Children's Hospital of Michigan

BACKGROUND: Emicizumab (ACE910) bridges activated factor IX and factor X to restore the function of activated factor VIII, which is deficient in persons with hemophilia A. This phase 3, multicenter trial assessed once-weekly subcutaneous emicizumab prophylaxis in persons with hemophilia A with factor VIII inhibitors. METHODS: We enrolled participants who were 12 years of age or older. Those who had previously received episodic treatment with bypassing agents were randomly assigned in a 2:1 ratio to emicizumab prophylaxis (group A) or no prophylaxis (group B). The primary end point was the difference in bleeding rates between group A and group B. Participants who had previously received prophylactic treatment with bypassing agents received emicizumab prophylaxis in group C. RESULTS: A total of 109 male participants with hemophilia A with inhibitors were enrolled. The annualized bleeding rate was 2.9 events (95% confidence interval [CI], 1.7 to 5.0) among participants who were randomly assigned to emicizumab prophylaxis (group A, 35 participants) versus 23.3 events (95% CI, 12.3 to 43.9) among those assigned to no prophylaxis (group B, 18 participants), representing a significant difference of 87% in favor of emicizumab prophylaxis (P<0.001). A total of 22 participants in group A (63%) had zero bleeding events, as compared with 1 participant (6%) in group B. Among 24 participants in group C who had participated in a noninterventional study, emicizumab prophylaxis resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing-agent prophylaxis (P<0.001). Overall, 198 adverse events were reported in 103 participants receiving emicizumab prophylaxis; the most frequent events were injection-site reactions (in 15% of participants). Thrombotic microangiopathy and thrombosis were reported in 2 participants each (in the primary analysis) who had received multiple infusions of activated prothrombin complex concentrate for breakthrough bleeding. No antidrug antibodies were detected. CONCLUSIONS: Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with inhibitors. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 1 ClinicalTrials.gov number, NCT02622321 .).

IMPORTANCE: The recent and ongoing coronavirus disease 2019 (COVID-19) pandemic has taken an unprecedented toll on adults critically ill with COVID-19 infection. While there is evidence that the burden of COVID-19 infection in hospitalized children is lesser than in their adult counterparts, to date, there are only limited reports describing COVID-19 in pediatric intensive care units (PICUs). OBJECTIVE: To provide an early description and characterization of COVID-19 infection in North American PICUs, focusing on mode of presentation, presence of comorbidities, severity of disease, therapeutic interventions, clinical trajectory, and early outcomes. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included children positive for COVID-19 admitted to 46 North American PICUs between March 14 and April 3, 2020. with follow-up to April 10, 2020. MAIN OUTCOMES AND MEASURES: Prehospital characteristics, clinical trajectory, and hospital outcomes of children admitted to PICUs with confirmed COVID-19 infection. RESULTS: Of the 48 children with COVID-19 admitted to participating PICUs, 25 (52%) were male, and the median (range) age was 13 (4.2-16.6) years. Forty patients (83%) had significant preexisting comorbidities; 35 (73%) presented with respiratory symptoms and 18 (38%) required invasive ventilation. Eleven patients (23%) had failure of 2 or more organ systems. Extracorporeal membrane oxygenation was required for 1 patient (2%). Targeted therapies were used in 28 patients (61%), with hydroxychloroquine being the most commonly used agent either alone (11 patients) or in combination (10 patients). At the completion of the follow-up period, 2 patients (4%) had died and 15 (31%) were still hospitalized, with 3 still requiring ventilatory support and 1 receiving extracorporeal membrane oxygenation. The median (range) PICU and hospital lengths of stay for those who had been discharged were 5 (3-9) days and 7 (4-13) days, respectively. CONCLUSIONS AND RELEVANCE: This early report describes the burden of COVID-19 infection in North American PICUs and confirms that severe illness in children is significant but far less frequent than in adults. Prehospital comorbidities appear to be an important factor in children. These preliminary observations provide an important platform for larger and more extensive studies of children with COVID-19 infection.

BACKGROUND: Emicizumab is a bispecific monoclonal antibody that bridges activated factor IX and factor X to replace the function of missing activated factor VIII, thereby restoring hemostasis. In a phase 3, multicenter trial, we investigated its use as prophylaxis in persons who have hemophilia A without factor VIII inhibitors. METHODS: We randomly assigned, in a 2:2:1 ratio, participants 12 years of age or older who had been receiving episodic treatment with factor VIII to receive a subcutaneous maintenance dose of emicizumab of 1.5 mg per kilogram of body weight per week (group A) or 3.0 mg per kilogram every 2 weeks (group B) or no prophylaxis (group C). The primary end point was the difference in rates of treated bleeding (group A vs. group C and group B vs. group C). Participants who had been receiving factor VIII prophylaxis received emicizumab at a maintenance dose of 1.5 mg per kilogram per week (group D); intraindividual comparisons were performed in those who had participated in a noninterventional study. RESULTS: A total of 152 participants were enrolled. The annualized bleeding rate was 1.5 events (95% confidence interval [CI], 0.9 to 2.5) in group A and 1.3 events (95% CI, 0.8 to 2.3) in group B, as compared with 38.2 events (95% CI, 22.9 to 63.8) in group C; thus, the rate was 96% lower in group A and 97% lower in group B (P<0.001 for both comparisons). A total of 56% of the participants in group A and 60% of those in group B had no treated bleeding events, as compared with those in group C, who all had treated bleeding events. In the intraindividual comparison involving 48 participants, emicizumab prophylaxis resulted in an annualized bleeding rate that was 68% lower than the rate with previous factor VIII prophylaxis (P<0.001). The most frequent adverse event was low-grade injection-site reaction. There were no thrombotic or thrombotic microangiopathy events, development of antidrug antibodies, or new development of factor VIII inhibitors. CONCLUSIONS: Emicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no prophylaxis among persons with hemophilia A without inhibitors; more than half the participants who received prophylaxis had no treated bleeding events. In an intraindividual comparison, emicizumab therapy led to a significantly lower bleeding rate than previous factor VIII prophylaxis. (Funded by F. Hoffmann-La Roche and Chugai Pharmaceutical; HAVEN 3 ClinicalTrials.gov number, NCT02847637 .).

Rapidly changing dietary practices and a sedentary lifestyle have led to increasing prevalence of childhood obesity (5-19 yr) in developing countries recently: 41.8% in Mexico, 22.1% in Brazil, 22.0% in India, and 19.3% in Argentina. Moreover, secular trends indicate increasing prevalence rates in these countries: 4.1 to 13.9% in Brazil during 1974-1997, 12.2 to 15.6% in Thailand during 1991-1993, and 9.8 to 11.7% in India during 2006-2009. Important determinants of childhood obesity include high socioeconomic status, residence in metropolitan cities, female gender, unawareness and false beliefs about nutrition, marketing by transnational food companies, increasing academic stress, and poor facilities for physical activity. Childhood obesity has been associated with type 2 diabetes mellitus, the early-onset metabolic syndrome, subclinical inflammation, dyslipidemia, coronary artery diseases, and adulthood obesity. Therapeutic lifestyle changes and maintenance of regular physical activity through parental initiative and social support interventions are the most important strategies in managing childhood obesity. Also, high-risk screening and effective health educational programs are urgently needed in developing countries.

IMPORTANCE: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births. OBJECTIVES: To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. DESIGN: Epidemiological and retrospective observational study. SETTING: Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test. MAIN OUTCOMES AND MEASURES: Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. RESULTS: Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. CONCLUSIONS AND RELEVANCE: Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.

BACKGROUND: There is growing attention towards increasing patient and service user engagement (PSUE) in biomedical and health services research. Existing variations in language and design inhibit reporting and indexing, which are crucial to comparative effectiveness in determining best practices. OBJECTIVE: This paper utilizes a systematic review and environmental scan to derive an evidence-based framework for PSUE. DESIGN: A metanarrative systematic review and environmental scan/manual search using scientific databases and other search engines, along with feedback from a patient advisory group (PAG). ELIGIBLE SOURCES: English-language studies, commentaries, grey literature and other sources (including systematic and non-systematic reviews) pertaining to patient and public involvement in biomedical and health services research. DATA EXTRACTED: Study description (e.g. participant demographics, research setting) and design, if applicable; frameworks, conceptualizations or planning schemes for PSUE-related endeavours; and methods for PSUE initiation and gathering patients'/service users' input or contributions. RESULTS: Overall, 202 sources were included and met eligibility criteria; 41 of these presented some framework or conceptualization of PSUE. Sources were synthesized into a two-part framework for PSUE: (i) integral PSUE components include patient and service user initiation, reciprocal relationships, colearning and re-assessment and feedback, (ii) sources describe PSUE at several research stages, within three larger phases: preparatory, execution and translational. DISCUSSION AND CONCLUSIONS: Efforts at developing a solid evidence base on PSUE are limited by the non-standard and non-empirical nature of much of the literature. Our proposed two-part framework provides a standard structure and language for reporting and indexing to support comparative effectiveness and optimize PSUE.

BACKGROUND: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS: Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02). CONCLUSIONS: Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).

IMPORTANCE: The literature focuses on mortality among children younger than 5 years. Comparable information on nonfatal health outcomes among these children and the fatal and nonfatal burden of diseases and injuries among older children and adolescents is scarce. OBJECTIVE: To determine levels and trends in the fatal and nonfatal burden of diseases and injuries among younger children (aged <5 years), older children (aged 5-9 years), and adolescents (aged 10-19 years) between 1990 and 2013 in 188 countries from the Global Burden of Disease (GBD) 2013 study. EVIDENCE REVIEW: Data from vital registration, verbal autopsy studies, maternal and child death surveillance, and other sources covering 14,244 site-years (ie, years of cause of death data by geography) from 1980 through 2013 were used to estimate cause-specific mortality. Data from 35,620 epidemiological sources were used to estimate the prevalence of the diseases and sequelae in the GBD 2013 study. Cause-specific mortality for most causes was estimated using the Cause of Death Ensemble Model strategy. For some infectious diseases (eg, HIV infection/AIDS, measles, hepatitis B) where the disease process is complex or the cause of death data were insufficient or unavailable, we used natural history models. For most nonfatal health outcomes, DisMod-MR 2.0, a Bayesian metaregression tool, was used to meta-analyze the epidemiological data to generate prevalence estimates. FINDINGS: Of the 7.7 (95% uncertainty interval [UI], 7.4-8.1) million deaths among children and adolescents globally in 2013, 6.28 million occurred among younger children, 0.48 million among older children, and 0.97 million among adolescents. In 2013, the leading causes of death were lower respiratory tract infections among younger children (905.059 deaths; 95% UI, 810,304-998,125), diarrheal diseases among older children (38,325 deaths; 95% UI, 30,365-47,678), and road injuries among adolescents (115,186 deaths; 95% UI, 105,185-124,870). Iron deficiency anemia was the leading cause of years lived with disability among children and adolescents, affecting 619 (95% UI, 618-621) million in 2013. Large between-country variations exist in mortality from leading causes among children and adolescents. Countries with rapid declines in all-cause mortality between 1990 and 2013 also experienced large declines in most leading causes of death, whereas countries with the slowest declines had stagnant or increasing trends in the leading causes of death. In 2013, Nigeria had a 12% global share of deaths from lower respiratory tract infections and a 38% global share of deaths from malaria. India had 33% of the world's deaths from neonatal encephalopathy. Half of the world's diarrheal deaths among children and adolescents occurred in just 5 countries: India, Democratic Republic of the Congo, Pakistan, Nigeria, and Ethiopia. CONCLUSIONS AND RELEVANCE: Understanding the levels and trends of the leading causes of death and disability among children and adolescents is critical to guide investment and inform policies. Monitoring these trends over time is also key to understanding where interventions are having an impact. Proven interventions exist to prevent or treat the leading causes of unnecessary death and disability among children and adolescents. The findings presented here show that these are underused and give guidance to policy makers in countries where more attention is needed.

Serotonin content, serotonin uptake sites, and serotonin receptor binding measured in animal studies are all higher in the developing brain, compared with adult values, and decline before puberty. Furthermore, a disruption of synaptic connectivity in sensory cortical regions can result from experimental increase or decrease of brain serotonin before puberty. The purpose of the present study was to determine whether brain serotonin synthesis capacity is higher in children than in adults and whether there are differences in serotonin synthesis capacity between autistic and nonautistic children. Serotonin synthesis capacity was measured in autistic and nonautistic children at different ages, using alpha[11C]methyl-L-tryptophan and positron emission tomography. Global brain values for serotonin synthesis capacity (K complex) were obtained for autistic children (n = 30), their nonautistic siblings (n = 8), and epileptic children without autism (n = 16). K-complex values were plotted according to age and fitted to linear and five-parameter functions, to determine developmental changes and differences in serotonin synthesis between groups. For nonautistic children, serotonin synthesis capacity was more than 200% of adult values until the age of 5 years and then declined toward adult values. Serotonin synthesis capacity values declined at an earlier age in girls than in boys. In autistic children, serotonin synthesis capacity increased gradually between the ages of 2 years and 15 years to values 1.5 times adult normal values and showed no sex difference. Significant differences were detected between the autistic and epileptic groups and between the autistic and sibling groups for the change with age in the serotonin synthesis capacity. These data suggest that humans undergo a period of high brain serotonin synthesis capacity during childhood, and that this developmental process is disrupted in autistic children.

The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.

Oxidative stress contributes to the complex pathophysiology of sickle cell disease. Oral therapy with pharmaceutical

Caffeine is the most widely consumed psychoactive drug in the world. Natural sources of caffeine include coffee, tea, and chocolate. Synthetic caffeine is also added to products to promote arousal, alertness, energy, and elevated mood. Over the past decade, the introduction of new caffeine-containing food products, as well as changes in consumption patterns of the more traditional sources of caffeine, has increased scrutiny by health authorities and regulatory bodies about the overall consumption of caffeine and its potential cumulative effects on behavior and physiology. Of particular concern is the rate of caffeine intake among populations potentially vulnerable to the negative effects of caffeine consumption: pregnant and lactating women, children and adolescents, young adults, and people with underlying heart or other health conditions, such as mental illness. Here, we review the research into the safety and safe doses of ingested caffeine in healthy and in vulnerable populations. We report that, for healthy adults, caffeine consumption is relatively safe, but that for some vulnerable populations, caffeine consumption could be harmful, including impairments in cardiovascular function, sleep, and substance use. We also identified several gaps in the literature on which we based recommendations for the future of caffeine research.

BACKGROUND: Although methods of viral attenuation in plasma-derived clotting-factor concentrates have improved, there is still a possibility that such concentrates may transmit certain blood-borne viruses. For this reason, the use of recombinant DNA-derived factor VIII (which is virus-free) to treat hemophilia A has generated considerable interest. METHODS: We conducted a multicenter trial in previously untreated children with hemophilia A. They received recombinant factor VIII for all treatment or for prophylaxis and were evaluated at their respective clinics at intervals of no more than three months. RESULTS: Between January 1, 1989, and July 1, 1992, 95 patients who could be evaluated received recombinant factor VIII. By September 1, 1992, they had received the concentrate exclusively for 2.4 months to 3.5 years (median, 1.5 years). All responded well, with no treatment failures. A total of 3315 infusions were administered; there were three reports of minor adverse reactions. Inhibitor antibodies to factor VIII developed in 16 of 81 patients tested for them, after a median of nine days of exposure to factor VIII treatment. Inhibitor titers were or became low in 9 of the 16 patients despite continued episodic treatment with the concentrate. Inhibitors disappeared completely in 4 patients and remained at a low level (< 10 Bethesda units) in 5 patients receiving episodic treatment. CONCLUSIONS: Transient or low levels of inhibitor, as observed in this study, may represent part of the natural history of hemophilia in infants. In view of the transient nature and lower concentration of the inhibitors detected and the generally satisfactory response to treatment, the benefits of recombinant factor VIII for the treatment of hemophilia seem to outweigh the risks.

= .013). Twenty-three patients experienced graft failure, and 70 patients (7%) died, with the most common cause of death being infection. The excellent outcome of a cohort transplanted over the course of 3 decades confirms the role of HLA-identical sibling transplantation for children and adults with SCD.

STUDY OBJECTIVES: To investigate the efficacy of melatonin compared to placebo in improving sleep parameters in patients with primary sleep disorders. DESIGN: PubMed was searched for randomized, placebo-controlled trials examining the effects of melatonin for the treatment of primary sleep disorders. Primary outcomes examined were improvement in sleep latency, sleep quality and total sleep time. Meta-regression was performed to examine the influence of dose and duration of melatonin on reported efficacy. PARTICIPANTS: Adults and children diagnosed with primary sleep disorders. INTERVENTIONS: Melatonin compared to placebo. RESULTS: Nineteen studies involving 1683 subjects were included in this meta-analysis. Melatonin demonstrated significant efficacy in reducing sleep latency (weighted mean difference (WMD) = 7.06 minutes [95% CI 4.37 to 9.75], Z = 5.15, p<0.001) and increasing total sleep time (WMD = 8.25 minutes [95% CI 1.74 to 14.75], Z = 2.48, p = 0.013). Trials with longer duration and using higher doses of melatonin demonstrated greater effects on decreasing sleep latency and increasing total sleep time. Overall sleep quality was significantly improved in subjects taking melatonin (standardized mean difference = 0.22 [95% CI: 0.12 to 0.32], Z = 4.52, p<0.001) compared to placebo. No significant effects of trial duration and melatonin dose were observed on sleep quality. CONCLUSION: This meta-analysis demonstrates that melatonin decreases sleep onset latency, increases total sleep time and improves overall sleep quality. The effects of melatonin on sleep are modest but do not appear to dissipate with continued melatonin use. Although the absolute benefit of melatonin compared to placebo is smaller than other pharmacological treatments for insomnia, melatonin may have a role in the treatment of insomnia given its relatively benign side-effect profile compared to these agents.

OBJECTIVES: We previously reported that children who were subjected to early socioemotional deprivation in Romanian orphanages showed glucose hypometabolism in limbic and paralimbic structures, including the orbital frontal gyrus, infralimbic prefrontal cortex, hippocampus/amygdala, lateral temporal cortex, and the brainstem. The present study used diffusion tensor imaging tractography to examine the integrity of white matter tracts that connect these brain regions. METHODS: Fractional anisotropy and apparent diffusion coefficient for uncinate fasciculus, stria terminalis, fornix, and cingulum were measured in 7 right-handed children (5 girls and 2 boys; mean age: 9.7 +/- 2.6 years) with a history of early severe socioemotional deprivation in Eastern European orphanages and compared with similar measurements in 7 right-handed normal children (4 girls and 3 boys; mean age: 10.7 +/- 2.8 years). RESULTS: Neuropsychological assessment of the orphans verified the relatively mild specific cognitive impairment and impulsivity consistent with previous studies of children who were adopted from Romanian orphanages. Fractional anisotropy values in the left uncinate fasciculus were decreased significantly in the early deprivation group compared with control subjects. Apparent diffusion coefficient values for the early deprivation group tended to be greater than that in control subjects in all of the tracts measured, without reaching statistical significance. CONCLUSION: Our study demonstrates in children who experienced socioemotional deprivation a structural change in the left uncinate fasciculus that partly may underlie the cognitive, socioemotional, and behavioral difficulties that commonly are observed in these children.

OBJECTIVE: The goal was to create a functional status outcome measure for large outcome studies that is well defined, quantitative, rapid, reliable, minimally dependent on subjective assessments, and applicable to hospitalized pediatric patients across a wide range of ages and inpatient environments. METHODS: Functional Status Scale (FSS) domains of functioning included mental status, sensory functioning, communication, motor functioning, feeding, and respiratory status, categorized from normal (score = 1) to very severe dysfunction (score = 5). The Adaptive Behavior Assessment System II (ABAS II) established construct validity and calibration within domains. Seven institutions provided PICU patients within 24 hours before or after PICU discharge, high-risk non-PICU patients within 24 hours after admission, and technology-dependent children. Primary care nurses completed the ABAS II. Statistical analyses were performed. RESULTS: A total of 836 children, with a mean FSS score of 10.3 (SD: 4.4), were studied. Eighteen percent had the minimal possible FSS score of 6, 44% had FSS scores of >or=10, 14% had FSS scores of >or=15, and 6% had FSS scores of >or=20. Each FSS domain was associated with mean ABAS II scores (P < .0001). Cells in each domain were collapsed and reweighted, which improved correlations with ABAS II scores (P < .001 for improvements). Discrimination was very good for moderate and severe dysfunction (ABAS II categories) and improved with FSS weighting. Intraclass correlations of original and weighted total FSS scores were 0.95 and 0.94, respectively. CONCLUSIONS: The FSS met our objectives and is well suited for large outcome studies.

No AccessJournal of UrologyReview Article1 Apr 1990Malignancies in Bladder Augmentations and Intestinal Conduits R. Bruce Filmer and Julia R. Spencer R. Bruce FilmerR. Bruce Filmer and Julia R. SpencerJulia R. Spencer View All Author Informationhttps://doi.org/10.1016/S0022-5347(17)40055-3AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail © 1990 by The American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetailsCited byGarnier S, Vendrell J, Boillot B, Karsenty G, Faure A, Blanc T, Soustelle L, Phe V, Even A, Chartier-Kastler E, Ravasse P, Poinas G, Leizour B, Costa P, Galmiche L, Iborra F, Bouali O, Game X, Solassol J and Kalfa N (2020) Malignancy after Augmentation Enterocystoplasty: A Nationwide Study of Natural History, Prognosis and Oncogene Panel AnalysisJournal of Urology, VOL. 204, NO. 1, (136-143), Online publication date: 1-Jul-2020.Wein A (2017) Re: Risk of Malignancy after Augmentation Cystoplasty: A Systematic ReviewJournal of Urology, VOL. 197, NO. 4, (1117-1117), Online publication date: 1-Apr-2017.Higuchi T, Fox J and Husmann D (2011) Annual Endoscopy and Urine Cytology for the 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for Long Segment Ureteral Replacement: A Pilot Study.Journal of Urology, VOL. 171, NO. 5, (1939-1942), Online publication date: 1-May-2004.RAWASHDEH Y, JØRGENSEN T, OLSEN L and DJURHUUS J (2018) THE OUTCOME OF DETRUSOR MYOTOMY IN CHILDREN WITH NEUROGENIC BLADDER DYSFUNCTIONJournal of Urology, VOL. 171, NO. 6 Part 2, (2654-2656), Online publication date: 1-Jun-2004.CLOSE C, TEKGUL S, GANESAN G, TRUE L and MITCHELL M (2018) Flow Cytometry Analysis of Proliferative Lesions at the Gastrocystoplasty AnastomosisJournal of Urology, VOL. 169, NO. 1, (365-368), Online publication date: 1-Jan-2003.ALI-EL-DEIN B, EL-TABEY N, ABDEL-LATIF M, ABDEL-RAHIM M and EL-BAHNASAWY M (2018) LATE URO-ILEAL CANCER AFTER INCORPORATION OF ILEUM INTO THE URINARY TRACTJournal of Urology, VOL. 167, NO. 1, (84-88), Online publication date: 1-Jan-2002.Vajda P, Kaiser L, Magyarlaki T, Farkas A, Vastyan A and Pinter A (2018) Histological Findings After Colocystoplasty And GastrocystoplastyJournal of Urology, VOL. 168, 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A, HUMPHREY P, MCDOUGALL E and CLAYMAN R (2018) LAPAROSCOPIC AUGMENTATION CYSTOPLASTY WITH DIFFERENT BIODEGRADABLE GRAFTS IN AN ANIMAL MODELJournal of Urology, VOL. 164, NO. 4, (1405-1411), Online publication date: 1-Oct-2000.N′DOW J, PEARSON J, BENNETT M, NEAL D and ROBSON C (2018) MUCIN GENE EXPRESSION IN HUMAN UROTHELIUM AND IN INTESTINAL SEGMENTS TRANSPOSED INTO THE URINARY TRACTJournal of Urology, VOL. 164, NO. 4, (1398-1404), Online publication date: 1-Oct-2000.JEDNAK R, SCHIMKE C, BARROSO U, BARTHOLD J and GONZÁLEZ R (2018) FURTHER EXPERIENCE WITH SEROMUSCULAR COLOCYSTOPLASTY LINED WITH UROTHELIUMJournal of Urology, VOL. 164, NO. 6, (2045-2049), Online publication date: 1-Dec-2000.MINGIN G, STOCK J and HANNA M (2018) THE MAINZ II POUCH: EXPERIENCE IN 5 PATIENTS WITH BLADDER EXSTROPHYJournal of Urology, VOL. 162, NO. 3 Part 1, (846-848), Online publication date: 1-Sep-1999.NAHAS W, IIZUKA F, MAZZUCCHI E, ANTONOPOULOS I, LUCON A and ARAP S (2018) ADENOCARCINOMA OF AN AUGMENTED 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PUNCH J, SCHWARTZ A and BLOOM D (2018) RENAL TRANSPLANTATION IN CHILDREN WITH SEVERE LOWER URINARY TRACT DYSFUNCTIONJournal of Urology, VOL. 161, NO. 1, (240-245), Online publication date: 1-Jan-1999.LENG W, BLALOCK H, FREDRIKSSON W, ENGLISH S and McGUIRE E (2018) ENTEROCYSTOPLASTY OR DETRUSOR MYECTOMY? COMPARISON OF INDICATIONS AND OUTCOMES FOR BLADDER AUGMENTATIONJournal of Urology, VOL. 161, NO. 3, (758-763), Online publication date: 1-Mar-1999.PIECHOTA H, DAHMS S, NUNES L, DAHIYA R, LUE T and TANAGHO E (2018) IN VITRO FUNCTIONAL PROPERTIES OF THE RAT BLADDER REGENERATED BY THE BLADDER ACELLULAR MATRIX GRAFTJournal of Urology, VOL. 159, NO. 5, (1717-1724), Online publication date: 1-May-1998.DUEL B, GONZALEZ R and BARTHOLD J (2018) ALTERNATIVE TECHNIQUES FOR AUGMENTATION CYSTOPLASTYJournal of Urology, VOL. 159, NO. 3, (998-1005), Online publication date: 1-Mar-1998.GOUSSE A, SAFIR M, CORTINA G, SAFMAN K and RAZ S (2018) TUBULOVILLOUS ADENOMA IN THE CECAL SEGMENT AFTER CECOCYSTOPLASTYJournal of Urology, VOL. 160, NO. 2, (490-491), Online publication date: 1-Aug-1998.DiSANDRO M, LI Y, BASKIN L, HAYWARD S and CUNHA G (2018) MESENCHYMAL-EPITHELIAL INTERACTIONS IN BLADDER SMOOTH MUSCLE DEVELOPMENT: EPITHELIAL SPECIFICITYJournal of Urology, VOL. 160, NO. 3 Part 2, (1040-1046), Online publication date: 1-Sep-1998.Schaefer B, Lorenz C, Back W, Moll R, Sun T, Schober C, Waag K and Kramer M (2018) AUTOLOGOUS TRANSPLANTATION OF UROTHELIUM INTO DEMUCOSALIZED GASTROINTESTINAL SEGMENTS: EVIDENCE FOR EPITHELIALIZATION AND DIFFERENTIATION OF IN VITRO EXPANDED AND TRANSPLANTED UROTHELIAL CELLSJournal of Urology, VOL. 159, NO. 1, (284-290), Online publication date: 1-Jan-1998.Barrington J, Fulford S, Griffiths D and Stephenson T (2018) Tumors in Bladder Remnant After Augmentation EnterocystoplastyJournal of Urology, VOL. 157, NO. 2, (482-486), Online publication date: 1-Feb-1997.Carr L and Herschorn S (2018) Early Development of Adenocarcinoma in a Young Woman Following Augmentation Cystoplasty for UndiversionJournal of Urology, VOL. 157, NO. 6, (2255-2256), Online publication date: 1-Jun-1997.Hickey D, Bakthavatsalam R, Bannon C, O'Malley K, Corr J and Little D (2018) Urological Complications of Pancreatic TransplantationJournal of Urology, VOL. 157, NO. 6, (2042-2048), 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Volume 143Issue 4April 1990Page: 671-678 Advertisement Copyright & Permissions© 1990 by The American Urological Association Education and Research, Inc.MetricsAuthor Information R. Bruce Filmer More articles by this author Julia R. Spencer More articles by this author Expand All Advertisement PDF downloadLoading ...

The 600% increase in medical radiation exposure to the US population since 1980 has provided immense benefit, but increased potential future cancer risks to patients. Most of the increase is from diagnostic radiologic procedures. The objectives of this review are to summarize epidemiologic data on cancer risks associated with diagnostic procedures, describe how exposures from recent diagnostic procedures relate to radiation levels linked with cancer occurrence, and propose a framework of strategies to reduce radiation from diagnostic imaging in patients. We briefly review radiation dose definitions, mechanisms of radiation carcinogenesis, key epidemiologic studies of medical and other radiation sources and cancer risks, and dose trends from diagnostic procedures. We describe cancer risks from experimental studies, future projected risks from current imaging procedures, and the potential for higher risks in genetically susceptible populations. To reduce future projected cancers from diagnostic procedures, we advocate the widespread use of evidence-based appropriateness criteria for decisions about imaging procedures; oversight of equipment to deliver reliably the minimum radiation required to attain clinical objectives; development of electronic lifetime records of imaging procedures for patients and their physicians; and commitment by medical training programs, professional societies, and radiation protection organizations to educate all stakeholders in reducing radiation from diagnostic procedures.

BACKGROUND: Data from racially and ethnically diverse US boys are needed to determine ages of onset of secondary sexual characteristics and examine secular trends. Current international studies suggest earlier puberty in boys than previous studies, following recent trend in girls. METHODS: Two hundred and twelve practitioners collected Tanner stage and testicular volume data on 4131 boys seen for well-child care in 144 pediatric offices across the United States. Data were analyzed for prevalence and mean ages of onset of sexual maturity markers. RESULTS: Mean ages for onset of Tanner 2 genital development for non-Hispanic white, African American, and Hispanic boys were 10.14, 9.14, and 10.04 years and for stage 2 pubic hair, 11.47, 10.25, and 11.43 years respectively. Mean years for achieving testicular volumes of ≥ 3 mL were 9.95 for white, 9.71 for African American, and 9.63 for Hispanic boys; and for ≥ 4 mL were 11.46, 11.75, and 11.29 respectively. African American boys showed earlier (P < .0001) mean ages for stage 2 to 4 genital development and stage 2 to 4 pubic hair than white and Hispanic boys. No statistical differences were observed between white and Hispanic boys. CONCLUSIONS: Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were 6 months to 2 years earlier than in past studies, depending on the characteristic and race/ethnicity. The causes and public health implications of this apparent shift in US boys to a lower age of onset for the development of secondary sexual characteristics in US boys needs further exploration.