An Egg Intervention Improves Dietary Intakes but Does Not Fill Intake Gaps for Multiple Micronutrients among Infants in Rural Bangladesh.

BACKGROUND: Eggs are nutrient-rich. Strengthening evidence of the impact of egg consumption on dietary quality can inform complementary feeding guidance. OBJECTIVES: We aimed to assess the effect of an egg intervention on dietary intakes among infants aged 6-12 mo in rural Bangladesh. METHODS: We conducted a cluster-randomized controlled trial allocating clusters (n = 566) to enteric pathogen control or placebo treatment, with daily provision of a protein-rich meal, isocaloric meal, egg, or control. Nutrition education was provided to all arms. Our focus here is on the egg and control arms. Infants were enrolled at 3 mo. From 6 mo, we visited households weekly to distribute eggs and measure compliance. A semistructured feeding questionnaire assessed 24-h intake at 6, 9, and 12 mo. Assessments were repeated in ∼10% of subjects 2-29 d later. Using NCI SAS macros, we estimated usual intake distributions for energy, protein, fat, and 18 micronutrients and the proportion meeting intake recommendations. We compared the outcomes between the arms using clustered bootstrapping. RESULTS: Data were available from 757 infants (137 clusters) and 943 infants (141 clusters) in the egg and control arms, respectively. In the egg arm compared with the control arm, the mean usual intakes were higher for energy (610 compared with 602 kcal/d, 9 mo; 669 compared with 658 kcal/d, 12 mo), crude protein (2.2 compared with 1.7 g/(kg·d), 9 mo; 2.4 compared with 1.9 g/(kg·d), 12 mo), available protein (2.0 compared with 1.6 g/(kg·d), 9 mo; 2.1 compared with 1.8 g/(kg·d), 12 mo), and for 13 and 14 micronutrients at 9 and 12 mo, respectively. The proportion meeting intake recommendations for most micronutrients was higher in the egg arm but remained <50% for 15 and 13 micronutrients at 9 and 12 mo, respectively. CONCLUSIONS: Daily egg consumption improved dietary intakes among Bangladeshi infants, but was insufficient to meet multiple micronutrient intake recommendations, demonstrating the need to be coupled with other strategies.

Growth in achondroplasia including stature, weight, weight-for-height and head circumference from CLARITY: achondroplasia natural history study-a multi-center retrospective cohort study of achondroplasia in the US.

BACKGROUND: Achondroplasia is the most common genetic skeletal disorder causing disproportionate short stature/dwarfism. Common additional features include spinal stenosis, midface retrusion, macrocephaly and a generalized spondylometaphyseal dysplasia which manifest as spinal cord compression, sleep disordered breathing, delayed motor skill acquisition and genu varus with musculoskeletal pain. To better understand the interactions and health outcomes of these potential complications, we embarked on a multi-center, natural history study entitled CLARITY (achondroplasia natural history study). One of the CLARITY objectives was to develop growth curves (length/height, weight, head circumference, weight-for-height) and corresponding reference tables of mean and standard deviations at 1 month increments from birth through 18 years for clinical use and research for achondroplasia patients. METHODS: All available retrospective anthropometry data including length/height, weight and head circumference from achondroplasia patients were collected at 4 US skeletal dysplasia centers (Johns Hopkins University, AI DuPont Hospital for Children, McGovern Medical School University of Texas Health, University of Wisconsin School of Medicine and Public Health). Weight-for-age values beyond 3 SD above the mean were excluded from the weight-for-height and weight-for-age curves to create a stricter tool for weight assessment in this population. RESULTS: Over 37,000 length/height, weight and head circumference measures from 1374 patients with achondroplasia from birth through 75 years of age were compiled in a REDCap database. Stature and weight data from birth through 18 years of age and head circumference from birth through 5 years of age were utilized to construct new length/height-for-age, weight-for-age, head circumference-for-age and weight-for-height curves. CONCLUSION: Achondroplasia-specific growth curves are essential for clinical care of growing infants and children with this condition. In an effort to provide prescriptive, rather than purely descriptive, references for weight in this population, extreme weight values were omitted from the weight-for-age and weight-for-height curves. This well-phenotyped cohort may be studied with other global achondroplasia populations (e.g. Europe, Argentina, Australia, Japan) to gain further insight into environmental or ethnic influences on growth.

Achondroplasia Natural History Study (CLARITY): a multicenter retrospective cohort study of achondroplasia in the United States.

PURPOSE: Achondroplasia is the most common short stature skeletal dysplasia (1:20,000-30,000), but the risk of adverse health outcomes from cardiovascular diseases, pain, poor function, excess weight, and sleep apnea is unclear. A multicenter retrospective natural history study was conducted to understand medical and surgical practices in achondroplasia. METHODS: Data from patients with achondroplasia evaluated by clinical geneticists at Johns Hopkins University, A.I. duPont Hospital for Children, McGovern Medical School UTHealth, and University of Wisconsin were populated into a REDCap database. All available retrospective medical records of anthropometry (length/height, weight, occipitofrontal circumference), surgery, polysomnography (PSG), and imaging (e.g., X-ray, magnetic resonance imaging) were included. RESULTS: Data from 1,374 patients (48.8% female; mean age 15.4 ± 13.9 years) constitute the primary achondroplasia cohort (PAC) with 496 subjects remaining clinically active and eligible for prospective studies. Within the PAC, 76.0% had a de novo FGFR3 pathologic variant and 1,094 (79.6%) had one or more achondroplasia-related surgeries. There are ≥37,000 anthropometry values, 1,631 PSGs and 10,727 imaging studies. CONCLUSION: This is the largest multicenter achondroplasia natural history study, providing a vast array of medical information for use in caring for these patients. This well-phenotyped cohort is a reference population against which future medical and surgical interventions can be compared.

Multiparametric MRI-ultrasound fusion prostate biopsy in patients without prior diagnosis of prostate cancer: beyond centers of excellence.

PURPOSE: Multiparametric magnetic resonance imaging (mpMRI)-ultrasound (US) fusion prostate biopsy (FBx) has demonstrated increased accuracy for prostate cancer detection at designated centers of excellence. There is a concern if their results can be reproduced in smaller centers. Here, we evaluate the outcomes of FBx from a smaller academic center. METHODS: A retrospective review of patients without a prior diagnosis of prostate cancer undergoing FBx from January 2014 to November 2019 was performed. Histopathological results were grouped into low-risk disease (Grade Group 1), intermediate-risk disease (Grade Group 2 and 3), and high-risk disease (Grade Group 4 or 5). Clinically significant (CS) prostate cancer was defined as Grade Group ≥ 2. RESULTS: Five hundred and six men were included. Median age (IQR) and PSA (IQR) were 65.2 (60.3-70.2) years and 6.9 (5.2-9.7) ng/ml, respectively. There was no difference in overall cancer detection between FBx and SBx (53.6% vs 56.4% p = .1507). CS cancer detection was significantly higher with FBx (39.6% vs 35.3, p = .0275). FBx also outperformed SBx in diagnosing CS disease in patients with prior history of negative prostate biopsy (36.9% vs 27.9%, p < .001). CONCLUSION: FBx detects a higher proportion of clinically significant disease and a lower proportion of clinically insignificant disease compared to SBx, in line with outcomes demonstrated by centers of excellence.

Blood pressure in adults with short stature skeletal dysplasias.

Hypertension, compounded by obesity, contributes to cardiovascular disease and mortality. Data describing hypertension prevalence in adults with short stature skeletal dysplasias are lacking, perhaps due to poor fit of typical adult blood pressure cuffs on rhizomelic or contracted upper extremities. Through health screening research, blood pressure was measured in short stature adults attending support group meetings and skeletal dysplasia clinics. Blood pressure was measured with a commercially available, narrower adult cuff on the upper and/or lower segment of the arm. Height, weight, age, gender, diagnosis, exercise, and medications were collected. Subjects were classified as normotensive, prehypertensive, or hypertensive for group analysis; no individual clinical diagnoses were made. In 403 short stature adults, 42% were hypertensive (systolic >140, diastolic >90 OR taking antihypertensive medications). For every BMI unit and 1 kg weight increase in males, there was a 9% and an 8% increase, respectively, in the odds of hypertension versus normotension. In females, the increase was 10% and 6%, respectively. In those with achondroplasia, the most common short stature dysplasia, males (n = 106) had 10% greater odds of hypertension versus normotension for every BMI unit and kilogram increase. In females with achondroplasia (n = 128), the odds of hypertension versus normotension was 8% greater for each BMI unit and 7% for each additional kilogram. These data suggest a high population prevalence of hypertension among short stature adults. Blood pressure must be monitored as part of routine medical care, and measuring at the forearm may be the only viable clinical option in rhizomelic short stature adults with elbow contractures.

A height-for-age growth reference for children with achondroplasia: Expanded applications and comparison with original reference data.

The height-for-age (HA) reference currently used for children with achondroplasia is not adaptable for electronic records or calculation of HA Z-scores. We report new HA curves and tables of mean and standard deviation (SD) HA, for calculating Z-scores, from birth-16 years in achondroplasia. Mixed longitudinal data were abstracted from medical records of achondroplasia patients from a single clinical practice (CIS, 1967-2004). Gender-specific height percentiles (5, 25, 50, 75, 95th) were estimated across the age continuum, using a 2 month window per time point smoothed by a quadratic smoothing algorithm. HA curves were constructed for 0-36 months and 2-16 years to optimize resolution for younger children. Mean monthly height (SD) was tabulated. These novel HA curves were compared to reference data currently in use for children with achondroplasia. 293 subjects (162 male/131 female) contributed 1,005 and 932 height measures, with greater data paucity with age. Mean HA tracked with original achondroplasia norms, particularly through mid-childhood (2-9 years), but with no evidence of a pubertal growth spurt. Standard deviation of height at each month interval increased from birth through 16 years. Birth length was lower in achondroplasia than average stature and, as expected, height deficits increased with age. A new HA reference is available for longitudinal growth assessment in achondroplasia, taking advantage of statistical modeling techniques and allowing for Z-score calculations. This is an important contribution to clinical care and research endeavors for the achondroplasia population.

Sources of Variation in Sweat Chloride Measurements in Cystic Fibrosis.

RATIONALE: Expanding the use of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors for the treatment of cystic fibrosis (CF) requires precise and accurate biomarkers. Sweat chloride concentration provides an in vivo assessment of CFTR function, but it is unknown the degree to which CFTR mutations account for sweat chloride variation. OBJECTIVES: To estimate potential sources of variation for sweat chloride measurements, including demographic factors, testing variability, recording biases, and CFTR genotype itself. METHODS: A total of 2,639 sweat chloride measurements were obtained in 1,761 twins/siblings from the CF Twin-Sibling Study, French CF Modifier Gene Study, and Canadian Consortium for Genetic Studies. Variance component estimation was performed by nested mixed modeling. MEASUREMENTS AND MAIN RESULTS: Across the tested CF population as a whole, CFTR gene mutations were found to be the primary determinant of sweat chloride variability (56.1% of variation) with contributions from variation over time (e.g., factors related to testing on different days; 13.8%), environmental factors (e.g., climate, family diet; 13.5%), other residual factors (e.g., test variability; 9.9%), and unique individual factors (e.g., modifier genes, unique exposures; 6.8%) (likelihood ratio test, P < 0.001). Twin analysis suggested that modifier genes did not play a significant role because the heritability estimate was negligible (H2 = 0; 95% confidence interval, 0.0-0.35). For an individual with CF, variation in sweat chloride was primarily caused by variation over time (58.1%) with the remainder attributable to residual/random factors (41.9%). CONCLUSIONS: Variation in the CFTR gene is the predominant cause of sweat chloride variation; most of the non-CFTR variation is caused by testing variability and unique environmental factors. If test precision and accuracy can be improved, sweat chloride measurement could be a valuable biomarker for assessing response to therapies directed at mutant CFTR.

Auditory force feedback substitution improves surgical precision during simulated ophthalmic surgery.

PURPOSE: To determine the extent that auditory force feedback (AFF) substitution improves performance during a simulated ophthalmic peeling procedure. METHODS: A 25-gauge force-sensing microforceps was linked to two AFF modes. The "alarm" AFF mode sounded when the force reached 9 mN. The "warning" AFF mode made beeps with a frequency proportional to the generated force. Participants with different surgical experience levels were asked to peel a series of bandage strips off a platform as quickly as possible without exceeding 9 mN of force. In study arm A, participants peeled with alarm and warning AFF modes, the order randomized within the experience level. In study arm B, participants first peeled without AFF, then alarm or warning AFF (order randomized within the experience level), and finally without AFF. RESULTS: Of the 28 "surgeon" participants, AFF improved membrane peeling performance, reducing average force generated (P < 0.01), SD of forces (P < 0.05), and force × time above 9 mN (P < 0.01). Short training periods with AFF improved subsequent peeling performance when AFF was turned off, with reductions in average force, SD of force, maximum force, time spent above 9 mN, and force × time above 9 mN (all P < 0.001). Except for maximum force, peeling with AFF reduced all force parameters (P < 0.05) more than peeling without AFF after completing a training session. CONCLUSIONS: AFF enables the surgeon to reduce the forces generated with improved precision during phantom membrane peeling, regardless of surgical experience. New force-sensing surgical tools combined with AFF offer the potential to enhance surgical training and improve surgical performance.

Normative growth charts for individuals with Costello syndrome.

Costello syndrome is a rare condition due to heterozygous germline mutations in the proto-oncogene HRAS. It affects multiple organ systems and includes severe failure-to-thrive, short stature, and macrocephaly. The goal of this study was to develop Costello syndrome-specific growth curves. We collected height, weight, and head circumference (OFC) measurements from 94 individuals (45 males and 49 females). Their HRAS mutation spectrum reflects previously published cohorts, with p.G12S in 77.7%. Participants received medical care, therefore our data does not reflect natural history per se, but rather growth with nutritional support. Due to limited cohort size, we analyzed data from males and females together. Weight-for-age data included 417 separate measurements from 80 individuals age 0-36 months, and 585 measurements from 82 individuals for age 0-10 years. Height-for-age data were derived from 391 measurements from 77 individuals age 0-36 months, and 591 measurements from 90 individuals age 0-10 years. Measurements obtained after growth hormone exposure in 15 individuals were excluded in this analysis. The OFC curve was derived from 221 measurements from 55 individuals age 0-36 months. Centiles (5th, 50th, and 95th) were estimated across the age continuum for each growth parameter, and compared to gender-specific curves for average stature individuals. The resulting curves demonstrate very slow weight gain in the first 2 years. Short stature is seen in many, but after age 4 years the 95th centile for height falls within the low normal range for average stature children. Head circumference curves largely overlap those for average stature, reflecting relative macrocephaly.

Decreased microglial activation in MS patients treated with glatiramer acetate.

Activated microglia are thought to be an important contributor to tissue damage in multiple sclerosis (MS). The level of microglial activation can be measured non-invasively using [(11)C]-R-PK11195, a radiopharmaceutical for positron emission tomography (PET). Prior studies have identified abnormalities in the level of [(11)C]-R-PK11195 uptake in patients with MS, but treatment effects have not been evaluated. Nine previously untreated relapsing-remitting MS patients underwent PET and magnetic resonance imaging of the brain at baseline and after 1 year of treatment with glatiramer acetate. Parametric maps of [(11)C]-R-PK11195 uptake were obtained for baseline and post-treatment PET scans, and the change in [(11)C]-R-PK11195 uptake pre- to post-treatment was evaluated across the whole brain. Region-of-interest analysis was also applied to selected subregions. Whole brain [(11)C]-R-PK11195 binding potential per unit volume decreased 3.17% (95% CI: -0.74, -5.53%) between baseline and 1 year (p = 0.018). A significant decrease was noted in cortical gray matter and cerebral white matter, and a trend towards decreased uptake was seen in the putamen and thalamus. The results are consistent with a reduction in inflammation due to treatment with glatiramer acetate, though a larger controlled study would be required to prove that association. Future research will focus on whether the level of baseline microglial activation predicts future tissue damage in MS and whether [(11)C]-R-PK11195 uptake in cortical gray matter correlates with cortical lesion load.

Effect of temperature on cystic fibrosis lung disease and infections: a replicated cohort study.

BACKGROUND: Progressive lung disease accounts for the majority of morbidity and mortality observed in cystic fibrosis (CF). Beyond secondhand smoke exposure and socio-economic status, the effect of specific environmental factors on CF lung function is largely unknown. METHODS: Multivariate regression was used to assess correlation between specific environmental factors, the presence of pulmonary pathogens, and variation in lung function using subjects enrolled in the U.S. CF Twin and Sibling Study (CFTSS: n = 1378). Significant associations were tested for replication in the U.S. CF Foundation Patient Registry (CFF: n = 16439), the Australian CF Data Registry (ACFDR: n = 1801), and prospectively ascertained subjects from Australia/New Zealand (ACFBAL: n = 167). RESULTS: In CFTSS subjects, the presence of Pseudomonas aeruginosa (OR = 1.06 per °F; p<0.001) was associated with warmer annual ambient temperatures. This finding was independently replicated in the CFF (1.02; p<0.001), ACFDR (1.05; p = 0.002), and ACFBAL (1.09; p = 0.003) subjects. Warmer temperatures (-0.34 points per °F; p = 0.005) and public insurance (-6.43 points; p<0.001) were associated with lower lung function in the CFTSS subjects. These findings were replicated in the CFF subjects (temperature: -0.31; p<0.001; insurance: -9.11; p<0.001) and similar in the ACFDR subjects (temperature: -0.23; p = 0.057). The association between temperature and lung function was minimally influenced by P. aeruginosa. Similarly, the association between temperature and P. aeruginosa was largely independent of lung function. CONCLUSIONS: Ambient temperature is associated with prevalence of P. aeruginosa and lung function in four independent samples of CF patients from two continents.

Quantification of the relative contribution of environmental and genetic factors to variation in cystic fibrosis lung function.

OBJECTIVE: To assess the relative contributions of environmental and genetic factors to variation in cystic fibrosis (CF) lung disease. STUDY DESIGN: Genetic and environmental contributions were quantified by use of intrapair correlations and differences in CF-specific forced expiratory volume in 1 second measures from 134 monozygous twins and 272 dizygous twins and siblings while in different living environments (ie, living with parents vs living alone), as well as by use of intraindividual differences in pulmonary function from a separate group of 80 siblings. RESULTS: Pulmonary function among monozygous twins was more similar than among dizygous twin and sibling pairs, regardless of living environment, affirming the role of genetic modifiers in CF pulmonary function. Regression modeling revealed that genetic factors account for 50% of pulmonary function variation, unique environmental or stochastic factors (36%), and shared environmental factors (14%; P < .0001). The intraindividual analysis produced similar estimates for the contributions of the unique and shared environment. The shared environment effects appeared primarily because of living with a sibling with CF (P = .003), rather than factors within the parental household (P = .310). CONCLUSIONS: Genetic and environmental factors contribute equally to pulmonary function variation in CF. Environmental effects are dominated by unique and stochastic effects rather than common exposures.

Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height.

BACKGROUND: Achondroplasia is the most common short stature skeletal dysplasia, with an estimated worldwide prevalence of 250 000. Body mass index (BMI)-for-age references are required for weight management guidance for children with achondroplasia, whose body proportions are unlike those of the average stature population. OBJECTIVE: This study used weight and height data in a clinical setting to derive smoothed BMI-for-age percentile curves for children with achondroplasia and explored the relation of BMI with its components, weight and height. DESIGN: This was a longitudinal observational study of anthropometric measures of children with achondroplasia from birth through 16 y of age. RESULTS: The analysis included 1807 BMI data points from 280 children (155 boys, 125 girls) with achondroplasia. As compared with the BMI of peers of average stature, the BMI in children with achondroplasia is higher at birth, lacks a steep increase in infancy and a later nadir between 1 and 2 y of age, and remains substantially higher through 16 y of age in both sexes. Patterns of change in height and weight in children with achondroplasia are unique in that there is no overlap in the height distribution after 6 mo of age and no spike in height velocity during infancy or puberty-the 2 periods of greatest linear growth in individuals of average stature. CONCLUSIONS: Sex- and age-specific BMI curves are available for children with achondroplasia (birth to 16 y of age) for health surveillance and future research to determine associations with health outcomes (eg, cardiovascular disease, diabetes, and indication for and outcome of surgery).

Sadness predicts death in older people.

OBJECTIVE: To determine if a question about symptoms of depression in a mail survey predicts mortality after adjusting for a large number of covariates. DESIGN: National cross-sectional survey of 141,589 enrollees in Medicare, age 65 and older. Analyses used multivariate logistic regression models with death as the outcome. RESULTS: Response to a question about sadness or anhedonia was associated with death in 2 years (OR = 1.32; 95% CI = 1.2, 1.4). Results were consistent across age, gender, and presence/absence of known heart disease. Other responses associated with death were older age, male gender, and self-reported cancers, shortness of breath, heart failure, smoking, and other characteristics. Higher education and being married appeared to protect from death. DISCUSSION: A single survey question about feelings of sadness or anhedonia is predictive of death in 2 years.