivo experiments in pigs receiving implantation at thoracic aorta. All 33 animals received test as well as control grafts with a plan for phased explantation at 2, 12 and 26 weeks. All animals underwent completion angiogram at the end of procedure as well as before graft explantation. Haemocompatibility tests for haemolysis and toxicity tests showed no adverse events in tested mice and rabbits. Completion angiogram showed intact anastamosis and patent graft in each animal in post-operative period and at explantation. Gross and histopathological examination showed well-encapsulated grafts, clean glistening neointima and no evidence of thrombus in both test and control grafts. Hydrogel sealed, fluoropassivated PET vascular prosthesis was found non-toxic, haemocompatible and remained patent in in vivo studies at planned intervals.

Preclinical evaluation of hydrogel sealed fluropassivated indigenous vascular prosthesis

PubMed Central

Unnikrishnan, Madathipat; Umashankar, P.R.; Viswanathan, Sidharth; Savlania, Ajay; Joseph, Roy; Muraleedharan, C.V.; Agrawal, Vivek; Shenoy, Sachin J.; Krishnan, Lissy K.; Mohanan, P.V.; Sabareeswaran, A.

2017-01-01

Background & objectives: Polyethylene terephthalate (PET) graft, designed and developed at our institute for vascular reconstruction, is porous to promote optimal incorporation and neointima formation, requiring pre-clotting or biomodification by sealing the pores before implantation. The objective of this study was to characterize, test and perform preclinical evaluation of hydrogel (alginate dialdehyde cross-linked gelatin) sealed fluoropassivated PET vascular prosthesis in pig model, so as to avoid pre-clotting, for its safety and efficacy before employing the indigenous and less expensive graft for clinical use. Methods: Hydrogel sealed, fluoropassivated PET vascular prosthesis were tested for haemocompatibility and toxicity followed by small animal toxicology tests and in vivo experiments in pigs receiving implantation at thoracic aorta. All 33 animals received test as well as control grafts with a plan for phased explantation at 2, 12 and 26 weeks. All animals underwent completion angiogram at the end of procedure as well as before graft explantation. Results: Haemocompatibility tests for haemolysis and toxicity tests showed no adverse events in tested mice and rabbits. Completion angiogram showed intact anastamosis and patent graft in each animal in post-operative period and at explantation. Gross and histopathological examination showed well-encapsulated grafts, clean glistening neointima and no evidence of thrombus in both test and control grafts. Interpretation & conclusions: Hydrogel sealed, fluoropassivated PET vascular prosthesis was found non-toxic, haemocompatible and remained patent in in vivo studies at planned intervals. PMID:29512608

A preclinical physiological assay to test modulation of knee joint pain in the spinal cord: effects of oxycodone and naproxen.

PubMed

Miranda, Jason A; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain.

A Preclinical Physiological Assay to Test Modulation of Knee Joint Pain in the Spinal Cord: Effects of Oxycodone and Naproxen

PubMed Central

Miranda, Jason A.; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain. PMID:25157947

The Development and Evaluation of a Measure Assessing School Nurses' Perceived Barriers to Addressing Pediatric Obesity

ERIC Educational Resources Information Center

Wu, Yelena P.; Steele, Ric G.

2011-01-01

School nurses represent an important resource for addressing pediatric obesity and weight-related health. However, school nurses perceive numerous barriers that prevent them from addressing the weight-related health of students. The current study developed and tested a new, comprehensive measure of nurses' perceptions of 10 types of barriers to…

Comparison between a pediatric health promotion center and a pediatric obesity clinic in detecting metabolic syndrome and non-alcoholic fatty liver disease in children.

PubMed

Yang, Hye Ran; Yi, Dae Yong; Choi, Hyoung Soo

2014-12-01

This study was done to evaluate the efficacy of health check-ups in children in detecting metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) by comparing the pediatric health promotion center with the pediatric obesity clinic. Children who visited a pediatric health promotion center (n=218) or a pediatric obesity clinic (n=178) were included. Anthropometric data, blood pressure, laboratory tests, and abdominal ultrasonography were evaluated. Two different criteria were applied to diagnose metabolic syndrome. The prevalence of metabolic syndrome in the 2 units was 3.2%-3.7% in a pediatric health promotion center and 23%-33.2% in a pediatric obesity clinic. Significant differences were observed in the prevalence of each component of metabolic syndrome between the 2 units including abdominal adiposity, blood pressure, serum triglycerides, and fasting blood glucose (P<0.05). The prevalence of NAFLD was 8.7% and 71.9% in the 2 units according to liver enzymes and 5.9% and 61.8% according to ultrasonography (P<0.05). The prevalence of metabolic syndrome and NAFLD was higher among patients visiting the obesity clinic targeting obese children than that among patients visiting the health promotion center offering routine check-ups. An obesity-oriented approach is required to prevent obesity-related health problems in children.

A validated pediatric transport survey: how is your team performing?

PubMed

McPherson, Mona L; Jefferson, Larry S; Graf, Jeanine M

2008-01-01

Understanding referring practitioners' satisfaction with pediatric transport services is useful for quality improvement. Formal survey methodology was applied to develop a pediatric transport satisfaction survey. Large metropolitan area in the Southwestern United States. A four-stage process was used to create a 20-item pediatric transport satisfaction survey. The final survey was analyzed for test-retest and internal consistency reliability, and surveys were mailed to a large practitioner base. The survey encompassed three domains: patient care, accessing the transport system, and communication. Test-retest and internal consistency reliability were good (final Cronbach alpha coefficient of 0.88.) Of the 229 providers responding, 69% were local (<60 miles), and 31% were served by our long distance transport team (>60 miles). Respondents reported that physicians selected the transport team in 82% of cases, whereas 9% reported that the charge nurse decided. Transport team selection was based on: (1) ease of initiation, (2) fastest arrival, (3) presence of a physician on the team, (4) stabilization time at the referring facility, and (5) team providing best follow-up. Satisfaction with our transport service was high, with a median survey score of 83 (interquartile [IQ] range, 74-92). Physicians and nurses reported equal satisfaction. Survey design methodology was successfully applied to assess satisfaction with pediatric transport. This transport survey offers a reliable measurement of providers' satisfaction with transport services.

The Use of Office-Based Sedation and General Anesthesia by Board Certified Pediatric Dentists Practicing in the United States

PubMed Central

Olabi, Nassim F.; Jones, James E.; Saxen, Mark A.; Sanders, Brian J.; Walker, LaQuia A.; Weddell, James A.; Schrader, Stuart M.; Tomlin, Angela M.

2012-01-01

The purpose of this study is to explore the use of office-based sedation by board-certified pediatric dentists practicing in the United States. Pediatric dentists have traditionally relied upon self-administered sedation techniques to provide office-based sedation. The use of dentist anesthesiologists to provide office-based sedation is an emerging trend. This study examines and compares these two models of office-based sedations. A survey evaluating office-based sedation of diplomates of the American Board of Pediatric Dentistry (ABPD) based on gender, age, years in practice, practice types, regions, and years as a diplomate of the ABPD was completed by 494 active members. The results were summarized using frequencies and percentages. Relationships of dentist age, gender, and number of years in practice with the use of intravenous (IV) sedation was completed using two-way contingency tables and Mantel-Haenszel tests for ordered categorical data. Relationships of office-based sedation use and the type of one's practice were examined using Pearson chi-square tests. Of the 1917 surveys e-mailed, 494 completed the survey for a response rate of 26%. Over 70% of board-certified US pediatric dentists use some form of sedation in their offices. Less than 20% administer IV sedation, 20 to 40% use a dentist anesthesiologist, and 60 to 70% would use dentist anesthesiologists if one were available. PMID:22428969

The use of office-based sedation and general anesthesia by board certified pediatric dentists practicing in the United States.

PubMed

Olabi, Nassim F; Jones, James E; Saxen, Mark A; Sanders, Brian J; Walker, Laquia A; Weddell, James A; Schrader, Stuart M; Tomlin, Angela M

2012-01-01

The purpose of this study is to explore the use of office-based sedation by board-certified pediatric dentists practicing in the United States. Pediatric dentists have traditionally relied upon self-administered sedation techniques to provide office-based sedation. The use of dentist anesthesiologists to provide office-based sedation is an emerging trend. This study examines and compares these two models of office-based sedations. A survey evaluating office-based sedation of diplomates of the American Board of Pediatric Dentistry (ABPD) based on gender, age, years in practice, practice types, regions, and years as a diplomate of the ABPD was completed by 494 active members. The results were summarized using frequencies and percentages. Relationships of dentist age, gender, and number of years in practice with the use of intravenous (IV) sedation was completed using two-way contingency tables and Mantel-Haenszel tests for ordered categorical data. Relationships of office-based sedation use and the type of one's practice were examined using Pearson chi-square tests. Of the 1917 surveys e-mailed, 494 completed the survey for a response rate of 26%. Over 70% of board-certified US pediatric dentists use some form of sedation in their offices. Less than 20% administer IV sedation, 20 to 40% use a dentist anesthesiologist, and 60 to 70% would use dentist anesthesiologists if one were available.

Penicillin skin testing is a safe and effective tool for evaluating penicillin allergy in the pediatric population.

PubMed

Fox, Stephanie J; Park, Miguel A

2014-01-01

Penicillin skin testing has been validated in the evaluation of adult patients with penicillin allergy. However, the commercially available benzylpenicilloyl polylysine (Pre-Pen) is not indicated in the pediatric population. Moreover, the safety and validity of penicillin skin testing in the pediatric population has not been well studied. We describe the safety and validity of penicillin skin testing in the evaluation of children with a history of penicillin allergy. Children (<18 years) with a history of penicillin allergy were evaluated with penicillin skin tests and were reviewed for basic demographics, penicillin skin test results, adverse drug reaction to penicillin after penicillin skin test, and adverse reaction to penicillin skin test. By using the χ(2) test, we compared the differences in the proportion of children and adults with a positive penicillin skin test. P value (<.05) was considered statistically significant. The institutional review board approved the study, and all the subjects signed written informed consents. A total of 778 children underwent penicillin skin testing; 703 of 778 patients had a negative penicillin skin test (90.4%), 66 had a positive test (8.5%), and 9 had an equivocal test (1.1%). Children were more likely to have a positive penicillin skin test (P < .0001) compared with adults (64 of 1759 [3.6%]); 369 of 703 patients with negative penicillin skin test (52%) were challenged with penicillin, and 14 of 369 patients (3.8%) had an adverse drug reaction. No adverse reactions to penicillin skin testing were observed. Penicillin skin testing was safe and effective in the evaluation of children with a history of penicillin allergy. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Advancing the Selection of Neurodevelopmental Measures in Epidemiological Studies of Environmental Chemical Exposure and Health Effects

PubMed Central

Youngstrom, Eric; LaKind, Judy S.; Kenworthy, Lauren; Lipkin, Paul H.; Goodman, Michael; Squibb, Katherine; Mattison, Donald R.; Anthony, Bruno J.; Anthony, Laura Gutermuth

2010-01-01

With research suggesting increasing incidence of pediatric neurodevelopmental disorders, questions regarding etiology continue to be raised. Neurodevelopmental function tests have been used in epidemiology studies to evaluate relationships between environmental chemical exposures and neurodevelopmental deficits. Limitations of currently used tests and difficulties with their interpretation have been described, but a comprehensive critical examination of tests commonly used in studies of environmental chemicals and pediatric neurodevelopmental disorders has not been conducted. We provide here a listing and critical evaluation of commonly used neurodevelopmental tests in studies exploring effects from chemical exposures and recommend measures that are not often used, but should be considered. We also discuss important considerations in selecting appropriate tests and provide a case study by reviewing the literature on polychlorinated biphenyls. PMID:20195443

Automated detection of ventricular pre-excitation in pediatric 12-lead ECG.

PubMed

Gregg, Richard E; Zhou, Sophia H; Dubin, Anne M

2016-01-01

With increased interest in screening of young people for potential causes of sudden death, accurate automated detection of ventricular pre-excitation (VPE) or Wolff-Parkinson-White syndrome (WPW) in the pediatric resting ECG is important. Several recent studies have shown interobserver variability when reading screening ECGs and thus an accurate automated reading for this potential cause of sudden death is critical. We designed and tested an automated algorithm to detect pediatric VPE optimized for low prevalence. Digital ECGs with 12 leads or 15 leads (12-lead plus V3R, V4R and V7) were selected from multiple hospitals and separated into a testing and training database. Inclusion criterion was age less than 16 years. The reference for algorithm detection of VPE was cardiologist annotation of VPE for each ECG. The training database (n=772) consisted of VPE ECGs (n=37), normal ECGs (n=492) and a high concentration of conduction defects, RBBB (n=232) and LBBB (n=11). The testing database was a random sample (n=763). All ECGs were analyzed with the Philips DXL ECG Analysis algorithm for basic waveform measurements. Additional ECG features specific to VPE, mainly delta wave scoring, were calculated from the basic measurements and the average beat. A classifier based on decision tree bootstrap aggregation (tree bagger) was trained in multiple steps to select the number of decision trees and the 10 best features. The classifier accuracy was measured on the test database. The new algorithm detected pediatric VPE with a sensitivity of 78%, a specificity of 99.9%, a positive predictive value of 88% and negative predictive value of 99.7%. This new algorithm for detection of pediatric VPE performs well with a reasonable positive and negative predictive value despite the low prevalence in the general population. Copyright © 2016 Elsevier Inc. All rights reserved.

Epsilon aminocaproic acid reduces blood transfusion and improves the coagulation test after pediatric open-heart surgery: a meta-analysis of 5 clinical trials.

PubMed

Lu, Jun; Meng, Haoyu; Meng, Zhaoyi; Sun, Ying; Pribis, John P; Zhu, Chunyan; Li, Quan

2015-01-01

Excessive postoperative blood loss after cardiopulmonary bypass is a common problem, especially in patients suffering from congenital heart diseases. The efficacy of epsilon aminocaproic acid (EACA) as a prophylactic treatment for postoperative bleeding after pediatric open-heart surgery has not been determined. This meta-analysis investigates the efficacy of EACA in the minimization of bleeding and blood transfusion and the maintenance of coagulation tests after pediatric open-heart surgery. A comprehensive literature search was performed to identify all randomized clinical trials on the subject. PubMed, Embase, the Cochrane Library, and the Chinese Medical Journal Network were screened. The primary outcome used for the analysis was postoperative blood loss. Secondary outcomes included postoperative blood transfusion, re-exploration rate and postoperative coagulation tests. The mean difference (MD) and risk ratio (RR) with 95% confidence intervals (CI) were used as summary statistics. Five trials were included in this meta-analysis of 515 patients. Prophylactic EACA was associated with a reduction in postoperative blood loss, but this difference did not reach statistical significance (MD: -7.08; 95% CI: -16.11 to 1.95; P = 0.12). Patients treated with EACA received fewer postoperative blood transfusions, including packed red blood cells (MD: -8.36; 95% CI: -12.63 to -4.09; P = 0.0001), fresh frozen plasma (MD: -3.85; 95% CI: -5.63 to -2.08; P < 0.0001), and platelet concentrate (MD: -10.66; 95% CI: -18.45 to -2.87; P = 0.007), and had a lower re-exploration rate (RR: 0.46; 95% CI: 0.23 to 0.92; P = 0.03). Prophylactic EACA also improved coagulation tests 6 hours after open-heart surgery. Prophylactic EACA minimizes postoperative blood transfusion and helps maintain coagulation in pediatric patients undergoing open-heart surgery. Therefore, the results of this study indicate that adjunctive EACA is a good choice for the prevention of postoperative blood transfusion following pediatric cardiac surgery.

Home urine C-peptide creatinine ratio (UCPCR) testing can identify type 2 and MODY in pediatric diabetes.

PubMed

Besser, Rachel E J; Shields, Beverley M; Hammersley, Suzanne E; Colclough, Kevin; McDonald, Timothy J; Gray, Zoe; Heywood, James J N; Barrett, Timothy G; Hattersley, Andrew T

2013-05-01

Making the correct diabetes diagnosis in children is crucial for lifelong management. Type 2 diabetes and maturity onset diabetes of the young (MODY) are seen in the pediatric setting, and can be difficult to discriminate from type 1 diabetes. Postprandial urinary C-peptide creatinine ratio (UCPCR) is a non-invasive measure of endogenous insulin secretion that has not been tested as a diagnostic tool in children or in patients with diabetes duration <5 yr. We aimed to assess whether UCPCR can discriminate type 1 diabetes from MODY and type 2 in pediatric diabetes. Two-hour postprandial UCPCR was measured in 264 patients aged <21 yr (type 1, n = 160; type 2, n = 41; and MODY, n = 63). Receiver operating characteristic curves were used to identify the optimal UCPCR cutoff for discriminating diabetes subtypes. UCPCR was lower in type 1 diabetes [0.05 (<0.03-0.39) nmol/mmol median (interquartile range)] than in type 2 diabetes [4.01 (2.84-5.74) nmol/mmol, p < 0.0001] and MODY [3.51 (2.37-5.32) nmol/mmol, p < 0.0001]. UCPCR was similar in type 2 diabetes and MODY (p = 0.25), so patients were combined for subsequent analyses. After 2-yr duration, UCPCR ≥ 0.7 nmol/mmol has 100% sensitivity [95% confidence interval (CI): 92-100] and 97% specificity (95% CI: 91-99) for identifying non-type 1 (MODY + type 2 diabetes) from type 1 diabetes [area under the curve (AUC) 0.997]. UCPCR was poor at discriminating MODY from type 2 diabetes (AUC 0.57). UCPCR testing can be used in diabetes duration greater than 2 yr to identify pediatric patients with non-type 1 diabetes. UCPCR testing is a practical non-invasive method for use in the pediatric outpatient setting. © 2013 John Wiley & Sons A/S.

New Breed of Mice May Improve Accuracy for Preclinical Testing of Cancer Drugs | Poster

Cancer.gov

A new breed of lab animals, dubbed “glowing head mice,” may do a better job than conventional mice in predicting the success of experimental cancer drugs—while also helping to meet an urgent need for more realistic preclinical animal models. The mice were developed to tolerate often-used light-emitting molecules, such as luciferase from fireflies and green fluorescent protein (GFP) from jellyfish. These “optical reporters” are useful for monitoring the effect of experimental therapies in live animals over time because they emit an immediate and easily detected light signal showing whether a tumor inside the animal’s body is shrinking as desired.

In vivo preclinical verification of a multimodal diffuse reflectance and correlation spectroscopy system for sensing tissue perfusion

NASA Astrophysics Data System (ADS)

Pakela, Julia M.; Lee, Seung Yup; Hedrick, Taylor L.; Vishwanath, Karthik; Helton, Michael C.; Chung, Yooree G.; Kolodziejski, Noah J.; Staples, Christopher J.; McAdams, Daniel R.; Fernandez, Daniel E.; Christian, James F.; O'Reilly, Jameson; Farkas, Dana; Ward, Brent B.; Feinberg, Stephen E.; Mycek, Mary-Ann

2017-02-01

In reconstructive surgery, impeded blood flow in microvascular free flaps due to a compromise in arterial or venous patency secondary to blood clots or vessel spasms can rapidly result in flap failures. Thus, the ability to detect changes in microvascular free flaps is critical. In this paper, we report progress on in vivo pre-clinical testing of a compact, multimodal, fiber-based diffuse correlation and reflectance spectroscopy system designed to quantitatively monitor tissue perfusion in a porcine model's surgically-grafted free flap. We also describe the device's sensitivity to incremental blood flow changes and discuss the prospects for continuous perfusion monitoring in future clinical translational studies.

Minnelide reduces tumor burden in preclinical models of osteosarcoma.

PubMed

Banerjee, Sulagna; Thayanithy, Venugopal; Sangwan, Veena; Mackenzie, Tiffany N; Saluja, Ashok K; Subramanian, Subbaya

2013-07-28

Osteosarcoma is the most common bone cancer in children and adolescents with a 5-year survival rate of about 70%. In this study, we have evaluated the preclinical therapeutic efficacy of the novel synthetic drug, Minnelide, a prodrug of triptolide on osteosarcoma. Triptolide was effective in significantly inducing apoptosis in all osteosarcoma cell lines tested but had no significant effect on the human osteoblast cells. Notably, Minnelide treatment significantly reduced tumor burden and lung metastasis in the orthotopic and lung colonization models. Triptolide/Minnelide effectively downregulated the levels of pro-survival proteins such as heat shock proteins, cMYC, survivin and targets the NF-κB pathway. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

SU-E-T-606: Performance of MR-Based 3D FXG Dosimetry for Preclinical Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Welch, M; Jaffray, D; Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON

Purpose: Technological advances have revolutionized preclinical radiation research to enable precise radiation delivery in preclinical models. Kilovoltage x-rays and complex geometries in preclinical radiation studies challenge conventional dosimetry methods. Previously developed gel-based dosimetry provides a viable means of accommodating complex geometries and accurately reporting dose at kV energies. This paper will describe the development and evaluation of gel-based ferrous xylenol-orange (FXG) dosimetry using a 7T preclinical imaging system. Methods: To confirm water equivalence, Zeff values were calculated for the FXG material, water and ICRU defined soft tissue. Proton T1 relaxivity response in FXG was measured using a preclinical 7T MRmore » and a small animal irradiator for a dose range of 1–22 Gy. FXG was contained in 50 ml centrifuge tubes and irradiated with a 225 kVp x-ray beam at a nominal dose rate of 2.3 Gy/min. Pre and post irradiation maps of the T1 relaxivity were collected using variable TR spin-echo imaging (TE 6.65 ms; TR 500, 750, 1000, 1500, 2000, 3000 and 5000 ms) with 2 mm thick slices, 0.325 mm/pixel, 3 averages and an acquisition time of 26 minutes. A linear fit to the change in relaxation rate (1/T1) for the delivered doses reported the gel sensitivity in units of ms{sup -1}Gy{sup -1}. Irradiation and imaging studies were repeated using three batches of gel over 72 hrs. Results: FXG has a Zeff of 3.8 for the 225 kVp spectrum used; differing from water and ICRU defined soft tissue by 0.5% and 2.5%, respectively. The average sensitivity for the FXG dosimeter was 31.5 ± 0.7 ms{sup -1}Gy{sup -1} (R{sup 2} = 0.9957) with a y-intercept of −29.4 ± 9.0 ms{sup -1}. Conclusion: Preliminary results for the FXG dosimeter properties, sensitivity, and dose linearity at preclinical energies is promising. Future work will explore anatomically relevant tissue inclusions to test MR performance. Student funding provided by The Terry Fox Foundation Strategic Initiative for Excellence in Radiation Research for the 21st Century at CIHR and the Gifford Ontario Student Opportunity Trust Fund.« less

The development of neural stimulators: a review of preclinical safety and efficacy studies.

PubMed

Shepherd, Robert K; Villalobos, Joel; Burns, Owen; Nayagam, David

2018-05-14

Given the rapid expansion of the field of neural stimulation and the rigorous regulatory approval requirements required before these devices can be applied clinically, it is important that there is clarity around conducting preclinical safety and efficacy studies required for the development of this technology. The present review examines basic design principles associated with the development of a safe neural stimulator and describes the suite of preclinical safety studies that need to be considered when taking a device to clinical trial. Neural stimulators are active implantable devices that provide therapeutic intervention, sensory feedback or improved motor control via electrical stimulation of neural or neuro-muscular tissue in response to trauma or disease. Because of their complexity, regulatory bodies classify these devices in the highest risk category (Class III), and they are therefore required to go through a rigorous regulatory approval process before progressing to market. The successful development of these devices is achieved through close collaboration across disciplines including engineers, scientists and a surgical/clinical team, and the adherence to clear design principles. Preclinical studies form one of several key components in the development pathway from concept to product release of neural stimulators. Importantly, these studies provide iterative feedback in order to optimise the final design of the device. Key components of any preclinical evaluation include: in vitro studies that are focussed on device reliability and include accelerated testing under highly controlled environments; in vivo studies using animal models of the disease or injury in order to assess safety and, given an appropriate animal model, the efficacy of the technology under both passive and electrically active conditions; and human cadaver and ex vivo studies designed to ensure the device's form factor conforms to human anatomy, to optimise the surgical approach and to develop any specialist surgical tooling required. The pipeline from concept to commercialisation of these devices is long and expensive; careful attention to both device design and its preclinical evaluation will have significant impact on the duration and cost associated with taking a device through to commercialisation. Carefully controlled in vitro and in vivo studies together with ex vivo and human cadaver trials are key components of a thorough preclinical evaluation of any new neural stimulator. © 2018 IOP Publishing Ltd.

The discovery and development of proteomic safety biomarkers for the detection of drug-induced liver toxicity.

PubMed

Amacher, David E

2010-05-15

Biomarkers are biometric measurements that provide critical quantitative information about the biological condition of the animal or individual being tested. In drug safety studies, established toxicity biomarkers are used along with other conventional study data to determine dose-limiting organ toxicity, and to define species sensitivity for new chemical entities intended for possible use as human medicines. A continuing goal of drug safety scientists in the pharmaceutical industry is to discover and develop better trans-species biomarkers that can be used to determine target organ toxicities for preclinical species in short-term studies at dose levels that are some multiple of the intended human dose and again later in full development for monitoring clinical trials at lower therapeutic doses. Of particular value are early, predictive, noninvasive biomarkers that have in vitro, in vivo, and clinical transferability. Such translational biomarkers bridge animal testing used in preclinical science and human studies that are part of subsequent clinical testing. Although suitable for in vivo preclinical regulatory studies, conventional hepatic safety biomarkers are basically confirmatory markers because they signal organ toxicity after some pathological damage has occurred, and are therefore not well-suited for short-term, predictive screening assays early in the discovery-to-development progression of new chemical entities (NCEs) available in limited quantities. Efforts between regulatory agencies and the pharmaceutical industry are underway for the coordinated discovery, qualification, verification and validation of early predictive toxicity biomarkers. Early predictive safety biomarkers are those that are detectable and quantifiable prior to the onset of irreversible tissue injury and which are associated with a mechanism of action relevant to a specific type of potential hepatic injury. Potential drug toxicity biomarkers are typically endogenous macromolecules in biological fluids with varying immunoreactivity which can present bioanalytical challenges when first discovered. The potential success of these efforts is greatly enhanced by recent advances in two closely linked technologies, toxicoproteomics and targeted, quantitative mass spectrometry. This review focuses on the examination of the current status of these technologies as they relate to the discovery and development of novel preclinical biomarkers of hepatotoxicity. A critical assessment of the current literature reveals two distinct lines of safety biomarker investigation, (1) peripheral fluid biomarkers of organ toxicity and (2) tissue or cell-based toxicity signatures. Improved peripheral fluid biomarkers should allow the sensitive detection of potential organ toxicity prior to the onset of overt organ pathology. Advancements in tissue or cell-based toxicity biomarkers will provide sensitive in vitro or ex vivo screening systems based on toxicity pathway markers. An examination of the current practices in clinical pathology and the critical evaluation of some recently proposed biomarker candidates in comparison to the desired characteristics of an ideal toxicity biomarker lead this author to conclude that a combination of selected biomarkers will be more informative if not predictive of potential animal organ toxicity than any single biomarker, new or old. For the practical assessment of combinations of conventional and/or novel toxicity biomarkers in rodent and large animal preclinical species, mass spectrometry has emerged as the premier analytical tool compared to specific immunoassays or functional assays. Selected and multiple reaction monitoring mass spectrometry applications make it possible for this same basic technology to be used in the progressive stages of biomarker discovery, development, and more importantly, routine study applications without the use of specific antibody reagents. This technology combined with other "omics" technologies can provide added selectivity and sensitivity in preclinical drug safety testing.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Amacher, David E.

Biomarkers are biometric measurements that provide critical quantitative information about the biological condition of the animal or individual being tested. In drug safety studies, established toxicity biomarkers are used along with other conventional study data to determine dose-limiting organ toxicity, and to define species sensitivity for new chemical entities intended for possible use as human medicines. A continuing goal of drug safety scientists in the pharmaceutical industry is to discover and develop better trans-species biomarkers that can be used to determine target organ toxicities for preclinical species in short-term studies at dose levels that are some multiple of the intendedmore » human dose and again later in full development for monitoring clinical trials at lower therapeutic doses. Of particular value are early, predictive, noninvasive biomarkers that have in vitro, in vivo, and clinical transferability. Such translational biomarkers bridge animal testing used in preclinical science and human studies that are part of subsequent clinical testing. Although suitable for in vivo preclinical regulatory studies, conventional hepatic safety biomarkers are basically confirmatory markers because they signal organ toxicity after some pathological damage has occurred, and are therefore not well-suited for short-term, predictive screening assays early in the discovery-to-development progression of new chemical entities (NCEs) available in limited quantities. Efforts between regulatory agencies and the pharmaceutical industry are underway for the coordinated discovery, qualification, verification and validation of early predictive toxicity biomarkers. Early predictive safety biomarkers are those that are detectable and quantifiable prior to the onset of irreversible tissue injury and which are associated with a mechanism of action relevant to a specific type of potential hepatic injury. Potential drug toxicity biomarkers are typically endogenous macromolecules in biological fluids with varying immunoreactivity which can present bioanalytical challenges when first discovered. The potential success of these efforts is greatly enhanced by recent advances in two closely linked technologies, toxicoproteomics and targeted, quantitative mass spectrometry. This review focuses on the examination of the current status of these technologies as they relate to the discovery and development of novel preclinical biomarkers of hepatotoxicity. A critical assessment of the current literature reveals two distinct lines of safety biomarker investigation, (1) peripheral fluid biomarkers of organ toxicity and (2) tissue or cell-based toxicity signatures. Improved peripheral fluid biomarkers should allow the sensitive detection of potential organ toxicity prior to the onset of overt organ pathology. Advancements in tissue or cell-based toxicity biomarkers will provide sensitive in vitro or ex vivo screening systems based on toxicity pathway markers. An examination of the current practices in clinical pathology and the critical evaluation of some recently proposed biomarker candidates in comparison to the desired characteristics of an ideal toxicity biomarker lead this author to conclude that a combination of selected biomarkers will be more informative if not predictive of potential animal organ toxicity than any single biomarker, new or old. For the practical assessment of combinations of conventional and/or novel toxicity biomarkers in rodent and large animal preclinical species, mass spectrometry has emerged as the premier analytical tool compared to specific immunoassays or functional assays. Selected and multiple reaction monitoring mass spectrometry applications make it possible for this same basic technology to be used in the progressive stages of biomarker discovery, development, and more importantly, routine study applications without the use of specific antibody reagents. This technology combined with other 'omics' technologies can provide added selectivity and sensitivity in preclinical drug safety testing.« less

Qualitative Evaluation of Pediatric Pain Behavior, Quality, and Intensity Item Candidates and the PROMIS Pain Domain Framework in Children With Chronic Pain.

PubMed

Jacobson, C Jeffrey; Kashikar-Zuck, Susmita; Farrell, Jennifer; Barnett, Kimberly; Goldschneider, Ken; Dampier, Carlton; Cunningham, Natoshia; Crosby, Lori; DeWitt, Esi Morgan

2015-12-01

As initial steps in a broader effort to develop and test pediatric pain behavior and pain quality item banks for the Patient-Reported Outcomes Measurement Information System (PROMIS), we used qualitative interview and item review methods to 1) evaluate the overall conceptual scope and content validity of the PROMIS pain domain framework among children with chronic/recurrent pain conditions, and 2) develop item candidates for further psychometric testing. To elicit the experiential and conceptual scope of pain outcomes across a variety of pediatric recurrent/chronic pain conditions, we conducted 32 semi-structured individual and 2 focus-group interviews with children and adolescents (8-17 years), and 32 individual and 2 focus-group interviews with parents of children with pain. Interviews with pain experts (10) explored the operational limits of pain measurement in children. For item bank development, we identified existing items from measures in the literature, grouped them by concept, removed redundancies, and modified the remaining items to match PROMIS formatting. New items were written as needed and cognitive debriefing was completed with the children and their parents, resulting in 98 pain behavior (47 self, 51 proxy), 54 quality, and 4 intensity items for further testing. Qualitative content analyses suggest that reportable pain outcomes that matter to children with pain are captured within and consistent with the pain domain framework in PROMIS. PROMIS pediatric pain behavior, quality, and intensity items were developed based on a theoretical framework of pain that was evaluated by multiple stakeholders in the measurement of pediatric pain, including researchers, clinicians, and children with pain and their parents, and the appropriateness of the framework was verified. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Anti-CD22 immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-positive hematologic malignancies of childhood: preclinical studies and phase I clinical trial.

PubMed

Wayne, Alan S; Kreitman, Robert J; Findley, Harry W; Lew, Glen; Delbrook, Cynthia; Steinberg, Seth M; Stetler-Stevenson, Maryalice; Fitzgerald, David J; Pastan, Ira

2010-03-15

Although most children with B-lineage acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma are cured, new agents are needed to overcome drug resistance and reduce toxicities of chemotherapy. We hypothesized that the novel anti-CD22 immunotoxin, RFB4(dsFv)-PE38 (BL22, CAT-3888), would be active and have limited nonspecific side effects in children with CD22-expressing hematologic malignancies. We conducted the first preclinical and phase I clinical studies of BL22 in that setting. Lymphoblasts from children with B-lineage ALL were assessed for CD22 expression by flow cytometry and for BL22 sensitivity by in vitro cytotoxicity assay. BL22 was evaluated in a human ALL murine xenograft model. A phase I clinical trial was conducted for pediatric subjects with CD22+ ALL and non-Hodgkin lymphoma. All samples screened were CD22+. BL22 was cytotoxic to blasts in vitro (median IC(50), 9.8 ng/mL) and prolonged the leukemia-free survival of murine xenografts. Phase I trial cohorts were treated at escalating doses and schedules ranging from 10 to 40 microg/kg every other day for three or six doses repeated every 21 or 28 days. Treatment was associated with an acceptable safety profile, adverse events were rapidly reversible, and no maximum tolerated dose was defined. Pharmacokinetics were influenced by disease burden consistent with rapid drug binding by CD22+ blasts. Although no responses were observed, transient clinical activity was seen in most subjects. CD22 represents an excellent target and anti-CD22 immunotoxins offer therapeutic promise in B-lineage hematologic malignancies of childhood.

L-MTP-PE and zoledronic acid combination in osteosarcoma: preclinical evidence of positive therapeutic combination for clinical transfer

PubMed Central

Biteau, Kevin; Guiho, Romain; Chatelais, Mathias; Taurelle, Julien; Chesneau, Julie; Corradini, Nadège; Heymann, Dominique; Redini, Françoise

2016-01-01

Osteosarcoma, the most frequent malignant primary bone tumor in pediatric patients is characterized by osteolysis promoting tumor growth. Lung metastasis is the major bad prognosis factor of this disease. Zoledronic Acid (ZA), a potent inhibitor of bone resorption is currently evaluated in phase III randomized studies in Europe for the treatment of osteosarcoma and Ewing sarcoma. The beneficial effect of the liposomal form of Muramyl-TriPeptide-Phosphatidyl Ethanolamine (L-mifamurtide, MEPACT®), an activator of macrophage populations has been demonstrated to eradicate lung metastatic foci in osteosarcoma. The objective of this study was to evaluate the potential therapeutic benefit and the safety of the ZA and L-mifamurtide combination in preclinical models of osteosarcoma, as a prerequisite before translation to patients. The effects of ZA (100 μg/kg) and L-mifamurtide (1 mg/kg) were investigated in vivo in xenogeneic and syngeneic mice models of osteosarcoma, at clinical (tumor proliferation, spontaneous lung metastases development), radiological (bone microarchitecture by microCT analysis), biological and histological levels. No interference between the two drugs could be observed on ZA-induced bone protection and on L-mifamurtide-induced inhibition of lung metastasis development. Unexpectedly, ZA and L-mifamurtide association induced an additional and in some cases synergistic inhibition of primary tumor progression. L-mifamurtide has no effect on tumor proliferation in vitro or in vivo, and macrophage population was not affected at the tumor site whatever the treatment. This study evidenced for the first time a significant inhibition of primary osteosarcoma progression when both drugs are combined. This result constitutes a first proof-of-principle for clinical application in osteosarcoma patients. PMID:27152244

SU-C-209-06: Improving X-Ray Imaging with Computer Vision and Augmented Reality

DOE Office of Scientific and Technical Information (OSTI.GOV)

MacDougall, R.D.; Scherrer, B; Don, S

Purpose: To determine the feasibility of using a computer vision algorithm and augmented reality interface to reduce repeat rates and improve consistency of image quality and patient exposure in general radiography. Methods: A prototype device, designed for use with commercially available hardware (Microsoft Kinect 2.0) capable of depth sensing and high resolution/frame rate video, was mounted to the x-ray tube housing as part of a Philips DigitalDiagnost digital radiography room. Depth data and video was streamed to a Windows 10 PC. Proprietary software created an augmented reality interface where overlays displayed selectable information projected over real-time video of the patient.more » The information displayed prior to and during x-ray acquisition included: recognition and position of ordered body part, position of image receptor, thickness of anatomy, location of AEC cells, collimated x-ray field, degree of patient motion and suggested x-ray technique. Pre-clinical data was collected in a volunteer study to validate patient thickness measurements and x-ray images were not acquired. Results: Proprietary software correctly identified ordered body part, measured patient motion, and calculated thickness of anatomy. Pre-clinical data demonstrated accuracy and precision of body part thickness measurement when compared with other methods (e.g. laser measurement tool). Thickness measurements provided the basis for developing a database of thickness-based technique charts that can be automatically displayed to the technologist. Conclusion: The utilization of computer vision and commercial hardware to create an augmented reality view of the patient and imaging equipment has the potential to drastically improve the quality and safety of x-ray imaging by reducing repeats and optimizing technique based on patient thickness. Society of Pediatric Radiology Pilot Grant; Washington University Bear Cub Fund.« less

Decreasing unnecessary utilization in acute bronchiolitis care: results from the value in inpatient pediatrics network.

PubMed

Ralston, Shawn; Garber, Matthew; Narang, Steve; Shen, Mark; Pate, Brian; Pope, John; Lossius, Michele; Croland, Trina; Bennett, Jeff; Jewell, Jennifer; Krugman, Scott; Robbins, Elizabeth; Nazif, Joanne; Liewehr, Sheila; Miller, Ansley; Marks, Michelle; Pappas, Rita; Pardue, Jeanann; Quinonez, Ricardo; Fine, Bryan R; Ryan, Michael

2013-01-01

Acute viral bronchiolitis is the most common diagnosis resulting in hospital admission in pediatrics. Utilization of non-evidence-based therapies and testing remains common despite a large volume of evidence to guide quality improvement efforts. Our objective was to reduce utilization of unnecessary therapies in the inpatient care of bronchiolitis across a diverse network of clinical sites. We formed a voluntary quality improvement collaborative of pediatric hospitalists for the purpose of benchmarking the use of bronchodilators, steroids, chest radiography, chest physiotherapy, and viral testing in bronchiolitis using hospital administrative data. We shared resources within the network, including protocols, scores, order sets, and key bibliographies, and established group norms for decreasing utilization. Aggregate data on 11,568 hospitalizations for bronchiolitis from 17 centers was analyzed for this report. The network was organized in 2008. By 2010, we saw a 46% reduction in overall volume of bronchodilators used, a 3.4 dose per patient absolute decrease in utilization (95% confidence interval [CI] 1.4-5.8). Overall exposure to any dose of bronchodilator decreased by 12 percentage points as well (95% CI 5%-25%). There was also a statistically significant decline in chest physiotherapy usage, but not for steroids, chest radiography, or viral testing. Benchmarking within a voluntary pediatric hospitalist collaborative facilitated decreased utilization of bronchodilators and chest physiotherapy in bronchiolitis. Copyright © 2012 Society of Hospital Medicine.

Developing and Pilot Testing the Readiness and Motivation Interview for Families in Pediatric Weight Management.

PubMed

Geller, Josie; Avis, Jillian; Srikameswaran, Suja; Zelichowska, Joanna; Dartnell, Katie; Scheuerman, Bailey; Perez, Arnaldo; Rasquinha, Allison; Brown, Krista E; Chanoine, Jean-Pierre; Ball, Geoff

2015-12-01

Clinical acumen is often used to assess families' motivation prior to initiating pediatric obesity management due to a lack of available tools. The purpose of this pilot study was to (i) develop and (ii) pilot test the "Readiness and Motivation Interview for Families" (RMI-Family) in pediatric weight management. We conducted 5 focus groups with parents (n = 15), youth with obesity (n = 11), and health care providers (n = 8) to explore perceptions of barriers to making healthy behaviour changes, which led to the creation of the RMI-Family as a semi-structured interview. Five domains (treat foods, overeating, emotional eating, total physical activity, and screen time) emerged from the focus groups to inform the development of the RMI-Family, which was then pilot tested with a sample of youth with obesity and their parents (n = 11 dyads). Interviewers administered the RMI-Family to youth (age 12.8 ± 1.7 years; body mass index [BMI] z-score: 2.71 ± 0.43) and parents (age 47.1 ± 3.7 years; BMI: 33.5 ± 10.1 kg/m(2)). The RMI-Family was feasible to administer, easily understood by families, and may be a useful tool for assessing families' motivation. Research is underway to determine the psychometric properties and utility of the RMI-Family in predicting clinical outcomes in pediatric weight management.

Federating clinical data from six pediatric hospitals: process and initial results for microbiology from the PHIS+ consortium.

PubMed

Gouripeddi, Ramkiran; Warner, Phillip B; Mo, Peter; Levin, James E; Srivastava, Rajendu; Shah, Samir S; de Regt, David; Kirkendall, Eric; Bickel, Jonathan; Korgenski, E Kent; Precourt, Michelle; Stepanek, Richard L; Mitchell, Joyce A; Narus, Scott P; Keren, Ron

2012-01-01

Microbiology study results are necessary for conducting many comparative effectiveness research studies. Unlike core laboratory test results, microbiology results have a complex structure. Federating and integrating microbiology data from six disparate electronic medical record systems is challenging and requires a team of varied skills. The PHIS+ consortium which is partnership between members of the Pediatric Research in Inpatient Settings (PRIS) network, the Children's Hospital Association and the University of Utah, have used "FURTHeR' for federating laboratory data. We present our process and initial results for federating microbiology data from six pediatric hospitals.

Targeting the phosphatidylinositol 3-kinase/Akt/mechanistic target of rapamycin signaling pathway in B-lineage acute lymphoblastic leukemia: An update.

PubMed

Simioni, Carolina; Martelli, Alberto M; Zauli, Giorgio; Vitale, Marco; McCubrey, James A; Capitani, Silvano; Neri, Luca M

2018-04-18

Despite considerable progress in treatment protocols, B-lineage acute lymphoblastic leukemia (B-ALL) displays a poor prognosis in about 15-20% of pediatric cases and about 60% of adult patients. In addition, life-long irreversible late effects from chemo- and radiation therapy, including secondary malignancies, are a growing problem for leukemia survivors. Targeted therapy holds promising perspectives for cancer treatment as it may be more effective and have fewer side effects than conventional therapies. The phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway is a key regulatory cascade which controls proliferation, survival and drug-resistance of cancer cells, and it is frequently upregulated in the different subtypes of B-ALL, where it plays important roles in the pathophysiology, maintenance and progression of the disease. Moreover, activation of this signaling cascade portends a poorer prognosis in both pediatric and adult B-ALL patients. Promising preclinical data on PI3K/Akt/mTOR inhibitors have documented their anticancer activity in B-ALL and some of these novel drugs have entered clinical trials as they could lead to a longer event-free survival and reduce therapy-associated toxicity for patients with B-ALL. This review highlights the current status of PI3K/Akt/mTOR inhibitors in B-ALL, with an emphasis on emerging evidence of the superior efficacy of synergistic combinations involving the use of traditional chemotherapeutics or other novel, targeted agents. © 2018 Wiley Periodicals, Inc.

Pre-diagnostic Clinical Presentations and Medical History Prior to the Diagnosis of Inflammatory Bowel Disease in Children.

PubMed

Kwon, Yong Hoon; Kim, Yong Joo

2013-09-01

The clinical presentations of inflammatory bowel disease (IBD) prior to diagnosis are so diverse or vague that many of them waste time before final diagnosis. This study was undertaken to know the medical history of the pediatric patients until the final diagnosis could be reached. The medical records of all pediatric patients who were diagnosed with IBD (Crohn's disease [CD] in 14 children, ulcerative colitis [UC] in 17) during the last 13 years were reviewed. We investigated the length of the diagnostic time lag, chief clinical presentation, and any useful laboratory predictor among the routinely performed examinations. Indeterminate colitis was not included. The mean ages of children at the final diagnosis was similar in both diseases. As for the pre-clinical past history of bowel symptoms in CD patients, 5 were previously healthy, 9 had had 1-3 gastrointestinal (GI) symptoms, weight loss, bloody stool, anemia and rectal prolapse. With UC, 9 were previously healthy, 8 had had 1-3 GI symptoms, bloody stool, anorexia. The average diagnostic time lag with CD was 3.36 months, and with UC 2.2 months. Body mass index (BMI) and the initial basic laboratory data (white blood cell, hemoglobin, mean corpuscular volume, serum albumin, and serum total protein) were lower in CD, statistically significant only in BMI. IBD shows diverse clinical symptoms before its classical features, making the patients waste time until diagnosis. It is important to concern possibility of IBD even in the mildly sick children who do not show the characteristic symptoms of IBD.

Optimization and Dose Estimation of Aerosol Delivery to Non-Human Primates.

PubMed

MacLoughlin, Ronan J; van Amerongen, Geert; Fink, James B; Janssens, Hettie M; Duprex, W Paul; de Swart, Rik L

2016-06-01

In pre-clinical animal studies, the uniformity of dosing across subjects and routes of administration is a crucial requirement. In preparation for a study in which aerosolized live-attenuated measles virus vaccine was administered to cynomolgus monkeys (Macaca fascicularis) by inhalation, we assessed the percentage of a nebulized dose inhaled under varying conditions. Drug delivery varies with breathing parameters. Therefore we determined macaque breathing patterns (tidal volume, breathing frequency, and inspiratory to expiratory (I:E) ratio) across a range of 3.3-6.5 kg body weight, using a pediatric pneumotachometer interfaced either with an endotracheal tube or a facemask. Subsequently, these breathing patterns were reproduced using a breathing simulator attached to a filter to collect the inhaled dose. Albuterol was nebulized using a vibrating mesh nebulizer and the percentage inhaled dose was determined by extraction of drug from the filter and subsequent quantification. Tidal volumes ranged from 24 to 46 mL, breathing frequencies from 19 to 31 breaths per minute and I:E ratios from 0.7 to 1.6. A small pediatric resuscitation mask was identified as the best fitting interface between animal and pneumotachometer. The average efficiency of inhaled dose delivery was 32.1% (standard deviation 7.5, range 24%-48%), with variation in tidal volumes as the most important determinant. Studies in non-human primates aimed at comparing aerosol delivery with other routes of administration should take both the inter-subject variation and relatively low efficiency of delivery to these low body weight mammals into account.

Roles of Vitamins D and K, Nutrition, and Lifestyle in Low-Energy Bone Fractures in Children and Young Adults.

PubMed

Karpiński, Michał; Popko, Janusz; Maresz, Katarzyna; Badmaev, Vladimir; Stohs, Sidney J

2017-07-01

The research on skeletal system health in children and young adults, while recognizing the important role of calcium and vitamin D, goes beyond these nutritional standards. This review focuses on the role of vitamin K in combination with vitamin D and other factors in bone health. The current understanding is that maintaining bone health and prevention of low-energy fractures in any pediatric population includes nutritional factors combined with an active lifestyle. Calcium, vitamin D, and vitamin K supplementation contribute independently and collectively to bone health. The beneficial role of vitamin K, particularly vitamin K2 as menaquinone-7 (MK-7), in bone and cardiovascular health is reasonably well supported scientifically, with several preclinical, epidemiological, and clinical studies published over the last decade. Osteocalcin and matrix-Gla (glutamate-containing) protein (MGP) exemplify vitamin K-dependent proteins involved in building bone matrix and keeping calcium from accumulating in the arterial walls, respectively. An important part of the mechanism of vitamin K involves carboxylation and posttranslational activation of the family of vitamin K-dependent proteins, which prevent expression of pro-inflammatory factors and support improvement in bone mineral concentration, bone mineral density, and the quality of bone matrix. Understanding the combined approach to a healthy skeletal system in children and young adults, including the roles of vitamins D and K, calcium, healthy diet, and exercise, is particularly important in view of reports of subclinical insufficiency of vitamins D and K in otherwise healthy pediatric populations with low-energy bone fractures.

Functional Observational Battery Testing for Nervous System Effects of Drugs and Other Chemicals

EPA Science Inventory

Screening for behavioral toxicity, or neurotoxicity, has become standard practice in preclinical safety pharmacology and toxicology. Behavior represents the integrated sum of activities mediated by the nervous system. Current screening batteries, such as the functional observat...

Metabolomics in Toxicology and Preclinical Research, a t4 Workshop Report

EPA Science Inventory

Metabolomics, the comprehensive analysis of metabolites in a biological system, provides detailed information about the biochemical/physiological condition of the test system, and of changes affected by anthropogenic chemicals. Metabolomic analysis is used in many fields, ranging...

The effect of transfers between health care facilities on costs and length of stay for pediatric burn patients.

PubMed

Myers, John; Smith, Michael; Woods, Charles; Espinosa, Claudia; Lehna, Carlee

2015-01-01

Hospitals vary widely in the services they offer to care for pediatric burn patients. When a hospital does not have the ability or capacity to handle a pediatric burn, the decision often is made to transfer the patient to another short-term hospital. Transfers may be based on available specialty coverage for children; which adult and non-teaching hospitals may not have available. The effect these transfers have on costs and length of stay (LOS) has on pediatric burn patients is not well established and is warranted given the prominent view that pediatric hospitals are inefficient or more costly. The authors examined inpatient admissions for pediatric burn patients in 2003, 2006, and 2009 using the Kids' Inpatient Database, which is part of the Healthcare Cost and Utilization Project. ICD-9-CM codes 940 to 947 were used to define burn injury. The authors tested if transfer status was associated with LOS and total charges for pediatric burn patients, while adjusting for traditional risk factors (eg, age, TBSA, insurance status, type of hospital [pediatric vs adult; teaching vs nonteaching]) by using generalized linear mixed-effects modeling. A total of n = 28,777 children had a burn injury. Transfer status (P < .001) and TBSA (P < .001) was independently associated with LOS, while age, insurance status, and type of hospital were not associated with LOS. Similarly, transfer status (P < .001) and TBSA (P < .001) was independently associated with total charges, while age, insurance status, and type of hospital were not associated with total charges. In addition, the data suggest that the more severe pediatric burn patients are being transferred from adult and non-teaching hospitals to pediatric and teaching hospitals, which may explain the increased costs and LOS seen at pediatric hospitals. Larger more severe burns are being transferred to pediatric hospitals with the ability or capacity to handle these conditions in the pediatric population, which has a dramatic impact on costs and LOS. As a result, unadjusted, pediatric hospitals are seen as being inefficient in treating pediatric burns. However, since pediatric hospitals see more severe cases, after adjustment, type of hospital did not influence costs and LOS. TBSA and transfer status were the predictors studied that independently affect costs and LOS.

Identification and preclinical testing of novel antiepileptic compounds.

PubMed

Meldrum, B S

1997-01-01

Procedures for identifying novel antiepileptic drugs (AEDs) are changing and need to change more. Widespread reliance on two primary screens has led to the identification of novel compounds that resemble either phenytoin (suppressing high-frequency repetitive firing in cultured neurons and prolonging inactivation of voltage-dependent sodium channels identified by the maximal electroshock test) or benzodiazepines (potentiating the inhibitory effect of gamma-aminobutyric acid (GABA), identified by the threshold pentylenetetrazol test). Advances in molecular neurobiology have identified specific molecular targets (subunits of ion channels, neurotransmitter receptors, and transporters) and have made them available in a form permitting high-throughput screening. AEDs can be designed to interact with specific sites on the target molecules. Alternatively, the molecular screens can be used to identify active components in natural products, including folk remedies. Preclinical in vivo screens can be improved by using animals with genetic or acquired epilepsies that have similar modifications in the properties of the target molecules as do human epilepsy syndromes. Future work is likely to define molecular targets for AEDs that will block or reverse chronic epileptogenesis.

Demographics of US pediatric contact dermatitis registry providers.

PubMed

Goldenberg, Alina; Jacob, Sharon E

2015-01-01

Children are as likely as adults to be sensitized and reactive to contact allergens. However, the prevailing data on pediatric allergic contact dermatitis are quantitatively and qualitatively limited because of a narrow geographic localization of data-reporting providers. The aim of the study was to present the first quarter results from the Loma Linda Pediatric Contact Dermatitis Registry focused on registered providers who self-identified as providing care for pediatric allergic contact dermatitis (ACD) within the United States. The US providers were invited to join the registry via completion of an online, secure, 11-question registration survey addressing demographics and clinical practice essentials. The presented results reflect data gathered within the first quarter of registry recruitment; registration is ongoing. Of 169 responders from 48 states, the majority of providers were female (60.4%), academic (55.6%), and dermatologists (76.3%). Based on individual provider averages, the minimum cumulative number of pediatric patch-test evaluations performed each year ranged between 1372 and 3468 children. The Pediatric Contact Dermatitis Registry provides a description of the current leaders in the realm of pediatric ACD and gaps, which are in need of attention. The registry allows for a collaborative effort to exchange information, educate providers, and foster investigative research with the hope of legislation that can reduce the disease burden of ACD in US children.

Psychosocial functioning in pediatric heart transplant recipients and their families.

PubMed

Cousino, Melissa K; Schumacher, Kurt R; Rea, Kelly E; Eder, Sally; Zamberlan, Mary; Jordan, Jessica; Fredericks, Emily M

2018-03-01

Across pediatric organ transplant populations, patient and family psychosocial functioning is associated with important health-related outcomes. Research has suggested that pediatric heart transplant recipients and their families are at increased risk for adverse psychosocial outcomes; however, recent investigation of psychosocial functioning in this population is lacking. This study aimed to provide a contemporary characterization of psychosocial functioning in pediatric heart transplant recipients and their families. Associations between psychosocial function, demographic variables, and transplant-related variables were investigated. Fifty-six parents/guardians of pediatric heart transplant recipients completed a comprehensive psychosocial screening measure during transplant follow-up clinic visits. Descriptive statistics, correlational analyses, and independent samples t tests were performed. Forty percent of pediatric heart transplant recipients and their families endorsed clinically meaningful levels of total psychosocial risk. One-third of patients presented with clinically significant psychological problems per parent report. Psychosocial risk was unassociated with demographic or transplant-related factors. Despite notable improvements in the survival of pediatric heart transplant recipients over the past decade, patients and families present with sustained psychosocial risks well beyond the immediate post-transplant period, necessitating mental health intervention to mitigate adverse impact on health-related outcomes. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pediatric medical device development by surgeons via capstone engineering design programs.

PubMed

Sack, Bryan S; Elizondo, Rodolfo A; Huang, Gene O; Janzen, Nicolette; Espinoza, Jimmy; Sanz-Cortes, Magdalena; Dietrich, Jennifer E; Hakim, Julie; Richardson, Eric S; Oden, Maria; Hanks, John; Haridas, Balakrishna; Hury, James F; Koh, Chester J

2018-03-01

There is a need for pediatric medical devices that accommodate the unique physiology and anatomy of pediatric patients that is increasingly receiving more attention. However, there is limited literature on the programs within children's hospitals and academia that can support pediatric device development. We describe our experience with pediatric device design utilizing collaborations between a children's hospital and two engineering schools. Utilizing the academic year as a timeline, unmet pediatric device needs were identified by surgical faculty and matched with an engineering mentor and a team of students within the Capstone Engineering Design programs at two universities. The final prototypes were showcased at the end of the academic year and if appropriate, provisional patent applications were filed. All twelve teams successfully developed device prototypes, and five teams obtained provisional patents. The prototypes that obtained provisional patents included a non-operative ureteral stent removal system, an evacuation device for small kidney stone fragments, a mechanical leech, an anchoring system of the chorio-amniotic membranes during fetal surgery, and a fetal oxygenation monitor during fetoscopic procedures. Capstone Engineering Design programs in partnership with surgical faculty at children's hospitals can play an effective role in the prototype development of novel pediatric medical devices. N/A - No clinical subjects or human testing was performed. Copyright © 2017 Elsevier Inc. All rights reserved.

Analysis of health care claims during the peri-transfer stage of transition from pediatric to adult care among juvenile idiopathic arthritis patients.

PubMed

Mannion, Melissa L; Xie, Fenglong; Baddley, John; Chen, Lang; Curtis, Jeffrey R; Saag, Kenneth; Zhang, Jie; Beukelman, Timothy

2016-09-05

To investigate the utilization of health care services before and after transfer from pediatric to adult rheumatology care in clinical practice. Using US commercial claims data from January 2005 through August 2012, we identified individuals with a JIA diagnosis code from a pediatric rheumatologist followed by any diagnosis code from an adult rheumatologist. Individuals had 6 months observable time before the last pediatric visit and 6 months after the first adult visit. Medication, emergency room, physical therapy use, and diagnosis codes were compared between the pediatric and adult interval using McNemar's test. The proportion of days covered (PDC) of TNFi for the time between last pediatric and first adult visit was calculated. We identified 58 individuals with JIA who transferred from pediatric to adult rheumatology care after the age of 14. The median age at the last pediatric rheumatology visit was 18.1 years old and the median transfer interval was 195 days. 29 % of patients received NSAIDs in the adult interval compared to 43 % in the pediatric interval (p = 0.06). In the pediatric interval, 71 % received a JRA and 0 % received an RA physician diagnosis code compared to 28 and 45 %, respectively, in the adult interval. The median PDC for patients receiving a TNFi was 0.75 during the transfer interval. Individuals with JIA who transferred to adult care were more likely receive a diagnosis of RA instead of JRA and were less likely to receive NSAIDs, but had no significant immediate changes to other medication use.

Management of hypothermia: impact of lecture-based interactive workshops on training of pediatric nurses.

PubMed

Altun, Insaf; Karakoç, Ali

2012-05-01

This study aimed to determine the efficacy of interactive workshop on the management of hypothermia and its impact on pediatric nurses' training. This is a pretest-to-posttest quasi-experimental descriptive study. Thirty pediatric nurses attended an interactive lecture-based interactive workshop on the management of hypothermia. Participants had to accept an invitation to the presentation before the training event. They completed the lecture, and a multiple-choice question test before and after the lecture was given. There was a significant improvement in mean test scores after the lecture when compared with those before the lecture (mean [SD], 15.5 [1.3] vs 5.0 [1.7], P < 0.001). The information gained in this study will be valuable as a baseline for further research and help guide improvements in the management of hypothermia with the ultimate goal of enhancing safe and quality patient care.