Development of an improved standard reference material for folate vitamers in human serum.

The US National Institute of Standards and Technology (NIST) developed a Standard Reference Material® (SRM®) 3949 Folate Vitamers in Frozen Human Serum to replace SRM 1955 Homocysteine and Folate in Human Serum. The presence of increased endogenous levels of folic acid and 5-methyltetrahydrofolate (5mTHF) in SRM 3949, enhanced folate stability via addition of ascorbic acid, and inclusion of values for additional minor folates are improvements over SRM 1955 that should better serve the clinical folate measurement community. The new SRM contains folates at three levels. To produce SRM 3949, pilot sera were collected from 15 individual donors, 5 of whom were given a 400-µg folic acid supplement 1 h prior to blood draw to increase serum levels of 5mTHF and folic acid for the high-level material. To stabilize the folates, 0.5% (mass concentration) ascorbic acid was added as soon as possible after preparation of serum. These pilot sera were screened for five folates plus the pyrazino-s-triazine derivative of 4-α-hydroxy-5-methyltetrahydrofolate (MeFox) at the US Centers for Disease Control and Prevention (CDC) by isotope dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS). Based on these results, a blending protocol was specified to obtain the three desired folate concentrations for SRM 3949. ID-LC-MS/MS analysis at the CDC and NIST was utilized to assign values for folic acid and 5mTHF, as well as several minor folates.

Development of a pregnancy-specific reference material for thyroid biomarkers, vitamin D, and nutritional trace elements in serum.

OBJECTIVES: Matrix differences among serum samples from non-pregnant and pregnant patients could bias measurements. Standard Reference Material 1949, Frozen Human Prenatal Serum, was developed to provide a quality assurance material for the measurement of hormones and nutritional elements throughout pregnancy. METHODS: Serum from non-pregnant women and women in each trimester were bottled into four levels based on pregnancy status and trimester. Liquid chromatography tandem mass spectrometry (LC-MS/MS) methods were developed and applied to the measurement of thyroid hormones, vitamin D metabolites, and vitamin D-binding protein (VDBP). Copper, selenium, and zinc measurements were conducted by inductively coupled plasma dynamic reaction cell MS. Thyroid stimulating hormone (TSH), thyroglobulin (Tg), and thyroglobulin antibody concentrations were analyzed using immunoassays and LC-MS/MS (Tg only). RESULTS: Certified values for thyroxine and triiodothyronine, reference values for vitamin D metabolites, VDBP, selenium, copper, and zinc, and information values for reverse triiodothyronine, TSH, Tg, and Tg antibodies were assigned. Significant differences in serum concentrations were evident for all analytes across the four levels (p≤0.003). TSH measurements were significantly different (p<0.0001) among research-only immunoassays. Tg concentrations were elevated in research-only immunoassays vs. Federal Drug Administration-approved automated immunoassay and LC-MS/MS. Presence of Tg antibodies increased differences between automated immunoassay and LC-MS/MS. CONCLUSIONS: The analyte concentrations' changes consistent with the literature and the demonstration of matrix interferences in immunoassay Tg measurements indicate the functionality of this material by providing a relevant matrix-matched reference material for the different stages of pregnancy.

The timing and aggressiveness of early government response to COVID-19: Political systems, societal culture, and more.

Factors that drove the early timing and strictness of government responses to COVID-19 for over 150 countries are examined using the daily Coronavirus Government Response Tracker data provided by the University of Oxford. Results show that authoritarian regimes tended to have an initial policy response somewhat weaker relative to democratic regimes at the early stages of the pandemic but pursed more aggressive containment policies over the latter part of the six-month period analyzed. Unitary regimes tended to have stronger policy measures in place early on relative to federalist states but relaxed these restrictions sooner. Countries with greater freedom (political rights and civil liberties) and those that spend less on public health also exhibited slower early policy responses, but caught up within three to four months after the pandemic reached their country. There is no evidence that women leaders, viewed as a whole, put in place more aggressive polices to combat the virus relative to their male counterparts. Nor is there any evidence that either island nations or countries that experienced the start of the pandemic later in the global wave pursued different policies that other nations. Policy implications are discussed as the how nations should prepare for future pandemics.

COVID-19 vaccine rollout-scale and speed carry different implications for corruption.

The sanctioning of different coronavirus vaccines (with some approved by regulators for public delivery, and others in the pipeline) has met with relief by many sections of the public and the government. However, partly due to the damages associated with the pandemic and the ensuing euphoria over vaccines' arrival, some of the challenges are mostly being ignored or are not recognized. This paper identifies some pitfalls and drawbacks in vaccine delivery. We argue that the somewhat unique tension between the speed of vaccine delivery and its scale can create opportunities for corrupt behavior that are often at odds with effective means to check abuse. While data on instances of abuse will emerge over time, it is useful to point out different avenues of abuse so that some preventive government actions can be undertaken. Specifically, we argue that the potential for out of turn delivery of vaccines and the stockpiling by unauthorized agents creates incentives for corruption, with the public or bureaucrats initiating corrupt transactions. An understanding of the potential avenues for corruption should guide the formulation of appropriate corruption-control policies and similar challenges that will be faced by policy makers in addressing future pandemics.

Accuracy of reporting of Aboriginality on administrative health data collections using linked data in NSW, Australia.

BACKGROUND: Aboriginal people are under-reported on administrative health data in Australia. Various approaches have been used or proposed to improve reporting of Aboriginal people using linked records. This cross-sectional study used self-reported Aboriginality from the NSW Patient Survey Program (PSP) as a reference standard to assess the accuracy of reporting of Aboriginal people on NSW Admitted Patient (APDC) and Emergency Department Data Collections (EDDC), and compare the accuracy of selected approaches to enhance reporting Aboriginality using linked data. METHODS: Ten PSP surveys were linked to five administrative health data collections, including APDC, EDDC, perinatal, and birth and death registration records. Accuracy of reporting of Aboriginality was assessed using sensitivity, specificity, and positive and negative predictive values (PPVs and NPVs) and F score for the EDDC and APDC as baseline and four enhancement approaches using linked records: "Most recent linked record", "Ever reported as Aboriginal", and two approaches using a weight of evidence, "Enhanced Reporting of Aboriginality (ERA) algorithm" and "Multi-stage median (MSM)". RESULTS: There was substantial under-reporting of Aboriginality on APDC and EDDC records (sensitivities 84 and 77% respectively) with PPVs of 95% on both data collections. Overall, specificities and NPVs were above 98%. Of people who were reported as Aboriginal on the PSP, 16% were not reported as Aboriginal on any of their linked records. Record linkage approaches generally increased sensitivity, accompanied by decrease in PPV with little change in overall F score for the APDC and an increase in F score for the EDDC. The "ERA algorithm" and "MSM" approaches provided the best overall accuracy. CONCLUSIONS: Weight of evidence approaches are preferred when record linkage is used to improve reporting of Aboriginality on administrative health data collections. However, as a substantial number of Aboriginal people are not reported as Aboriginal on any of their linked records, improvements in reporting are incomplete and should be taken into account when interpreting results of any analyses. Enhancement of reporting of Aboriginality using record linkage should not replace efforts to improve recording of Aboriginal people at the point of data collection and addressing barriers to self-identification for Aboriginal people.

Cardiac procedures in ST-segment-elevation myocardial infarction - the influence of age, geography and Aboriginality.

BACKGROUND: Timely restoration of bloodflow acute ST-segment elevation myocardial infarction (STEMI) reduces myocardial damage and improves prognosis. The objective of this study was describe the association of demographic factors with hospitalisation rates for STEMI and time to angiography, Percutaneous Coronary Intervention (PCI) and Coronary Artery Bypass Graft (CABG) in New South Wales (NSW) and the Australian Capital Territory (ACT), Australia. METHODS: This was an observational cohort study using linked population health data. We used linked records of NSW and the ACT hospitalisations and the Australian Government Medicare Benefits Schedule (MBS) for persons aged 35 and over hospitalised with STEMI in the period 1 July 2010 to 30 June 2014. Survival analysis was used to determine the time between STEMI admission and angiography, PCI and CABG, with a competing risk of death without cardiac procedure. RESULTS: Of 13,117 STEMI hospitalisations, 71% were among males; 55% were 65-plus years; 64% lived in major cities, and 2.6% were Aboriginal people. STEMI hospitalisation occurred at a younger age in males than females. Angiography and PCI rates decreased with age: angiography 69% vs 42% and PCI 60% vs 34% on day 0 for ages 35-44 and 75-plus respectively. Lower angiography and PCI rates and higher CABG rates were observed outside major cities. Aboriginal people with STEMI were younger and more likely to live outside a major city. Angiography, PCI and CABG rates were similar for Aboriginal and non-Aboriginal people of the same age and remoteness area. CONCLUSIONS: There is a need to improve access to definitive revascularisation for STEMI among appropriately selected older patients and in regional areas. Aboriginal people with STEMI, as a population, are disproportionately affected by access to definitive revascularisation outside major cities. Improving access to timely definitive revascularisation in regional areas may assist in closing the gap in cardiovascular outcomes between Aboriginal and non-Aboriginal people.

The role of the CCQM OAWG in providing SI traceable calibrators for organic chemical measurements.

Metrological traceability for organic chemical measurements is a documented unbroken chain of calibrations with stated uncertainties that ideally link the measurement result for a sample to a primary calibrator in appropriate SI units (e.g., mass fraction). A comprehensive chemical purity determination of the organic calibrator is required to ensure a true assessment of this result. We explore the evolution of chemical purity capabilities across metrology institute members of the Consultative Committee for Amount of Substance: Metrology in Chemistry and Biology's Organic Analysis Working Group (OAWG). The OAWG work program has promoted the development of robust measurement capabilities, using indirect "mass balance" determinations via rigorous assessment of impurities and direct determination using quantitative nuclear magnetic resonance spectroscopy methods. A combination of mass balance and qNMR has been shown to provide a best practice approach. Awareness of the importance of the traceability of organic calibrators continues to grow across stakeholder groups, particularly in key areas such as clinical chemistry where activities related to the Joint Committee for Traceability in Laboratory Medicine have raised the profile of traceable calibrators.

Liquid chromatography with absorbance detection and with isotope-dilution mass spectrometry for determination of isoflavones in soy standard reference materials.

Two independent analytical approaches, based on liquid chromatography with absorbance detection and liquid chromatography with mass spectrometric detection, have been developed for determination of isoflavones in soy materials. These two methods yield comparable results for a variety of soy-based foods and dietary supplements. Four Standard Reference Materials (SRMs) have been produced by the National Institute of Standards and Technology to assist the food and dietary supplement community in method validation and have been assigned values for isoflavone content using both methods. These SRMs include SRM 3234 Soy Flour, SRM 3236 Soy Protein Isolate, SRM 3237 Soy Protein Concentrate, and SRM 3238 Soy-Containing Solid Oral Dosage Form. A fifth material, SRM 3235 Soy Milk, was evaluated using the methods and found to be inhomogeneous for isoflavones and unsuitable for value assignment. Graphical Abstract Separation of six isoflavone aglycones and glycosides found in Standard Reference Material (SRM) 3236 Soy Protein Isolate.

Rigorous evaluation of chemical measurement uncertainty: Liquid chromatographic analysis methods using detector response factor calibration.

Chemical measurement methods are designed to promote accurate knowledge of a measurand or system. As such, these methods often allow elicitation of latent sources of variability and correlation in experimental data. They typically implement measurement equations that support quantification of effects associated with calibration standards and other known or observed parametric variables. Additionally, multiple samples and calibrants are usually analyzed to assess accuracy of the measurement procedure and repeatability by the analyst. Thus, a realistic assessment of uncertainty for most chemical measurement methods is not purely bottom-up (based on the measurement equation) or top-down (based on the experimental design), but inherently contains elements of both. Confidence in results must be rigorously evaluated for the sources of variability in all of the bottom-up and top-down elements. This type of analysis presents unique challenges due to various statistical correlations among the outputs of measurement equations. One approach is to use a Bayesian hierarchical (BH) model which is intrinsically rigorous, thus making it a straightforward method for use with complex experimental designs, particularly when correlations among data are numerous and difficult to elucidate or explicitly quantify. In simpler cases, careful analysis using GUM Supplement 1 (MC) methods augmented with random effects meta analysis yields similar results to a full BH model analysis. In this article we describe both approaches to rigorous uncertainty evaluation using as examples measurements of 25-hydroxyvitamin D3 in solution reference materials via liquid chromatography with UV absorbance detection (LC-UV) and liquid chromatography mass spectrometric detection using isotope dilution (LC-IDMS).

Chemical purity using quantitative 1H-nuclear magnetic resonance: a hierarchical Bayesian approach for traceable calibrations.

Chemical purity assessment using quantitative 1H-nuclear magnetic resonance spectroscopy is a method based on ratio references of mass and signal intensity of the analyte species to that of chemical standards of known purity. As such, it is an example of a calculation using a known measurement equation with multiple inputs. Though multiple samples are often analyzed during purity evaluations in order to assess measurement repeatability, the uncertainty evaluation must also account for contributions from inputs to the measurement equation. Furthermore, there may be other uncertainty components inherent in the experimental design, such as independent implementation of multiple calibration standards. As such, the uncertainty evaluation is not purely bottom up (based on the measurement equation) or top down (based on the experimental design), but inherently contains elements of both. This hybrid form of uncertainty analysis is readily implemented with Bayesian statistical analysis. In this article we describe this type of analysis in detail and illustrate it using data from an evaluation of chemical purity and its uncertainty for a folic acid material.

Candidate Reference Measurement Procedure for the Determination of (24R),25-Dihydroxyvitamin D3 in Human Serum Using Isotope-Dilution Liquid Chromatography-Tandem Mass Spectrometry.

The two major forms of vitamin D, vitamin D3 and vitamin D2, are metabolized in the liver through hydroxylation to 25-hydroxyvitamin D species, and then further hydroxylated in the kidney to various dihydroxyvitamin D species. (24R),25-Dihydroxyvitamin D3 ((24R),25(OH)2D3) is a major catabolite of 25-hydroxyvitamin D metabolism and is an important vitamin D metabolite used as a catabolism marker and indicator of kidney disease. The National Institute of Standards and Technology has recently developed a reference measurement procedure for the determination of (24R),25(OH)2D3 in human serum using isotope-dilution LC-MS/MS. The (24R),25(OH)2D3 and added deuterated labeled internal standard (24R),25(OH)2D3-d6 were extracted from serum matrix using liquid-liquid extraction prior to LC-MS/MS analysis. Chromatographic separation was performed using a fused-core C18 column. Atmospheric pressure chemical ionization in the positive ion mode and multiple reaction monitoring were used for LC-MS/MS. The accuracy of the measurement of (24R),25(OH)2D3 was evaluated by recovery studies of measuring (24R),25(OH)2D3 in gravimetrically prepared spiked samples of human serum with known (24R),25(OH)2D3 levels. The recoveries of the added (24R),25(OH)2D3 averaged 99.0% (0.8% SD), and the extraction efficiencies averaged 95% (2% SD). Excellent repeatability was demonstrated with CVs of ∼1%. The limit of quantitation at a signal-to-noise ratio of ∼10 was 0.2 ng/g. Potential isomeric interferences from other endogenous species and from impurity components of the reference standard were investigated. LC baseline resolution of (24R),25(OH)2D3 from these isomers was achieved within 35 min. This method was used for value assignment of (24R),25(OH)2D3 in Standard Reference Materials of Vitamin D Metabolites in Human Serum, which can serve as an accuracy base for routine methods used in clinical laboratories.

Metrological approaches to organic chemical purity: primary reference materials for vitamin D metabolites.

Given the critical role of pure, organic compound primary reference standards used to characterize and certify chemical Certified Reference Materials (CRMs), it is essential that associated mass purity assessments be fit-for-purpose, represented by an appropriate uncertainty interval, and metrologically sound. The mass fraction purities (% g/g) of 25-hydroxyvitamin D (25(OH)D) reference standards used to produce and certify values for clinical vitamin D metabolite CRMs were investigated by multiple orthogonal quantitative measurement techniques. Quantitative (1)H-nuclear magnetic resonance spectroscopy (qNMR) was performed to establish traceability of these materials to the International System of Units (SI) and to directly assess the principal analyte species. The 25(OH)D standards contained volatile and water impurities, as well as structurally-related impurities that are difficult to observe by chromatographic methods or to distinguish from the principal 25(OH)D species by one-dimensional NMR. These impurities have the potential to introduce significant biases to purity investigations in which a limited number of measurands are quantified. Combining complementary information from multiple analytical methods, using both direct and indirect measurement techniques, enabled mitigation of these biases. Purities of 25(OH)D reference standards and associated uncertainties were determined using frequentist and Bayesian statistical models to combine data acquired via qNMR, liquid chromatography with UV absorbance and atmospheric pressure-chemical ionization mass spectrometric detection (LC-UV, LC-ACPI-MS), thermogravimetric analysis (TGA), and Karl Fischer (KF) titration.

The impact of cross-jurisdictional patient flows on ascertainment of hospitalisations and cardiac procedures for ST-segment-elevation myocardial infarction in an Australian population.

Introduction: The patient journey for residents of New South Wales (NSW) Australia with ST-elevation myocardial infarction (STEMI) often involves transfer between hospitals and these can include stays in hospitals in other jurisdictions. Objective: To estimate the change in enumeration of STEMI hospitalisations and time to subsequent cardiac procedures for NSW residents using cross-jurisdictional linkage of administrative health data. Methods: Records for NSW residents aged 20 years and over admitted to hospitals in NSW and four adjacent jurisdictions (Australian Capital Territory, Queensland, South Australia, and Victoria) between 1 July 2013 and 30 June 2018 with a principal diagnosis of STEMI were linked with records of the Australian Government Medicare Benefits Schedule (MBS). The number of STEMI hospitalisations, and rates of angiography, percutaneous coronary intervention and coronary artery bypass graft were compared for residents of different local health districts within NSW with and without inclusion of cross-jurisdictional data. Results: Inclusion of cross-jurisdictional hospital and MBS data increased the enumeration of STEMI hospitalisations for NSW residents by 8% (from 15,420 to 16,659) and procedure rates from 85.6% to 88.2%. For NSW residents who lived adjacent to a jurisdictional border, hospitalisation counts increased by up to 210% and procedure rates by up to 70 percentage points. Conclusions: Cross-jurisdictional linked hospital data is essential to understand patient journeys of NSW residents who live in border areas and to evaluate adherence to treatment guidelines for STEMI. MBS data are useful where hospital data are not available and for procedures that may be conducted in out-patient settings.

Development of Kudzu (Pueraria Montana var. lobata) Reference Materials for the Determination of Isoflavones and Toxic Elements.

BACKGROUND: In collaboration with the Office of Dietary Supplements at the National Institutes of Health, the National Institute of Standards and Technology issued a suite of botanical matrix reference materials (RMs) and Standard Reference Material® (SRM) for determination of isoflavones and toxic elements in kudzu dietary supplement ingredients. OBJECTIVE: RM 8650 Pueraria montana var. lobata (Kudzu) Rhizome, SRM 3268 Pueraria montana var. lobata (Kudzu) Extract, and RM 8652 Kudzu-Containing Solid Oral Dosage Form were issued with values assigned for isoflavones (puerarin, daidzin, and daidzein), toxic elements (arsenic, cadmium, and lead), and selenium. METHODS: Isoflavone values were assigned using liquid chromatography with UV absorbance or mass spectrometry detection. Element values were assigned using inductively coupled plasma mass spectrometry and results from an interlaboratory comparison exercise. RESULTS: Mass fractions for puerarin were 32.2 ± 3.2 mg/g, 128 ± 13 mg/g, and 68.2 ± 6.9 mg/g in RM 8650, SRM 3268, and RM 8652, respectively. Arsenic increases from 156 ± 14 ng/g to 849 ± 83 ng/g and cadmium decreases from 348 ± 14 ng/g to 82.1 ± 4.9 ng/g from rhizome to extract. CONCLUSION: The kudzu RM/SRM suite complements previously issued soy-related SRMs with values assigned for isoflavones, which have been studied for their potential health benefits, and expands the analytical resource by providing values for puerarin, an isoflavone not found in soy. HIGHLIGHTS: The three new kudzurmaterials are for use in the determination of isoflavones, toxic elements, and selenium. For the isoflavones, these new kudzu materials provide higher levels of daidzin and daidzein than existing soy-related SRMs, and they provide a value for an isoflavone not in existing SRMs (puerarin). Toxic elements in RM 8650 and SRM 3268 provide new botanical matrixes for use by dietary supplement manufacturers for the verification of the safety of their raw materials.

Effect of erythropoiesis-stimulating agents on healthcare utilization, costs, and outcomes in chronic kidney disease.

BACKGROUND: Anemia commonly complicates chronic kidney disease (CKD). Treating anemia of CKD with erythropoiesis-stimulating agents (ESAs) may attenuate cardiovascular and renal sequelae, reducing morbidity, mortality, and healthcare costs. OBJECTIVE: To compare clinical outcomes, healthcare utilization, and costs in ESA-treated and untreated patients with anemia of CKD who are not on dialysis. METHODS: This retrospective claims analysis considered more than 13 million US health plan members for outpatient, inpatient, emergency department, and prescription experience. Eligible patients were aged 15 years or older with 2 or more ICD-9 diagnoses of CKD or 1 or more CKD diagnosis and 1 or more claims for ESA within 12 months. The first CKD diagnosis within the study period (January 1, 2000-December 31, 2003) defined the index date. Anemia was ascertained by ICD-9 codes or ESA claims on or after the CKD index date. Patients were censored for dialysis, transplant, inpatient death, disenrollment, or study end. Utilization and costs per patient per month were compared between ESA and non-ESA patients. Generalized linear modeling identified predictors of total and anemia-related costs. RESULTS: Of 26,244 patients with CKD, 8188 (31.2%) had anemia; of those, only 14.6% (n = 1197) received ESAs. ESA recipients had lower total monthly healthcare costs than did untreated anemic patients ($3876 vs $4758; p = 0.0061). Lower monthly inpatient and emergency department costs in treated versus untreated anemic patients ($2507 vs $3849 and $46.56 vs $81, respectively; both p < 0.0001) outweighed higher outpatient and laboratory costs from ESA use ($602 vs $397 and $23.50 vs $14.34, respectively; both p < 0.0001). Multivariate analysis revealed that ESA users had lower adjusted monthly total costs ($2962 vs $3373) compared with non-ESA patients. CONCLUSIONS: ESA use was associated with mean total cost savings of $411 per patient per month, reflecting reduced inpatient and emergency department visits and costs, and with lower inpatient mortality and longer time to dialysis. The low (14.6%) ESA treatment rate for anemia highlights the continuing deficit in CKD care.

Development of Standard Reference Material (SRM) 2973 Vitamin D Metabolites in Frozen Human Serum (High Level).

The National Institute of Standards and Technology (NIST), in collaboration with the National Institutes of Health Office of Dietary Supplements and the Vitamin D Standardization Program, has recently issued a new serum-matrix Standard Reference Material (SRM): 2973 Vitamin D Metabolites in Frozen Human Serum (High Level). SRM 2973 was designed to provide a serum material with a total 25-hydroxyvitamin D [25(OH)D] concentration near 100 nmol/L to complement the existing serum-based SRMs with values assigned for total 25(OH)D between 20 and 80 nmol/L. Values were assigned for 25-hydroxyvitamin D2 [25(OH)D2], 25-hydroxyvitamin D3 [25(OH)D3], 3-epi-25(OH)D3, and total 25(OH)D [the sum of 25(OH)D2 + 25(OH)D3] using the NIST isotope dilution LC with tandem MS (MS/MS) reference measurement procedure (RMP) and related methods. SRM 2973 has a certified value of 98.4 ± 2.1 nmol/L for 25(OH)D3 and reference values of 1.59 ± 0.05 nmol/L for 25(OH)D2 and 5.23 ± 0.20 nmol/L for 3-epi-25(OH)D3. In addition, a candidate RMP for 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3] based on LC-MS/MS was used to assign values to SRM 2973 and the existing SRM 972a Vitamin D Metabolites in Frozen Human Serum. Reference values for 24R,25(OH)2D3 were assigned to SRM 2973 (7.51 ± 0.26 nmol/L) and the four levels of SRM 972a: Level 1 (6.38 ± 0.23 nmol/L), Level 2 (3.39 ± 0.12 nmol/L), Level 3 (3.88 ± 0.013 nmol/L), and Level 4 (6.32 ± 0.22 nmol/L). The development of SRM 2973 [with a higher concentration of 25(OH)D3] and the addition of values for 24R,25(OH)2D3 assigned to both SRM 972a and SRM 2973 provide laboratories involved in vitamin D measurements with improved QA tools.

Role of the National Institute of Standards and Technology (NIST) in Support of the Vitamin D Initiative of the National Institutes of Health, Office of Dietary Supplements.

Since 2005, the National Institute of Standards and Technology (NIST) has collaborated with the National Institutes of Health (NIH), Office of Dietary Supplements (ODS) to improve the quality of measurements related to human nutritional markers of vitamin D status. In support of the NIH-ODS Vitamin D Initiative, including the Vitamin D Standardization Program (VDSP), NIST efforts have focused on (1) development of validated analytical methods, including reference measurement procedures (RMPs); (2) development of Standard Reference Materials (SRMs); (3) value assignment of critical study samples using NIST RMPs; and (4) development and coordination of laboratory measurement QA programs. As a result of this collaboration, NIST has developed RMPs for 25-hydroxyvitamin D2 [25(OH)D2], 25(OH)D3, and 24R,25-dihydroxyvitamin D3 [24R,25(OH)2D3]; disseminated serum-based SRMs with values assigned for 25(OH)D2, 25(OH)D3, 3-epi-25(OH)D3, and 24R,25(OH)2D3; assigned values for critical samples for VDSP studies, including an extensive interlaboratory comparison and reference material commutability study; provided an accuracy basis for the Vitamin D External Quality Assurance Scheme; coordinated the first accuracy-based measurement QA program for the determination of 25(OH)D2, 25(OH)D3, and 3-epi-25(OH)D3 in human serum/plasma; and developed methods and SRMs for the determination of vitamin D and 25(OH)D in food and supplement matrix SRMs. The details of these activities and their benefit and impact to the NIH-ODS Vitamin D Initiative are described.

Interlaboratory Comparison for the Determination of 24,25-Dihydroxyvitamin D3 in Human Serum Using Liquid Chromatography with Tandem Mass Spectrometry.

Six laboratories associated with the Vitamin D Standardization Program (VDSP) participated in an interlaboratory comparison of LC with tandem MS (MS/MS) methods for the determination of 24,25-dihydroxyvitamin D3 [24,25(OH)2D3] in human serum. The laboratories analyzed two different serum-based Standard Reference Materials (SRMs) intended for use in the determination of 25-hydroxyvitamin D and 30 samples from the Vitamin D External Quality Assessment Scheme (DEQAS). All laboratory methods for 24,25(OH)2D3 were based on isotope dilution LC-MS/MS; three of the methods used derivatization of the vitamin D metabolites before LC-MS/MS. Laboratory results were compared to the National Institute of Standards and Technology (NIST) results, which were obtained using their newly developed candidate reference measurement procedure for 24,25(OH)2D3. Laboratory results for the SRM samples varied in comparability to the NIST results, with one laboratory in excellent agreement (-1.6% mean bias), three laboratories at 10-15% mean bias, and the remaining laboratory at 36% mean bias. For the 30 DEQAS samples, the mean bias for the five laboratories ranged from 6 to 15%; however, the SD of the bias ranged from 8 to 29%. As a result of this intercomparison study, one laboratory discovered and corrected a method calculation error and another laboratory modified and improved their LC-MS/MS method.

A comparison of mortality and costs associated with FOLFOX versus FOLFIRI in stage IV colorectal cancer.

OBJECTIVE: To examine cost and mortality among stage IV colorectal cancer (CRC) patients treated with 5-fluorouracil (5FU)/leucovorin/oxaliplatin (FOLFOX) or 5FU/leucovorin/irinotecan (FOLFIRI). METHODS: Adult CRC patients newly treated with FOLFOX or FOLFIRI were identified from a large database using medical and pharmacy claims for services delivered January 1, 2002 through December 31, 2005. Cancer stage for a subset of patients was abstracted from medical records. Outcomes were annualized costs calculated for 4 years of observation, and deaths as recorded by the National Death Index. Cost was analyzed using generalized linear modeling; mortality was modeled using Cox proportional hazards analysis. RESULTS: Unadjusted annualized median and mean costs were $134,401 and $152,213, respectively, for the FOLFOX cohort (n = 41) and $103,150 and $107,994 for the FOLFIRI cohort (n = 86). Death occurred among five (12%) FOLFOX and 42 (53%) FOLFIRI patients. Adjusted analysis revealed no significant difference in cost between cohorts, even after adjusting for reduced irinotecan costs due to generic availability. Incremental costs associated with one additional life saved per year were only $1,236 higher for patients treated with FOLFOX compared with FOLFIRI. Cox analysis revealed a significant survival advantage for FOLFOX over FOLFIRI (HR = 5.2; 95% CI: 1.7-15.8). CONCLUSIONS: A significant survival benefit was seen for CRC patients receiving FOLFOX versus FOLFIRI; multivariate analysis revealed no significant cost differences. However, the small sample size may have resulted in lack of adequate power to detect a difference between cohorts. There may be factors influencing mortality that were not included in the multivariate modeling.

Periprocedural drug therapy in carotid artery stenting: the need for more evidence.

Carotid artery stenting (CAS) is a widely accepted alternative for patients at high risk for carotid endarterectomy (CEA). However, the role, indications, and evidence for many pharmacologic agents that are used adjunctively in the periprocedural setting have not been established. Several drugs are commonly used before, during, and after CAS, but their uses have not been standardized. Large prospective cohort studies with good validity or randomized trials are needed to demonstrate efficacy, predict outcome, and determine the optimal use of these medications in patients undergoing CAS to improve patient care and obtain optimal outcomes. Several conclusions can be made: (1) dual-antiplatelet therapy (aspirin and clopidogrel) is commonly used for CAS; (2) the most commonly used regimen is aspirin 325 mg and clopidogrel 75 mg per day, but the optimal time of therapy is unknown; and (3) the dose and regimen of other agents used for CAS are not established.