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Prior research has shown that cancer risk varies by geography, but scan statistics methods for identifying cancer clusters in case-control studies have been limited in their ability to identify multiple clusters and adjust for participant-level risk factors. We develop a method to identify geographic patterns of breast cancer odds using the Wisconsin Women's Health Study, a series of 5 population-based case-control studies of female Wisconsin residents aged 20-79 enrolled in 1988-2004 (cases=16,076, controls=16,795). We create sets of potential clusters by overlaying a 1 km grid over each county-neighborhood and enumerating a series of overlapping circles. Using a two-step approach, we fit a penalized binomial regression model to the number of cases and trials in each grid cell, penalizing all potential clusters by the least absolute shrinkage and selection operator (Lasso). We use BIC to select the number of clusters, which are included in a participant-level logistic regression model. We identify 15 geographic clusters, resulting in 23 areas of unique geographic odds ratios. After adjustment for known risk factors, confidence intervals narrowed but breast cancer odds ratios did not meaningfully change; one additional hotspot was identified. By considering multiple overlapping spatial clusters simultaneously, we discern gradients of spatial odds across Wisconsin.

Purpose To examine the relationships of retinal vessel geometric characteristics (RVGCs) to the incidence and progression of diabetic retinopathy (DR). Design Observational, prospective cohort study. Participants Nine hundred ninety-six persons with type 1 diabetes mellitus (T1DM) and 1370 persons with type 2 diabetes mellitus (T2DM) seen at a baseline examination who were eligible for follow-up examinations at subsequent 5-year intervals. A total of 3846 person-interval data from these follow-up examinations are the basis for the analyses. Methods Diabetic retinopathy and macular edema were assessed by grading of 30° stereoscopic color fundus photographs. Retinal vessel geometric characteristics were assessed using the Singapore I Vessel Assessment program from a digitized copy of 1 of the field 1 fundus photographs obtained at baseline and follow-up. Main Outcome Measures The 5-year incidence of any DR, progression of DR, and incidence of proliferative diabetic retinopathy (PDR) and clinically significant macular edema (CSME) in right eyes. Results Incident DR occurred in 45%, progression in 32%, PDR in 10%, and CSME in 5%. While adjusting for glycated hemoglobin, duration of diabetes, and other factors, retinal arteriolar simple tortuosity was associated significantly with the incidence of any DR (odds ratio [OR], 1.17; 95% confidence interval [CI], 1.01–1.35). Retinal venular branching angle was associated significantly with progression of DR (OR, 1.18; 95% CI, 1.03–1.36), retinal venular curvature tortuosity was associated significantly with the incidence of PDR (OR, 1.15; 95% CI, 1.01–1.30), and retinal venular branching angle (OR, 1.41; 95% CI, 1.10–1.82) was associated significantly with the incidence of CSME. There were no significant associations of other RVGCs with any of the DR outcomes in the full multivariate model. Inclusion of all possible RVGCs did not improve the predictive value of the models that already included retinal vessel diameter and baseline DR severity level. Conclusions Retinal vessel geometric characteristics of the retinal venules were associated with progression of DR; however, most of the RVGCs measured from digitized fundus photographs added little to the assessment of risk of incidence and progression of DR when other risk factors were considered in T1DM and T2DM.

Background Studies indicate that the nasal microbiome may correlate strongly with the presence or future risk of childhood asthma. Objectives In this study, we tested whether developmental trajectories of the nasopharyngeal microbiome in early life and the composition of the microbiome during illnesses were related to risk of childhood asthma. Methods Children participating in the Childhood Origins of Asthma study (n=285) provided nasopharyngeal mucus samples in the first two years of life, during routine healthy study visits (2, 4, 6, 9, 12, 18 and 24 months of age) and episodes of respiratory illnesses, which were analyzed for respiratory viruses and bacteria. We identified developmental trajectories of early-life microbiome composition, as well as predominant bacteria during respiratory illnesses, and correlated these with presence of asthma at 6, 8, 11, 13 and 18 years of age. Results Of the four microbiome trajectories identified, a Staphylococcus-dominant microbiome in the first 6 months of life was associated with increased risk of recurrent wheezing by age 3 years and asthma that persisted throughout childhood. In addition, this trajectory was associated with the early onset of allergic sensitization. During wheezing illnesses, detection of rhinoviruses and predominance of Moraxella were associated with asthma that persisted throughout later childhood. Conclusion In infancy, the developmental composition of the microbiome during healthy periods and the predominant microbes during acute wheezing illnesses are both associated with the subsequent risk of developing persistent childhood asthma. Clinical Implication Identifying factors that promote early colonization with S. aureus may lead to future interventional studies to prevent childhood asthma., Capsule summary: In a birth cohort study, early colonization of the upper airway with Staphylococcus aureus and detection of rhinoviruses and Moraxella catarrhalis during illnesses were associated with subsequent childhood asthma.

Background Farm exposures may reduce the risk of atopic dermatitis (AD) in children, but this is controversial and US data are limited. Objective This study was conducted to identify patterns of farm exposure in Wisconsin family farms that modify AD incidence and prevalence in early childhood. Methods Environmental exposures, health history, and clinical outcomes were prospectively recorded for 111 farm families and 129 non–farm families enrolled in the Wisconsin Infant Study Cohort birth cohort study. Exposures from the prenatal and early postnatal (2-month) visits were evaluated together with parental report of AD diagnosis by a health care provider through age 24 months. Latent class analysis was performed with prenatal and early postnatal farm-exposure variables to assign farm children to 3 classes. Results Overall, children of farm families had reduced AD incidence (P = .03). Within farm families, exposures including poultry (3% vs 28%; P = .003), pig (4% vs 25%; P = .04), feed grain (13% vs 34%; P = .02), and number of animal species were inversely associated with AD incidence. Among the latent class groups, children in families with diverse or more intense farm exposures (classes A and B) had reduced AD incidence, whereas low-exposure (class C) infants had AD incidence similar to that in nonfarm children. Conclusions Infants in Wisconsin farm families had reduced AD incidence, and patterns of farm exposures further defined AD risk. These findings suggest that exposure to diverse farm animals, feed, and bedding during the prenatal period and in early infancy reduce the risk of early-onset AD, a phenotype associated with multiple other atopic diseases.

Spatial cluster detection is an important tool in many areas such as sociology, botany and public health. Previous work has mostly taken either hypothesis testing framework or Bayesian framework. In this paper, we propose a few approaches under a frequentist variable selection framework for spatial cluster detection. The forward stepwise methods search for multiple clusters by iteratively adding currently most likely cluster while adjusting for the effects of previously identified clusters. The stagewise methods also consist of a series of steps, but with tiny step size in each iteration. We study the features and performances of our proposed methods using simulations on idealized grids or real geographic area. From the simulations, we compare the performance of the proposed methods in terms of estimation accuracy and power of detections. These methods are applied to the the well-known New York leukemia data as well as Indiana poverty data.

Background Sex influences the risk of wheezing illnesses and the prevalence of asthma throughout childhood. Objective To better understand the mechanisms of these effects, we analyzed longitudinal relationships between sex, lung physiology, and asthma in the Childhood Origins of ASThma birth cohort study. Methods Childhood Origins of ASThma birth cohort study children were followed prospectively from birth and assessed annually. Results of spirometry, fractional exhaled nitric oxide (Feno), mannitol provocation testing, and 3 He gas magnetic resonance imaging were assessed by sex using multivariate models including age, asthma diagnosis, and wheezing histories. Results Girls had higher prebronchodilator forced expiratory volume in 0.5 seconds/forced vital capacity values than did boys (mean difference, 0.017; 95% CI, 0.000-0.034; P = .05) of equivalent age. Postbronchodilator findings were more pronounced, with boys demonstrating reduced forced expiratory volume in 0.5 seconds/forced vital capacity values than did girls of equivalent age (mean difference, 0.032; 95% CI, 0.014-0.049; P = .0005). Conversely, girls were noted to have higher ventilation defects on 3 He magnetic resonance imaging than did boys ( P = .01). No differences were noted in the rate of positive responses to mannitol provocation or Feno measurements. Conclusions Lower airflow values are present by spirometry for prepubertal boys than for age-matched girls; however, greater 3 He ventilation defects were noted in girls. This could represent a greater degree of subclinical air trapping in prepubertal girls because residual volumes are not detected on standard spirometric readings. No differences were noted between the 2 sexes with airway hyperresponsiveness (mannitol provocation testing) or inflammation (Feno). Prospective peripubertal follow-up will determine whether these differences persist or change with the de novo expression and remission of asthma based on sex and age.

Given larger bone size in men, bone mineral density (BMD) precision might differ between sexes. This study compared dual-energy X-ray absorptiometry BMD precision of 3 International Society for Clinical Densitometry-certified technologists in older men and women. Each technologist scanned a cohort of 30 men and 30 women (total n = 180) by using a Lunar iDXA densitometer (GE Healthcare, Madison, WI). Each volunteer had 2 lumbar spine and bilateral hip scans with repositioning between examinations. BMD least significant change was calculated. Age and body mass index did not differ between men and women. Mean height and weight were greater in men, 174.6 cm ± 6.9 and 81.6 kg ± 11.1 respectively, (p0.0001) than in women, 161.5 cm ± 5.9/69.1 kg ± 14.2, respectively. Bone area was greater in men (p0.0001) at all sites. BMD least significant change was statistically better (p0.05) in women at the mean total femur (0.014 vs 0.018 g/cm(2)) and left femoral neck (0.025 vs 0.038 g/cm(2)), but not different at either total femur, the right femoral neck, or lumbar spine (all p0.05). In conclusion, statistically significant male/female differences in BMD precision were observed at the mean total femur and left femoral neck. Given the small magnitude of difference in g/cm(2) and inconsistent pattern, that is, no right femoral neck difference, there is virtually no clinical difference in BMD precision between sexes. These data do not support a need for sex-specific precision analyses.

Objective To describe the relationships of lifestyle characteristics to changes in vision and incidence of visual impairment (VI) over a 20-year period in the Beaver Dam Eye Study (BDES). Design Longitudinal, population-based cohort study. Participants A cohort of 4926 persons aged 43 to 86 years participated in the baseline examinations in 1988–1990, and 3721, 2962, 2375, and 1913 persons participated in follow-up examinations in 1993–1995, 1998–2000, 2003–2005, and 2008–2010, respectively. Methods Best-corrected visual acuity (BCVA) measured by a modified Early Treatment Diabetic Retinopathy Study protocol. Main Outcome Measures Change in number of letters read correctly and incidence of VI based on BCVA in the better eye assessed at each examination over a 20-year period. Results The 20-year cumulative incidence of VI was 5.4%. There was a mean loss of 1.6 letters between examinations, with a 20-year loss of 6.6 letters. While adjusting for age, income, and age-related macular degeneration (AMD) severity, being a current or past smoker was related to a greater change in the numbers of letters lost. Persons who had not consumed alcoholic beverages over the past year and sedentary persons had higher odds of incident VI than persons who drank occasionally or who were physically active. For example, in women with early AMD and annual household income less than $10 000, the estimated 20-year cumulative incidence of VI in those who drank occasionally and were physically active was 5.9% compared with 25.8% in women who had not consumed alcoholic beverages over the past year and were sedentary. Conclusions Three modifiable behaviors—smoking, drinking alcohol, and physical activity—were associated with changes in vision. Further evidence that changes in these behaviors will result in less loss of vision is needed because of the expected increase in the burden of VI due to the aging of the population.

Purpose: Genome wide association studies have identified common single nucleotide polymorphisms (SNPs) associated with breast cancer risk. Many of these SNPs have an unknown biologic significance. Hormonal risk factors may mediate the relationships between these loci and breast cancer risk. We explored the relation between breast cancer susceptibility loci and menstrual factors using data from two population-based studies. Methods: In the first dataset, composed of 1328 women ages 20–74 years without a breast cancer diagnosis who participated in an established population-based study conducted in three U.S. states, we used linear regression to assess the associations between 13 previously-identified breast cancer loci with age at menarche, age at natural menopause and the reproductive lifespan. The reproductive lifespan is defined as the time between age at menarche and age at natural menopause, excluding time for pregnancy, oral contraceptive use and lactation. A polygenic risk score created as the sum of the number of risk allele copies in the SNPs was also evaluated for an association with menstrual traits. Significant results were then evaluated in the second dataset comprised of 1353 women ages 43–86 years recruited as part of a cohort study based in Beaver Dam, WI. Results: Polygenic score and 13 loci were not associated with either age at menarche or reproductive lifespan. Two SNPs were associated with age at natural menopause; each increase in the number of copies of the minor allele (A) of rs17468277 (CASP8) was associated with a 1.12 year decrease in age at natural menopause (p = 0.02). The minor allele (G) of SNP rs10941679 (5p12) (p = 0.01) was associated with a 1.01 year increase in age at natural menopause, although these results were not replicated in the follow-up study (p = 0.14 and 0.98, respectively). Conclusions: We did not find evidence to support the hypothesis that breast cancer susceptibility loci are related to menstrual factors. The following are the 18 highest scoring abstracts of those submitted for presentation at the 37th Annual ASPO meeting held March 10–12, 2013, in Memphis, TN.

Background Little is known about the relationships between sociodemographic characteristics and ratings of provider communication behavior among women with depression in the United States. This study uses the Andersen Behavioral Model to examine the relationships among predisposing, enabling, and need factors and ratings of perceived patient–provider communication in women with depression. Methods The sample consisted of women with depression who visited any provider in the previous 12 months in the 2002–2008 Medical Expenditure Panel Survey ( n = 3,179; weighted n = 4,707,255). Multivariate logistic regression was used to examine the independent contribution of predisposing, enabling, and need factors on providers' communication behavior measures. Findings Black (non-Hispanic) women were more likely to report that providers always listened carefully (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.01–1.94), explained so they understood (OR, 1.53; 95% CI, 1.10–2.11), and showed respect for what they had to say (OR, 1.39; 95% CI, 1.01–1.92). Women participating in the paid workforce and those without a usual source of care were at increased risk for less favorable experiences. Conclusions Participation in the paid workforce and lack of a usual source of care were associated with an increased likelihood of less optimal communication experiences. Implications for Practice and/or Policy Ensuring that women with depression have reliable access to a continuous source of care and expanding the availability of nonemergent, after-hours care may be instrumental for improving patient–provider communication in this population.

Purpose To describe visual impairment (VI) over a 20-year period and its associations with age-related eye diseases and socioeconomic factors in the Beaver Dam Eye Study. Design Population-based cohort study. Participants Four thousand nine hundred twenty-six persons 43 to 86 years of age participated in the baseline examination phase from 1988 through 1990, and 3721, 2962, 2375, and 1913 persons participated in follow-up examinations each spaced 5 years apart from 1993 through 1995, 1998 through 2000, 2003 through 2005, and 2008 through 2010, respectively. Methods Best-corrected visual acuity after refraction, assessed by the Early Treatment Diabetic Retinopathy Study protocol. Main Outcome Measures Incidence of VI, defined as best-corrected visual acuity of poorer than 20/40 in the better eye in persons with one or both eyes 20/40 or better at the beginning of a 5-year interval, and incidence of severe VI, defined as best-corrected visual acuity of 20/200 or worse in the better eye in persons with one or both eyes better than 20/200 at the beginning of a 5-year interval. Results Overall incidence of VI between examinations (5-year interval) was 1.4% (varying from 0.1% in persons 50–54 years of age to 14.6% in those 85 years of age and older), whereas for severe VI it was 0.4% (varying from 0.0% in persons 50–54 years of age to 6.9% in those ≥85 years of age). The incidence of VI decreased for each period after adjustment for age, from the first 5-year interval between examinations (1988–1990 to 1993–1995) to the fourth and most recent 5-year interval (2003–2005 to 2008–2010; odds ratio fourth interval vs. first interval, 0.53; 95% confidence interval, 0.32–0.87; P = 0.01). This period effect was no longer significant after adjustment for age-related macular degeneration. Age-related macular degeneration remained the leading cause of incident severe VI (54% of eyes with incident severe VI, which was as low as 40% and as high as 57% for specific visits), with no evidence of a trend across visits. The overall frequency of VI correctable with new refraction was 38% of all eyes with VI. Conclusions These data provide population-based estimates that show a high (15%) 5-year incidence of VI in persons 85 years of age and older. Age-related macular degeneration remained the leading cause of severe VI in this population over the 20 years of the study. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Objective To describe the relationships of intima–media thickness (IMT), plaque in the carotid artery, angina, myocardial infarction (MI), and stroke to the 10-year cumulative incidence of early and late age-related macular degeneration (AMD) and progression of AMD. Design Cohort study. Participants A total of 1700 persons aged 53 to 96 years who participated in both the Epidemiology of Hearing Loss Study and the Beaver Dam Eye Study in 1998–2000, with photographs gradable for AMD at 5-year (2003–2005) and 10-year (2008–2010) follow-up examinations. Methods The IMT and presence of plaque were assessed using B-mode ultrasonography of the carotid artery. Presence of angina, MI, and stroke were defined on the basis of a self-reported history of physician diagnosis. The presence and severity of AMD were determined by systematic grading of stereoscopic color fundus photographs. Main Outcome Measures Age-related macular degeneration. Results The 10-year cumulative incidence of early AMD was 15.7%, and the 10-year cumulative incidence of late AMD was 4.0%. After adjusting for age, sex, body mass index, smoking status, age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) genotypes, and other factors, mean IMT was associated with the 10-year incidence of early AMD (odds ratio [OR] per 0.1 mm IMT, 1.11; 95% confidence interval [CI], 1.00–1.21; P = 0.03) and late AMD (OR per 0.1 mm IMT, 1.27; CI, 1.10–1.47; P = 0.001). Mean IMT was associated with the 10-year incidence of pure geographic atrophy (OR per 0.1 mm IMT, 1.31; CI, 1.05–1.64; P = 0.02) but not exudative AMD (OR per 0.1 mm IMT, 1.14; CI, 0.97–1.34; P = 0.11). Similar associations were found for maximum IMT. The number of sites with plaque was related to the incidence of late AMD (OR per 0.1 mm IMT, 2.79 for 4–6 sites vs. none; CI, 1.06–7.37; P = 0.04) but not to early AMD. A history of angina, MI, or stroke was not related to any incident AMD outcome. Conclusions In these population-based data, carotid artery IMT and carotid plaques had a weak relationship to the incidence of late AMD that was independent of systemic and genetic risk factors. Angina, MI, and stroke were not related to AMD. It is unclear whether the carotid IMT is a risk indicator of processes affecting Bruch's membrane and the retinal pigment epithelium, or a measure of atherosclerosis affecting susceptibility to AMD. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

This report identifies a radius dual-energy X-ray absorptiometry (DXA) confounder and technical approach to avoid this inaccuracy. Initially, a precision study revealed substantial differences ( p 2 between 3 technologists that each performed assessments in 30 men and 30 women. Subsequently, visual examination of all 360 forearm DXA images, including bone, soft tissue, neutral, and air point-typing was performed. Errors in automated "soft tissue" identification were observed; compared with the manufacturer's ideal depiction, suboptimal soft tissue point-typing was present in 30/360 scans (8.3%) involving 27 individuals. These point-typing deviations appeared to result from inclusion of forearm positioner slots at the scan field edges or clothing covering the forearm. Twenty-four individuals had a paired scan appropriately point-typed, thus allowing evaluation of the effect on BMD measurement. In those with incorrect point-typing associated with positioner slots, the mean one-third radius BMD was ∼7% higher. In conclusion, positioner slots at the edges of the distal scan field can lead to automated soft tissue identification inaccuracies and consequent erroneous one-third radius BMD measurement. DXA technologists should avoid slot inclusion in forearm scans and evaluate point-typing as part of routine analysis.

To identify factors contributing to the declining prevalence of hearing impairment in more recent generations.We used data on hearing thresholds and potential risk factors of hearing impairment collected from studies in Beaver Dam, Wisconsin, the Epidemiology of Hearing Loss Study (1993-1995, n=3753; 1998-2000, n=2800 and 2003-2005, n=2395), the concurrent Beaver Dam Eye Study on the same cohort, and a subgroup (n=2173) of the Beaver Dam Offspring Study (2005-2008).Educational attainment significantly reduced the odds ratio (OR) of the birth cohort effect on hearing impairment from 0.90 to 0.93, while a history of ear infection had a reverse effect on the decreasing trend (significantly changing the OR from 0.93 to 0.94). Occupational noise exposure, smoking, and a history of cardiovascular disease, while associated with hearing impairment, did not attenuate the cohort effect. The cohort effect remained significant after known risk factors were adjusted (OR=0.93; 95% confidence interval, 0.89-0.97).These data provide strong evidence that environmental, lifestyle, or other modifiable factors contribute to the etiology of hearing impairment and add support to the idea that hearing impairment in adults may be prevented or delayed.

The Framingham Global Cardiovascular Disease (FRS-CVD) risk assessment is a proposed alternative for the assessment of hard coronary heart disease (FRS-CHD) event risk. Beyond heart attack and death, FRS-CVD risk adds the end points of cerebrovascular disease, angina, heart failure, and peripheral vascular disease.We sought to estimate the population impact of using FRS-CVD instead of FRS-CHD risk prediction on U.S. adults.We analyzed FRS-CHD and FRS-CVD risk in men age 45-74 and women age 55-74 without cardiovascular disease or diabetes, using the National Health and Nutrition Examination Survey 2005-2006. We stratified the population into 10-year risk categories: low:6%, moderate ≥ 6 to10%, moderate high ≥ 10 to20%, and high ≥ 20% by both risk models, and assessed change in risk category distribution and achievement of lipid goals.We analyzed 1020 subjects who statistically represent approximately 50 million U.S. adults. When the FRS-CVD was used, we found that 63% of men and 74% of women increase at least one risk category compared with when the FRS-CHD is used. Overall, the low-risk population decreases from 52% to 16% and the high-risk group increases from 4% to 20%. Of the subjects changing risk categories, 30% will now fail to meet their new corresponding lipid goals.FRS-CVD end points are more comprehensive, yet the population implications of such a change may be profound. The use of a FRS-CVD risk model significantly increases the intermediate and high-risk groups, thus increasing the number of individuals eligible for novel risk assessment tools such as high-sensitivity C-reactive protein, coronary calcium scoring, and more frequent use of pharmacotherapy.

Background Obesity has been proposed to be a risk factor for the development of childhood asthma. Objective We sought to examine weight status from birth to age 5 years in relation to the occurrence of asthma at ages 6 and 8 years. Methods Two hundred eighty-five full-term high-risk newborns with at least 1 asthmatic/atopic parent enrolled in the Childhood Origin of Asthma project were studied from birth to age 8 years. Overweight was defined by weight-for-length percentiles of greater than the 85th percentile before the age of 2 years and a body mass index percentile of greater than the 85th percentile at ages 2 to 5 years. Results No significant concurrent association was found between overweight status and wheezing/asthma occurrence at each year of age. In contrast, longitudinal analyses revealed complex relationships between being overweight and asthma. Being overweight at age 1 year was associated with a decreased risk of asthma at age 6 (odds ratio [OR], 0.32; P = .02) and 8 (OR, 0.35; P = .04) years, as well as better lung function. However, being overweight beyond infancy was not associated with asthma occurrence. In fact, only children who were overweight at age 5 years but not at age 1 year had an increased risk of asthma at age 6 years (OR, 5.78; P = .05). Conclusion In children genetically at high risk of asthma, being overweight at age 1 year was associated with a decreased risk of asthma and better lung function at ages 6 and 8 years. However, being overweight beyond infancy did not have any protective effect and even could confer a higher risk for asthma.

Objectives Compare three commonly used methods to combine the impacts of multiple health conditions on SF-6D health utility scores. Study Design and Setting We used data from the 1998–2004 Medicare Health Outcomes Survey to compare three commonly suggested models of multiple health conditions' impacts on health-related quality of life: additive, minimum, and multiplicative. We modeled SF-6D scores using information about 15 health conditions, both unadjusted and adjusted for age, sex, education, and income. Model performance was assessed using mean squared error, mean predictive error by number of health conditions, and mean predictive error for groups with specific combinations of health conditions. Results Ninety-five thousand one hundred ninety-five observations were used for model estimation, and 94,794 observations were used for model testing. The adjusted models always had better performance than the unadjusted models. The multiplicative model showed smaller mean predictive error than the other models in both those younger than 65 years and those 65 years and older. Mean predictive error for the multiplicative model was generally within the minimally important difference of the SF-6D. Conclusion All tested models are imperfect in these Medicare data, but the multiplicative model performed best.

Objective To examine the 25-year cumulative incidence of visual impairment (VI) and its relation to various risk factors. Design Population-based study. Participants Nine hundred fifty-five insulin-taking persons living in an 11-county area in southern Wisconsin with type 1 diabetes diagnosed before age 30 years who participated in a baseline (1980–1982) and at least 1 of 4 follow-up (4-, 10-, 14-, and 25-year) examinations or who died before the first follow-up examination (n = 64). Methods Best-corrected visual acuity (VA) was measured using a modification of the Early Treatment Diabetic Retinopathy Study protocol. Visual impairment and severe VI were defined as best-corrected VA in the better eye of 20/40 or worse and 20/200 or worse, respectively. Main Outcome Measures Incidence of VI. Results The 25-year cumulative incidences of any VI and severe VI (accounting for competing risk of death) were 13% and 3%, respectively. Multivariate models showed increased risk of VI was associated (hazard ratio, 95% confidence interval, and P value) with more severe baseline retinopathy (1.14 per 1-step increase in retinopathy level; 1.03–1.27; P = 0.01), presence of cataract (2.49 versus absence; 1.53–4.04; P P P = 0.03), and currently smoking (vs. never smoked, 1.63; 1.01–2.61; P = 0.04), but not proteinuria. Conclusions These data show that the 25-year cumulative incidence of VI is related to modifiable risk factors and, therefore, that VI may be reduced by better glycemic and blood pressure control and avoidance of smoking. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Objective To examine relationships of period of diagnosis of type 1 diabetes mellitus (T1DM) to the prevalence of visual impairment (VI). Design Population-based longitudinal study. Participants Nine hundred fifty-five persons (3719 participant visits) 4 to 80 years of age at baseline who lived in an 11-county area in southern Wisconsin who were diagnosed with T1DM before 30 years of age contributed to the prevalence of VI. Methods Five eye examination visits occurred in the following periods: 1980 through 1982, 1984 through 1986, 1990 through 1992, 1995 through 1996, and 2005 through 2007. Age of diagnosis of T1DM was grouped as before 1960, 1960 through 1969, 1970 through 1974, and 1975 through 1979. Best-corrected visual acuity (VA) using a modification of the Early Treatment Diabetic Retinopathy protocol was measured. Main Outcome Measures Visual impairment was defined as best-corrected VA in the better eye of 20/40 or worse. Results While controlling for duration of T1DM, there was a lower prevalence of VI for more recent periods of diagnosis of diabetes (odds ratio per category, 0.91; 95% confidence interval, 0.88–0.93; P Conclusions More recently diagnosed T1DM was associated with a lower prevalence of VI. This is likely because of the diminishing incidence of proliferative diabetic retinopathy (PDR) and clinically significant macular edema (CSME) resulting from better glycemic control and more timely interventions with photocoagulation for CSME and PDR in those with more recently diagnosed T1DM. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

The aim of this study is to determine which maneuvers result in greatest cross-sectional area (CSA) of the internal jugular vein (IJV) and reduce collapsibility as measured by ultrasound during simulated venipuncture.A total of 52 healthy adult volunteers were prospectively studied in an academic emergency department. Cross-sectional area of the IJV was recorded at baseline, with Valsalva, hepatic pressure, and a combination of hepatic pressure plus Valsalva. Subjects were studied in supine and Trendelenburg. Measurements were repeated using pressure applied to the ultrasound transducer to simulate venipuncture and evaluate degree of IJV collapse. Repeated measures analysis of variance models were used to assess the effects of the maneuvers on the diameter equivalent of the cross-sectional area (CRADE).With simulated venipuncture, both Valsalva and Trendelenburg position were significantly (P.0001) associated with increased CSA of the IJV. Valsalva in either Trendelenburg or supine position was associated with the largest CRADE (1.20 and 1.13 cm, respectively). Without simulated venipuncture, CSA of the IJV were increased in all settings (P.0001), but the relative impacts of Valsalva and Trendelenburg position were similar. Hepatic pressure had no impact on CSA of the IJV (P = .94).All maneuvers with the exception of hepatic pressure led to a statistically significant increase in IJV CSA as compared with baseline with and without simulated venipuncture. Valsalva was the only maneuver, when used alone or in combination, to increase the CSA by greater than 50% and prevent collapse by 50% or more under simulated venipuncture.

Diabetic retinopathy (DR) is an important cause of visual impairment, especially in persons 25–65 years of age.1–3 While epidemiological studies have described the incidence of DR.1,4–26 and relationships to various risk factors, many of these studies have been in persons with type 2 diabetes and few have examined these relationships over a long period of time.11,20–26 Even fewer studies have examined regression of DR and associated factors.11 Recent changes in rates of progression and improvement of DR would be expected with the more widespread use of intensive glycemic and blood pressure control.1,15,27–29 In this report, we extend our previous observations by describing the 25-year progression and regression of DR, the incidence of proliferative diabetic retinopathy (PDR), and changes in the prevalence of PDR in a large cohort of persons with type 1 diabetes mellitus participating in the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR).11

Objective To examine relationships of age, period, and birth cohort with the 5-year incidence of age-related macular degeneration (AMD). Design Population-based cohort study with 4 examination visits 5 years apart from 1988 through 1990, 1993 through 1995, 1998 through 2000, and 2003 through 2005. Participants Two thousand nine hundred sixty-eight persons (6603 participant visits) and 3588 persons (8184 participant visits) 43 to 86 years of age at baseline contributing to the incidence of early and late AMD, respectively. Methods Grading of stereoscopic fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. Main Outcome Measures Five-year incidence of early AMD. Results While controlling for age, there was a lower 5-year incidence of early AMD in later rather than in earlier birth cohorts (odds ratio per increasing category, 0.70; 95% confidence interval, 0.62–0.78; P Conclusions Lower incidence of early AMD in more recent birth cohorts is likely the result of unmeasured risk factors for early AMD. Further study of possible unmeasured risk factors that may have caused this cohort effect may help to identify new modifiable risk factors for AMD. Diminishing incidence of early AMD in later birth cohorts would be expected to result in lower long-term estimates of future incidence of AMD than do current estimates that do not take this effect into account. Financial Disclosure(s) The authors have no proprietary or commercial interest in any materials discussed in this article.

Summary. Background: It is probable that the variety and frequency of delayed adverse vascular events after splenectomy are underappreciated. Splenectomy is performed for a wide variety of conditions, and delayed postsplenectomy hazards are not often studied. Objective: To estimate the relative risk of adverse vascular events in members of hereditary spherocytosis families who have or have not had a splenectomy. Methods: Members of families in which hereditary spherocytosis exists were systematically questioned about adverse vascular events. Results: The cumulative incidence of arterial and venous events at age 70 years was greater in persons who had undergone a splenectomy for spherocytosis (arterial, 22% females, 32% males; venous, 20% females, 19% males) than in affected persons who did not undergo splenectomy (arterial, 3% females, 2% males; venous, 6% females, 4% males) or non-affected family members (arterial, 10% females, 17% males; venous, 4% females, 12% males). Affected subjects who undergo splenectomy are at greatly increased risk of arterial events as compared to affected subjects who do not undergo splenectomy [arterial, hazard ratio (HR) 7.2, 95% confidence interval (CI) 2.8–17.2; venous, HR 3.3, 95% CI 1.1–9.8]. Conclusion: There is a significant, long-lasting, increased risk of adverse arterial and venous thromboembolic events after splenectomy performed for hereditary spherocytosis. A review of the literature indicates that this is also true when splenectomy is performed for several other indications.

Background There is evidence that CD4 + CD25 high T-regulatory cells are important for establishing tolerance to allergens, but information in children is limited. Objective To test the hypothesis that greater numbers and function of CD4 + CD25 high T cells are associated with a reduced risk of childhood allergies and wheezing. Methods A cohort of 151 six-year-old children from atopic families was analyzed for peripheral blood CD4 + CD25 high and CD4 + CD25 int T cells by flow cytometry and for clinical and immunologic correlates of atopy. The associations between these variables were assessed by regression analysis. Results Factors positively associated with % CD4 + CD25 high /CD4 T cells were male sex, number of positive allergen-specific IgE tests, total IgE, season, and 1-month average total pollen count preceding blood draw. The percentage of CD4 + CD25 high /total CD4 T cells did not correlate with induced cytokine production, and correlated negatively with suppressive capacity of CD4 + CD25 + T cells ( r = –0.45; P = .034). The percentage of CD4 + CD25 int /CD4 T cells was 54% higher in pollen-sensitized children compared with nonsensitized children in spring ( P = .023 for interaction), and correlated positively with IL-5, IL-10, and IL-13 ( P ≤ .001 for all). Conclusion Our findings suggest that blood CD4 + CD25 high cells are a mixture of activated and regulatory T cells, and that these cells could be seasonally regulated by environmental factors such as pollen exposure. Clinical implications Seasonal increases in CD4CD25 high expression in children with allergy may represent systemic immune activation caused by pollen exposures.

Robbins JA, Kays SA, Gangnon RE, Hind JA, Hewitt AL, Gentry LR, Taylor AJ. The effects of lingual exercise in stroke patients with dysphagia. Objective To examine the effects of lingual exercise on swallowing recovery poststroke. Design Prospective cohort intervention study, with 4- and 8-week follow-ups. Setting Dysphagia clinic, tertiary care center. Participants Ten stroke patients (n=6, acute: ≤3mo poststroke; n=4, chronic: >3mo poststroke), age 51 to 90 years (mean, 69.7y). Intervention Subjects performed an 8-week isometric lingual exercise program by compressing an air-filled bulb between the tongue and the hard palate. Main Outcome Measures Isometric and swallowing lingual pressures, bolus flow parameters, diet, and a dysphagia-specific quality of life questionnaire were collected at baseline, week 4, and week 8. Three of the 10 subjects underwent magnetic resonance imaging at each time interval to measure lingual volume. Results All subjects significantly increased isometric and swallowing pressures. Airway invasion was reduced for liquids. Two subjects increased lingual volume. Conclusions The findings indicate that lingual exercise enables acute and chronic dysphagic stroke patients to increase lingual strength with associated improvements in swallowing pressures, airway protection, and lingual volume.

Purpose To describe the 15-year cumulative incidence of signs of early and late age-related macular degeneration (AMD). Design Population-based cohort study. Participants We included 3917 persons, 43 to 86 years of age at the time of a baseline examination in 1988 through 1990 and with information collected in follow-up in 1993 through 1995, and/or 1998 through 2000, and/or 2003 through 2005. Methods Grading of stereoscopic fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. Main Outcome Measures Cumulative incidence of drusen type and size, pigmentary abnormalities, geographic atrophy, and exudative AMD accounting for competing risk of death. Results The 15-year cumulative incidence was 14.3% for early AMD (the presence of either soft indistinct drusen or the presence of pigmentary abnormalities together with any type of drusen) and 3.1% for late AMD (presence of exudative AMD or geographic atrophy). There was an increased incidence of AMD lesions with age ( P P Conclusions We document the long-term incidence of signs of AMD and a continuum from small hard drusen to late AMD in older persons in the population. The 15-year cumulative incidence of late AMD in people ≥ 75 years of age (8%) indicates a public health problem of significant proportions because the United States population this age is expected to increase by 54% between 2005 and 2025.

Background Sex and age are known to influence the clinical expression of asthma and allergic diseases. Objective We sought to evaluate whether immune response profiles also vary by sex and age. Methods We performed a prospective birth cohort study (Childhood Origins of Asthma) designed to evaluate interactions among age, sex, immune responses, and virus infections on the development of asthma and allergic diseases. Two hundred eighty-nine subjects were enrolled at birth, and 275 maintained prospective follow-up for 3 years. Cytokine response profiles at birth, 1, and 3 years of age; rates of wheezing, atopic dermatitis, and viral illnesses; and biomarkers of atopy, including total and specific IgE levels and peripheral eosinophil counts, were evaluated. Results PHA-induced IFN-γ responses were higher in boys at 1 year of age (median, 35 vs 19 pg/mL; P P = .07). Among children who wheezed during the third year of life, boys had increased IFN-γ, IL-5, and IL-13 responses at age 3 years ( P P = .008, and P = .01, respectively). Boys also demonstrated increased rates of sensitization ( P = .05 at year 1), total IgE levels ( P = .03 at year 1 and P = .006 at year 3), and peripheral eosinophil counts (2.62 vs 1.85; P = .05 at year 3). Conclusion Sex-specific differences in immune responses develop during early childhood; some of these differences developmentally proceed, whereas others occur in parallel to the clinical expression of various atopic phenotypes. Clinical implications The differential expression of atopic diseases between boys and girls in early childhood is accompanied by sex-specific differences in immune response profiles.

In this note, we consider weighted log-rank statistics applied to clustered survival data with variable cluster sizes and arbitrary treatment assignments within clusters. Specifically, we verify that the contribution over the time interval for which the risk set proportion is arbitrarily small (the so-called “tail instability”) is asymptotically negligible. These results were claimed but not proven by Gangnon and Kosorok [2004. Sample-size formula for clustered survival data using weighted log-rank statistics. Biometrika 91, 263–275.] who developed sample size formulas in this context. The main difficulty is that standard martingale methods cannot be used on account of the dependencies within clusters, and new methods are required.

One of the fundamental tenets of medicine has been the centrality of the profession as a life calling; physicians work long hours and routinely sacrifice personal interests for professional demands. In 1993, only 13% of clinical faculty and 6% of basic science faculty members of U.S. medical schools worked part-time.1 Historically, female physicians have been more likely than their male counterparts to work less than full time. Yet, despite increasing numbers of women in medicine and increased interest in personal time for self and family, U.S. medical workforce projections have forecast only a 3% decrease in the anticipated full-time equivalent of physicians over the next 10 years. (aut. ref.)

In this study, we hypothesized that use of the lowest T-score among four lumbar vertebral bodies would lessen the impact of degenerative arthritis and other artifacts on diagnostic categorization at this site and increase study sensitivity, classifying more men with prior fracture as osteoporotic than the other two methods of lumbar spine analysis. Bone density studies of 533 male veterans measured between January and October 2002 were reviewed to determine diagnostic classification using the L1–L4 average, International Society for Clinical Densitometry (ISCD)-determined, and lowest lumbar vertebral body T-score. We calculated sensitivity and specificity of the three methods of spine analysis, using spine osteoporosis to indicate a positive test and prior fracture as the true indicator of osteoporosis. The lowest lumbar T-score performed with similar sensitivity and specificity to that of the lowest hip or wrist T-score in the ability to classify men with prior fracture as osteoporotic, whereas the average L1–L4 and ISCD-determined T-scores performed with lower sensitivity, but better specificity. In conclusion, this retrospective study suggests that use of the lowest vertebral body T-score among men increases diagnostic sensitivity of lumbar spine bone mass measurement. Prospective studies are needed to determine which of these three methods of lumbar spine analysis best predicts future fragility fracture in men and women.

Background Asthma is a chronic respiratory disease that often originates in early childhood. Although candidate gene studies have identified many potential asthma susceptibility genes in adult populations, few have studied associations with immune phenotypes in the first year that might be early clinical markers of asthma. Objective The aim of this study was to assess the contribution of genetic variation to cytokine response profiles and atopic phenotypes in the first year of life in the Childhood Origin of Asthma cohort. Methods Two hundred seven European American children participating in the Childhood Origin of Asthma study were genotyped for 61 single nucleotide polymorphisms in 35 genes involved in immune regulation. We examined the relationship between these single nucleotide polymorphisms and PHA-induced cytokine (IL-5, IL-10, IL-13, and IFN-γ) response profiles at birth and at year 1, respiratory syncytial virus–induced wheezing and atopic dermatitis in the first year of life, and total IgE levels, peripheral blood eosinophil counts, and allergic sensitization at age 1 year. The data were analyzed by using censored regression for quantitative measurements and logistic regression for qualitative phenotypes. Results The 237Gly allele of the high-affinity IgE receptor β chain ( FCER1B ) and a silent substitution in the nitric oxide synthase ( NOS)2A gene were associated with reduced IL-13 responses in cord blood ( P = .0025 and P = .0062, respectively). A significant gene-gene interaction between FCER1B 237Gly and NOS2A D346D was detected, with individuals carrying the minor allele for both polymorphisms having the lowest cord blood IL-13 levels. Furthermore, the IL13 110Gln allele showed an association with increased IgE levels at year 1 ( P = .0026), and the colony-stimulating factor 2 ( CSF2 ) 117Thr allele showed an association with a greater increase in IL-5 responses during the first year ( P = .0092). The TGF-β1 ( TGFB1 ) –509T allele was associated with respiratory syncytial virus–related wheezing in the first year ( P = .0005). None of the polymorphisms included in this study were associated with atopic dermatitis during the first year or a positive RAST result at 1 year of age. Conclusion These data suggest that variations in genes involved in immune regulation are associated with biologic and clinical phenotypes in the first year of life that might increase the risk for the subsequent development of childhood asthma.

Background Detection of either viral or bacterial pathogens is associated with wheezing in children; however, the influence of both bacteria and viruses on illness symptoms has not been described. Objective We evaluated bacterial detection during the peak rhinovirus season in children with and without asthma to determine whether an association exists between bacterial infection and the severity of rhinovirus-induced illnesses. Methods Three hundred eight children (166 with asthma and 142 without asthma) aged 4 to 12 years provided 5 consecutive weekly nasal samples during September and scored cold and asthma symptoms daily. Viral diagnostics and quantitative PCR for Streptococcus pneumoniae , Haemophilus influenzae , and Moraxella catarrhalis were performed on all nasal samples. Results Detection rates were 53%, 17%, and 11% for H influenzae , S pneumoniae , and M catarrhalis , respectively, with detection of rhinovirus increasing the risk of detecting bacteria within the same sample (odds ratio [OR], 2.0; 95% CI, 1.4-2.7; P P = .02). In the absence of rhinovirus, S pneumoniae was associated with increased cold symptoms (mean, 2.7 [95% CI, 2.0-3.5] vs 1.8 [95% CI, 1.5-2.2]; P = .006) and moderate asthma exacerbations (18% [95% CI, 12% to 27%] vs 9.2% [95% CI, 6.7% to 12%]; P = .006). In the presence of rhinovirus, S pneumoniae was associated with increased moderate asthma exacerbations (22% [95% CI, 16% to 29%] vs 15% [95% CI, 11% to 20%]; P = .01). Furthermore, M catarrhalis detected alongside rhinovirus increased the likelihood of experiencing cold symptoms, asthma symptoms, or both compared with isolated detection of rhinovirus (OR, 2.0 [95% CI, 1.0-4.1]; P = .04). Regardless of rhinovirus status, H influenzae was not associated with respiratory symptoms. Conclusion Rhinovirus infection enhances detection of specific bacterial pathogens in children with and without asthma. Furthermore, these findings suggest that M catarrhalis and S pneumoniae contribute to the severity of respiratory tract illnesses, including asthma exacerbations.

Rationale Interleukin-10 (IL-10) response profiles and the timing and nature of environmental exposures may contribute to the development of allergic sensitization during early childhood. Methods Cord blood obtained from infants enrolled in the COAST project were stimulated in vitro with phytohemagglutinin (PHA) for 24 hours, and supernatant fluids were analyzed for IL-10 by ELISA. Values for IL-10 secretion were compared to allergen-specific IgE results evaluated at age 2 years for the following antigens: D. farinae, D. pteronyssinus, Alternaria alternata , dog dander, cat dander, milk, egg, peanut, and soy. Results Infants who were sensitized to any aeroallergen had significantly lower levels of IL-10 than those that were not (median 89.7 vs 107.4 pg/ml, p=0.04). When individual allergens were evaluated, IL-10 secretion profiles were not associated with sensitization to mites or Alternaria , but were significantly lower with both dog (median 73.7 vs 107.0 pg/ml, p=0.001) and cat (median 71.4 vs 107.3 pg/ml, p=0.007) sensitization. IL-10 secretion profiles were not associated with the development of food allergen sensitization (median 97.9 vs 104.6 pg/ml, p=0.18). Conclusions Reduced IL-10 responses at birth are associated with increased risk for the development of sensitization to some, but not all, allergens following early life exposures.