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BACKGROUND: Studies have questioned whether the current Recommended Dietary Allowance (RDA) of 2.4 microg vitamin B-12/d is adequate. OBJECTIVE: We examined the association between dietary vitamin B-12 intake and biomarkers of vitamin B-12 status. DESIGN: Dietary vitamin B-12 intake was estimated, and biomarkers of vitamin B-12 status were measured, in healthy men and women (n = 299; age range: 18-50 y) who were recruited from a Florida community. The National Cancer Institute Diet History Questionnaire was used. Plasma cobalamin, total transcobalamin, holo-transcobalamin, methylmalonic acid (MMA), total homocysteine (tHcy), and autoantibodies against intrinsic factor (IF) and Helicobacter pylori were analyzed in blood samples. RESULTS: Antibodies to H. pylori were detected in 12% of subjects (35/299), and negative results for IF antibodies were obtained for all subjects. The intake of vitamin B-12 correlated significantly with cobalamin, holo-transcobalamin, MMA, and tHcy. Subjects were divided into quintiles on the basis of their dietary vitamin B-12 intake (range: 0.42-22.7 microg/d), and biomarkers of vitamin B-12 status were plotted against estimated dietary vitamin B-12 intake. All biomarkers appeared to level off at a daily dietary vitamin B-12 intake between 4.2 and 7.0 microg. CONCLUSION: In persons with normal absorption, our data indicate that an intake of 4-7 microg vitamin B-12/d is associated with an adequate vitamin B-12 status, which suggests that the current RDA of 2.4 microg vitamin B-12/d might be inadequate for optimal biomarker status even in a healthy population between 18 and 50 y of age. © 2010 American Society for Nutrition. [ABSTRACT FROM AUTHOR]

BACKGROUND: US adults have access to multiple sources of folic acid. The contribution of these sources to usual intakes above the tolerable upper intake level (UL) (1000 microg/d) and to folate and vitamin B-12 status is unknown. OBJECTIVE: The objective was to estimate usual folic acid intake above the UL and adjusted serum and red blood cell folate, vitamin B-12, methylmalonic acid, and homocysteine concentrations among US adults by 3 major folic acid intake sources-enriched cereal-grain products (ECGP), ready-to-eat cereals (RTE), and supplements (SUP)-categorized into 4 mutually exclusive consumption groups. DESIGN: We used data from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 (n = 8258). RESULTS: Overall, 2.7% (95% CI: 1.9%, 3.5%) of adults consumed more than the UL of folic acid. The proportions of those who consumed folic acid from ECGP only, ECGP+RTE, ECGP+SUP, and ECGP+RTE+SUP were 42%, 18%, 25%, and 15%, respectively. Of 60% of adults who did not consume supplements containing folic acid (ECGP only and ECGP+RTE), 0% had intakes that exceeded the UL. Of 34% and 6% of adults who consumed supplements with an average of < or = 400 and >400 microg folic acid/d, <1% and 47.8% (95% CI: 39.6%, 56.0%), respectively, had intakes that exceeded the UL. Consumption of RTE and/or supplements with folic acid was associated with higher folate and vitamin B-12 and lower homocysteine concentrations, and consumption of supplements with vitamin B-12 was associated with lower methylmalonic acid concentrations (P < 0.001). CONCLUSION: At current fortification levels, US adults who do not consume supplements or who consume an average of < or =400 microg folic acid/d from supplements are unlikely to exceed the UL in intake for folic acid. [ABSTRACT FROM AUTHOR]

BACKGROUND: A common genetic polymorphism [transcobalamin (TC) 776C-->G] may affect the function of transcobalamin, the protein required for vitamin B-12 cellular uptake and metabolism. Remethylation of homocysteine is dependent on the production of 5-methyltetrahydrofolate and adequate vitamin B-12 for the methionine synthase reaction. OBJECTIVES: The objectives were to assess the influence of the TC 776C--> G polymorphism on concentrations of the transcobalamin-vitamin B-12 complex (holo-TC) and to determine the combined effects of the TC 776C-->G and methylenetetrahydrofolate reductase (MTHFR) 677C-->T polymorphisms and vitamin B-12 status on homocysteine concentrations. DESIGN: Healthy, nonpregnant women (n = 359; aged 20-30 y) were screened to determine plasma vitamin B-12, serum holo-TC, and plasma homocysteine concentrations and TC 776C-->G and MTHFR 677C-->T genotypes. RESULTS: The serum holo-TC concentration for women with the variant TC 776 GG genotype was significantly different (P = 0.0213) from that for subjects with the CC genotype (74 +/- 37 and 87 +/- 33 pmol/L, respectively). An inverse relation was observed between plasma homocysteine concentrations and both serum holo-TC (P G polymorphism negatively affects the serum holo-TC concentration and provide additional evidence that vitamin B-12 status modulates the homocysteine concentration in this population. Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Although the length of a hospital stay is very limited for patients with heart failure, many patients attempt to resume some activities of daily living soon after arrival at home. Home care nurses routinely assess symptoms indicative of recurrent heart failure and the need for hospital readmission. The purpose of this comparative study was to determine whether there was a significant difference in diastolic blood pressure and oxygen saturation after walking for 6 min. Twenty adults with heart failure in an outpatient cardiology clinic were evaluated after the 6-min walk test. Athough diastolic blood pressure and oxygen saturation were not significantly different after walking for 6 min, functional status was significantly related to oxygen saturation. Further study with home care clients is needed to evaluate the relation between activity and oxygen saturation. [ABSTRACT FROM AUTHOR]

This study was conducted as an initial investigation of in vivo folate kinetics in healthy men (n = 4) and made use of a chronic-administration protocol with stable-isotope labeling. Subjects were given 0.453 micromol (200 micrograms) total folic acid in aqueous solution daily throughout the 18-wk study while they consumed self-selected folate-adequate diets. After a 2-wk pretrial period with unlabeled folic acid, subjects were given 0.227 micromol (100 micrograms) pteroyl-L-[2H4]glutamic acid/d ([2H4]folic acid) combined with 0.227 micromol nonlabeled folic acid or [2H2]pteroylhexaglutamic acid/d for the next 8 wk; then for the next 8 wk the [2H4]folic acid was withdrawn and the subjects received only nonlabeled folic acid. Little unmetabolized folic acid was excreted in urine. Isotopic enrichment of urinary folate during [2H4]folic acid administration and withdrawal was consistent with a kinetic model having a rapid turnover pool and a slow turnover pool. In contrast with previous two-pool models, provisions were made for folate turnover by urinary folate excretion (as measured here) and by fecal excretion and catabolic processes. The precision of modeling will be improved in future studies by measurement of enrichment of additional pools. However, this study shows clearly the slow turnover of the whole-body folate pool (

Key research findings relative to the question of whether maternal use of folic acid before and during pregnancy reduces the chance that offspring will be born with a congenital heart defect or an orofacial cleft are reviewed in this paper. Observational studies in general support an association between maternal use of multivitamins containing folic acid and a reduction in the occurrence of congenital heart defects and orofacial clefts. Results from one randomized controlled trial (RCT) provide the strongest evidence that multivitamins prevent congenital heart defects, but this RCT did not provide evidence that multivitamins prevent orofacial clefts. In addition, most observational and interventional studies are not designed to detect an independent effect from folic acid. Early studies suggested that periconceptional multivitamin use was associated with an increased occurrence of both miscarriages and multiple births, which has resulted in a great deal of controversy about the safety of folic acid use during pregnancy. We also review reports that were designed to answer these questions with more definitive data. When more substantial evidence about the effect of periconceptional folic acid on the occurrence of congenital heart defects and orofacial clefts is reported, we will have additional support for promoting folic acid intervention programs. All women capable of becoming pregnant should continue to consume 400 mug/d of folic acid in addition to a healthy diet as advised. Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Background: Differences in rotational range of motion (ROM) compared to humeral retrotorsion (HRT)-corrected rotational ROM exist in healthy baseball athletes, but it is unclear whether these differences exist in a pathological population., Purpose/hypothesis: The purpose of this study was to determine if there are disparities between objectively measured differences in ROM and HRT-corrected deficits in injured baseball players. It was hypothesized that disparities would exist between (1) the side-to-side difference in glenohumeral external rotation (GER) and the HRT-corrected glenohumeral external rotation deficit (GERD) and (2) the side-to-side difference in glenohumeral internal rotation (GIR) and the HRT-corrected glenohumeral internal rotation deficit (GIRD)., Study Design: Cross-sectional study; Level of evidence, 3., Methods: Data from 172 baseball players with shoulder or elbow injuries (45 shoulder, 127 elbow) were reviewed in July 2023. GER and GIR were measured on the injured and noninjured sides of all players, and diagnostic ultrasound was used to measure HRT. Dependent t tests were run to compare the side-to side differences in GER and GIR with the HRT-corrected GERD and GIRD, respectively., Results: In the players with a shoulder injury, there was a significant disparity between the side-to-side difference in GER and the HRT-corrected GERD (2°± 14° vs -13°± 15°, respectively) and between the side-to-side difference in GIR and the HRT-corrected GIRD (-14°± 8° vs 2°± 9°, respectively) ( P < .001 for both). Similarly, players with an elbow injury had significant disparities between the side-to-side difference in GER and the HRT-corrected GERD (6°± 9° vs -10°± 9°, respectively) and between the side-to-side difference in GIR and the HRT-corrected GIRD (-12°± 8° vs 4°± 10°, respectively) ( P < .001 for both)., Conclusion: The results supported our hypothesis that there were disparities between objectively measured differences in GER and GIR compared with the HRT-corrected GERD and GIRD in injured baseball players. Consideration must be given to osseous adaptations that occur at the glenohumeral joint when evaluating and treating this population., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: J.E.C. has received education payments, nonconsulting fees, and royalty or licenses from Arthrex. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2024.)

Objective: To estimate the national and regional population attributable fraction (PAF) and potential number of preventable anemia cases for three nutritional risk factors (iron, red blood cell folate [RBCF], and vitamin B12 deficiencies) among women of childbearing age in Belize., Methods: A national probability-based household and micronutrient survey capturing sociodemographic and health information was conducted among 937 nonpregnant Belizean women aged 15-49 years. Blood samples were collected to determine hemoglobin, ferritin, alpha-1-glycoprotein (AGP), RBCF, and vitamin B12 status. All analyses used sample weights and design variables to reflect a complex sample survey. Logistic regression was used to determine adjusted prevalence risk (aPR) ratios, which were then used to estimate national and regional PAF for anemia., Results: The overall prevalence of anemia (hemoglobin <12 g/dL) was 21.2% (95% CI [18.7, 25.3]). The prevalence of anemia was significantly greater among women with iron deficiency (59.5%, 95% CI [48.7, 69.5]) compared to women without iron deficiency (15.2%, 95% CI [12.2, 18.3]; aPR 3.9, 95% CI [2.9, 5.1]). The three nutritional deficiencies examined contributed to 34.6% (95% CI [22.1, 47.1]) of the anemia cases. If all these nutritional deficiencies could be eliminated, then an estimated 5 953 (95% CI [3 807, 8 114]) anemia cases could be prevented., Conclusions: This study suggests that among women of child-bearing age in Belize, anemia cases might be reduced by a third if three modifiable nutritional risk factors (iron, RBCF, and vitamin B12 deficiencies) could be eliminated. Fortification is one potential strategy to improve nutritional status and reduce the burden of anemia in this population., Competing Interests: Conflict of interest. None declared.

The current exploratory study examines the impact of the rapid acceleration of telehealth during the COVID-19 pandemic from the perspective of healthcare providers. Understanding provider perspectives, particularly in terms of adaptations made during this critical time, is a useful lens into service innovation in times of crisis and can help elucidate successful strategies for continuing the use of telehealth during the postpandemic period. Fourteen providers from 11 different service agencies in a southeastern state were interviewed. Findings identified three themes: (1) dynamic adaptations enacted by healthcare providers at the onset of the pandemic, such as hybrid services, rapid innovations in workflow, collective decision making among providers, and outreach to educate patients; (2) the relaxation of policies by regulators/insurers, focused most often on reimbursement of services; and (3) how patient engagement was impacted via telehealth, including openness to telehealth, more family-level accessibility, and reduced no-show rates. Implications for social workers include heightened professional training on telehealth as well as increasing the critical role that social workers serve in educating providers and patients on telehealth., (© 2024 National Association of Social Workers.)

Baseball athletes across all levels of play are at an increased risk for upper extremity injury due to the supraphysiologic demands on the shoulder and elbow during overhead throwing. Little league baseball players present with a unique subset of injuries that can affect the growth plate, commonly at the shoulder or the elbow. Ascertaining a diagnosis and plan of care for little league shoulder (LLS) historically focuses on the proximal humeral physis in skeletally immature throwing athletes presenting with shoulder pain. However, while not a current standard of care, posterior glenoid dysplasia is often present in youth baseball athletes presenting with LLS, warranting a shift in the way clinicians evaluate for and treat the youth baseball athlete's pathologic shoulder. Therefore, purpose of this narrative review is 2-fold: first, to describe the current standard of care as it relates to a diagnosis of LLS, and second, to critically describe a comprehensive evaluation process for youth throwing athletes with shoulder pain that includes screening for evidence of posterior glenoid dysplasia. This paper summarizes the current state of the available evidence for anatomic considerations of LLS in the baseball athletes throwing shoulder. Additionally, we provide a framework for clinical evaluation using a multidisciplinary approach to evaluate the entire kinetic chain of the youth baseball athlete presenting with LLS and posterior glenoid dysplasia. A case study is presented to describe common presentations, clinical and objective examinations, and a plan of care from time of evaluation to return to throwing., (© 2024 The Author(s).)

Aim: To examine postpartum opioid prescribing practices. Materials & methods: Obstetricians were interviewed about opioids: choice of opioid, clinical factors considered when prescribing, thoughts/beliefs about prescribing, and typical counseling provided. Inductive thematic analyses were used to identify themes. Results: A total of 38 interviews were analyzed. Several key points emerged. The choice of opioid, dosing and number of pills prescribed varied widely. The mode of delivery is the primary consideration for prescribing opioids. All providers would prescribe opioids to breastfeeding women. Some providers offered counseling on nonopioid treatment of pain. Discussion: At two large tertiary centers in Pennsylvania, the 38 physicians interviewed wrote 38 unique opioid prescriptions. Patient counseling addressed short-term pain management, but not the chronic overuse of opioids.

Purpose: The purpose of this study was to develop and provide initial evidence of the validity and reliability of the Rural Practice Awareness and Skills Scale (RPASS)., Methods: A pool of 63 items was reviewed by an expert panel, subjected to 2 additional face validity checks, and reduced to 39 items. The scale was then completed by 333 participants, and an exploratory factor analysis and confirmatory factor analysis were conducted., Findings: Results revealed a 3-factor, 20-item scale with evidence of reliability and convergent validity., Conclusions: RPASS has utility for advancing research to support recruitment and retention of rural health providers and ultimately enhance rural health care delivery., (© 2021 National Rural Health Association.)

Background: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear., Objectives: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study., Methods: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50-79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5'-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined., Results: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (-13.0%; 95% CI: -17.3%, -8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities., Conclusions: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Social workers and other healthcare professionals face increasing pressure to expand access, efficiency, and quality of healthcare to rural patients. Telehealth has become a viable and necessary tool to address gaps in healthcare for rural areas. Unfortunately, little is known about the benefits and challenges of using these services to meet the needs of rural communities. This mixed-methods study examines telehealth implementation among healthcare organizations in a predominantly rural state. Seventeen providers from 11 organizations were interviewed. Most had used live video conferencing, and about a third used mobile technologies, but fewer providers had experience with store-and-forward or remote patient monitoring. Analyses of qualitative data collected via interviews revealed two main themes among benefits of telehealth implementation: (1) increased inter- and intra-agency coordination and (2) savings in time, travel, and efficiency. Three main themes emerged among barriers to telehealth: (1) organizational capacity, (2) patient skills and comfort, and (3) provider knowledge and skills. Recommendations are provided for social workers and other healthcare professionals related to expanding utilization of telehealth services to improve access to healthcare for rural populations., (© 2021 National Association of Social Workers.)

Background: Humeral torsion (HT) has been linked to pitching arm injury risk after controlling for shoulder range of motion. Currently measuring HT uses expensive equipment, which inhibits clinical assessment. Developing an HT predictive model can aid clinical baseball arm injury risk examination. Therefore, the purpose of this study was to develop and internally validate an HT prediction model using standard clinical tests and measures in professional baseball pitchers., Methods: An 11-year (2009-2019) prospective professional baseball cohort was used for this study. Participants were included if they were able to participate in all practices and competitions and were under a Minor League Baseball contract. Preseason shoulder range of motion (external rotation [ER], internal rotation [IR], horizontal adduction [HA]) and HT were collected each season. Player age, arm dominance, arm injury history, and continent of origin were also collected. Examiners were blinded to arm dominance. An a priori power analysis determined that 244 players were needed for accurate prediction models. Missing data was low (<3%); thus, a complete case analysis was performed. Model development followed the transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) recommendations. Regression models with restricted cubic splines were performed. Following primary model development, bootstrapping with 2000 iterations were performed to reduce overfitting and assess optimism shrinkage. Prediction model performance was assessed through root mean square error (RMSE), R 2 , and calibration slope with 95% confidence intervals (CIs). Sensitivity analyses included dominant and nondominant HT., Results: A total of 407 professional pitchers (age: 23.2 [standard deviation 2.4] years, left-handed: 17%; arm history prevalence: 21%) participated. Predictors with the highest influence within the model include IR (0.4, 95% CI 0.3, 0.5; P < .001), ER (-0.3, 95% CI -0.4, -0.2; P < .001), HA (0.3, 95% CI 0.2, 0.4; P < .001), and arm dominance (right-handed: -1.9, 95% CI -3.6, -0.1; P = .034). Final model RMSE was 12, R 2 was 0.41, and calibration was 1.00 (95% CI 0.94, 1.06). Sensitivity analyses demonstrated similar model performance., Conclusions: Every 3° of IR explained 1° of HT. Every 3° of ER explained 1° less of HT, and every 7° of HA explained 1° of HT. Right-handers had 2° less HT. Models demonstrated good predictive performance. This predictive model can be used by clinicians to infer HT using standard clinical test and measures. These data can be used to enhance professional baseball arm injury examination., (Copyright © 2021 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background: Ulnar collateral ligament (UCL) reconstruction (UCLR) of the elbow has received much attention given the rise in incidence among baseball pitchers. Stress ultrasonography has been demonstrated to be a critical evaluation tool of the UCL. No study has dynamically evaluated the ability of UCLR to restore normal kinematics., Purpose/hypothesis: The purpose of this study was to compare ulnohumeral gapping during a moving valgus stress test as well as UCL thickness between professional pitchers with and without UCLR. We hypothesized that the ulnohumeral joint will display greater gapping and the UCL graft will be thicker in pitchers after UCLR compared with uninjured pitchers., Study Design: Cross-sectional study; Level of evidence, 3., Methods: Ultrasonography was used to measure the medial ulnohumeral joint distance and the UCL thickness of 70 asymptomatic professional baseball pitchers; 6 of the participants had a history of UCLR. Images were captured of the dominant (D) and nondominant (ND) elbows at the maximal cocking position under 2 loaded conditions within the moving valgus stress test arc: (1) gravity stress and (2) 2.5 kg (5.5 lb) of valgus force using a dynamometer. Intra- and interrater reliability of the measurements was established with intraclass correlation coefficients (ICCs). Separate mixed-model analyses of variance (D side × UCL) were used to compare the D and ND elbow variables between pitchers with and without a history of UCLR., Results: All measurements displayed good reliability according to ICCs. Pitchers with a history of UCLR demonstrated less gapping (5.6 ± 2.9 vs 4.2 ± 1.2 mm; P = .002) and greater UCL graft thickness (0.17 ± 0.07 vs 0.11 ± 0.08 mm; P = .03) compared with the native ligament in pitchers without prior UCL injury., Conclusion: Our data demonstrated that the UCLR results in a thicker, stiffer construct with less medial elbow gapping than the anatomical UCL. Using ultrasound to evaluate the UCL was a reliable, efficient, and clinically feasible method to assess UCL thickness and joint gapping in players with a history of UCLR. Future studies may consider this approach to evaluate surgical techniques and graft types for UCLR., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: M.J.K. has received educational support from Arthrex and Peerless Surgical, consulting fees from Arthrex, speaking fees from Arthrex, and hospitality payments from Exactech. C.A.T. has received research support from Arthrex and Neurotech-Kneehab, consulting fees from Breg, speaking fees from Arthrex, and stock/stock options in Players Health and Trex. D.J.G. has received educational support from Arthrex and hospitality payments from Encore Medical, Mid-Atlantic Surgical, Smith & Nephew, and Stryker. M.L.S. has received educational support from Arthrex. D.J.W. has received research support from Zimmer Biomet; educational support from Peerless Surgical; consulting fees from Arthrex, Ceterix, and Zimmer Biomet; and speaking fees from Arthrex. R.J.H. has received grant support from Encore Medical, educational support from Arthrex, consulting fees from Arthrex and Pacira Pharmaceuticals, speaking fees from Arthrex, and royalties from Encore Medical. T.J.N. has received educational support from Gemini Mountain and consulting fees from Stryker. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2021.)

Background: Choline plays an integral role in one-carbon metabolism in the body, but it is unclear whether genetic polymorphisms are associated with variations in plasma choline and its metabolites., Objectives: This study aimed to evaluate the association of genetic variants in choline and one-carbon metabolism with plasma choline and its metabolites., Methods: We analyzed data from 1423 postmenopausal women in a case-control study nested within the Women's Health Initiative Observational Study. Plasma concentrations of choline, betaine, dimethylglycine (DMG), and trimethylamine N-oxide were determined in 12-h fasting blood samples collected at baseline (1993-1998). Candidate and tagging single-nucleotide polymorphisms (SNPs) were genotyped in betaine-homocysteine S-methyltransferase (BHMT), BHMT2, 5,10-methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (NADP+ dependent 1) (MTHFD1), 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), and 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR). Linear regression was used to derive percentage difference in plasma concentrations per variant allele, adjusting for confounders, including B-vitamin biomarkers. Potential effect modification by plasma vitamin B-12, vitamin B-6, and folate concentrations and folic-acid fortification periods was examined., Results: The candidate SNP BHMT R239Q (rs3733890) was associated with lower concentrations of plasma betaine and DMG concentrations (-4.00% and -6.75% per variant allele, respectively; both nominal P < 0.05). Another candidate SNP, BHMT2 rs626105 A>G, was associated with higher plasma DMG concentration (13.0%; P < 0.0001). Several tagSNPs in these 2 genes were associated with plasma concentrations after correction for multiple comparisons. Vitamin B-12 status was a significant effect modifier of the association between the genetic variant BHMT2 rs626105 A>G and plasma DMG concentration., Conclusions: Genetic variations in metabolic enzymes were associated with plasma concentrations of choline and its metabolites. Our findings contribute to the knowledge on the variation in blood nutrient concentrations in postmenopausal women., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Axon guidance requires interactions between extracellular signaling molecules and transmembrane receptors, but how appropriate context-dependent decisions are coordinated outside the cell remains unclear. Here we show that the transmembrane glycoprotein Dystroglycan interacts with a changing set of environmental cues that regulate the trajectories of extending axons throughout the mammalian brain and spinal cord. Dystroglycan operates primarily as an extracellular scaffold during axon guidance, as it functions non-cell autonomously and does not require signaling through its intracellular domain. We identify the transmembrane receptor Celsr3/Adgrc3 as a binding partner for Dystroglycan, and show that this interaction is critical for specific axon guidance events in vivo. These findings establish Dystroglycan as a multifunctional scaffold that coordinates extracellular matrix proteins, secreted cues, and transmembrane receptors to regulate axon guidance., Competing Interests: LL, NP, CG, KW No competing interests declared, FT Reviewing editor, eLife, (© 2019, Lindenmaier et al.)

One-carbon metabolism is essential for multiple cellular processes and can be assessed by the concentration of folate metabolites in the blood. One-carbon metabolites serve as methyl donors that are required for epigenetic regulation. Deficiencies in these metabolites are associated with a variety of poor health outcomes, including adverse pregnancy complications. DNA methylation is known to vary with one-carbon metabolite concentration, and therefore may modulate the risk of adverse pregnancy outcomes. This study addresses changes in one-carbon indices over pregnancy and the relationship between maternal and child DNA methylation and metabolite concentrations by leveraging data from 24 mother-infant dyads. Five of the 13 metabolites measured from maternal blood and methylation levels of 993 CpG sites changed over the course of pregnancy. In dyads, maternal and fetal one-carbon concentrations were highly correlated, both early in pregnancy and at delivery. The 993 CpG sites whose methylation levels changed over pregnancy in maternal blood were also investigated for associations with metabolite concentrations in infant blood at delivery, where five CpG sites were associated with the concentration of at least one metabolite. Identification of CpG sites that change over pregnancy may result in better characterization of genes and pathways involved in maintaining a healthy, term pregnancy.

Inadequate folate status in women of reproductive age (WRA) can lead to adverse health consequences of public health significance, such as megaloblastic anemia (folate deficiency) and an increased risk of neural tube defect (NTD)-affected pregnancies (folate insufficiency). Our review aims to evaluate current data on folate status of WRA. We queried eight databases and the World Health Organization Micronutrients Database, identifying 45 relevant surveys conducted between 2000 and 2014 in 39 countries. Several types of folate assays were used in the analysis of blood folate, and many surveys used folate cutoffs not matched to the assay. To allow better comparisons across surveys, we attempted to account for these differences. The prevalence of folate deficiency was >20% in many countries with lower income economies but was typically <5% in countries with higher income economies. Only 11 surveys reported the prevalence of folate insufficiency, which was >40% in most countries. Overall, folate status data for WRA globally are limited and must be carefully interpreted due to methodological issues. Future surveys would benefit from using the microbiologic assay to assess folate status, along with assay-matched cutoffs to improve monitoring and evaluation of folic acid interventions, thus informing global efforts to prevent NTDs., (© 2018 The Authors. Annals of the New York Academy of Sciences. The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication.)

Background: Ulnar collateral ligament (UCL) injury of the elbow is a common and debilitating problem seen frequently among elite baseball pitchers. Ultrasound is a useful diagnostic tool in evaluating UCL injuries., Hypothesis: Evaluation with stress ultrasound of the elbow to measure the morphology of the UCL and the ulnohumeral joint space gapping is indicative of higher risk of UCL injury among professional baseball pitchers., Study Design: Cohort study; Level of evidence, 2., Methods: Ultrasound imaging was used to assess the medial joint laxity of the elbow of 70 asymptomatic professional baseball pitchers during spring training. Medial joint laxity and UCL morphology were assessed with OsiriX imaging software under 2 conditions-gravity valgus load and 5.5 lb of valgus load per a handheld dynamometer-with the shoulder in the maximal cocking position and the elbow in 90° of flexion. Two trials of resting position, elbow gapping, and UCL thickness were collected, measured, and averaged for data analysis. Intra- and interrater reliabilities were established and maintained, with intraclass correlation coefficients in the acceptable range for all measures (0.84-0.99). One-way analysis of variance was used to compare dominant variables between those pitchers who sustained a subsequent UCL injury and those who did not. A receiver operating curve was used to identify pitchers who, based on elbow gapping measures (by cut score), were at high risk versus low risk for UCL injury., Results: Players who went on to injure the UCL (n = 7) displayed a significantly wider opening under 5.5 lb of applied stress (6.5 ± 1.2 vs 5.3 ± 1.2 mm, P = .01) when compared with pitchers without UCL injury history (n = 63); they also presented a trend toward wider dominant arm resting joint opening (4.9 ± 1.2 vs 4.0 ± 1.1 mm, P = .07). Professional pitchers with valgus stress ulnohumeral joint gapping ≥5.6 mm (area underneath the curve, 0.77; P = .02) of the dominant arm were at a 6-times greater risk of sustaining a UCL tear requiring reconstruction within a season., Conclusion: Our data suggest that ultrasound evaluation of UCL morphology may be indicative of pitchers who are at risk of sustaining UCL injury and that it may improve player assessment., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: M.S. has received hospitality payments from DePuy Synthes. B.K.M. has received a grant from DePuy Orthopaedics and hospitality payments from DePuy Synthes and Stryker. J.M.T. is a consultant for Arthrex, DePuy Mitek, and Zimmer; has received hospitality payments from Peerless Surgical, DePuy, Arthrex, and Zimmer; has received educational support from Peerless Surgical; is a paid speaker/presenter for Arthrex and Mitek; and receives royalties from Arthrex. M.J.K. is a consultant for Arthrex; has received educational support from Arthrex; has received hospitality payments from Arthrex, Peerless Surgical, and Pacira Pharmaceuticals; and is a paid speaker/presenter for Pacira Pharmaceuticals and Arthrex. T.J.N. is a consultant for Stryker and Histogenics, has received hospitality payments from Stryker, and has received research support from Histogenics.

Objective: Lifestyle factors associated with obesity may alter epigenome-regulated gene expression. Most studies examining epigenetic changes in obesity have analyzed DNA 5´-methylcytosine (5mC) in whole blood, representing a weighted average of several distantly related and regulated leukocyte classes. To examine leukocyte-specific differences associated with obesity, a pilot study examining 5mC in three distinct leukocyte types isolated from peripheral blood of women with normal weight and obesity was conducted., Methods: CD4 + T cells, CD8 + T cells, and CD16 + neutrophils were reiteratively isolated from blood, and 5mC levels were measured across >450,000 CG sites., Results: Nineteen CG sites were differentially methylated between women with obesity and with normal weight in CD4 + cells, 16 CG sites in CD8 + cells, and 0 CG sites in CD16 + neutrophils (q < 0.05). There were no common differentially methylated sites between the T-cell types. The amount of visceral adipose tissue was strongly associated with the methylation level of 79 CG sites in CD4 + cells, including 4 CG sites in CLSTN1's promoter, which, this study shows, may regulate its expression., Conclusions: The methylomes of various leukocytes respond differently to obesity and levels of visceral adipose tissue. Highly significant differentially methylated sites in CD4 + and CD8 + cells in women with obesity that have apparent biological relevance to obesity were identified., (© 2018 The Obesity Society.)

Reliable folate status data for women of reproductive age (WRA) to assess global risk for neural tube defects (NTDs) are needed. We focus on a recent recommendation by the World Health Organization that a specific "optimal" red blood cell (RBC) folate concentration be used as the sole indicator of NTD risk within a population and discuss how to best apply this guidance to reach the goal of assessing NTD risk globally. We also emphasize the importance of using the microbiologic assay (MBA) as the most reliable assay for obtaining comparable results for RBC folate concentration across time and countries, the need for harmonization of the MBA through use of consistent key reagents and procedures within laboratories, and the requirement to apply assay-matched cutoffs for folate deficiency and insufficiency. To estimate NTD risk globally, the ideal scenario would be to have country-specific population-based surveys of RBC folate in WRA determined utilizing a harmonized MBA, as was done in recent studies in Guatemala and Belize. We conclude with guidance on next steps to best navigate the road map toward the goal of generating reliable folate status data on which to assess NTD risk in WRA in low- and middle-income countries., (© 2017 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.)

In this paper we review the evidence basis for prevention of folic acid-sensitive neural tube defects (NTDs) through public health interventions in women of reproductive age (WRA), the proven vehicles for delivery of folic acid, and what is needed to effectively scale these, and provide a snapshot of potential innovations that require future research. Our primary focus is on the global situation affecting large-scale food fortification (LSFF) with folic acid, in particular the fortification of wheat flour and maize meal. Our overarching conclusion is that folic acid fortification is an evidence-based intervention that reduces the prevalence of NTDs, and that LSFF with folic acid is underutilized. Thus, food fortification with folic acid should be a component of most national public health strategies, in particular where folate status is insufficient and a fortifiable food vehicle, processed by a centralized industry, is consumed regularly by WRA. The evidence shows that there is still much work needed (1) to build the enabling environment and expand programs where there is currently no legislation, (2) to improve the low quality of delivery of existing programs, and (3) to measure and sustain programs by generating new coverage data and demonstrating evidence of impact in low- and middle-income countries., (© 2018 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.)

Background/objectives: Obesity and maternal folate deficiency are associated with increased risk for neural tube defects (NTDs). Limited knowledge exists on the impact of folate status or obesity on DNA methylation of genes related to NTD risk and folate metabolism., Subjects/methods: Women (18-35y) with normal weight (NW; BMI 18.5-24.9kg/m 2 ; n=12) and obesity (OB; BMI >30kg/m 2 ; n=6) were provided FA (800μg/d) for 8-weeks. Serum folate concentration and changes in DNA methylation across 2098 CpG sites in 91 genes related to NTD risk and folate metabolism were examined., Results: Serum folate concentration increased in both groups following FA supplementation, but OB maintained a relative lower concentration (NW; 38.36±2.50-71.41±3.02nmol/L and OB; 27.12±3.09-56.85±3.90nmol/L). Methylation of 56 and 99 CpG sites changed in response to supplementation in NW and OB, respectively, and majority of these sites decreased in methylation in both groups. Only 4 CpG sites responded to supplementation in both groups. Gene ontology analysis revealed a response to supplementation in 61 biological processes (BPs) from the selected genes. Five of the 61 BPs were identified only in NW, including neural tube closure, while 13 of the 61 BPs were enriched only in OB, including folate metabolism, vitamin B12 metabolism and methylation related processes., Conclusions: Changes in DNA methylation in genes related to NTD risk and folate metabolism in response to FA supplementation were different in NW and OB. Increased NTD risk and abnormal folate metabolism in obesity may be due to a distinctive epigenetic response to folate status in these genes., (Published by Elsevier Ltd.)

Folate, a water-soluble vitamin, is a key source of one-carbon groups for DNA methylation, but studies of the DNA methylation response to supplemental folic acid yield inconsistent results. These studies are commonly conducted using whole blood, which contains a mixed population of white blood cells that have been shown to confound results. The objective of this study was to determine if CD16+ neutrophils may provide more specific data than whole blood for identifying DNA methylation response to chronic folic acid supplementation. The study was performed in normal weight (BMI 18.5 - 24.9 kg/m2) women (18 - 35 y; n = 12), with blood samples taken before and after 8 weeks of folic acid supplementation at 800 μg/day. DNA methylation patterns from whole blood and isolated CD16+ neutrophils were measured across >485,000 CpG sites throughout the genome using the Infinium HumanMethylation450 BeadChip. Over the course of the 8-week supplementation, 6746 and 7513 CpG sites changed (p < 0.05) in whole blood and CD16+ neutrophils, respectively. DNA methylation decreased in 68.4% (whole blood) and 71.8% (CD16+ neutrophils) of these sites. There were only 182 CpG sites that changed in both the whole blood and CD16+ neutrophils, 139 of which changed in the same direction. These results suggest that the genome-wide DNA methylation response to chronic folic acid supplementation is different between whole blood and CD16+ neutrophils and that a single white blood cell type may function as a more specific epigenetic reporter of folate status than whole blood.

Background: Folate deficiency, vitamin B-12 deficiency, and anemia can have adverse effects on birth outcomes. Also, low vitamin B-12 reduces the formation of metabolically active folate. Objectives: We sought to establish the baseline prevalence of and factors associated with folate deficiency and insufficiency, vitamin B-12 deficiency, and anemia among women of childbearing age (WCBA) in Belize. Methods: In 2011, a national probability-based survey was completed among Belizean nonpregnant WCBA aged 15-49 y. Blood samples for determination of hemoglobin, folate (RBC and serum), and vitamin B-12 (plasma) and sociodemographic and health information were collected from 937 women. RBC and serum folate concentrations were measured by microbiologic assay (MBA). Folate status was defined based on both the WHO-recommended radioproteinbinding assay and the assay adjusted for the MBA. Results: The national prevalence estimates for folate deficiency in WCBA, based on serum and RBC folate concentrations by using the assay-matched cutoffs, were 11.0% (95% CI: 8.6%, 14.0%) and 35.1% (95% CI: 31.3%, 39.2%), respectively. By using the assay-matched compared with the WHO-recommended cutoffs, a substantially higher prevalence of folate deficiency was observed based on serum (6.9% absolute difference) and RBC folate (28.9% absolute difference) concentrations. The prevalence for RBC folate insufficiency was 48.9% (95% CI: 44.8%, 53.1%). Prevalence estimates for vitamin B-12 deficiency and marginal deficiency and anemia were 17.2% (95% CI: 14.2%, 20.6%), 33.2% (95% CI: 29.6%, 37.1%), and 22.7% (95% CI: 19.5%, 26.2%), respectively. The adjusted geometric means of the RBC folate concentration increased significantly ( P -trend < 0.001) in WCBA who had normal vitamin B-12 status relative to WCBA who were vitamin B-12 deficient. Conclusions: In Belize, the prevalence of folate and vitamin B-12 deficiencies continues to be a public health concern among WCBA. Furthermore, low folate status co-occurred with low vitamin B-12 status, underlining the importance of providing adequate vitamin B-12 and folic acid intake through approaches such as mandatory food fortification., Competing Interests: 2: Author disclosures: J Rosenthal, N Largaespada, LB Bailey, M Cannon, CJ Alverson, D Ortiz, GPA Kauwell, J Sniezek, R Figueroa, R Daly, and P Allen, no conflicts of interest., (© 2017 American Society for Nutrition.)