Standardizing Electronic Health Record Data on AD/ADRD to Accelerate Health Equity in Prevention, Detection, and Treatment.

Improving the prevention, detection, and treatment of Alzheimer's disease and Alzheimer's disease related dementias (AD/ADRD) across racial, ethnic, and other diverse populations is a national priority. To this end, this paper proposes the development of the Standard Health Record for Dementia (SHRD, pronounced "shared") for collecting and sharing AD/ADRD real-world data (RWD). SHRD would replace the current unstandardized, fragmented, or missing state of key RWD with an open source, consensus-based, and interoperable common data standard. This paper describes how SHRD could leverage the best practices of the Minimal Common Oncology Data Elements (mCODETM) initiative to advance prevention, detection, and treatment; gain adoption by clinicians and electronic health record (EHR) vendors; and establish sustainable business and governance models. It describes a range of potential use cases to advance equity, including strengthening public health surveillance by facilitating AD/ADRD registry reporting; improving case detection and staging; and diversifying participation in clinical trials.

Thoracolumbar kyphosis in patients with mucopolysaccharidoses: clinical outcomes and predictive radiographic factors for progression of deformity.

AIMS: Clinical and radiological data were reviewed for all patients with mucopolysaccharidoses (MPS) with thoracolumbar kyphosis managed non-operatively or operatively in our institution. METHODS: In all 16 patients were included (eight female: eight male; 50% male), of whom nine had Hurler, five Morquio and two Hunter syndrome. Six patients were treated non-operatively (mean age at presentation of 6.3 years; 0.4 to 12.9); mean kyphotic progression +1.5(o)/year; mean follow-up of 3.1 years (1 to 5.1) and ten patients operatively (mean age at presentation of 4.7 years; 0.9 to 14.4); mean kyphotic progression 10.8(o)/year; mean follow-up of 8.2 years; 4.8 to 11.8) by circumferential arthrodesis with posterior instrumentation in patients with flexible deformities (n = 6). RESULTS: In the surgical group (mean age at surgery of 6.6 years; 2.4 to 16.8); mean post-operative follow-up of 6.3 years (3.5 to 10.3), mean pre-operative thoracolumbar kyphosis of 74.3(o) (42(o) to 110(o)) was corrected to mean of 28.6(o) (0(o) to 65(o)) post-operatively, relating to a mean deformity correction of 66.9% (31% to 100%). Surgical complications included a deep wound infection treated by early debridement, apical non-union treated by posterior re-grafting, and stable adjacent segment spondylolisthesis managed non-operatively. Thoracolumbar kyphosis > +38(o) at initial presentation was identified as predicting progressively severe deformity with 90% sensitivity and 83% specificity. DISCUSSION: This study demonstrates that severe thoracolumbar kyphosis in patients with MPS can be effectively treated by circumferential arthrodesis. Severity of kyphosis at initial presentation may predict progression of thoracolumbar deformity. Patients with MPS may be particularly susceptible to post-operative complications due to the underlying connective tissue disorder and inherent immunological compromise. TAKE HOME MESSAGE: Clinical and radiological data were reviewed for all patients with mucopolysaccharidoses with thoracolumbar kyphosis managed non-operatively or operatively in our institution.

The natural history of primary anterior dislocation of the glenohumeral joint in adolescence.

The natural history of primary anterior dislocation of the glenohumeral joint in adolescent patients remains unclear and there is no consensus for management of these patients. The objectives of this study were to report the natural history of primary anterior dislocation of the glenohumeral joint in adolescent patients and to identify the risk factors for recurrent dislocation. We reviewed prospectively-collected clinical and radiological data on 133 adolescent patients diagnosed with a primary anterior dislocation of the glenohumeral joint who had been managed non-operatively at our hospital between 1996 and 2008. There were 115 male (86.5%) and 18 female patients (13.5%) with a mean age of 16.3 years (13 to 18) and a mean follow-up of 95.2 months (1 to 215). During follow-up, 102 (absolute incidence of 76.7%) patients had a recurrent dislocation. The median interval between primary and recurrent dislocation was ten months (95% CI 7.4 to 12.6). Applying survival analysis the likelihood of having a stable shoulder one year after the initial injury was 59% (95% CI 51.2 to 66.8), 38% (95% CI 30.2 to 45.8%) after two years, 21% (95% CI 13.2 to 28.8) after five years, and 7% (95% CI 1.1 to 12.9) after ten years. Neither age nor gender significantly predicted recurrent dislocation during follow-up. We conclude that adolescent patients with a primary anterior dislocation of the glenohumeral joint have a high rate of recurrent dislocation, which usually occurs within two years of their initial injury: these patients should be considered for early operative stabilisation.

Epigenetics of osteoarticular diseases: recent developments.

A variety of osteoarticular conditions possess an underlying genetic aetiology. Large-scale genome-wide association studies have identified several genetic loci associated with osteoarticular conditions, but were unable to fully account for their estimated heritability. Epigenetic modifications including DNA methylation, histone modification, nucleosome positioning, and microRNA expression may help account for this incomplete heritability. This articles reviews insights from epigenetic studies in osteoarticular diseases, focusing on osteoarthritis, but also examines recent advances in rheumatoid arthritis, osteoporosis, systemic lupus erythematosus (SLE), ankylosing spondylitis, and sarcoma. Genome-wide methylation studies are permitting identification of novel candidate genes and molecular pathways, and the pathogenic mechanisms with altered methylation status are beginning to be elucidated. These findings are gradually translating into improved understanding of disease pathogenesis and clinical applications. Functional studies in osteoarthritis, rheumatoid arthritis, and SLE are now identifying downstream molecular alterations that may confer disease susceptibility. Epigenetic markers are being validated as prognostic and therapeutic disease biomarkers in sarcoma, and clinical trials of hypomethylating agents as treatments for sarcoma are being conducted. In concert with advances in throughput and cost-efficiency of available technologies, future epigenetic research will enable greater characterisation and treatment for both common and rare osteoarticular diseases.

Pilot randomized trial demonstrating reversal of obesity-related abnormalities in reward system responsivity to food cues with a behavioral intervention.

OBJECTIVES: Obesity is associated with hyperactivation of the reward system for high-calorie (HC) versus low-calorie (LC) food cues, which encourages unhealthy food selection and overeating. However, the extent to which this hyperactivation can be reversed is uncertain, and to date there has been no demonstration of changes by behavioral intervention. SUBJECTS AND METHODS: We used functional magnetic resonance imaging to measure changes in activation of the striatum for food images at baseline and 6 months in a pilot study of 13 overweight or obese adults randomized to a control group or a novel weight-loss intervention. RESULTS: Compared to controls, intervention participants achieved significant weight loss (-6.3±1.0 kg versus +2.1±1.1 kg, P<0.001) and had increased activation for LC food images with a composition consistent with that recommended in the behavioral intervention at 6 months versus baseline in the right ventral putamen (P=0.04), decreased activation for HC images of typically consumed foods in the left dorsal putamen (P=0.01). There was also a large significant shift in relative activation favoring LC versus HC foods in both regions (P<0.04). CONCLUSIONS: This study provides the first demonstration of a positive shift in activation of the reward system toward healthy versus unhealthy food cues in a behavioral intervention, suggesting new avenues to enhance behavioral treatments of obesity.

Posterior spinal fusion for adolescent idiopathic thoracolumbar/lumbar scoliosis: clinical outcomes and predictive radiological factors for extension of fusion distal to caudal end vertebra.

Clinical, radiological, and Scoliosis Research Society-22 questionnaire data were reviewed pre-operatively and two years post-operatively for patients with thoracolumbar/lumbar adolescent idiopathic scoliosis treated by posterior spinal fusion using a unilateral convex segmental pedicle screw technique. A total of 72 patients were included (67 female, 5 male; mean age at surgery 16.7 years (13 to 23)) and divided into groups: group 1 included 53 patients who underwent fusion between the vertebrae at the limit of the curve (proximal and distal end vertebrae); group 2 included 19 patients who underwent extension of the fusion distally beyond the caudal end vertebra. A mean scoliosis correction of 80% (45% to 100%) was achieved. The mean post-operative lowest instrumented vertebra angle, apical vertebra translation and trunk shift were less than in previous studies. A total of five pre-operative radiological parameters differed significantly between the groups and correlated with the extension of the fusion distally: the size of the thoracolumbar/lumbar curve, the lowest instrumented vertebra angle, apical vertebra translation, the Cobb angle on lumbar convex bending and the size of the compensatory thoracic curve. Regression analysis allowed an equation incorporating these parameters to be developed which had a positive predictive value of 81% in determining whether the lowest instrumented vertebra should be at the caudal end vertebra or one or two levels more distal. There were no differences in the Scoliosis Research Society-22 outcome scores between the two groups (p = 0.17). In conclusion, thoracolumbar/lumbar curves in patients with adolescent idiopathic scoliosis may be effectively treated by posterior spinal fusion using a unilateral segmental pedicle screw technique. Five radiological parameters correlate with the need for distal extension of the fusion, and an equation incorporating these parameters reliably informs selection of the lowest instrumented vertebra.

Quantitative PCR analysis used to characterize physiological changes in brain tissue of senescent sockeye salmon.

Senescence varies considerably among fishes, and understanding the evolutionary basis for this diversity has become an important area of study. For rapidly senescing species such as Pacific salmon, senescence is a complex process as these fish are initiating anorexia while migrating to natal spawning grounds, and die within days of reproduction. To better understand senescence in Pacific salmon we examined expression patterns for a suite of genes in brain tissue of pre-senescent and senescent sockeye salmon. Interestingly, a significant increase in expression of genes involved in telomere repair and immune activity was observed in senescent salmon. These data provide insight into physiological changes in salmon undergoing senescence and the factors contributing to variation in observed senescence rates among individuals and populations.

Transcriptome sequencing and high-resolution melt analysis advance single nucleotide polymorphism discovery in duplicated salmonids.

Until recently, single nucleotide polymorphism (SNP) discovery in nonmodel organisms faced many challenges, often depending upon a targeted-gene approach and Sanger sequencing of many individuals. The advent of next-generation sequencing technologies has dramatically improved discovery, but validating and testing SNPs for use in population studies remain labour intensive. Here, we detail a SNP discovery and validation pipeline that incorporates 454 pyrosequencing, high-resolution melt analysis (HRMA) and 5' nuclease genotyping. We generated 4.59×10(8) bp of redundant sequence from transcriptomes of two individual chum salmon, a highly valued species across the Pacific Rim. Nearly 26000 putative SNPs were identified--some as heterozygotes and some as homozygous for different nucleotides in the two individuals. For validation, we selected 202 templates containing single putative SNPs and conducted HRMA on 10 individuals from each of 19 populations from across the species range. Finally, 5' nuclease genotyping validated 37 SNPs that conformed to Hardy-Weinberg equilibrium expectations. Putative SNPs expressed as heterozygotes in an ascertainment individual had more than twice the validation rate of those homozygous for different alleles in the two fish, suggesting that many of the latter may have been paralogous sequence variants. Overall, this validation rate of 37/202 suggests that we have found more than 4500 templates containing SNPs for use in this population set. We anticipate using this pipeline to significantly expand the number of SNPs available for the studies of population structure and mixture analyses as well as for the studies of adaptive genetic variation in nonmodel organisms.

Food cravings and energy regulation: the characteristics of craved foods and their relationship with eating behaviors and weight change during 6 months of dietary energy restriction.

OBJECTIVE: To examine characteristics of craved foods in relation to dietary energy restriction (ER) with high (HG) and low glycemic load (LG) diets. DESIGN: Assessments of food cravings before and during a randomized controlled trial of HG and LG diets provided for 6 months. SUBJECTS: Thirty-two healthy, overweight women aged 20-42 years. MEASUREMENTS: Self-reported food cravings and dietary intake, body weight, weight history and measures of eating behaviors. RESULTS: Foods craved at baseline were more than twice as high in energy density as the habitual diet (3.7+/-1.5 vs 1.7+/-0.3 kcal/g; P<0.001), and on average were lower in protein (P<0.001) and fiber (P<0.001) and higher in fat (P=0.002). There were no statistically significant changes in nutritional characteristics of craved foods after 6 months of ER. There was a significant relationship between reported portion size of craved food consumed at baseline and lifetime high body mass index (r=0.49, P=0.005). Additionally, there was a significant association between susceptibility to hunger and craving frequency at baseline, and there were significant relationships between hunger score, craving frequency, strength and percentage of time that cravings are given in to after 6 months of ER. In multiple regression models, subjects who lost a greater percentage of weight craved higher energy-dense foods at month 6 of ER, but also reported giving in to food cravings less frequently (adjusted R (2)=0.31, P=0.009). CONCLUSION: High energy density and fat content, and low protein and fiber contents were identifying characteristics of craved foods. The relationships between craving variables and hunger score suggest that the relative influence of hunger susceptibility on cravings may be important before and especially after ER. Portion size of craved foods and frequency of giving in to food cravings appear to be important areas for focus in lifestyle modification programs for long-term weight loss.

Eating patterns and dietary composition in relation to BMI in younger and older adults.

OBJECTIVE: To compare relative associations of eating patterns and dietary composition with body mass index (BMI) in younger (aged 20-59 years, n=1792) and older (aged 60-90 years, n=893) participants in the Continuing Survey of Food Intakes by Individuals, collected 1994-1996. METHODS: Data from two 24-h dietary recalls from individuals reporting physiologically plausible energy intake (within +/-22% of predicted energy requirements, based on previously published methods) were used. RESULTS: Mean reported energy intake was 96 and 95% of predicted energy requirements in younger and older subjects, respectively. Older subjects were less likely than younger subjects to skip a meal, but snacking was common in both age groups. Fiber density was significantly higher in the older group. A higher BMI in both age groups was associated with a higher total daily energy intake, and higher energy intakes at all eating occasions. In both age groups, eating frequency was positively associated with energy intake, and eating more than three times a day was associated with being overweight or obese. In the younger group but not the older group, a lower fiber density coupled with higher percentage of energy from fat was independently associated with having a higher BMI. CONCLUSIONS: While no one eating occasion contributes more than any other to excess adiposity, eating more often than three times a day may play a role in overweight and obesity in both younger and older persons. A reduced satiety response to dietary fiber in addition to lower energy expenditure may potentially further contribute to weight gain in older persons.

Dynamics of {beta}-amyloid reductions in brain, cerebrospinal fluid, and plasma of {beta}-amyloid precursor protein transgenic mice treated with a {gamma}-secretase inhibitor.

gamma-Secretase inhibitors are one promising approach to the development of a therapeutic for Alzheimer's disease (AD). gamma-Secretase inhibitors reduce brain beta-amyloid peptide (Abeta), which is believed to be a major contributor in the etiology of AD. Transgenic mice overexpressing the human beta-amyloid precursor protein (APP) are valuable models to examine the dynamics of Abeta changes with gamma-secretase inhibitors in plaque-free and plaque-bearing animals. BMS-299897 2-[(1R)-1-[[(4-chlorophenyl)sulfony](2,5-difluorophenyl)amino]ethyl]-5-fluorobenzenepropanoic acid, a gamma-secretase inhibitor, showed dose- and time dependent reductions of Abeta in brain, cerebrospinal fluid (CSF), and plasma in young transgenic mice, with a significant correlation between brain and CSF Abeta levels. Because CSF and brain interstitial fluid are distinct compartments in composition and location, this correlation could not be assumed. In contrast, aged transgenic mice with large accumulations of Abeta in plaques showed reductions in CSF Abeta in the absence of measurable changes in plaque Abeta in the brain after up to 2 weeks of treatment. Hence, CSF Abeta levels were a valuable measure of gamma-secretase activity in the central nervous system in either the presence or absence of plaques. Transgenic mice were also used to examine potential side effects due to Notch inhibition. BMS-299897 was 15-fold more effective at preventing the cleavage of APP than of Notch in vitro. No changes in the maturation of CD8(+) thymocytes or of intestinal goblet cells were observed in mice treated with BMS-299897, showing that it is possible for gamma-secretase inhibitors to reduce brain Abeta without causing Notch-mediated toxicity.

Stunted children gain less lean body mass and more fat mass than their non-stunted counterparts: a prospective study.

The aim of the present study was to analyse the changes in body composition of stunted children during a follow-up period and to test the hypothesis of a tendency to accumulate body fat as a consequence of undernutrition early in life. We selected fifty boys and girls aged 11 to 15, who were residents of slums in Sao Paulo, Brazil. Twenty were stunted (S) and thirty had normal stature (NS). The children's nutritional status and body composition were assessed through anthropometry and dual-energy X-ray absorptiometry, at the beginning of the present study and after 3 years, and changes in lean mass (LM and LM%) and fat mass (FM and FM%) were calculated. Stunted boys accumulated more body fat (FM%: S=1.62%, NS=-3.40%; P=0.003) and gained less lean mass (LM%: S=-1.46, NS=3.21%; P=0.004). Stunted girls gained less lean mass (S=7.87 kg, NS=11.96 kg; P=0.032) and had significantly higher values of FM% at follow-up when compared with their baseline values (P=0.008), whereas non-stunted girls had a non-significant difference in FM% over time (P=0.386). These findings are important to understand the factors involved in the increased prevalence of overweight and obesity among poor populations, which appear to be associated with hunger during infancy and/or childhood.

Acute neurosteroid modulation and subunit isolation of the gamma-aminobutyric acidA receptor in the bullfrog, Rana catesbeiana.

The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has multiple receptors. In mammals, the GABA(A) receptor subtype is modulated by neurosteroids. However, whether steroid interaction with the GABA(A) receptor is unique to mammals or a conserved feature in vertebrates is unknown. Thus, neurosteroid modulation of the GABA(A) receptor was investigated in the brain of the bullfrog (Rana catesbeiana) using the mammalian GABA(A) receptor agonist [(3)H]muscimol. Two neurosteroids, allopregnanolone and pregnenolone sulfate, affected [(3)H]muscimol specific binding in bullfrog brain membrane preparations. Allopregnanolone significantly increased [(3)H]muscimol specific binding in a dose- and time-dependent manner. The pattern of allopregnanolone modulation supports the hypothesis that the bullfrog brain possesses both high-affinity and low-affinity [(3)H]muscimol binding sites. Unlike allopregnanolone, pregnenolone sulfate showed biphasic modulation with increased [(3)H]muscimol specific binding at low nanomolar concentrations and decreased specific binding at micromolar concentrations. Additionally, three cDNA fragments with significant homology to mammalian GABA(A) receptor subunits were isolated from the bullfrog brain. These fragments belong to the alpha1, beta1, and gamma2 subunit families. In mammals, GABA(A) receptors composed of these specific subunit isoforms are effectively modulated by neurosteroids, including allopregnanolone. Neurosteroid modulation of the amphibian brain GABA(A) receptor is therefore supported by both [(3)H]muscimol binding studies and subunit sequences. Allopregnanolone and pregnenolone sulfate modulation of this receptor may thus represent a significant mechanism for steroid influence on amphibian brain and behavior.

Relative influence of diet and physical activity on cardiovascular risk factors in urban Chinese adults.

OBJECTIVE: The relative influence of dietary factors vs physical activity on cardiovascular risk factors are poorly understood. We investigated these factors in a population whose traditional diet may have both positive (high plant-based) and negative (high refined carbohydrate) aspects, and whose physical activity levels (PALs) vary widely. DESIGN: Cross-sectional study. SUBJECTS: A total of 130 weight stable adults aged 35-49 y (BMI 18-35 kg/m(2)) living in urban Beijing, China. MEASUREMENTS: Dietary intake (by food frequency questionnaire), PAL as the ratio of predicted total to resting energy expenditure), percent body fat (by deuterium oxide dilution), and central adiposity (waist circumference and waist to hip ratio) were assessed. Biochemical parameters (total cholesterol, low- and high-density lipoprotein cholesterol (LDL-C; HDL-C), triglyceride (TG), apolipoproteins A-I and B, glucose, insulin, and homocysteine and its related vitamins), blood pressure and presence of the metabolic syndrome (having >/=3 risk factors of central adiposity, HDL-C, TG, glucose, blood pressure) were also examined. RESULTS: Mean values for cardiovascular risk factors were relatively low, but 19% of subjects had the metabolic syndrome. Using validated methods for measuring food intake and energy expenditure, we found that an adverse cardiovascular risk profile was associated with a diet high in carbohydrate, low in polyunsaturated fat, and low in fruit and vegetables, independent of body fatness and its distribution. While dietary factors predicted individual cardiovascular risk factors more consistently than PAL, avoidance of low PAL reduced the risk of having the metabolic syndrome. CONCLUSION: These results suggest that, regardless of total body fatness and fat distribution, multiple unfavorable dietary factors and low physical activity independently increase the risk for cardiovascular disease. Avoidance of a sedentary lifestyle additionally reduces the risk of developing the metabolic syndrome.

Energy requirements of urban Chinese adults with manual or sedentary occupations, determined using the doubly labeled water method.

OBJECTIVE: To examine total energy expenditure (TEE) in relation to occupation and reported leisure time activities in free-living Chinese adults, and to determine whether measured TEE values differ from current international dietary energy recommendations. SETTING AND SUBJECTS: Seventy three weight-maintaining adults aged 35-49 y, leading unrestricted lives in urban Beijing, with a wide variety of occupations. DESIGN AND METHODS: A cross-sectional study in which TEE was determined by doubly labeled water, body composition by deuterium oxide ((2)H(2)O) dilution, resting energy expenditure (pREE) by prediction equations, and occupational and leisure time activities by questionnaire. RESULTS: For men and women respectively, TEE averaged 12.10+/-0.32 and 9.53+/-0.23 MJ/day (P<0.001), and physical activity level (PAL=TEE/pREE) was 1.77+/-0.04 and 1.66+/-0.02 (P<0.05). Fat-free mass (FFM) was the single best predictor of TEE (adjusted r(2)=0.71, P<0.001). Occupational category (light, moderate and heavy) further predicted TEE, independent of FFM (adjusted multiple r(2)=0.82, P<0.001). Both TEE adjusted for weight and PAL increased with occupational category. Measured TEE was slightly but significantly higher than the 1985 FAO/WHO/UNU estimates for women with light occupations, but did not differ from estimates for men with light occupations, or for adults with moderate or heavy occupations. CONCLUSION: Level of occupational activity, but not duration or type of leisure activity, significantly predicted TEE in free-living urban Chinese adults. Current energy requirement recommendations slightly underestimated the energy needs of women with light occupations but were accurate for men and women with moderate and heavy occupations. SPONSORSHIP: NIH grants DK53404 and F32-DK09747.

Dietary energy density and weight regulation.

Dietary energy density (ED) has been suggested as an important determinant of energy intake and, therefore, energy regulation. This review summarizes published studies on the effects of dietary ED on hunger, satiety, energy intake, and body weight in healthy individuals, and compares the relative effects of ED manipulated by dietary fat only, fat and fiber, water, and type of sweetener. In short-term studies, consumption of low-ED foods promotes satiety, reduces hunger, and decreases energy intake with no marked differences between different dietary manipulations used to change ED. In addition, low-ED diets promote moderate weight loss in long-term studies. In studies lasting longer than 6 months, weight loss was more than three times as great in individuals consuming diets both low in fat and high in fiber compared with diets only low in fat (-3.4 kg versus -1.0 kg). Combined, these studies suggest that diets low in fat and high in fiber may be the most effective low-ED diets for promoting weight loss. Further research is needed on the effects of dietary ED by changing water or sweetener content.

Dietary fiber and weight regulation.

The influence of dietary fiber on energy regulation remains controversial. This review summarizes published studies on the effects of dietary fiber on hunger, satiety, energy intake, and body composition in healthy individuals. Under conditions of fixed energy intake, the majority of studies indicate that an increase in either soluble or insoluble fiber intake increases postmeal satiety and decreases subsequent hunger. When energy intake is ad libitum, mean values for published studies indicate that consumption of an additional 14 g/day fiber for >2 days is associated with a 10% decrease in energy intake and body weight loss of 1.9 kg over 3.8 months. Furthermore, obese individuals may exhibit a greater suppression of energy intake and body weight loss (mean energy intake in all studies was reduced to 82% by higher fiber intake in overweight/obese people versus 94% in lean people; body weight loss was 2.4 kg versus 0.8 kg). These amounts are very similar to the mean changes in energy intake and body weight changes observed when dietary fat content is lowered from 38% to 24% of energy intake in controlled studies of nonobese and obese subjects. The observed changes in energy intake and body weight occur both when the fiber is from naturally high-fiber foods and when it is from a fiber supplement. In view of the fact that mean dietary fiber intake in the United States is currently only 15 g/day (i.e., approximately half the American Heart Association recommendation of 25-30 g/day), efforts to increase dietary fiber in individuals consuming <25 g/day may help to decrease the currently high national prevalence of obesity.