Christine K. Lee

Quantifying Fractal Dynamics of Human Respiration: Age and Gender Effects

AbstractWe sought to quantify the fractal scaling properties of human respiratory dynamics and determine whether they are altered with healthy aging and gender. Continuous respiratory datasets (obtained by inductive plethysmography) were collected from 40 healthy adults (10 young men, 10 young women, 10 elderly men, and 10 elderly women) during 120 min of spontaneous breathing. The interbreath interval (IBI) time series were extracted by a new algorithm and fractal scaling exponents that quantify power-law correlations were computed using detrended fluctuation analysis. Under supine, resting, and spontaneous breathing conditions, both healthy young and elderly subjects had scaling exponents for the IBI time series that indicate long-range (fractal) correlations across multiple time scales. Furthermore, the scaling exponents (mean ± SD) for the IBI time series were significantly (p < 0.03) lower (indicating decreased correlations) in the healthy elderly male 0.60 ± 0.08) compared to the young male (0.68 ± 0.07), young female (0.70 ± 0.07), and elderly female (0.67 ± 0.06) subjects. These results provide evidence for fractal organization in physiologic human breathing cycle dynamics, and for their degradation in elderly men. These findings may have implications for modeling integrated respiratory control mechanisms, quantifying their changes in aging or disease, and assessing the outcome of interventions aimed toward restoring normal physiologic respiratory dynamics.

Mutations in POMT1 Are Found in a Minority of Patients With Walker-Warburg Syndrome

Walker–Warburg syndrome (WWS) is an autosomal recessive disorder of infancy characterized by hydrocephalus, agyria, retinal dysplasia, congenital muscular dystrophy, and over migration of neurons through a disrupted pial surface resulting in leptomeningeal heterotopia. Although previous work identified mutations in the o‐mannosyl transferase, POMT1, in 6 out of 30 WWS families [Beltran‐Valero de Bernabe et al., 2002 ], the incidence of POMT1 mutations in WWS is not known. We sequenced the entire coding region of POMT1 in 30 consecutive, unselected patients with classic WWS. Two novel heterozygous mutations were found in two patients from non‐consanguineous parents, whereas 28 other patients failed to show any POMT1 mutations. One patient was found to be heterozygous for a transition, g.1233T > A, which predicts p.Y352X. A second patient was found also to be heterozygous for a transition g.1790C > G, which predicts p.S537R. As an additional determination of the frequency of the POMT1 mutations in WWS, we tested for linkage of WWS to POMT1 in six consanguineous families. All six demonstrated heterozygosity and negative LOD scores at the POMT1 locus. From these data we show that POMT1 is an uncommon cause of WWS, the incidence of coding region mutations in this population of WWS being less than 7%. We conclude that while the incidence of POMT1 mutations in WWS can be as high as 20% as reported by Beltran‐Valero de Bernabe et al. [ 2002 ] and it can be as low as ∼7%, as reported here.

Serum biomarkers and transient elastography as predictors of advanced liver fibrosis in a United States cohort: the Boston children's hospital experience.

OBJECTIVE To evaluate and compare the ability of serum hyaluronic acid (HA) and human cartilage glycoprotein-39 (YKL-40) values, as well as transient elastography (TE) findings, to predict advanced hepatic fibrosis in a cohort from a single pediatric center. STUDY DESIGN Subjects who underwent liver biopsy analysis within 12 months before enrollment were eligible for this prospective study. HA and YKL-40 measurements were obtained within 1 month of TE. A METAVIR score of F3 or F4 was considered to indicate advanced fibrosis. RESULTS A total of 128 patients (51% males) aged 1.4 months to 27.6 years (22% aged <2 years) were enrolled. Thirty-one subjects had data on only HA and YKL-40 measurements, and 97 subjects had data on both blood tests and TE. For the prediction of advanced fibrosis, the area under the receiver operating characteristic curve (AUC) values were 0.83 for TE, 0.72 for HA, and 0.52 for YKL-40. The AUC of 0.83 for TE was statistically significantly greater than the AUCs for HA (P = .03) and YKL-40 (P < .0001). Optimal cutpoints for predicting F3-F4 fibrosis were 8.6 kPa for TE (P < .0001), 43 ng/mL for HA (P < .0001), and 26.2 ng/mL for YKL-40 (P = .85). The combination of TE and HA was not better than TE alone for predicting advanced fibrosis (P = .15). CONCLUSION In this study, which evaluated TE, HA, and YKL-40 to predict liver fibrosis in children in the US, YKL-40 had no predictive value and TE was superior to HA, but the addition of HA did not improve the performance of TE. Our data suggest that TE and HA may be useful noninvasive tools for assessing liver fibrosis in children.

The Natural History of Primary Sclerosing Cholangitis in Children: A Large Single-center Longitudinal Cohort Study

Objectives: Data regarding pediatric primary sclerosing cholangitis (PSC) natural history are limited. We describe a large pediatric PSC cohort with longitudinal follow-up. Methods: The present study records review of pediatric patients with PSC diagnosed between 1984 and 2014. Results: N = 120 (63% M) ages 1 to 21 years (median 14 years) at diagnosis. 27% (31/113) had autoimmune sclerosing cholangitis (ASC), 24% had exclusive small duct PSC, METAVIR stage was F3-F4 in 41%. Eighty-one percent of patients with PSC had inflammatory bowel disease (IBD); most had ulcerative/indeterminate colitis (72/97), typically pancolitis (40/72). PSC-IBD was more common than ASC-IBD (85% vs 68%, P = 0.03). Median follow-up was 3.7 years (interquartile range [IQR] 1.5, 6.9). Median gamma glutamyl transferase decreased from baseline of 221 U/L (IQR 110, 425) to 104 U/L by 1 year postdiagnosis ([IQR 18,229], P < 0.0001), and then changed little. Mean fibrosis stage at diagnosis was 2.3 ± 1.4 (N = 91), and at 1 to 5 years was 2.6 ± 1.3 (N = 20). Transplant-free survival at 10 year was 89%; there were 6 liver transplants, 2 in patients with small duct PSC and 4 with diffuse large duct PSC. Although the cirrhosis rate was not significantly different in PSC with IBD versus without (22% vs 41%, P = 0.06), the former had a lower rate of liver transplantation (2% vs 18%, P = 0.01). The rate of cirrhosis was lower in patients diagnosed with IBD before PSC (15% vs 31%, P = 0.05). Conclusions: In this largest reported pediatric PSC cohort, liver transplantation rate at 10 years was lower than that reported in adults. ASC and PSC had similar biochemical abnormalities and degree of fibrosis at diagnosis. PSC that developed after IBD diagnosis had a milder course, possibly reflecting earlier disease detection or milder phenotype.

EMX2-independent familial schizencephaly: clinical and genetic analyses.

Schizencephaly is a human brain malformation distinguished by full‐thickness unilateral or bilateral clefts through the neocortex. Heterozygous mutations in the EMX2 locus are reported to give rise to schizencephaly. However, the comprehensive identification of causative genetic loci is precluded by a lack of large pedigrees and genome‐wide linkage analyses. We present here a large Turkish pedigree with three individuals with schizencephaly. The similarity of clinical signs in affected individuals strongly suggests an underlying genetic cause; however, genome‐wide linkage analysis rules out EMX2 linkage and instead suggests additional candidate loci. These results indicate that genetic forms of schizencephaly are likely to be heterogeneous.

Pediatric hepatobiliary disease.

Purpose of review This review summarizes publications in pediatric hepatobiliary disease from the past year. These studies contribute to the understanding of the epidemiology, histopathology, predictors of outcome and treatment of some important pediatric liver and biliary disorders. Recent findings Advances in nonalcoholic fatty liver disease, primary sclerosing cholangitis, neonatal hemochromatosis, acute liver failure (from the Pediatric Acute Liver Failure Study Group), and liver transplantation are summarized. Summary Continued investigation into these hepatobiliary disorders has the potential to significantly impact the health of children.

Hepatitis C: Issues in Children

Hepatitis C infection is a global health problem. Most infected children have not been identified. Perinatal transmission is the most common mode of acquisition. Liver disease owing to chronic hepatitis C virus (HCV) infection progresses slowly in individuals infected early in life. Serious complications rarely affect patients during childhood. Successful treatment of HCV in adults has improved and recommendations have changed. Treatment in children should be deferred until direct-acting antivirals and interferon-free regimens are available to this population. If treatment cannot be deferred, regimens including peginterferon and ribavirin can be given to children with compensated liver disease.

Treating HCV infection in children

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Lung ultrasound compared to chest X-ray for diagnosis of pediatric pneumonia: A meta-analysis

Although a clinical diagnosis, the standard initial imaging modality for patients with concern for pediatric community acquired pneumonia (pCAP) is a chest x‐ray (CXR), which has a relatively high false negative rate, exposes patients to ionizing radiation, and may not be available in resource limited settings. The primary objective of this meta‐analysis is to evaluate the accuracy of lung ultrasound (LUS) compared to CXR for the diagnosis of pCAP.

Validation of Transient Elastography Cut Points to Assess Advanced Liver Fibrosis in Children and Young Adults: The Boston Children's Hospital Experience

Objective To derive an optimal liver stiffness measurement cut point to discriminate METAVIR fibrosis stage F4 and to validate both METAVIR fibrosis stage F3‐F4 and F4 cut points in a separate cohort. Study Design Patients at Boston Childrens Hospital with liver stiffness measurement from 2006 to 2016 and liver biopsy ≤12 months before screening were eligible. Patients enrolled 2006‐2011 were used to calibrate liver stiffness measurement cut points and those enrolled 2011‐2016 for validation. Diagnostic performance was assessed by receiver operating curve analysis. Results In total, 267 subjects were enrolled (97 calibration, 170 validation). The cohorts were similar with 54% male, aged 0‐29 years (median 13 years), and liver diseases including 21% autoimmune, 19% viral, 11% nonalcoholic fatty liver, 9% cholestatic, and 9% primary sclerosing cholangitis. Cut points to discriminate F3‐F4 and F4 were >8.6 kPa and >11.5 kPa with 81% and 84% accuracy, respectively. Applied to the validation cohort, accuracy was 67% and 75%, respectively. In 44 fasted subjects, the accuracy was 73% and 80%, respectively. Conclusion This study validates previously determined liver stiffness measurement cut points of 8.6 kPa and 11.5 kPa to predict METAVIR F3‐F4 and F4 fibrosis in children and young adults in separate cohorts. With increasing data on the utility and validity of liver stiffness measurement in children, transient elastography may help identify patients with greater risk of advanced fibrosis and those who need liver biopsy assessment and/or surveillance for the complications of cirrhosis in a variety of liver disorders.