Intellectual disability and autism in propionic acidemia: a biomarker-behavioral investigation implicating dysregulated mitochondrial biology.

Propionic acidemia (PA) is an autosomal recessive condition (OMIM #606054), wherein pathogenic variants in PCCA and PCCB impair the activity of propionyl-CoA carboxylase. PA is associated with neurodevelopmental disorders, including intellectual disability (ID) and autism spectrum disorder (ASD); however, the correlates and mechanisms of these outcomes remain unknown. Using data from a subset of participants with PA enrolled in a dedicated natural history study (n = 33), we explored associations between neurodevelopmental phenotypes and laboratory parameters. Twenty (61%) participants received an ID diagnosis, and 12 of the 31 (39%) who were fully evaluated received the diagnosis of ASD. A diagnosis of ID, lower full-scale IQ (sample mean = 65 ± 26), and lower adaptive behavior composite scores (sample mean = 67 ± 23) were associated with several biomarkers. Higher concentrations of plasma propionylcarnitine, plasma total 2-methylcitrate, serum erythropoietin, and mitochondrial biomarkers plasma FGF21 and GDF15 were associated with a more severe ID profile. Reduced 1-13C-propionate oxidative capacity and decreased levels of plasma and urinary glutamine were also associated with a more severe ID profile. Only two parameters, increased serum erythropoietin and decreased plasma glutamine, were associated with ASD. Plasma glycine, one of the defining features of PA, was not meaningfully associated with either ID or ASD. Thus, while both ID and ASD were commonly observed in our PA cohort, only ID was robustly associated with metabolic parameters. Our results suggest that disease severity and associated mitochondrial dysfunction may play a role in CNS complications of PA and identify potential biomarkers and candidate surrogate endpoints.

Abnormal chondrocyte development in a zebrafish model of cblC syndrome restored by an MMACHC cobalamin binding mutant.

Variants in the MMACHC gene cause combined methylmalonic acidemia and homocystinuria cblC type, the most common inborn error of intracellular cobalamin (vitamin B12) metabolism. cblC is associated with neurodevelopmental, hematological, ocular, and biochemical abnormalities. In a subset of patients, mild craniofacial dysmorphia has also been described. Mouse models of Mmachc deletion are embryonic lethal but cause severe craniofacial phenotypes such as facial clefts. MMACHC encodes an enzyme required for cobalamin processing and variants in this gene result in the accumulation of two metabolites: methylmalonic acid (MMA) and homocysteine (HC). Interestingly, other inborn errors of cobalamin metabolism, such as cblX syndrome, are associated with mild facial phenotypes. However, the presence and severity of MMA and HC accumulation in cblX syndrome is not consistent with the presence or absence of facial phenotypes. Thus, the mechanisms by which mutations in MMACHC cause craniofacial defects are yet to be completely elucidated. Here we have characterized the craniofacial phenotypes in a zebrafish model of cblC (hg13) and performed restoration experiments with either a wildtype or a cobalamin binding deficient MMACHC protein. Homozygous mutants did not display gross morphological defects in facial development but did have abnormal chondrocyte nuclear organization and an increase in the average number of neighboring cell contacts, both phenotypes were fully penetrant. Abnormal chondrocyte nuclear organization was not associated with defects in the localization of neural crest specific markers, sox10 (RFP transgene) or barx1. Both nuclear angles and the number of neighboring cell contacts were fully restored by wildtype MMACHC and a cobalamin binding deficient variant of the MMACHC protein. Collectively, these data suggest that mutation of MMACHC causes mild to moderate craniofacial phenotypes that are independent of cobalamin binding.

Biomarkers to predict disease progression and therapeutic response in isolated methylmalonic acidemia.

Methylmalonic Acidemia (MMA) is a heterogenous group of inborn errors of metabolism caused by a defect in the methylmalonyl-CoA mutase (MMUT) enzyme or the synthesis and transport of its cofactor, 5'-deoxy-adenosylcobalamin. It is characterized by life-threatening episodes of ketoacidosis, chronic kidney disease, and other multiorgan complications. Liver transplantation can improve patient stability and survival and thus provides clinical and biochemical benchmarks for the development of hepatocyte-targeted genomic therapies. Data are presented from a US natural history protocol that evaluated subjects with different types of MMA including mut-type (N = 91), cblB-type (15), and cblA-type MMA (17), as well as from an Italian cohort of mut-type (N = 19) and cblB-type MMA (N = 2) subjects, including data before and after organ transplantation in both cohorts. Canonical metabolic markers, such as serum methylmalonic acid and propionylcarnitine, are variable and affected by dietary intake and renal function. We have therefore explored the use of the 1-13 C-propionate oxidation breath test (POBT) to measure metabolic capacity and the changes in circulating proteins to assess mitochondrial dysfunction (fibroblast growth factor 21 [FGF21] and growth differentiation factor 15 [GDF15]) and kidney injury (lipocalin-2 [LCN2]). Biomarker concentrations are higher in patients with the severe mut0 -type and cblB-type MMA, correlate with a decreased POBT, and show a significant response postliver transplant. Additional circulating and imaging markers to assess disease burden are necessary to monitor disease progression. A combination of biomarkers reflecting disease severity and multisystem involvement will be needed to help stratify patients for clinical trials and assess the efficacy of new therapies for MMA.

ZBTB11 dysfunction: spectrum of brain abnormalities, biochemical signature and cellular consequences.

Bi-allelic pathogenic variants in ZBTB11 have been associated with intellectual developmental disorder, autosomal recessive 69 (MRT69; OMIM 618383). We report five patients from three families with novel, bi-allelic variants in ZBTB11. We have expanded the clinical phenotype of MRT69, documenting varied severity of atrophy affecting different brain regions and described combined malonic and methylmalonic aciduria as a biochemical manifestation. As ZBTB11 encodes for a transcriptional regulator, we performeded chromatin immunoprecipitation-sequencing targeting ZBTB11 in fibroblasts from patients and controls. Chromatin immunoprecipitation-sequencing revealed binding of wild-type ZBTB11 to promoters in 238 genes, among which genes encoding proteins involved in mitochondrial functions and RNA processing are over-represented. Mutated ZBTB11 showed reduced binding to 61 of the targeted genes, indicating that the variants act as loss of function. Most of these genes are related to mitochondrial functions. Transcriptome analysis of the patient fibroblasts revealed dysregulation of mitochondrial functions. In addition, we uncovered that reduced binding of the mutated ZBTB11 to ACSF3 leads to decreased ACSF3 transcript level, explaining combined malonic and methylmalonic aciduria. Collectively, these results expand the clinical spectrum of ZBTB11-related neurological disease and give insight into the pathophysiology in which the dysfunctional ZBTB11 affect mitochondrial functions and RNA processing contributing to the neurological and biochemical phenotypes.

The vitamin B12 processing enzyme, mmachc, is essential for zebrafish survival, growth and retinal morphology.

Cobalamin C (cblC) deficiency, the most common inborn error of intracellular cobalamin metabolism, is caused by mutations in MMACHC, a gene responsible for the processing and intracellular trafficking of vitamin B12. This recessive disorder is characterized by a failure to metabolize cobalamin into adenosyl- and methylcobalamin, which results in the biochemical perturbations of methylmalonic acidemia, hyperhomocysteinemia and hypomethioninemia caused by the impaired activity of the downstream enzymes, methylmalonyl-CoA mutase and methionine synthase. Cobalamin C deficiency can be accompanied by a wide spectrum of clinical manifestations, including progressive blindness, and, in mice, manifests with very early embryonic lethality. Because zebrafish harbor a full complement of cobalamin metabolic enzymes, we used genome editing to study the loss of mmachc function and to develop the first viable animal model of cblC deficiency. mmachc mutants survived the embryonic period but perished in early juvenile life. The mutants displayed the metabolic and clinical features of cblC deficiency including methylmalonic acidemia, severe growth retardation and lethality. Morphologic and metabolic parameters improved when the mutants were raised in water supplemented with small molecules used to treat patients, including hydroxocobalamin, methylcobalamin, methionine and betaine. Furthermore, mmachc mutants bred to express rod and/or cone fluorescent reporters, manifested a retinopathy and thin optic nerves (ON). Expression analysis using whole eye mRNA revealed the dysregulation of genes involved in phototransduction and cholesterol metabolism. Zebrafish with mmachc deficiency recapitulate the several of the phenotypic and biochemical features of the human disorder, including ocular pathology, and show a response to established treatments.

Probing the functional consequence and clinical relevance of CD320 p.E88del, a variant in the transcobalamin receptor gene.

The biological and clinical significance of the p.E88del variant in the transcobalamin receptor, CD320, is unknown. This allele is annotated in ClinVar as likely benign, pathogenic, and of uncertain significance. To determine functional consequence and clinical relevance of this allele, we employed cell culture and genetic association studies. Fibroblasts from 16 CD320 p.E88del homozygotes exhibited reduced binding and uptake of cobalamin. Complete ascertainment of newborns with transiently elevated C3 (propionylcarnitine) in New York State demonstrated that homozygosity for CD320 p.E88del was over-represented (7/348, p < 6 × 10-5 ). Using population data, we estimate that ~85% of the p.E88del homozygotes born in the same period did not have elevated C3, suggesting that cobalamin metabolism in the majority of these infants with this genotype is unaffected. Clinical follow-up of 4/9 homozygous individuals uncovered neuropsychological findings, mostly in speech and language development. None of these nine individuals exhibited perturbation of cobalamin metabolism beyond the newborn stage even during periods of acute illness. Newborns homozygous for this allele in the absence of other factors are at low risk of requiring clinical intervention, although more studies are required to clarify the natural history of various CD320 variants across patient populations.

Improvements in Neighborhood Socioeconomic Conditions May Improve Resident Diet.

Neighborhood socioeconomic conditions (NSECs) are associated with resident diet, but most research has been cross-sectional. We capitalized on a natural experiment in Pittsburgh, Pennsylvania, in which 1 neighborhood experienced substantial investments and a sociodemographically similar neighborhood that did not, to examine pathways from neighborhood investments to changed NSECs and changed dietary behavior. We examined differences between renters and homeowners. Data were from a random sample of households (n = 831) in each of these low-income Pittsburgh neighborhoods that were surveyed in 2011 and 2014. Structural equation modeling tested direct and indirect pathways from neighborhood to resident dietary quality, adjusting for individual-level sociodemographics, with multigroup testing by homeowners versus renters. Neighborhood investments were directly associated with improved dietary quality for renters (ß = 0.27, 95% confidence interval (CI): 0.05, 0.50) and homeowners (ß = 0.51, 95% CI: 0.10, 0.92). Among renters, investments also were associated with dietary quality through a positive association with commercial prices (ß = 0.34, 95% CI: 0.15, 0.54) and a negative association with residential prices (ß = -0.30, 95% CI: -0.59, -0.004). Among homeowners, we did not observe any indirect pathways from investments to dietary quality through tested mediators. Investing in neighborhoods may support resident diet through improvements in neighborhood commercial environments for renters, but mechanisms appear to differ for homeowners.

Severity modeling of propionic acidemia using clinical and laboratory biomarkers.

PURPOSE: To conduct a proof-of-principle study to identify subtypes of propionic acidemia (PA) and associated biomarkers. METHODS: Data from a clinically diverse PA patient population ( https://clinicaltrials.gov/ct2/show/NCT02890342 ) were used to train and test machine learning models, identify PA-relevant biomarkers, and perform validation analysis using data from liver-transplanted participants. k-Means clustering was used to test for the existence of PA subtypes. Expert knowledge was used to define PA subtypes (mild and severe). Given expert classification, supervised machine learning (support vector machine with a polynomial kernel, svmPoly) performed dimensional reduction to define relevant features of each PA subtype. RESULTS: Forty participants enrolled in the study; five underwent liver transplant. Analysis with k-means clustering indicated that several PA subtypes may exist on the biochemical continuum. The conventional PA biomarkers, plasma total 2-methylctirate and propionylcarnitine, were not statistically significantly different between nontransplanted and transplanted participants motivating us to search for other biomarkers. Unbiased dimensional reduction using svmPoly revealed that plasma transthyretin, alanine:serine ratio, GDF15, FGF21, and in vivo 1-13C-propionate oxidation, play roles in defining PA subtypes. CONCLUSION: Support vector machine prioritized biomarkers that helped classify propionic acidemia patients according to severity subtypes, with important ramifications for future clinical trials and management of PA.

1-13C-propionate breath testing as a surrogate endpoint to assess efficacy of liver-directed therapies in methylmalonic acidemia (MMA).

PURPOSE: To develop a safe and noninvasive in vivo assay of hepatic propionate oxidative capacity. METHODS: A modified 1-13C-propionate breath test was administered to 57 methylmalonic acidemia (MMA) subjects, including 19 transplant recipients, and 16 healthy volunteers. Isotopomer enrichment (13CO2/12CO2) was measured in exhaled breath after an enteral bolus of sodium-1-13C-propionate, and normalized for CO2 production. 1-13C-propionate oxidation was then correlated with clinical, laboratory, and imaging parameters collected via a dedicated natural history protocol. RESULTS: Lower propionate oxidation was observed in patients with the severe mut0 and cblB subtypes of MMA, but was near normal in those with the cblA and mut- forms of the disorder. Liver transplant recipients demonstrated complete restoration of 1-13C-propionate oxidation to control levels. 1-13C-propionate oxidation correlated with cognitive test result, growth indices, bone mineral density, renal function, and serum biomarkers. Test repeatability was robust in controls and in MMA subjects (mean coefficient of variation 6.9% and 12.8%, respectively), despite widely variable serum methylmalonic acid concentrations in the patients. CONCLUSION: Propionate oxidative capacity, as measured with 1-13C-propionate breath testing, predicts disease severity and clinical outcomes, and could be used to assess the therapeutic effects of liver-targeted genomic therapies for MMA and related disorders of propionate metabolism. TRIAL REGISTRATION: This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078.

Critical analysis and limitations of resting ankle-brachial index in the diagnosis of symptomatic peripheral arterial disease patients and the role of diabetes mellitus and chronic kidney disease.

BACKGROUND: The ankle-brachial index (ABI) may underestimate the severity of peripheral arterial disease (PAD) in patients with noncompressible vessels. This study analyzed limitations of the ABI and toe-brachial index (TBI), if done alone, in patients with symptomatic PAD, diagnosed by duplex ultrasound (DUS) examination, particularly in patients with diabetes and chronic kidney disease (CKD). METHODS: This is a retrospective review of prospectively collected data. All patients underwent resting ABIs, TBI, and/or DUS. An ABIs of 0.90 or less in either leg was considered abnormal, and the term inconclusive ABIs (noncompressibility) was used if the ABI was 1.3 or greater. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy (OA) of ABIs in detecting 50% or greater stenosis of any arterial segment based on DUS were determined. A TBI of less than 0.7 was considered abnormal. RESULTS: We included 2226 ABIs and 1383 DUS examinations: 46% of patients had diabetes, 16% had CKD, and 39% had coronary artery disease. Fifty-three percent of the ABIs were normal, 34% were abnormal, and 13% were inconclusive. For patients with limb-threatening ischemia, 40% had normal ABIs, 40% abnormal ABIs, and 20% were inconclusive. The sensitivity and OA for ABIs in detecting 50% or greater stenosis in the whole series were 57% (95% confidence interval [CI], 53.7-61.2) and 74% (95% CI, 71.9-76.6); for diabetics 51% (95% CI, 46.1-56.3) and 66% (95% CI, 62.3-69.8); nondiabetics 66% (95% CI, 59.9-70.9) and 81% (95% CI, 78.2-83.9). For patients with CKD, the sensitivity and OA for ABIs in detecting 50% or greater stenosis was 43% (95% CI, 34.3-52.7) and 67% (95% CI, 60.2-73.0) versus patients with no CKD 60% (95% CI, 56.3-64.6) and 76% (95% CI, 73.1-78.1). If patients with inconclusive ABIs were excluded, these values were 69% (95% CI, 65.2-72.9) and 80% (95% CI, 77.2-81.9) in the whole series; 67% (95% CI, 61.6-72.7) and 75% (95% CI, 70.5-78.4) for diabetics; and 63% (95% CI, 51.3-73.0) and 78% (95% CI, 70.6-83.9) for patients with CKD. Thirty-three percent of TBIs were normal and 67% were abnormal. The sensitivity and OA for abnormal TBI in detecting 50% or greater stenosis were 85% (95% CI, 78.9-90.0) and 75% (95% CI, 70.1-80.2) in the whole series; 84% (95% CI, 76.0-90.3) and 74% (95% CI, 67.1-80.2) for diabetics; and 77% (95% CI, 61.4-88.2) and 72% (95% CI, 59.9-82.3) for patients with CKD. For those with inconclusive ABIs, these values for TBI were 75% and 69%. CONCLUSIONS: Of symptomatic patients with PAD with 50% or greater stenosis on DUS examination, 43% had normal/inconclusive resting ABIs (49% in diabetics and 57% in CKD). TBI may help in patients with inconclusive ABIs. These patients should undergo further imaging to determine proper treatment.

Factors related to health civic engagement: results from the 2018 National Survey of Health Attitudes to understand progress towards a Culture of Health.

BACKGROUND: Civic engagement, including voting, volunteering, and participating in civic organizations, is associated with better psychological, physical and behavioral health and well-being. In addition, civic engagement is increasingly viewed (e.g., in Robert Wood Johnson Foundation's Culture of Health action framework) as a potentially important driver for raising awareness of and addressing unhealthy conditions in communities. As such, it is important to understand the factors that may promote civic engagement, with a particular focus on the less-understood, health civic engagement, or civic engagement in health-related and health-specific activities. Using data from a nationally representative sample of adults in the United States (U.S.), we examined whether the extent to which individuals feel they belong in their community (i.e., perceived sense of community) and the value they placed on investing in community health were associated with individuals' health civic engagement. METHODS: Using data collected on 7187 nationally representative respondents from the 2018 National Survey of Health Attitudes, we examined associations between sense of community, valued investment in community health, and perceived barriers to taking action to invest in community health, with health civic engagement. We constructed continuous scales for each of these constructs and employed multiple linear regressions adjusting for multiple covariates including U.S. region and city size of residence, educational attainment, family income, race/ethnicity, household size, employment status, and years living in the community. RESULTS: Participants who endorsed (i.e., responded with mostly or completely) all 16 sense of community scale items endorsed an average of 22.8% (95%CI: 19.8-25.7%) more of the health civic engagement scale items compared with respondents who did not endorse any of the sense of community items. Those who endorsed (responded that it was an important or top priority) all items capturing valued investment in community health endorsed 14.0% (95%CI: 11.2-16.8%) more of the health civic engagement items than those who did not endorse any valued investment in community health items. CONCLUSIONS: Health civic engagement, including voting and volunteering to ultimately guide government decisions about health issues, may help improve conditions that influence health and well-being for all. Focusing on individuals' sense of community and highlighting investments in community health may concurrently be associated with increased health civic engagement and improved community and population health.

An audit tool for longitudinal assessment of the health-related characteristics of urban neighborhoods: implementation methods and reliability results.

BACKGROUND: Improving the neighborhood environment may help address chronic disease and mortality. To identify neighborhood features that are predictors of health, objective assessments of the environment are used. Multiple studies have reported on cross-sectional assessments of health-related neighborhood features using direct observation. As study designs expand to better understand causation and predictors of change, there is a need to test whether direct observation methods are adequate for longitudinal assessment. To our knowledge, this is the first study to report on the reliability of repeated measurements of the neighborhood environment, and their stability, over time. METHODS: The Pittsburgh Hill/Homewood Research on Neighborhood Change and Health (PHRESH) study conducted longitudinal assessments in two low-income, African American neighborhoods at three waves (years 2012, 2015, 2017). The PHRESH audit tool is a modification of earlier validated tools, with an emphasis on environment features relevant for physical activity, sleep, and obesogenic behaviors. Trained data-collector pairs conducted direct observations of a 25% sample of street segments in each neighborhood. At each wave, we audited a sub-sample of street segments twice and assessed reliability using percentage inter-observer agreement and krippendorf's alpha statistics. Stability of these items was assessed as exhibiting moderate or high agreement at every time point. RESULTS: Across waves, a majority (81%) of the items consistently demonstrated moderate to high agreement except for items such as public/communal space, amount of shade, sidewalk features, number of traffic lanes, garden/flower bed/planter, art/statue/monument, amount of trash, and physical disorder. The list of items with poor agreement includes features that are easy to miss (e.g. flower bed/planter), hard to assess from outside (e.g. public/communal space), or may change quickly (e.g. amount of trash). CONCLUSION: In this paper, we have described implementation methods, reliability results and lessons learned to inform future studies of change. We found the use of consistent methods allowed us to conduct reliable, replicable longitudinal assessments of the environment. Items that did not exhibit stability are less useful for detecting real change over time. Overall, the PHRESH direct observation tool is an effective and practical instrument to detect change in the neighborhood environment.

Chronic kidney disease in propionic acidemia.

PURPOSE: Propionic acidemia (PA) is a severe metabolic disorder characterized by multiorgan pathology, including renal disease. The prevalence of chronic kidney disease (CKD) in PA patients and factors associated with CKD in PA are not known. METHODS: Thirty-one subjects diagnosed with PA underwent laboratory and clinical evaluations through a dedicated natural history study at the National Institutes of Health (ClinicalTrials.gov identifier: NCT02890342). RESULTS: Cross-sectional analysis of the creatinine-based estimated glomerular filtration rate (eGFR) in subjects with native kidneys revealed an age-dependent decline in renal function (P < 0.002). Among adults with PA, 4/8 (50%) had eGFR <60 mL/min/1.73 m2. There was a significant discrepancy between eGFRs calculated using estimating equations based on serum creatinine compared with serum cystatin C (P < 0.0001). The tubular injury marker, plasma lipocalin-2, and plasma uric acid were strongly associated with CKD (P < 0.0001). The measured 24-hour creatinine excretion was below normal, even after adjusting for age, height, and sex. CONCLUSION: CKD is common in adults with PA and is associated with age. The poor predictive performance of standard eGFR estimating equations, likely due to reduced creatine synthesis in kidney and liver, could delay the recognition of CKD and management of ensuing complications in this population.

Rice with reduced stomatal density conserves water and has improved drought tolerance under future climate conditions.

Much of humanity relies on rice (Oryza sativa) as a food source, but cultivation is water intensive and the crop is vulnerable to drought and high temperatures. Under climate change, periods of reduced water availability and high temperature are expected to become more frequent, leading to detrimental effects on rice yields. We engineered the high-yielding rice cultivar 'IR64' to produce fewer stomata by manipulating the level of a developmental signal. We overexpressed the rice epidermal patterning factor OsEPF1, creating plants with substantially reduced stomatal density and correspondingly low stomatal conductance. Low stomatal density rice lines were more able to conserve water, using c. 60% of the normal amount between weeks 4 and 5 post germination. When grown at elevated atmospheric CO2 , rice plants with low stomatal density were able to maintain their stomatal conductance and survive drought and high temperature (40°C) for longer than control plants. Low stomatal density rice gave equivalent or even improved yields, despite a reduced rate of photosynthesis in some conditions. Rice plants with fewer stomata are drought tolerant and more conservative in their water use, and they should perform better in the future when climate change is expected to threaten food security.

Results from a natural experiment: initial neighbourhood investments do not change objectively-assessed physical activity, psychological distress or perceptions of the neighbourhood.

BACKGROUND: Few studies have assessed objectively measured physical activity (PA), active transportation, psychological distress and neighborhood perceptions among residents of a neighborhood before and after substantial improvements in its physical environment. Also, most research-to-date has employed study designs subject to neighborhood selection, which may introduce bias in reported findings. We built upon a previously enrolled cohort of households from two low-income predominantly African American Pittsburgh neighborhoods, matched on socio-demographic composition including race/ethnicity, income and education. One of the two neighborhoods received substantial neighborhood investments over the course of this study including, but not limited to public housing development and greenspace/landscaping. We implemented a natural experiment using matched intervention and control neighborhoods and conducted pre-post assessments among the cohort. Our comprehensive assessments included accelerometry-based PA, active transportation, psychological distress and perceptions of the neighborhood, with assessments conducted both prior to and following the neighborhood changes. In 2013, we collected data from 1003 neighborhood participants and in 2016, we re-interviewed 676 of those participants. We conducted an intent to treat analysis, with a difference-in-difference estimator using attrition weighting to account for nonresponse between 2013 and 2016. In addition, we derived an individual-level indicator of exposure to neighbourhood investment and estimated effect of exposure to investment on the same set of outcomes using covariate-adjusted models. RESULTS: We observed no statistically significant differences in activity, psychological distress, satisfaction with one's neighborhood as a place to live or any of the other measures we observed prior to and after the neighborhood investments between the intervention and control neighborhoods or those exposed vs not exposed to investments. CONCLUSIONS: Using this rigorous study design, we observed no significant changes in the intervention neighborhood above and beyond secular trends present in the control neighborhood. Although neighborhood investment may have other benefits, we failed to see improvement in PA, psychological distress or related outcomes in the low-income African American neighborhoods in our study. This may be an indication that improvements in the physical environment may not directly translate into improvements in residents' physical activity or health outcomes without additional individual-level interventions. It is also possible that these investments were not dramatic enough to spur change within the three year period. Additional studies employing similar design with other cohorts in other settings are needed to confirm these results. TRIAL REGISTRATION: Trial Registration is not applicable since we did not prospectively assign individuals to a health-related intervention.

Making health a shared value: Lessons from nurse-designed models of care.

BACKGROUND: Nurse-designed models of community-based care reflect a broad definition of health; family- and community-centricity; relationships; and group and public health approaches. PURPOSE: To examine how nurse-designed models of care have addressed "making health a shared value" based on the framework of the Culture of Health. METHOD: A mixed-methods design included an online survey completed by 37 of 41 of "Edge Runners" (American Academy of Nursing-designated nurse innovators) and telephone interviews with 13 of the 37. Data were analyzed using descriptive statistics and standard content analysis. FINDINGS: Two main areas of "making health a shared value" were increasing the perceptions that individual health is interdependent with the health of the community and community health promotion. Themes were the value of social support (interventions that engage an individual's inner circle and a group environment to reveal shared experiences); messaging (a holistic definition of health, the value of both culturally- and medically-accurate information, and the business case); and building trust (expertise sits locally and trust takes time). DISCUSSION: Refinement of the COH framework may be warranted and can provide strategies for making health a shared value within a community. Shifting the orientation of healthcare organizations must be a long-term, deliberate goal.

Promoting a Culture of Health Through Cross-Sector Collaborations.

In this study, we explore the experiences of innovative nurses who have developed cross-sector collaborations toward promoting a culture of health, with the aim of identifying lessons that can inform similar efforts of other health care professionals. We used a mixed-methods approach based on data from both an online survey and telephone interviews. A majority of the participants had significant collaborations with health care providers and non-health care providers. Strong partners included mental health providers, specialists, and primary care providers on the health side, and for non-health partners, the strongest collaborations were with community leaders, research institutions, and local businesses. Themes that emerged for successful collaborations included having to be embedded in both the community and in institutions of power, ensuring that a shared vision and language with all partners are established, and leading with strength and tenacity. A focus on building a culture of health will grow as payment policy moves away from fee-for-service toward models that focus on incentivizing population health. Effective efforts to promote a culture of health require cross-sector collaborations that draw on long-term, trusting relationships among leaders. Health care practitioners can be important leaders and "bridgers" in collaborations, but they must possess or develop the knowledge, attitudes, and skills of "bilingual" facilitators, partners, and "relationship builders."

Genetic modifiers of neurofibromatosis type 1-associated café-au-lait macule count identified using multi-platform analysis.

Neurofibromatosis type 1 (NF1) is an autosomal dominant, monogenic disorder of dysregulated neurocutaneous tissue growth. Pleiotropy, variable expressivity and few NF1 genotype-phenotype correlates limit clinical prognostication in NF1. Phenotype complexity in NF1 is hypothesized to derive in part from genetic modifiers unlinked to the NF1 locus. In this study, we hypothesized that normal variation in germline gene expression confers risk for certain phenotypes in NF1. In a set of 79 individuals with NF1, we examined the association between gene expression in lymphoblastoid cell lines with NF1-associated phenotypes and sequenced select genes with significant phenotype/expression correlations. In a discovery cohort of 89 self-reported European-Americans with NF1 we examined the association between germline sequence variants of these genes with café-au-lait macule (CALM) count, a tractable, tumor-like phenotype in NF1. Two correlated, common SNPs (rs4660761 and rs7161) between DPH2 and ATP6V0B were significantly associated with the CALM count. Analysis with tiled regression also identified SNP rs4660761 as significantly associated with CALM count. SNP rs1800934 and 12 rare variants in the mismatch repair gene MSH6 were also associated with CALM count. Both SNPs rs7161 and rs4660761 (DPH2 and ATP6V0B) were highly significant in a mega-analysis in a combined cohort of 180 self-reported European-Americans; SNP rs1800934 (MSH6) was near-significant in a meta-analysis assuming dominant effect of the minor allele. SNP rs4660761 is predicted to regulate ATP6V0B, a gene associated with melanosome biology. Individuals with homozygous mutations in MSH6 can develop an NF1-like phenotype, including multiple CALMs. Through a multi-platform approach, we identified variants that influence NF1 CALM count.

An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1.

Derivatives of vitamin B12 (cobalamin) are essential cofactors for enzymes required in intermediary metabolism. Defects in cobalamin metabolism lead to disorders characterized by the accumulation of methylmalonic acid and/or homocysteine in blood and urine. The most common inborn error of cobalamin metabolism, combined methylmalonic acidemia and hyperhomocysteinemia, cblC type, is caused by mutations in MMACHC. However, several individuals with presumed cblC based on cellular and biochemical analysis do not have mutations in MMACHC. We used exome sequencing to identify the genetic basis of an X-linked form of combined methylmalonic acidemia and hyperhomocysteinemia, designated cblX. A missense mutation in a global transcriptional coregulator, HCFC1, was identified in the index case. Additional male subjects were ascertained through two international diagnostic laboratories, and 13/17 had one of five distinct missense mutations affecting three highly conserved amino acids within the HCFC1 kelch domain. A common phenotype of severe neurological symptoms including intractable epilepsy and profound neurocognitive impairment, along with variable biochemical manifestations, was observed in all affected subjects compared to individuals with early-onset cblC. The severe reduction in MMACHC mRNA and protein within subject fibroblast lines suggested a role for HCFC1 in transcriptional regulation of MMACHC, which was further supported by the identification of consensus HCFC1 binding sites in MMACHC. Furthermore, siRNA-mediated knockdown of HCFC1 expression resulted in the coordinate downregulation of MMACHC mRNA. This X-linked disorder demonstrates a distinct disease mechanism by which transcriptional dysregulation leads to an inborn error of metabolism with a complex clinical phenotype.

A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias.

PURPOSE: Medical foods for methylmalonic acidemias (MMAs) and propionic acidemias contain minimal valine, isoleucine, methionine, and threonine but have been formulated with increased leucine. We aimed to assess the effects of imbalanced branched-chain amino acid intake on metabolic and growth parameters in a cohort of patients with MMA ascertained via a natural history study. METHODS: Cross-sectional anthropometric and body-composition measurements were correlated with diet content and disease-related biomarkers in 61 patients with isolated MMA (46 mut, 9 cblA, and 6 cblB). RESULTS: Patients with MMA tolerated close to the recommended daily allowance (RDA) of complete protein (mut(0): 99.45 ± 32.05% RDA). However, 85% received medical foods, in which the protein equivalent often exceeded complete protein intake (35%). Medical food consumption resulted in low plasma valine and isoleucine concentrations, prompting paradoxical supplementation with these propiogenic amino acids. Weight- and height-for-age z-scores correlated negatively with the leucine-to-valine intake ratio (r = -0.453; P = 0.014; R(2) = 0.209 and r = -0.341; P = 0.05; R(2) = 0.123, respectively). CONCLUSION: Increased leucine intake in patients with MMA resulted in iatrogenic amino acid deficiencies and was associated with adverse growth outcomes. Medical foods for propionate oxidation disorders need to be redesigned and studied prospectively to ensure efficacy and safety.Genet Med 18 4, 386-395.