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• Patients with RDP are more likely to experience dysarthria than familial controls. • Patients with RDP are more likely to experience voice dysfunction than controls. • Dysarthria in RDP was associated with concordant cranial nerve 9–11 dysfunction. • Dysarthria in RDP was associated with BFMDRS speech dysfunction and oral dystonia. • Quantitative speech assessment may have potential as an outcome to detect change over time or treatment effect in RDP. Bulbar symptoms are frequent in patients with rapid-onset dystonia-parkinsonism (RDP). RDP is caused by ATP1A3 mutations, with onset typically within 30 days of stressor exposure. Most patients have impairments in speech (dysarthria) and voice (dysphonia). These have not been quantified. We aimed to formally characterize these in RDP subjects as compared to mutation negative family controls. We analyzed recordings in 32 RDP subjects (male = 21, female = 11) and 29 mutation negative controls (male = 15, female = 14). Three raters, blinded to mutation status, rated speech and vocal quality. Dysarthria was classified by subtype. Dysphonia was rated via the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale. We used general neurological exams and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) to assess dysarthria, dystonia, and speech/swallowing dysfunction. The presence of dysarthria was more frequent in RDP subjects compared to controls (72% vs. 17%, p < 0.0001). GRBAS voice ratings were worse in the RDP cohort across nearly all categories. Dysarthria in RDP was associated with concordant cranial nerve 9–11 dysfunction (54%, p = 0.048), speech/swallowing dysfunction (96%, p = 0.0003); and oral dystonia (88%, p = 0.001). Quantitative voice and speech analyses are important in assessing RDP. Subjects frequently experience dysarthria and dysphonia. Dystonia is not the exclusive voice abnormality present in this population. In our analysis, RDP subjects more frequently experienced bulbar symptoms than controls. GRBAS scores are useful in quantifying voice impairment, potentially allowing for better assessments of progression or treatment effects. Future directions include using task-specific diagnostic and perceptual voice evaluation tools to further assess laryngeal dystonia. [ABSTRACT FROM AUTHOR]

Objective To compare serum uric acid levels in adolescents born prematurely and adolescents born at term and to assess the correlation between serum uric acid and blood pressure (BP) in those born prematurely. Study design In this observational cohort study, 124 adolescents born prematurely and 44 adolescents born at term were studied at 14 years of age. Multivariate analyses were used to describe the relationship of premature birth to serum uric acid while adjusting for confounding variables. Pearson correlation was used to describe the relationship between uric acid and systolic BP among those born prematurely. Results Adjusting for race, sex, maternal hypertension, and fetal growth, we found that preterm adolescents had greater serum uric acid levels than adolescents born at term (adjusted mean difference 0.46, 95% CI 0.10-0.81 mg/dL; 27.4, 6-48.2 µmol/L; P = .012). Among those born prematurely, uric acid was positively correlated with systolic BP (Pearson correlation coefficient: 0.29, 0.12-0.44; P = .0013). Conclusions Serum uric acid levels are greater in adolescents born prematurely than in those born at term, and this difference could contribute to greater BP among individuals born prematurely. [ABSTRACT FROM AUTHOR]

A detailed understanding of influenza movement in communities during yearly epidemics is needed to inform improved influenza control programs. We sought to determine the relative timing of influenza presentation and symptom onset by age group and influenza strain. Prospective, laboratory-confirmed surveillance was performed over three moderate influenza seasons in emergency departments and inpatient settings of both medical centers in Winston-Salem, NC. Influenza disease presented first in school age children through community epidemics of influenza A(H1N1)pdm09 and influenza B, and first in persons 5–49 years old for influenza A(H3N2). This finding indicates that influenza prevention in persons 5–49 years of age may be particularly important in influenza epidemic control. [ABSTRACT FROM AUTHOR]

Background & Aims: The aim of this study was to assess the analytic validity of self-reported family history of hemochromatosis or iron overload. Methods: A total of 141 probands, 549 family members, and 641 controls participated in the primary care Hemochromatosis and Iron Overload Screening Study. Participants received a postscreening clinical examination and completed questionnaires about personal and family histories of hemochromatosis or iron overload, arthritis, diabetes, liver disease, and heart disease. We evaluated sensitivities and specificities of proband-reported family history, and concordance of HFE genotype C282Y/C282Y in probands and siblings who reported having hemochromatosis or iron overload. Results: The sensitivities of proband-reported family history ranged from 81.4% for hemochromatosis or iron overload to 18.4% for liver disease; specificities for diabetes, liver disease, and heart disease were greater than 94%. Hemochromatosis or iron overload was associated with a positive family history across all racial/ethnic groups in the study (odds ratio, 14.53; 95% confidence intervals, 7.41–28.49; P < .0001) and among Caucasians (odds ratio, 16.98; 95% confidence intervals, 7.53–38.32; P < .0001). There was 100% concordance of HFE genotype C282Y/C282Y in 6 probands and 8 of their siblings who reported having hemochromatosis or iron overload. Conclusions: Self-reported family history of hemochromatosis or iron overload can be used to identify individuals whose risk of hemochromatosis or iron overload and associated conditions is increased. These individuals could benefit from further evaluation with iron phenotyping and HFE mutation analysis. [Copyright &y& Elsevier]

Bivariate mixture modeling was used to analyze joint population distributions of transferrin saturation (TS) and serum ferritin concentration (SF) measured in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Four components (C1, C2, C3, and C4) with successively age-adjusted increasing means for TS and SF were identified in data from 26,832 African Americans, 12,620 Asians, 12,264 Hispanics, and 43,254 whites. The largest component, C2, had normal mean TS (21% to 26% for women, 29% to 30% for men) and SF (43–82 μg/L for women, 165–242 μg/L for men), which consisted of component proportions greater than 0.59 for women and greater than 0.68 for men. C3 and C4 had progressively greater mean values for TS and SF with progressively lesser component proportions. C1 had mean TS values less than 16% for women (<20% for men) and SF values less than 28 μg/L for women (<47 μg/L for men). Compared with C2, adjusted odds of iron deficiency were significantly greater in C1 (14.9–47.5 for women, 60.6–3530 for men), adjusted odds of liver disease were significantly greater in C3 and C4 for African-American women and all men, and adjusted odds of any HFE mutation were increased in C3 (1.4–1.8 for women, 1.2–1.9 for men) and in C4 for Hispanic and white women (1.5 and 5.2, respectively) and men (2.8 and 4.7, respectively). Joint mixture modeling identifies a component with lesser SF and TS at risk for iron deficiency and 2 components with greater SF and TS at risk for liver disease or HFE mutations. This approach can identify populations in which hereditary or acquired factors influence metabolism measurement. [Copyright &y& Elsevier]

Homozygosity for a novel hemochromatosis (HFE) gene splice site mutation (IVS5+1 G/A) was previously reported in a 48-year-old Vietnamese man residing in Germany who had an elevated serum ferritin (SF) and transferrin saturation (TS) and severe iron overload on liver biopsy. This mutation was not found in 222 controls of central European origin but has been found in Southeast Asians living in Vietnam without evidence of iron overload. Hemochromatosis and iron overload screening (HEIRS) Study is an ongoing, multiethnic, primary care-based study of 101,168 North American adults, including 12,772 Asians, a group that the HEIRS Study found has a significantly higher than expected prevalence of elevated serum TS and SF but very low prevalence of the common C282Y and H63D HFE alleles usually associated with hereditary hemochromatosis. It was hypothesized that the IVS5+1 G/A splice site mutation might explain some elevated biochemical iron measures in North American Asians. Overall, 200 Vietnamese subjects from the Los Angeles Field Center who had TS and SF values greater than the 75th percentile of all HEIRS Study participants after adjusting for covariates and 149 controls randomly selected to represent this Vietnamese population were genotyped. Among cases, 1 homozygous mutant and 7 heterozygotes were found; among controls, 1 homozygous mutant and 4 heterozygotes were found yielding an allele frequency of 2.32% for cases and 2.04% for controls (P > 0.5). This finding suggests that the HFE IVS5+1 G/A splice site mutation is not the major explanation for unexpectedly high prevalence of TS and SF in North American Asians. [Copyright &y& Elsevier]

Homozygosity for the C282Y mutation of the hemochromatosis gene on chromosome 6p (HFE) is a common genetic trait that increases susceptibility to iron overload. The authors describe and apply methodology developed for the analysis of phenotypic and genotypic data from 46,136 non-Hispanic Caucasians, a subset of the multi-ethnic cohort enrolled in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. For analysis of the distribution of transferrin saturation (TS), mixtures of normal distributions were considered and the expectation-maximization (EM) algorithm was applied for parameter estimation. Maximized log-likelihoods were compared, and significance was assessed by resampling. Sensitivity, specificity, and predictive values from the modeled subpopulations were compared with the actual observed genotypes for C282Y and H63D mutations in the HFE gene. A strong association between HFE genotype and TS subpopulations was found in these data collected from different geographic regions, confirming the external validity of the statistical approach when applied to population-based data. It was concluded that mixture modeling of phenotypic data may provide a clinical guide for screening with gender-specific thresholds to identify potential samples for genetic testing. [Copyright &y& Elsevier]

Background: Dermatomyositis affects visible skin and causes disease symptoms that can affect patients'' quality of life (QOL). Methods: In all, 71 patients with dermatomyositis or dermatomyositis sine myositis completed two QOL measures (the Skindex-16 and the Dermatology Life Quality Index) and a visual analog scale for pruritus. Disease severity was assessed by Physician''s Global Assessment. Results: The mean Dermatology Life Quality Index score was 10.7 and the mean Skindex-16 score was 51.1. Itching contributed to impact on both the Dermatology Life Quality Index and Skindex-16. Females reported worse QOL. Limitations: The effect of treatment on quality of life was not assessed in these analyses. Conclusion: QOL impairment in dermatomyositis is greater than in other skin conditions including psoriasis and atopic dermatitis. Pruritus is an important treatable factor that significantly impacts QOL for patients with dermatomyositis. [Copyright &y& Elsevier]

Background & Aims: Typical hemochromatosis patients are homozygous for the C282Y mutation of the HFE gene. However, approximately 50% of women and 20% of men do not have an increase in serum ferritin level. This study assessed factors, genetic and otherwise, that may modify biochemical expression in C282Y homozygotes. Methods: Hemochromatosis families that each had at least 2 untreated C282Y homozygotes were included. Nonexpressors were defined as having a ferritin level less than 300 μg/L for a male and a ferritin level less than 200 μg/L for a female. A multivariate linear stepwise regression analysis was performed to assess the contribution of sex, age, and the presence of a nonexpressor in the family on serum ferritin level. Heritability calculations were performed using variance component analysis. Results: Fifty-three pedigrees consisting of 148 C282Y homozygotes (92 males, 56 females) were identified. Twenty-nine homozygotes were nonexpressors (19.6%), of which 11 of 29 were male (37.9%) (P = .0054). Based on multivariate analysis, highly significant associations with increased ferritin levels in C282Y homozygotes were male sex (P = .00005), increasing age (P = .009), and absence of a nonexpressor in the family (P = .01). Variance component modeling using age, sex, and C282Y genotype as covariates in 39 pedigrees (n = 296) showed a residual heritability for serum ferritin of .35 ± .10 (P < .001). Conclusions: These findings suggest that male sex is the major clinical factor associated with an increased serum ferritin level in hemochromatosis. In addition, these results support the hypothesis that other genes contribute to the variance in serum ferritin concentration among C282Y homozygotes. [Copyright &y& Elsevier]

The onset of symptoms in Rapid-onset dystonia-parkinsonism (RDP) is typically over days to weeks and is often triggered by stressors like fever or childbirth. Limited information is available on how the motor and nonmotor symptoms evolve over the course of the disease. Our longitudinal study analyzed data from a cohort of RDP patients, documenting their symptoms across multiple visits. We characterized the phenotypic evolution of 14 individuals positive for ATP1A3 mutations (7 females, 7 males; mean examination age = 37 years, mean age of onset = 20 years). We focused on neurologic, cognitive, and neuropsychological data collected during in-person visits (mean interval between testing = 5½ years). Initially, all participants exhibited bulbar symptoms. Headaches were noted in 50 %, seizures in 31 %, and tremors in 36 %. At follow-up, 29 % of those initially without headaches developed them, 22 % without prior seizures experienced them, and 56 % previously without tremors developed them. No improvements were seen in those with headaches; however, seizures and tremors improved in 25 % and 80 % of cases, respectively. For Burke-Fahn-Marsden Dystonia Rating Scale, Unified Parkinson's Disease Rating Scale, and International Cooperative Ataxia Rating Scale scores, improvement consisted of the reduction of the symptom. Cognitive functions improved from mildly impaired to low-average, and psychiatric evaluations indicated mild anxiety levels, slight increases in obsessive-compulsive behaviors, and decreased depression scores over time. This longitudinal analysis highlights the complex evolution of RDP, demonstrating significant variability in motor function and other symptoms such as headaches, seizures, and tremors. • Information on how Rapid-onset dystonia-parkinsonism evolves over time is limited. • Changes in dystonia severity over time are highly heterogeneous. • Evolution of motor function is not related to symptoms' severity at first visit. • Cognitive performance seems to gradually improve. • Progressive deterioration is not obvious over the average 5-year studied time span. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the relationship between maternal preeclampsia resulting in premature delivery and adiposity in the offspring during adolescence. Study design: The 172 study participants were 14 years old and had very low birth weight. We compared height, weight, body mass index (BMI), percent fat, waist circumference, and triceps and subscapular skin fold thicknesses between those born prematurely secondary to preeclampsia (n = 51; 22 male) and those born prematurely after normotensive pregnancies (n = 121; 55 male). Multiple linear regression analysis was used to adjust for potential confounders (maternal BMI, antenatal steroid exposure, and race) and to evaluate potential explanatory variables (fetal, infancy, and childhood weight gain, and caloric intake, level of fitness, and physical activity at 14 years). Results: When adjusted for potential prenatal confounders (antenatal steroid exposure and race), adolescent male offspring of preeclamptic pregnancies had higher BMI (4.0 kg/m2 [1.5, 6.6]) (mean difference [95% CI]), waist circumference (11.8 cm [3.8, 19.7]), triceps (4.6 mm [0.6, 8.6]) and subscapular skinfold thicknesses (6.2 mm [1.5, 10.9]), and percent body fat (4.1% [−0.1, 8.3]). Adjusting for infancy and childhood weight gain attenuated these group differences. There were no group differences among females. Conclusion: Male adolescent offspring born prematurely of women with preeclampsia have higher measures of adiposity than those born prematurely of normotensive pregnancies. [Copyright &y& Elsevier]

We sought to determine whether maternal vaccination during pregnancy was associated with a reduced risk of laboratory-confirmed influenza hospitalizations in infants <6 months old. Active population-based, laboratory-confirmed influenza surveillance was conducted in children hospitalized with fever and/or respiratory symptoms in 3 US counties from November through April during the 2002 through 2009 influenza seasons. The exposure, influenza vaccination during pregnancy, and the outcome, positive/negative influenza testing among their hospitalized infants, were compared using logistic regression analyses. Among 1510 hospitalized infants <6 months old, 151 (10%) had laboratory-confirmed influenza and 294 (19%) mothers reported receiving influenza vaccine during pregnancy. Eighteen (12%) mothers of influenza-positive infants and 276 (20%) mothers of influenza-negative infants were vaccinated (unadjusted odds ratio, 0.53; 95% confidence interval, 0.32–0.88 and adjusted odds ratio, 0.52; 95% confidence interval, 0.30–0.91). Infants of vaccinated mothers were 45-48% less likely to have influenza hospitalizations than infants of unvaccinated mothers. Our results support the current influenza vaccination recommendation for pregnant women. [Copyright &y& Elsevier]

Objective: To determine the prevalence and correlates of elevated blood pressure (BP) in youth with type 1 or type 2 diabetes mellitus by using data from the SEARCH Study. Study design: The analysis included youth aged 3 to 17 years with type 1 (n = 3691) and type 2 diabetes mellitus (n = 410) who attended a research visit. Elevated BP was defined as systolic or diastolic values ≥95 percentile, regardless of drug use. In youth with elevated BP, awareness was defined as self-report of an earlier diagnosis. Control was defined as BP values <90th percentile and <120/90 mm Hg in youth with an earlier diagnosis who were taking BP medications. Results: The prevalence of elevated BP in youth with type 1 diabetes mellitus was 5.9%; minority ethnic groups, obese adolescents, and youth with poor glycemic control were disproportionately affected. In contrast, 23.7% of adolescents with type 2 diabetes mellitus had elevated BP (P < .0001), Similarly, 31.9% of youth with type 2 diabetes mellitus and elevated BP were aware, compared with only 7.4% of youth with type 1 diabetes mellitus (P < .0001). Once BP was diagnosed and treated, control was similar in type 1 (57.1%) and type 2 diabetes mellitus (40.6%). Conclusions: Our findings identify high-risk groups of youth with diabetes mellitus at which screening and treatment efforts should be directed. [ABSTRACT FROM AUTHOR]

Objective: To discuss vascular stiffness commonly encountered in children with type 1 diabetes mellitus (T1DM). Study design: We examined 535 subjects with T1DM (14.6 years; 53% male, 88% non-Hispanic white) and 241 healthy control subjects (17.8 years; 42% male, 39% non-Hispanic white). Abnormalities in brachial distensibility (BrachD), pulse wave velocity, and augmentation index corrected to a HR of 75 (AIx-75) were examined. Results: Subjects with T1DM had higher body mass index, LDL-cholesterol, fasting glucose, and blood pressure than control subjects. Diabetic subjects had lower BrachD and higher AIx-75 indicating increased stiffness. Age-adjusted pulse wave velocity–trunk (aorto-femoral) was higher in cases (all P ≤ < .05). Increased peripheral stiffness was more common than central stiffness in subjects with T1DM (low BrachD in 33% vs high PWV-trunk in 9.9%). Male subjects with type 1 diabetes had a higher prevalence of VS abnormalities than females. Presence of T1DM, male sex, and increased mean arterial pressure were the most consistent independent determinants of vascular stiffness. Conclusions: Increased vascular stiffness is present in youth with T1DM with peripheral abnormalities predominating especially in males. Traditional risk factors are important correlates. Identifying early vascular abnormalities in youth with T1DM will allow for implementation of more aggressive risk factor management. [Copyright &y& Elsevier]

Abstract: We estimated the potential impact of parental Tdap immunization before delivery, at delivery and at the 2-week newborn visit on U.S. infant pertussis hospitalizations. We used published data for pertussis hospitalization rates among U.S. infants aged 0–4 months, the Tdap vaccine efficacy in adults, and the proportion of infants with pertussis <6 months of age in which either parent was the source (16–40% from mothers and 16–20% from fathers). Immunizing parents before pregnancy or ≥2 weeks prior to delivery should reduce pertussis hospitalizations among infants 0–4 months by 2694–9314 if both parents are vaccinated, and by 1347–6909 if only mothers are vaccinated. Greater reductions in pertussis hospitalizations would be achieved if parents are immunized ≥2 weeks prior to delivery than after delivery or the 2-week newborn visit. Although immunizing parents prior to pregnancy or delivery is best, immunizing parents in the postpartum period should provide protection to that newborn and to infants of subsequent pregnancies. [Copyright &y& Elsevier]

Abstract: Background: A woman from Italy presented with dystonic leg symptoms at the age of 59. Rapid-onset dystonia-parkinsonism (RDP) was not suspected until 3 affected children (2 male, 1 female) with presentations consistent with the disorder were recognized. Methods: The mother and four of her children (3 with and 1 without dystonia) were evaluated with an extensive battery including standardized history questionnaire and rating scales. In addition, all four children had cognitive testing and three of the four children had psychiatric interviews. Results: In this family, a T613M mutation in the ATP1A3 gene was confirmed, the most common mutation present in patients with RDP. The proband''s limb dystonia was atypical of RDP, symptoms of the others affected included dysarthria, asymmetric limb dystonia, and dysphagia more consistent with RDP. The two sons developed dystonia-parkinsonism in adolescence after consuming large amounts of alcohol. All 3 of those with psychiatric interviews reached diagnosable thresholds for mood disorder (bipolar or dysthymia) and some form of anxiety disorder. Conclusions: The phenotype and age of onset is broader than previously reported in RDP, suggesting that it could be under-reported. Prior to this study, neuropsychologic symptoms associated with RDP were under-appreciated. Those patients who are at risk or suspected of having RDP should be cautioned to avoid excessive alcohol intake. Further study is needed to assess if the cognitive and psychiatric features are part of a broader RDP phenotype and this may have implications for future research into genetic susceptibility for psychiatric disease. [Copyright &y& Elsevier]

Abstract: We estimated the potential impact of administering the first dose of rotavirus vaccine at 6 weeks (42 days of life) instead of 2 months of age, which is permissible for all U.S. vaccines recommended at 2 months of age, on rotavirus hospitalization rates. We used published data for hospitalization rates, vaccine coverage, and vaccine efficacy after one dose and assumed a two-week delay in seroconversion after vaccine administration in the United States. Administering the first dose of rotavirus vaccine at 6 weeks instead of 8 weeks of age should have prevented 1110, 1660, and 2210 rotavirus hospitalizations among U.S. infants <3 months of age in 2006 when the vaccine was first introduced. This estimated benefit represents a 2–4% reduction in rotavirus hospitalizations among children <5 years of age. [Copyright &y& Elsevier]