Digital biomarkers: 3PM approach revolutionizing chronic disease management - EPMA 2024 position.

Non-communicable chronic diseases (NCDs) have become a major global health concern. They constitute the leading cause of disabilities, increased morbidity, mortality, and socio-economic disasters worldwide. Medical condition-specific digital biomarker (DB) panels have emerged as valuable tools to manage NCDs. DBs refer to the measurable and quantifiable physiological, behavioral, and environmental parameters collected for an individual through innovative digital health technologies, including wearables, smart devices, and medical sensors. By leveraging digital technologies, healthcare providers can gather real-time data and insights, enabling them to deliver more proactive and tailored interventions to individuals at risk and patients diagnosed with NCDs. Continuous monitoring of relevant health parameters through wearable devices or smartphone applications allows patients and clinicians to track the progression of NCDs in real time. With the introduction of digital biomarker monitoring (DBM), a new quality of primary and secondary healthcare is being offered with promising opportunities for health risk assessment and protection against health-to-disease transitions in vulnerable sub-populations. DBM enables healthcare providers to take the most cost-effective targeted preventive measures, to detect disease developments early, and to introduce personalized interventions. Consequently, they benefit the quality of life (QoL) of affected individuals, healthcare economy, and society at large. DBM is instrumental for the paradigm shift from reactive medical services to 3PM approach promoted by the European Association for Predictive, Preventive, and Personalized Medicine (EPMA) involving 3PM experts from 55 countries worldwide. This position manuscript consolidates multi-professional expertise in the area, demonstrating clinically relevant examples and providing the roadmap for implementing 3PM concepts facilitated through DBs.

Increased usual physical activity is associated with a blunting of the triglyceride response to a high-fat meal.

BACKGROUND: Postprandial lipemia (PPL), defined as a prolonged or elevated rise in triglycerides that accompanies fat feeding, is a significant risk factor for coronary heart disease and associated comorbidities. The impact of PPL on coronary heart disease risk is underscored by the preponderance of each day spent in the postprandial state. OBJECTIVE: In this study, we evaluated cross-sectionally the association between usual (ie, noninterventional) physical activity and the 6-hour triglyceride response to a standardized high-fat meal. METHODS: The high-fat meal intervention was carried out in 671 apparently healthy individuals as part of the Heredity and Phenotype Intervention Heart Study. Triglyceride levels were measured in the fasting state and during 6 hours after administration of a standardized fat challenge. We defined PPL response as the triglyceride area under the fat load curve (AUC) and measured physical activity using accelerometers that were worn continuously over a 7-day period. RESULTS: Physical activity levels decreased with increasing age and were higher in men than women (both P < .001). The triglyceride AUC increased with increasing age in both men and women (both P < .001) and was also higher in men than in women (age-adjusted P = 9.2 × 10-12). Higher physical activity levels were associated with a lower triglyceride AUC (P = .003), adjusting for age, sex, body mass index, and fasting low-density lipoprotein. CONCLUSION: These results suggest that the protective benefits of physical activity on cardiovascular health may operate, at least in part, through reduction of the PPL triglyceride response.

Results From a Trial of an Online Diabetes Prevention Program Intervention.

INTRODUCTION: Online Diabetes Prevention Programs (DPPs) can be scaled up and delivered broadly. However, little is known about real-world effectiveness and how outcomes compare with in-person DPP. This study examined online DPP weight loss and participation outcomes and secondarily compared outcomes among participating individuals with parallel in-person interventions. STUDY DESIGN: A large non-randomized trial supplemented by a comparative analysis of participating individuals from a concurrent trial of two parallel in-person programs: in-person DPP and the Veterans Administration's standard of care weight loss program (MOVE!). SETTING/PARTICIPANTS: Obese/overweight Veterans with prediabetes enrolled in online DPP (n = 268) between 2013 and 2014. Similar eligibility criteria were used to enroll in-person participants between 2012 and 2014 (n = 273 in-person DPP, n = 114 MOVE!) within a separate trial. INTERVENTION: Online DPP included a virtual group format, live e-coach, weekly modules delivered asynchronously, and wireless home scales. In-person programs included eight to 22 group-based, face-to-face sessions. MAIN OUTCOMES MEASURES: Weight change at 6 and 12 months using wirelessly uploaded home scale data or electronic medical record weights from clinical in-person visits. Outcomes were analyzed between 2015 and 2017. RESULTS: From 1,182 invitations, 268 (23%) participants enrolled in online DPP. Among these, 158 (56%) completed eight or more modules; mean weight change was -4.7kg at 6 months and -4.0kg at 12 months. In a supplemental analysis of participants completing one or more sessions/modules, online DPP participants were most likely to complete eight or more sessions/modules (87% online DPP vs 59% in-person DPP vs 55% MOVE!, p < 0.001). Online and in-person DPP participants lost significantly more weight than MOVE! participants at 6 and 12 months; there was no significant difference in weight change between online and in-person DPP. CONCLUSIONS: An intensive, multifaceted online DPP intervention had higher participation but similar weight loss compared to in-person DPP. An intensive, multifaceted online DPP intervention may be as effective as in-person DPP and help expand reach to those at risk.

Does mental health influence weight loss in adults with prediabetes? Findings from the VA Diabetes Prevention Program.

OBJECTIVES: Mental illness may impact outcomes from structured behavioral weight loss interventions. This secondary analysis investigated the influence of mental health on weight loss among Veterans with prediabetes enrolled in either an in-person diabetes prevention program (DPP) or the usual care weight management program (MOVE!) designed to help patients achieve weight loss through changes in physical activity and diet. METHODS: Prediabetes was defined by Hemoglobin A1c between 5.7 and 6.4% or Fasting Plasma Glucose 100-125 mg/dL and no use of antiglycemic medications during the past six months. Veterans Health Administrative data were used to assign Veterans into one of three mental health diagnoses: severe mental illness (SMI), affective disorder (AD) without SMI, or No SMI/No AD. The influence of mental health on weight changes at 6 and 12 months was modeled using linear mixed-effects regression. RESULTS: On average, Veterans with prediabetes (n = 386) were 59 years old (SD = 10.0 years), with a BMI of 34.8 kg/m2 (SD = 5.3 kg/m2) and A1c of 6.0% (SD = 0.2%). The sample consisted of 12% (n = 47), 39% (n = 150), and 49% (n = 189) diagnosed with SMI, AD and No SMI/No AD, respectively. Across interventions, Veterans with SMI lost less weight than those with AD or No SMI/No AD. From baseline to 6 months, weight loss was significantly less for Veterans with SMI (1.53 kg) compared to Veterans with AD (3.85 kg) or No SMI/No AD (3.73 kg). This weight loss trend by mental health diagnosis continued from baseline to 12 months but was no longer statistically significant at 12 months. CONCLUSION: Weight loss was not clinically or statistically different among Veterans with prediabetes diagnosed with AD or No SMI/No AD. However, Veterans diagnosed with SMI exhibited less weight loss over 6 months than Veterans with AD or No SMI/No AD and though not statistically significant, the trend continued to 12 months, suggesting that SMI may influence weight loss outcomes.

Individual differences in regulatory mode moderate the effectiveness of a pilot mHealth trial for diabetes management among older veterans.

mHealth tools to help people manage chronic illnesses have surged in popularity, but evidence of their effectiveness remains mixed. The aim of this study was to address a gap in the mHealth and health psychology literatures by investigating how individual differences in psychological traits are associated with mHealth effectiveness. Drawing from regulatory mode theory, we tested the role of locomotion and assessment in explaining why mHealth tools are effective for some but not everyone. A 13-week pilot study investigated the effectiveness of an mHealth app in improving health behaviors among older veterans (n = 27) with poorly controlled Type 2 diabetes. We developed a gamified mHealth tool (DiaSocial) aimed at encouraging tracking of glucose control, exercise, nutrition, and medication adherence. Important individual differences in longitudinal trends of adherence, operationalized as points earned for healthy behavior, over the course of the 13-week study period were found. Specifically, low locomotion was associated with unchanging levels of adherence during the course of the study. In contrast, high locomotion was associated with generally stronger adherence although it exhibited a quadratic longitudinal trend. In addition, high assessment was associated with a marginal, positive trend in adherence over time while low assessment was associated with a marginal, negative trend. Next, we examined the relationship between greater adherence and improved clinical outcomes, finding that greater adherence was associated with greater reductions in glycated hemoglobin (HbA1c) levels. Findings from the pilot study suggest that mHealth technologies can help older adults improve their diabetes management, but a "one size fits all" approach may yield suboptimal outcomes.

Implementation findings from a hybrid III implementation-effectiveness trial of the Diabetes Prevention Program (DPP) in the Veterans Health Administration (VHA).

BACKGROUND: The Diabetes Prevention Program (DPP) is an effective lifestyle intervention to reduce incidence of type 2 diabetes. However, there are gaps in knowledge about how to implement DPP. The aim of this study was to evaluate implementation of DPP via assessment of a clinical demonstration in the Veterans Health Administration (VHA). METHODS: A 12-month pragmatic clinical trial compared weight outcomes between the Veterans Affairs Diabetes Prevention Program (VA-DPP) and the usual care MOVE!® weight management program (MOVE!). Eligible participants had a body mass index (BMI) ≥30 kg/m2 (or BMI ≥ 25 kg/m2 with one obesity-related condition), prediabetes (glycosylated hemoglobin (HbA1c) 5.7-6.5% or fasting plasma glucose (FPG) 100-125 mg/dL), lived within 60 min of their VA site, and had not participated in a weight management program within the last year. Established evaluation and implementation frameworks were used to guide the implementation evaluation. Implementation barriers and facilitators, delivery fidelity, participant satisfaction, and implementation costs were assessed. Using micro-costing methods, costs for assessment of eligibility and scheduling and maintaining adherence per participant, as well as cost of delivery per session, were also assessed. RESULTS: Several barriers and facilitators to Reach, Adoption, Implementation, Effectiveness and Maintenance were identified; barriers related to Reach were the largest challenge encountered by site teams. Fidelity was higher for VA-DPP delivery compared to MOVE! for five of seven domains assessed. Participant satisfaction was high in both programs, but higher in VA-DPP for most items. Based on micro-costing methods, cost of assessment for eligibility was $68/individual assessed, cost of scheduling and maintaining adherence was $328/participant, and cost of delivery was $101/session. CONCLUSIONS: Multi-faceted strategies are needed to reach targeted participants and successfully implement DPP. Costs for assessing patients for eligibility need to be carefully considered while still maximizing reach to the targeted population.

Diabetes Prevention Program Translation in the Veterans Health Administration.

INTRODUCTION: This clinical demonstration trial compared the effectiveness of the Veterans Affairs Diabetes Prevention Program (VA-DPP) with an evidence-based usual care weight management program (MOVE!®) in the Veterans Health Administration health system. DESIGN: Prospective, pragmatic, non-randomized comparative effectiveness study of two behavioral weight management interventions. SETTING/PARTICIPANTS: Obese/overweight Veterans with prediabetes were recruited from three geographically diverse VA sites between 2012 and 2014. INTERVENTION: VA-DPP included 22 group-based intensive lifestyle change sessions. MAIN OUTCOME MEASURES: Weight change at 6 and 12 months, hemoglobin A1c (HbA1c) at 12 months, and VA health expenditure changes at 15 months were assessed using VA electronic health record and claims data. Between- and within-group comparisons for weight and HbA1c were done using linear mixed-effects models controlling for age, gender, race/ethnicity, baseline outcome values, and site. Analyses were conducted in 2015-2016. RESULTS: A total of 387 participants enrolled (273 VA-DPP, 114 MOVE!). More VA-DPP participants completed at least one (73.3% VA-DPP vs 57.5% MOVE! p=0.002); four (57.5% VA-DPP vs 42.5% MOVE!, p=0.007); and eight or more sessions (42.5% VA-DPP vs 31% MOVE!, p=0.035). Weight loss from baseline was significant at both 6 (p<0.001) and 12 months (p<0.001) for VA-DPP participants, but only significant at 6 months for MOVE! participants (p=0.004). Between groups, there were significant differences in 6-month weight loss (-4.1 kg VA-DPP vs -1.9 kg MOVE!, p<0.001), but not 12-month weight loss (-3.4 kg VA-DPP vs -2.0 kg MOVE!, p=0.16). There were no significant differences in HbA1c change or outpatient, inpatient, and total VA expenditures. CONCLUSIONS: VA-DPP participants had higher participation rates and weight loss at 6 months, but similar weight, HbA1c, and health expenditures at 12 months compared to MOVE! PARTICIPANTS: Features of VA-DPP may help enhance the capability of MOVE! to reach a larger proportion of the served population and promote individual-level weight maintenance.

Eating behavior disinhibition predicts insulin resistance in the Old Order Amish.

BACKGROUND: Eating behavior is influenced by genetics and environment, and is associated with many obesity related conditions. OBJECTIVE: We assessed the relationship between self-reported disinhibition scores and insulin resistance assessed during an oral glucose tolerance test (OGTT). DESIGN: The study included 779 volunteers from the Amish Family Diabetes Study; 77 with Type 2 Diabetes Mellitus, 133 with Impaired Glucose Tolerance (IGT) and 569 with Normal Glucose Tolerance (NGT). All patients with IGT and NGT completed oral glucose tolerance tests (OGTT), and had insulin levels measured during the OGTT. Volunteers completed the Three-Factor Eating Questionnaire to quantify self-perceived disinhibition. CONCLUSIONS: Higher disinhibition scores are associated with higher fasting insulin levels and insulin area under the curve during an OGTT. These results suggest a highly significant, positive correlation between the eating behavior disinhibition and insulin insensitivity. Treatments aimed at modifying eating behavior may be helpful in mitigating insulin resistance.

The CAPN2/CAPN8 Locus on Chromosome 1q Is Associated with Variation in Serum Alpha-Carotene Concentrations.

BACKGROUND/AIMS: Alpha-carotene is a provitamin A carotenoid present in fruits and vegetables. Higher serum concentrations of α-carotene have been associated with lower risk of cancer and all-cause mortality. Previous studies have suggested that genetic variants influence serum concentrations of provitamin A carotenoids, but to date no variants have been robustly associated with serum α-carotene concentrations. The aim of this study was to identify genetic associations with serum α-carotene concentrations using the genome-wide association study (GWAS) approach. METHODS: A GWAS of serum α-carotene concentrations was conducted in 433 Old Order Amish adults who had consumed a 6-day controlled diet. Linear regression models adjusting for age, gender, and family structure were utilized to evaluate associations between genetic variants and serum α-carotene concentrations. RESULTS: Genome-wide significant associations with α-carotene concentrations were observed for loci on chromosome 1q41 between the genes CAPN2 and CAPN8 (rs12137025, p = 3.55 × 10-8), chromosome 2p21 in PRKCE (rs2594495, p = 1.01 × 10-8), and chromosome 4q34 (rs17830069, p = 2.89 × 10-8). CONCLUSIONS: We identified 3 novel loci associated with serum α-carotene concentrations among a population that consumed a controlled diet. While replication is necessary, the CAPN2/CAPN8 locus provides compelling evidence for an association with serum α-carotene concentrations and may suggest a relationship with the development and progression of cancers.

A Common Variant in the SETD7 Gene Predicts Serum Lycopene Concentrations.

Dietary intake and higher serum concentrations of lycopene have been associated with lower incidence of prostate cancer and other chronic diseases. Identifying determinants of serum lycopene concentrations may thus have important public health implications. Prior studies have suggested that serum lycopene concentrations are under partial genetic control. The goal of this research was to identify genetic predictors of serum lycopene concentrations using the genome-wide association study (GWAS) approach among a sample of 441 Old Order Amish adults that consumed a controlled diet. Linear regression models were utilized to evaluate associations between genetic variants and serum concentrations of lycopene. Variant rs7680948 on chromosome 4, located in the intron region of the SETD7 gene, was significantly associated with serum lycopene concentrations (p = 3.41 × 10(-9)). Our findings also provided nominal support for the association previously noted between SCARB1 and serum lycopene concentrations, although with a different SNP (rs11057841) in the region. This study identified a novel locus associated with serum lycopene concentrations and our results raise a number of intriguing possibilities regarding the nature of the relationship between SETD7 and lycopene, both of which have been independently associated with prostate cancer. Further investigation into this relationship might help provide greater mechanistic understanding of these associations.

Implementation of a prediabetes identification algorithm for overweight and obese Veterans.

Type 2 diabetes prevention is an important national goal for the Veteran Health Administration (VHA): one in four Veterans has diabetes. We implemented a prediabetes identification algorithm to estimate prediabetes prevalence among overweight and obese Veterans at Department of Veterans Affairs (VA) medical centers (VAMCs) in preparation for the launch of a pragmatic study of Diabetes Prevention Program (DPP) delivery to Veterans with prediabetes. This project was embedded within the VA DPP Clinical Demonstration Project conducted in 2012 to 2015. Veterans who attended orientation sessions for an established VHA weight-loss program (MOVE!) were recruited from VAMCs with geographically and racially diverse populations using existing referral processes. Each site implemented and adapted the prediabetes identification algorithm to best fit their local clinical context. Sites relied on an existing referral process in which a prediabetes identification algorithm was implemented in parallel with existing clinical flow; this approach limited the number of overweight and obese Veterans who were assessed and screened. We evaluated 1,830 patients through chart reviews, interviews, and/or laboratory tests. In this cohort, our estimated prevalence rates for normal glycemic status, prediabetes, and diabetes were 29% (n = 530), 28% (n = 504), and 43% (n = 796), respectively. Implementation of targeted prediabetes identification programs requires careful consideration of how prediabetes assessment and screening will occur.

Taste perception, associated hormonal modulation, and nutrient intake.

It is well known that taste perception influences food intake. After ingestion, gustatory receptors relay sensory signals to the brain, which segregates, evaluates, and distinguishes the stimuli, leading to the experience known as "flavor." It is well accepted that five taste qualities ­ sweet, salty, bitter, sour, and umami ­ can be perceived by animals. In this review, the anatomy and physiology of human taste buds, the hormonal modulation of taste function, the importance of genetic chemosensory variation, and the influence of gustatory functioning on macronutrient selection and eating behavior are discussed. Individual genotypic variation results in specific phenotypes of food preference and nutrient intake. Understanding the role of taste in food selection and ingestive behavior is important for expanding our understanding of the factors involved in body weight maintenance and the risk of chronic diseases including obesity, atherosclerosis, cancer, diabetes, liver disease, and hypertension.

Implementation and evaluation of the VA DPP clinical demonstration: protocol for a multi-site non-randomized hybrid effectiveness-implementation type III trial.

BACKGROUND: The Diabetes Prevention Program (DPP) study showed that lifestyle intervention resulted in a 58% reduction in incidence of type 2 diabetes among individuals with prediabetes. Additional large randomized controlled trials have confirmed these results, and long-term follow-up has shown sustained benefit 10-20 years after the interventions ended. Diabetes is a common and costly disease, especially among Veterans, and despite strong evidence supporting the feasibility of type 2 diabetes prevention, the DPP has not been widely implemented. The first aim of this study will evaluate implementation of the Veterans Affairs (VA) DPP in three VA medical centers. The second aim will assess weight and hemoglobin A1c (A1c) outcomes, and the third aim will determine the cost-effectiveness and budget impact of implementation of the VA DPP from a health system perspective. METHODS/DESIGN: This partnered multi-site non-randomized systematic assignment study will use a highly pragmatic hybrid effectiveness-implementation type III mixed methods study design. The implementation and administration of the VA DPP will be funded by clinical operations while the evaluation of the VA DPP will be funded by research grants. Seven hundred twenty eligible Veterans will be systematically assigned to the VA DPP clinical demonstration or the usual care VA MOVE!® weight management program. A multi-phase formative evaluation of the VA DPP implementation will be conducted. A theoretical program change model will be used to guide the implementation process and assess applicability and feasibility of the DPP for VA. The Consolidated Framework for Implementation Research (CFIR) will be used to guide qualitative data collection, analysis, and interpretation of barriers and facilitators to implementation. The RE-AIM framework will be used to assess Reach, Effectiveness, Adoption, Implementation, and Maintenance of the VA DPP. Twelve-month weight and A1c change will be evaluated for the VA DPP compared to the VA MOVE! PROGRAM: Mediation analyses will be conducted to identify whether program design differences impact outcomes. DISCUSSION: Findings from this pragmatic evaluation will be highly applicable to practitioners who are tasked with implementing the DPP in clinical settings. In addition, findings will determine the effectiveness and cost-effectiveness of the VA DPP in the Veteran population.

Vitamin and supplement use among old order amish: sex-specific prevalence and associations with use.

BACKGROUND: Complementary and alternative medicine (CAM) in the form of vitamin and supplement use is increasingly prevalent in the United States. The interplay between CAM use and use of conventional medications is not well studied. We examined this issue in Old Order Amish (OOA), a population lacking several factors known to influence supplement use, whose culture and barriers to conventional medications may result in high rates of supplement use. OBJECTIVE: We characterized the patterns of supplement use in OOA, including the extent to which CAM use aggregates in families, and assessed whether higher use of supplements is associated with lower medication use. DESIGN: We conducted a cross-sectional study of conventional medications and supplements in 2,372 adult Amish from the Lancaster County, PA, area. Data were collected through face-to-face interviews. Supplements were subcategorized as herbal vs vitamin/mineral supplements. RESULTS: Seventy-seven percent of all Amish adults reported current supplement use, whereas 22% reported medication use. Women used supplements more often and used more supplements than men, and familial aggregation of supplement use was stronger in family pairs involving women. Supplement use was associated with less medication use after controlling for age, sex, body mass index, and self-reported histories of hypertension, diabetes, and hyperlipidemia (adjusted odds ratio [OR] 0.96, 95% CI 0.92 to 1.00; P=0.047). This association was driven primarily by use of herbal supplements (adjusted OR 0.94, 95% CI 0.89 to 0.99; P=0.025) as vitamin/mineral supplements were not associated with different use of medication (adjusted OR 0.99, 95% CI 0.90 to 1.09; P=0.8). In analyses limited to cardiovascular medications and cardiovascular supplements in participants with hyperlipidemia, hypertension, or diabetes, supplement use was not associated with conventional medication use. CONCLUSIONS: OAA, particularly women, take dietary supplements much more frequently than they use conventional medications. Use of herbal supplements is associated with less use of conventional medications, whereas vitamin/mineral supplement use is not.

TAS2R bitter taste receptors regulate thyroid function.

Dysregulation of thyroid hormones triiodothyronine and thyroxine (T3/T4) can impact metabolism, body composition, and development. Thus, it is critical to identify novel mechanisms that impact T3/T4 production. We found that type 2 taste receptors (TAS2Rs), which are activated by bitter-tasting compounds such as those found in many foods and pharmaceuticals, negatively regulate thyroid-stimulating hormone (TSH)-dependent Ca(2+) increases and TSH-dependent iodide efflux in thyrocytes. Immunohistochemical Tas2r-dependent reporter expression and real-time PCR analyses reveal that human and mouse thyrocytes and the Nthy-Ori 3-1 human thyrocyte line express several TAS2Rs. Five different agonists for thyrocyte-expressed TAS2Rs reduced TSH-dependent Ca(2+) release in Nthy-Ori 3-1 cells, but not basal Ca(2+) levels, in a dose-dependent manner. Ca(2+) responses were unaffected by 6-n-propylthiouracil, consistent with the expression of an unresponsive variant of its cognate receptor, TAS2R38, in these cells. TAS2R agonists also inhibited basal and TSH-dependent iodide efflux. Furthermore, a common TAS2R42 polymorphism is associated with increased serum T4 levels in a human cohort. Our findings indicate that TAS2Rs couple the detection of bitter-tasting compounds to changes in thyrocyte function and T3/T4 production. Thus, TAS2Rs may mediate a protective response to overingestion of toxic materials and could serve as new druggable targets for therapeutic treatment of hypo- or hyperthyroidism.

The role of rs2237781 within GRM8 in eating behavior.

INTRODUCTION: The glutamate receptor, metabotropic 8 gene (GRM8) encodes a G-protein-coupled glutamate receptor and has been associated with smoking behavior and liability to alcoholism implying a role in addiction vulnerability. Data from animal studies suggest that GRM8 may be involved in the regulation of the neuropeptide Y and melanocortin pathways and might influence food intake and metabolism. This study aimed to investigate the effects of the genetic variant rs2237781 within GRM8 on human eating behavior. METHODS: The initial analysis included 548 Sorbs from Germany who have been extensively phenotyped for metabolic traits and who completed the German version of the three-factor eating questionnaire. In addition, we analyzed two independent sample sets comprising 293 subjects from another German cohort and 430 Old Order Amish individuals. Genetic associations with restraint, disinhibition, and hunger were assessed in an additive linear regression model. RESULTS: Among the Sorbs the major G allele of rs2237781 was significantly associated with increased restraint scores in eating behavior (P = 1.9 × 10(-4); ß = +1.936). The German cohort and the Old Order Amish population revealed a trend in the same direction for restraint (P = 0.242; ß = +0.874; P = 0.908; ß = +0.096; respectively). A meta-analysis resulted in a combined P = 3.1 × 10(-3) (Z-score 2.948). CONCLUSION: Our data suggest that rs2237781 within GRM8 may influence human eating behavior factors probably via pathways involved in addictive behavior.

The ABCG8 G574R variant, serum plant sterol levels, and cardiovascular disease risk in the Old Order Amish.

OBJECTIVE: To determine whether long-term exposure to moderate elevations in plasma plant sterol levels increases risk for atherosclerosis. METHODS AND RESULTS: In Old Order Amish participants aged 18 to 85 years, with (n=110) and without (n=181) 1 copy of the ABCG8 G574R variant, we compared mean plasma levels of plant sterols and cholesterol precursors and carotid intima-media wall thickness. Carriers of a single 574R allele had increased plant sterol levels (eg, 35%-37% higher plasma levels of sitosterol, campesterol, and stigmasterol) and increased plant sterol/cholesterol ratios (P<0.001 for all). 574R carriers had significantly decreased levels of lathosterol and lanosterol, precursors in a pathway for endogenous cholesterol synthesis, suggesting that plant sterols may alter regulation of genes involved in cholesterol synthesis. The G574R variant was not associated with high-density lipoprotein cholesterol or low-density lipoprotein cholesterol levels. Compared with noncarriers, 574R carriers had decreased carotid intima-media wall thickness (0.62 versus 0.66 mm; age- and sex-adjusted P=0.03). Adjustment for body weight, blood pressure, and standard lipid measures (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides) did not alter this association. CONCLUSIONS: Although the G574R variant is associated with moderately elevated plant sterol levels, carriers of the 574R allele had modestly lower levels of carotid wall thickness compared with noncarriers.

Analysis of the gut microbiota in the old order Amish and its relation to the metabolic syndrome.

Obesity has been linked to the human gut microbiota; however, the contribution of gut bacterial species to the obese phenotype remains controversial because of conflicting results from studies in different populations. To explore the possible dysbiosis of gut microbiota in obesity and its metabolic complications, we studied men and women over a range of body mass indices from the Old Order Amish sect, a culturally homogeneous Caucasian population of Central European ancestry. We characterized the gut microbiota in 310 subjects by deep pyrosequencing of bar-coded PCR amplicons from the V1-V3 region of the 16S rRNA gene. Three communities of interacting bacteria were identified in the gut microbiota, analogous to previously identified gut enterotypes. Neither BMI nor any metabolic syndrome trait was associated with a particular gut community. Network analysis identified twenty-two bacterial species and four OTUs that were either positively or inversely correlated with metabolic syndrome traits, suggesting that certain members of the gut microbiota may play a role in these metabolic derangements.

The neuropsychiatry of vitamin B12 deficiency in elderly patients.

Vitamin B12 deficiency is a common cause of neuropsychiatric symptoms in elderly persons. Malabsorption accounts for the majority of cases. Vitamin B12 deficiency has been associated with neurologic, cognitive, psychotic, and mood symptoms, as well as treatment-resistance. Clinician awareness should be raised to accurately diagnose and treat early deficiencies to prevent irreversible structural brain damage, because current practice can be ineffective at identifying cases leading to neuropsychiatric sequelae. This clinical review focuses on important aspects of the recognition and treatment of vitamin B12 deficiency and neuropsychiatric manifestations of this preventable illness in elderly patients.

Determinants of blood pressure response to low-salt intake in a healthy adult population.

Although the beneficial effects of lowering salt intake in hypertensive patients are widely appreciated, the impact of promoting dietary salt restriction for blood pressure (BP) reduction at the population level remains controversial. The authors used 24-hour ambulatory BP monitoring to characterize the determinants of systolic BP (SBP) response to low-salt intake in a large, relatively healthy Amish population. Patients received a high- and low-sodium diet for 6 days each, separated by a 6- to 14-day washout period. Variance component analysis was used to assess the association of several variables with SBP response to low-salt diet. Mean SBP was 0.7 ± 5.8 mm Hg and 1.3 ± 6.1 mm Hg lower on the low-salt compared with the high-salt diet during daytime (P=.008) and nighttime (P<.0001), respectively. SBP response to a low-salt diet was significantly associated with increasing age and pre-intervention SBP, in both daytime and nighttime, while the association with female sex and SBP response to cold pressor test (CPT) was significant only during nighttime. Our results suggest that salt reduction may have greater BP-lowering effects on women, older individuals, individuals with higher SBP, and individuals with higher SBP response to CPT.