Laney S. Light

Impact of maternal immunization on influenza hospitalizations in infants

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.

ATP1A3 mutations in infants: a new rapid-onset dystonia-Parkinsonism phenotype characterized by motor delay and ataxia.

We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid‐onset dystonia–Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre‐existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.

Examining Gender Differences in Risk Factors for Suicide Attempts Made 1 and 7 Years Later in a Nationally Representative Sample

OBJECTIVES This study examined the prospective risk factors for making a nonfatal suicide attempt and whether they varied by gender. METHODS We used data from the National Longitudinal Study of Adolescent Health. A nationally representative sample of 10,828 youth was assessed over three different time points spanning 7 years. We conducted multivariable logistic regression to examine the main and interactive effects on the odds of making a suicide attempt 1 and 7 years later. RESULTS Regardless of an individuals gender, multivariable analyses indicated unique risk factors including suicidal ideation, depressive symptoms, a friends past history of attempted and completed suicide, and a family members past history of attempted suicide that were significantly associated with increased odds of suicide attempts made 1 and 7 years later. Parental loss predicted likelihood of suicide attempt 1 year later but not 7 years later. Moderational analyses indicated that gender did not interact with most of the risk factors. However, post hoc probing of two significant interaction terms indicated that young age was a risk factor for making a nonfatal suicide attempt 1 year later for females but not for males, and that females with high somatic symptoms had a greater risk for making a nonfatal suicide attempt as compared with those with low somatic symptoms and with males with low or high somatic symptoms. CONCLUSION These results indicate similar risk factors for nonfatal suicide attempts among males and females. However, younger age and somatic symptoms were reported to be risk factors for females but not for males, suggesting the need for targeted interventions with young females with somatic complaints.

Psychiatric disorders in rapid-onset dystonia-parkinsonism.

Objective: Rapid-onset dystonia-parkinsonism (RDP) is caused by a variety of missense mutations in the ATP1A3 gene. Psychiatric comorbidity has been reported, although systematic examination of psychiatric disease in individuals with RDP is lacking. This study examines psychiatric morbidity for 23 patients with RDP in 10 families with family member control subjects and in 3 unrelated patients with RDP, totaling 56 individuals. Methods: Twenty-nine ATP1A3 mutation–positive individuals were examined; 26 exhibited motor symptoms (motor manifesting carrier [MMC]) and 3 did not (nonmotor manifesting carriers [NMC]). Twenty-seven ATP1A3 mutation-negative participants (noncarriers [NC]) were included. Rates of psychiatric illness for patients with RDP and related asymptomatic gene mutation carriers were compared with those for related nonmutation carriers. Outcome measures included the Unified Parkinsons Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale, Instrumental Activities of Daily Living, Composite International Diagnostic Interview, Structured Clinical Interview for DSM-IV, Hamilton Depression Scale, Hamilton Anxiety Scale, and Yale-Brown Obsessive-Compulsive Scale. Results: NMC participants did not report any history of psychiatric disorder. Findings in MMC and NC groups included anxiety (MMC 48, NC 41%), mood (MMC 50%, NC 22%), psychotic (MMC 19%, NC 0%), and substance abuse/dependence (MMC 38%, NC 27%). Conclusions: ATP1A3 mutations cause a wide spectrum of motor and nonmotor features. Psychotic symptoms tended to emerge before or concurrent with motor symptom onset, suggesting that this could be another expression of the ATP1A3 gene mutation.

Buffy coat specimens remain viable as a DNA source for highly multiplexed genome-wide genetic tests after long term storage

BackgroundBlood specimen collection at an early study visit is often included in observational studies or clinical trials for analysis of secondary outcome biomarkers. A common protocol is to store buffy coat specimens for future DNA isolation and these may remain in frozen storage for many years. It is uncertain if the DNA remains suitable for modern genome wide association (GWA) genotyping.MethodsWe isolated DNA from 120 Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial buffy coats sampling a range of storage times up to 9 years and other factors that could influence DNA yield. We performed TaqMan SNP and GWA genotyping to test whether the DNA retained integrity for high quality genetic analysis.ResultsWe tested two QIAGEN automated protocols for DNA isolation, preferring the Compromised Blood Protocol despite similar yields. We isolated DNA from all 120 specimens (yield range 1.1-312 ug per 8.5 ml ACD tube of whole blood) with only 3/120 samples yielding < 10 ug DNA. Age of participant at blood draw was negatively associated with yield (mean change -2.1 ug/year). DNA quality was very good based on gel electrophoresis QC, TaqMan genotyping of 6 SNPs (genotyping no-call rate 1.1% in 702 genotypes), and excellent quality GWA genotyping data (maximum per sample genotype missing rate 0.64%).ConclusionsWhen collected as a long term clinical trial or biobank specimen for DNA, buffy coats can be stored for up to 9 years in a -80degC frozen state and still produce high yields of DNA suitable for GWA analysis and other genetic testing.Trial RegistrationThe Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is registered with ClinicalTrials.gov, number NCT00000620.

New triggers and non-motor findings in a family with rapid-onset dystonia-parkinsonism

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 probands 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.

Protective Behaviors and High-Risk Drinking among Entering College Freshmen.

OBJECTIVES To explore the use of protective behaviors to reduce risks associated with alcohol consumption among adolescents during the summer preceding college enrollment. METHODS Survey data were collected in fall 2006 and 2007 that assessed demographic characteristics, drinking behaviors, and use of protective behaviors in the 3 months preceding the survey. RESULTS Female participants reported using 4 out of 10 protective behaviors more often than did males, and using protective behaviors was significantly related to fewer negative drinking-related consequences. CONCLUSIONS Findings highlight potential benefits of using protective behaviors and the need to promote effective behaviors.

Sickle Cell Trait, Hemoglobin C Trait and Invasive Pneumococcal Disease

Background: The cause of historically higher rates of invasive pneumococcal disease among blacks than whites has remained unknown. We tested the hypothesis that sickle cell trait or hemoglobin C trait is an independent risk factor for invasive pneumococcal disease. Method: Eligible children were born in Tennessee (1996-2003), had a newborn screen, enrolled in TennCare aged <1 year, and resided in a Tennessee county with laboratory-confirmed, pneumococcal surveillance. Race/ethnicity was ascertained from birth certificates. Children were followed through 2005 until loss of enrollment, pneumococcal disease episode, fifth birthday, or death. We calculated incidence rates by race/ethnicity and hemoglobin type before and after pneumococcal conjugate vaccine (PCV7) introduction. Poisson regression analyses compared invasive pneumococcal disease rates among blacks with sickle cell trait or hemoglobin C trait with whites and blacks with normal hemoglobin, controlling for age, gender, time (pre-PCV7, transition year, or post-PCV7) and high-risk conditions (eg, heart disease). Results: Over 10 years, 415 invasive pneumococcal disease episodes occurred during 451,594 observed child-years. Before PCV7 introduction, disease rates/100,000 child-years were 2941 for blacks with sickle cell disease, 258 for blacks with sickle cell trait or hemoglobin C trait and 188, 172, and 125 for blacks, whites, and Hispanics with normal hemoglobin. Post-PCV7, rates declined for all groups. Blacks with sickle cell trait or hemoglobin C trait had 77% (95% CI = 22-155) and 42% (95% CI = 1-100) higher rates than whites and blacks with normal hemoglobin. Conclusion: Black children with sickle cell trait or hemoglobin C trait have an increased risk of invasive pneumococcal disease.

The effect of intensive risk factor management in type 2 diabetes on inflammatory biomarkers.

AIMS To determine whether intensive risk factor management reduced markers of inflammation in middle-aged and older people with type 2 diabetes who either had, or were at risk for cardiovascular disease (CVD), and whether these effects were mediated by adiposity. METHODS The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was a multicenter double 2 by 2 factorial randomized controlled trial of 10,251 middle-aged and older people who had type 2 diabetes, a GHbA1c of 7.5% or greater, and evidence of CVD or CVD risk factors. Biomarkers were assessed in a subset of 562 participants. Intervention effects on high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were tested using linear regression models. RESULTS A significantly lower average hs-CRP was noted in the intensive versus the standard glycemic group (p=0.029). Adjusting for change in BMI or waist circumference resulted in larger differences in adjusted hs-CRP (p<0.001 and p<0.002, respectively) between the glycemic intervention groups. CONCLUSIONS Intensive glycemic control was associated with a reduction in hs-CRP in this study population. Intervention associated increases in adiposity suppressed the beneficial effect of intensive glycemic control on lowering hs-CRP.

Is silent myocardial infarction more common in women with type 2 diabetes than in men

OBJECTIVE Our aim was to determine if silent myocardial infarction (MI) is more common in women with type 2 diabetes than in men. Our secondary aim was to examine the relationships between silent MI and risk factors for cardiovascular disease. RESEARCH DESIGN AND METHODS The Action to Control Cardiovascular Risk in Diabetes (ACCORD) database was used to determine if women had more silent MI on baseline electrocardiograms (ECGs) than did men with a similar unremarkable cardiovascular history. MI was diagnosed using ECG analysis according to the Minnesota code. Multivariable logistic regression analysis was used to compare demographic and clinical associations. Interactive effects of risk factors by gender were tested using a forward selection algorithm. RESULTS Men were found to have a higher prevalence of silent MI on baseline ECGs than women (6% vs 4%, P = .001). Women had lower odds of silent MI than men after adjusting for other risk factors (OR = 0.80, P = .04). Race and ethnicity were significantly associated with silent MI (P = .02), with Asians having the highest and African Americans and Hispanics having lower odds relative to whites. CONCLUSIONS Our main findings provide no evidence that silent MI, as detected by the Minnesota code, was more common in women than in men in the ACCORD cohort. If, as in the general population, the women in ACCORD are found to have a higher heart disease mortality rate than the men, it seems unlikely that failure to recognize clinically silent heart disease in the years before study enrollment could be a major cause.