An omicron-specific neutralizing antibody test predicts neutralizing activity against XBB 1.5.

Introduction: Understanding the immune status of an individual using neutralizing antibody testing is complicated by the continued evolution of the SARS-CoV-2 virus. Previous work showed that assays developed against the wildtype strain of SARS-CoV-2 were insufficient predictors of neutralization of omicron variants, thus we developed an omicron-specific flow cytometry-based neutralizing antibody test and performed experiments to assess how well it compared to an omicron-specific PRNT assay (gold standard) and whether it could predict neutralizing activity to more recent omicron subvariants such as XBB.1.5. Methods: Accuracy of a novel flow cytometry-based neutralizing antibody (FC-NAb) assay was determined by comparison with an omicron-specific PRNT assay. A series of samples were evaluated in both the omicron FC-NAb assay and a second test was designed to assess neutralization of XBB.1.5. Results: Good concordance between the omicron FC-NAb test and the omicron PRNT was demonstrated (AUC = 0.97, p <0.001; sensitivity = 94%, specificity = 100%, PPV = 100%, and NPV = 97%). A strong linear relationship between the omicron FC-NAb and neutralization of XBB1.5 was observed (r = 0.83, p<0.001). Additionally, the omicron FC-NAb test was a very strong predictor of positive XBB1.5 NAb activity (AUC = 0.96, p<0.001; sensitivity = 94%, specificity = 90%, positive predictive value = 90%, and negative predictive values = 94%). Discussion: Our data suggest that despite continued evolution of the SARS-CoV-2 spike protein, the omicron FC-NAb assay described here is a good predictor of XBB1.5 neutralizing activity, as evidenced by a strong correlation and good predictive performance characteristics.

A mathematical model of the within-host kinetics of SARS-CoV-2 neutralizing antibodies following COVID-19 vaccination.

Compelling evidence continues to build to support the idea that SARS-CoV-2 Neutralizing Antibody (NAb) levels in an individual can serve as an important indicator of the strength of protective immunity against infection. It is not well understood why NAb levels in some individuals remain high over time, while in others levels decline rapidly. In this work, we present a two-state mathematical model of within-host NAb dynamics in response to vaccination. By fitting only four host-specific parameters, the model is able to capture individual-specific NAb levels over time as measured by the AditxtScore™ for NAbs. The model can serve as a foundation for predicting NAb levels in the long-term, understanding connections between NAb levels, protective immunity, and breakthrough infections, and potentially guiding decisions about whether and when a booster vaccination may be warranted.

Simultaneous measurement of multiple variant-specific SARS-CoV-2 neutralizing antibodies with a multiplexed flow cytometric assay.

Introduction: Neutralizing antibodies (NAbs) have been recognized as surrogates of protection against SARS-CoV-2; however, the emergence of variants/subvariants escaping neutralization suggests that laboratory assessments of NAbs against the ancestral/wild type (WT) antigens likely overestimate the degree of protection. Methods: A novel flow cytometry-based multiplex test system was developed for the simultaneous detection of NAbs of multiple SARS-CoV-2 variants. SARS-CoV-2 antibodies (Abs) including IgG, IgM, IgA isotypes were measured in the same system. Samples from negative, convalesced, vaccinated, boosted, and breakthrough infection (BTI) populations were tested for both NAbs and Abs. Results: NAbs induced by WT showed neutralization activity that correlated strongly to all variants (R2 > 0.85) except omicron BA.1/BA.2 (R2 <0.50). Two doses of vaccine elicited very little protective immunity against BA.1/BA.2, though a booster dose significantly improved NAbs for all variants. NAbs/Abs increased more following BTI than after a booster, suggesting that hybrid immunity (vaccination + natural immunity) was more robust to all variants including BA.1/BA.2. BTIs occurring in the omicron era led to stronger NAb responses against BA.1/BA.2 than did older BTIs. In all comparisons, the RBD antigens demonstrated greater differences between WT and BA.1/BA.2 than the spike antigens. Discussion: Taken together, we demonstrated that both Ab and NAb against multiple SARS-CoV-2 variants/subvariants can be reliably detected on the same multiplex platform. Distinguishing NAbs to the appropriate antigenic target of prevalent variants offers the best correlate of protection and aids individual decisions about the appropriateness and cadence of vaccine boosters and other exposure mitigation strategies.

Low-Density Lipoprotein Cholesterol Corrected for Lipoprotein(a) Cholesterol, Risk Thresholds, and Cardiovascular Events.

Background Conventional "low-density lipoprotein cholesterol (LDL-C)" assays measure cholesterol content in both low-density lipoprotein and lipoprotein(a) particles. To clarify the consequences of this methodological limitation for clinical care, our study aimed to compare associations of "LDL-C" and corrected LDL-C with risk of cardiovascular disease and to assess the impact of this correction on the classification of patients into guideline-recommended LDL-C categories. Methods and Results Lipoprotein(a) cholesterol content was estimated as 30% of lipoprotein(a) mass and subtracted from "LDL-C" to obtain corrected LDL-C values (LDL-Ccorr30). Hazard ratios for cardiovascular disease (defined as coronary heart disease, stroke, or coronary revascularization) were quantified by individual-patient-data meta-analysis of 5 statin landmark trials from the Lipoprotein(a) Studies Collaboration (18 043 patients; 5390 events; 4.7 years median follow-up). When comparing top versus bottom quartiles, the multivariable-adjusted hazard ratio for cardiovascular disease was significant for "LDL-C" (1.17; 95% CI, 1.05-1.31; P=0.005) but not for LDL-Ccorr30 (1.07; 95% CI, 0.93-1.22; P=0.362). In a routine laboratory database involving 531 144 patients, reclassification of patients across guideline-recommended LDL-C categories when using LDL-Ccorr30 was assessed. In "LDL-C" categories of 70 to <100, 100 to <130, 130 to <190, and ≥190 mg/dL, significant proportions (95% CI) of participants were reassigned to lower LDL-C categories when LDL-Ccorr30 was used: 30.2% (30.0%-30.4%), 35.1% (34.9%-35.4%), 32.9% (32.6%-33.1%), and 41.1% (40.0%-42.2%), respectively. Conclusions "LDL-C" was associated with incident cardiovascular disease only when lipoprotein(a) cholesterol content was included in its measurement. Refinement in techniques to accurately measure LDL-C, particularly in patients with elevated lipoprotein(a) levels, is warranted to assign risk to the responsible lipoproteins.

Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC.

OBJECTIVE: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region. RESEARCH DESIGN AND METHODS: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects (n = 1,985) and control subjects (n = 2,219). The same approach was applied to a LADA cohort (n = 1,428) using population-based control subjects (n = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects). RESULTS: The strongest associations in the MHC class II region (rs3957146, ß [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly HLA-B*39 (ß [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, ß [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA. CONCLUSIONS: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes.

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

Lipoprotein(a) Mass Levels Increase Significantly According to APOE Genotype: An Analysis of 431 239 Patients.

OBJECTIVE: Lipoprotein(a) [Lp(a)] levels are genetically determined by hepatocyte apolipoprotein(a) synthesis, but catabolic pathways also influence circulating levels. APOE genotypes have different affinities for the low-density lipoprotein (LDL) receptor and LDL-related protein-1, with ε2 having the weakest binding to LDL receptor at <2% relative to ε3 and ε4. APPROACH AND RESULTS: APOE genotypes (ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4), Lp(a) mass, directly measured Lp(a)-cholesterol levels, and a variety of apoB-related lipoproteins were measured in 431 239 patients. The prevalence of APOE traits were ε2: 7.35%, ε3: 77.56%, and ε4: 15.09%. Mean (SD) Lp(a) levels were 65% higher in ε4/ε4 compared with ε2/ε2 genotypes and increased significantly according to APOE genotype: ε2/ε2: 23.4 (29.2), ε2/ε3: 31.3 (38.0), ε2/ε4: 32.8 (38.5), ε3/ε3: 33.2 (39.1), ε3/ε4: 35.5 (41.6), and ε4/ε4: 38.5 (44.1) mg/dL (P<0.0001). LDL-cholesterol, apoB, Lp(a)-cholesterol, LDL-cholesterol corrected for Lp(a)-cholesterol content, LDL-particle number, and small, dense LDL also had similar patterns. Patients with LDL-cholesterol ≥250 mg/dL, who are more likely to have LDL receptor mutations and reduced affinity for apoB, had higher Lp(a) levels across all apoE isoforms, but particularly in patients with ε2 alleles, compared with LDL <250 mg/dL. The lowest Lp(a) mass levels were present in patients with ε2 isoforms and lowest LDL-cholesterol. CONCLUSIONS: APOE genotypes strongly influence Lp(a) and apoB-related lipoprotein levels. This suggests that differences in affinity of apoE proteins for lipoprotein clearance receptors may affect Lp(a) catabolism, suggesting a competition between Lp(a) and apoE protein for similar receptors.

From Value Assessment to Value Cocreation: Informing Clinical Decision-Making with Medical Claims Data.

Big data and advances in analytical processes represent an opportunity for the healthcare industry to make better evidence-based decisions on the value generated by various tests, procedures, and interventions. Value-based reimbursement is the process of identifying and compensating healthcare providers based on whether their services improve quality of care without increasing cost of care or maintain quality of care while decreasing costs. In this article, we motivate and illustrate the potential opportunities for payers and providers to collaborate and evaluate the clinical and economic efficacy of different healthcare services. We conduct a case study of a firm that offers advanced biomarker and disease state management services for cardiovascular and cardiometabolic conditions. A value-based analysis that comprised a retrospective case/control cohort design was conducted, and claims data for over 7000 subjects who received these services were compared to a matched control cohort. Study subjects were commercial and Medicare Advantage enrollees with evidence of CHD, diabetes, or a related condition. Analysis of medical claims data showed a lower proportion of patients who received biomarker testing and disease state management services experienced a MI (p < 0.01) or diabetic complications (p < 0.001). No significant increase in cost of care was found between the two cohorts. Our results illustrate the opportunity healthcare payers such as Medicare and commercial insurance companies have in terms of identifying value-creating healthcare interventions. However, payers and providers also need to pursue system integration efforts to further automate the identification and dissemination of clinically and economically efficacious treatment plans to ensure at-risk patients receive the treatments and interventions that will benefit them the most.

Comparison of cardiometabolic risk biomarkers from a national clinical laboratory with the US adult population.

BACKGROUND: Clinical laboratory patient databases are an untapped source of valuable diagnostic and prognostic information. However, the lack of associated clinical and/or demographic information and questionable generalizability to nonpatient populations often limit utility of these data. OBJECTIVES: This study compared levels of cardiometabolic biomarkers between a national clinical laboratory patient cohort (Health Diagnostic Laboratory [HD Lab]) and the US population as inferred from the National Health and Nutrition Examination Survey (NHANES, 2011-2012). METHODS: Sample sizes for HD Lab ranged from 199,000 to 739,000 and for NHANES from 2200 to 5300. The latter were weighted to represent the adult US population (∼220 million). Descriptive statistics were compared for body mass index, 5 lipid biomarkers, and 3 glycemic biomarkers. RESULTS: Using age- and sex-matched data, mean biomarker values (mg/dL unless noted) and percent differences (%) for HD Lab vs NHANES were body mass index (kg/m(2)), 29.1 vs 28.6 (1.7%); total cholesterol, 185 vs 193 (-4.1%); apolipoprotein B, 92 vs 90 (2.2%); low-density lipoprotein cholesterol, 107 vs 115 (-7%); high-density lipoprotein cholesterol, 53 vs 53 (0%); triglycerides, 128 vs 127 (0.8%); glucose, 99 vs 108 (-8.3%); insulin (uU/mL), 13.7 vs 13.4 (2.2%); and hemoglobin A1c (%), 5.6 vs 5.8 (-3.4%). Although all differences were statistically significant, only low-density lipoprotein cholesterol and glucose differed by more than 5%. These may reflect a greater use of medications among HD Lab patients and/or preanalytical factors. CONCLUSIONS: Cardiometabolic risk markers from a national clinical laboratory were broadly similar to those of the US population; thus, with certain caveats, data from the former may be generalizable to the latter.

Biomarkers of cholesterol homeostasis in a clinical laboratory database sample comprising 667,718 patients.

BACKGROUND: Circulating noncholesterol sterols/stanols (NCS) are used in clinical lipidology as surrogate measures of cholesterol synthesis and absorption, where they can be valuable tools in assessing cholesterol metabolism and personalizing therapies in patients with dyslipidemia. OBJECTIVES: To describe the distributions of plasma NCS concentrations and inter-NCS correlations in a large cohort of American patients constituting a clinical laboratory database, and to investigate the relationship between circulating NCS, age, sex, and apolipoprotein E (APOE) genotype. METHODS: A total of 667,718 patient blood samples submitted for testing to Health Diagnostic Laboratory, Inc. (Richmond, VA) were analyzed for cholesterol absorption markers (sitosterol, campesterol, and cholestanol) and one cholesterol synthesis marker (desmosterol). NCS percentiles were determined, along with intermarker correlations (Pearson's R). Analysis of variance was used to assess the effect of age and sex on NCS level, and to evaluate the relationship between cholesterol synthesis/absorption status and APOE genotype in a subset of 336,866 patients. RESULTS: Mean NCS concentrations were: sitosterol, 2.45 µg/mL; campesterol, 3.3 µg/mL; cholestanol, 2.92 µg/mL; and desmosterol 0.99 µg/mL. The correlations between each NCS and its ratio to total cholesterol ranged from 0.72 (cholestanol) to 0.94 (desmosterol). NCS levels were significantly affected by age and sex (P < .0001), and prevalence of cholesterol hyperabsorption was higher in APOE ε4 allele carriers compared with the other APOE genotypes. CONCLUSIONS: We have described sample distributions of NCS biomarkers and characterized their relationship to age, sex, and APOE genotype. These data may facilitate research into altered cholesterol homeostasis and human disease, and help physicians optimize lipid-lowering therapies.

Discordance between apolipoprotein B and low-density lipoprotein particle number is associated with insulin resistance in clinical practice.

BACKGROUND: Discordance between measures of atherogenic lipoprotein particle number (apolipoprotein B [ApoB] and low-density lipoprotein [LDL] particle number by nuclear magnetic resonance spectroscopy [LDL-PNMR]) is not well understood. Appropriate treatment considerations in such cases are unclear. OBJECTIVES: To assess discordance between apoB determined by immunoassay and LDL-PNMR in routine clinical practice, and to characterize biomarker profiles and other clinical characteristics of patients identified as discordant. METHODS: Two retrospective cohorts were evaluated. First, 412,013 patients with laboratory testing performed by Health Diagnostic Laboratory, Inc., as part of routine care; and second, 1411 consecutive patients presenting for risk assessment/reduction at 6 US outpatient clinics. Discordance was quantified as a percentile difference (LDL-PNMR percentile - apoB percentile) and attainment of percentile cutpoints (LDL-PNMR ≥ 1073 nmol/L or apoB ≥ 69 mg/dL). A wide range of cardiovascular risk factors were compared. RESULTS: ApoB and LDL-PNMR values were highly correlated (R(2) = 0.79), although substantial discordance was observed. Similar numbers of patients were identified as at-risk by LDL-PNMR when apoB levels were < 69 mg/dL (5%-6%) and by apoB values when LDL-PNMR was < 1073 nmol/L (6%-7%). Discordance (LDL-PNMR > apoB) was associated with insulin resistance, smaller LDL particle size, increased systemic inflammation, and low circulating levels of "traditional" lipids, whereas discordance (apoB > LDL-PNMR) was associated with larger LDL particle size, and elevated levels of lipoprotein(a) and lipoprotein-associated phospholipase A2 (Lp-PLA2). CONCLUSION: Discordance between apoB and LDL-PNMR in routine clinical practice is more widespread than currently recognized and may be associated with insulin resistance.

Serum α-hydroxybutyrate (α-HB) predicts elevated 1†h glucose levels and early-phase ß-cell dysfunction during OGTT.

OBJECTIVE: Serum α-hydroxybutyrate (α-HB) is elevated in insulin resistance and diabetes. We tested the hypothesis that the α-HB level predicts abnormal 1 h glucose levels and ß-cell dysfunction inferred from plasma insulin kinetics during a 75 g oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS: This cross-sectional study included 217 patients at increased risk for diabetes. 75 g OGTTs were performed with multiple postload glucose and insulin measurements over a 30-120 min period. OGTT responses were analyzed by repeated measures analysis of variance (ANOVA). Multivariable logistic regression was used to predict 1 h glucose ≥155 mg/dL with α-HB added to traditional risk factors. RESULTS: Mean±SD age was 51±15 years (44% male, 25% with impaired glucose tolerance). Fasting glucose and insulin levels, but not age or body mass index (BMI), were significantly higher in the second/third α-HB tertiles (>3.9 µg/mL) than in the first tertile. Patients in the second/third α-HB tertiles exhibited a higher glucose area under the receiver operating characteristics curve (AUC) and reduced initial slope of insulin response during OGTT. The AUC for predicting 1 h glucose ≥155 mg/dL was 0.82 for a base model that included age, gender, BMI, fasting glucose, glycated hemoglobin (HbA1c), and insulin, and increased to 0.86 with α-HB added (p=0.015), with a net reclassification index of 52% (p<0.0001). CONCLUSIONS: Fasting serum α-HB levels predicted elevated 1 h glucose during OGTT, potentially due to impaired insulin secretion kinetics. This association persisted even in patients with an otherwise normal insulin-glucose homeostasis. Measuring serum α-HB could thus provide a rapid, inexpensive screening tool for detecting early subclinical hyperglycemia, ß-cell dysfunction, and increased risk for diabetes.

Comprehensive biomarker testing of glycemia, insulin resistance, and beta cell function has greater sensitivity to detect diabetes risk than fasting glucose and HbA1c and is associated with improved glycemic control in clinical practice.

Blood-based biomarker testing of insulin resistance (IR) and beta cell dysfunction may identify diabetes risk earlier than current glycemia-based approaches. This retrospective cohort study assessed 1,687 US patients at risk for cardiovascular disease (CVD) under routine clinical care with a comprehensive panel of 19 biomarkers and derived factors related to IR, beta cell function, and glycemic control. The mean age was 53 ± 15, 42 % were male, and 25 % had glycemic indicators consistent with prediabetes. An additional 45 % of the patients who had normal glycemic indicators were identified with IR or beta cell abnormalities. After 5.3 months of median follow-up, significantly more patients had improved than worsened their glycemic status in the prediabetic category (35 vs. 9 %; P < 0.0001) and in the "high normal" category (HbA1c values of 5.5-5.6; 56 vs. 18 %, p < 0.0001). Biomarker testing can identify IR early, enable and inform treatment, and improve glycemic control in a high proportion of patients.

Does APOE genotype modify the relations between serum lipid and erythrocyte omega-3 fatty acid levels?

Earlier reports indicated that patients with the apolipoprotein APOE ε4 allele responded to fish oil supplementation with a rise in serum low-density lipoprotein cholesterol (LDL-C) compared to ε3 homozygotes. In this study, we used clinical laboratory data to test the hypothesis that the cross-sectional relation between RBC omega-3 fatty acid status (the Omega-3 Index) and LDL-C was modified by APOE genotype. Data from 136,701 patients were available to compare lipid biomarker levels across Omega-3 Index categories associated with heart disease risk in all APOE genotypes. We found no adverse interactions between APOE genotype and the Omega-3 Index for LDL-C, LDL particle number, apoB, HDL-C, or triglycerides. However, we did find evidence that ε2 homozygotes lack an association between omega-3 status and LDL-C, apoB, and LDL particle number. In summary, we found no evidence for a deleterious relationship between lipid biomarkers and the Omega-3 Index by APOE genotype.

The changing role of ancillary health care service providers: an evaluation of Health Diagnostic Laboratory, Inc.

In an effort to reduce cost and improve quality, health care payers have enacted a number of incentives to motivate providers to focus their efforts on achieving better clinical outcomes and reducing the prevalence and progression of disease. In response to these incentives, providers are entering into new arrangements such as accountable care organizations and patient-centered medical homes to redesign delivery processes and achieve quality and cost objectives. This article reports the results of a study designed to evaluate the impact on cost and quality of care resulting from services provided by Health Diagnostic Laboratory, Inc., a clinical laboratory with a comprehensive care model. The results show that patients who utilized these laboratory services experienced lower total cost of care (23% reduction, P<0.01) and improved lipid profiles during the follow-up period. Total cost reductions were related to cost reductions found in both inpatient and ambulatory care. These findings suggest that accountable care organizations, patient-centered medical homes, and other groups entering shared savings initiatives should consider the potential role ancillary service providers with comprehensive care models can play in the delivery of integrated care.

Comparative effects of an acute dose of fish oil on omega-3 fatty acid levels in red blood cells versus plasma: implications for clinical utility.

BACKGROUND: Omega-3 fatty acid (n-3 FA) biostatus can be estimated with red blood cell (RBC) membranes or plasma. The matrix that exhibits the lower within-person variability and is less affected by an acute dose of n-3 FA is preferred in clinical practice. OBJECTIVE: We compared the acute effects of a large dose of n-3 FA on RBC and plasma levels of eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA). METHODS: Healthy volunteers (n = 20) were given 4 capsules containing 3.6 g of n-3 FA with a standardized breakfast. Blood samples were drawn at 0, 2, 4, 6, 8, and 24 hours. The EPA + DHA content of RBC membranes and plasma (the latter expressed as a percentage of total FA and as a concentration) were determined. General linear mixed models were used to analyze the mean response profiles in FA changes over time for plasma and RBCs. RESULTS: At 6 hours after load, the plasma concentration of EPA + DHA had increased by 47% (95% confidence interval [CI], 24% to 73%) and the plasma EPA + DHA percentage of total FA by 19% (95% CI, 4.7% to 36%). The RBC EPA + DHA percentage of composition was unchanged [-0.6% (95% CI, -2.6% to 1.5%)]. At 24 hours, the change in both of the plasma EPA + DHA markers was 10-fold greater than that in RBCs. CONCLUSIONS: An acute dose of n-3 FA (eg, a meal of oily fish or fish oil supplements) taken within a day before a doctor's visit can elevate levels of EPA + DHA in plasma, whether expressed as a percentage or a concentration, but not in RBC membranes. Similar to hemoglobin A1c, which is not affected by an acute glycemic deviation, RBCs provide a more reliable estimate of a patient's chronic EPA + DHA status than does plasma.

Erythrocyte omega-3 fatty acids increase and linoleic acid decreases with age: observations from 160,000 patients.

BACKGROUND: The fatty acid (FA) composition of the red blood cell (RBC) has been reported to provide prognostic information regarding risk for coronary heart disease (CHD). In particular, the Omega-3 Index (RBC eicosapentaenoic acid+docosahexaenoic acid, EPA+DHA) has been shown to be independently and inversely related to risk for sudden cardiac death and for acute coronary syndromes. Higher linoleic acid (n-6) and lower trans FA levels have also been associated with improved CHD outcomes. Accordingly, the RBC FA panel has recently been introduced in routine clinical laboratory testing. OBJECTIVE: The purpose of this study was to define age- and gender-based norms for RBC FA levels. METHODS: RBC FA profiles from about 160,000 patients (48% from males, 52% from females) were measured at Health Diagnostic Laboratory. These data were used to create age decade and gender-specific norms (percentiles). FA values were expressed as a percent of total identified FA. RESULTS: Compared to men, women generally had higher C18 trans levels, and between the ages of 10-29 years, they had DHA and lower EPA levels. Among the major FA classes, saturated (41% of total) and trans (∼0.85%) fats did not vary appreciably by age, whereas monounsaturated fats tended to rise slightly. Of the two major n-6 polyunsaturates, arachidonic and linoleic acids, the former was unchanged across decades (16.4% abundance) whereas the latter decreased by about 2 percentage points (13.0-11.1%). The overall median Omega-3 Index was 4.5%, and across the decades it increased by about 1.5 percentage points. The Omega-3 Index and linoleic acid stabilized after age 70. CONCLUSION: Whereas RBC saturated, mono- and polyunsaturated FA levels are generally stable across the lifespan, there is a shift in the composition of the latter, with an increase in the Omega-3 Index and a decrease in linoleic acid. Higher DHA and lower EPA levels in younger women is consistent with enhanced conversion of EPA to DHA during the early reproductive years. The availability of RBC FA norms will facilitate research into the relationships between altered FA status and human disease, and will help physicians evaluate the n-3 FA status of their patients.

delta(9)-Tetrahydrocannabinol-dependent mice undergoing withdrawal display impaired spatial memory.

RATIONALE: Cannabis users display a constellation of withdrawal symptoms upon drug discontinuation, including sleep disturbances, irritability, and possibly memory deficits. In cannabinoid-dependent rodents, the CB(1) antagonist rimonabant precipitates somatic withdrawal and enhances forskolin-stimulated adenylyl cyclase activity in cerebellum, an effect opposite that of acutely administered ∆(9)-tetrahydrocannabinol (THC), the primary constituent in cannabis. OBJECTIVES: Here, we tested whether THC-dependent mice undergoing rimonabant-precipitated withdrawal display short-term spatial memory deficits, as assessed in the Morris water maze. We also evaluated whether rimonabant would precipitate adenylyl cyclase superactivation in hippocampal and cerebellar tissue from THC-dependent mice. RESULTS: Rimonabant significantly impaired spatial memory of THC-dependent mice at lower doses than those necessary to precipitate somatic withdrawal behavior. In contrast, maze performance was near perfect in the cued task, suggesting sensorimotor function and motivational factors were unperturbed by the withdrawal state. Finally, rimonabant increased adenylyl cyclase activity in cerebellar, but not in hippocampal, membranes. CONCLUSIONS: The memory disruptive effects of THC undergo tolerance following repeated dosing, while the withdrawal state leads to a rebound deficit in memory. These results establish spatial memory impairment as a particularly sensitive component of cannabinoid withdrawal, an effect that may be mediated through compensatory changes in the cerebellum.

Prostate needle biopsy quality in reduction by dutasteride of prostate cancer events study: worldwide comparison of improvement with investigator training and centralized laboratory processing.

OBJECTIVES: To compare biopsy quality factors among study sites worldwide at entry and at year 2 in the reduction by dutasteride of prostate cancer events study. The accuracy of prostate cancer detection is influenced by the length and number of biopsy cores. METHODS: Biopsy quality factors at entry and at year 2 were compared for subjects enrolled from 6 geographic regions: North America, South America, Western Europe, Central/Eastern Europe, Australia, and Africa. Investigator training was provided for prostate biopsy collection before year 2, emphasizing core length and number of cores obtained. RESULTS: Data were collected prospectively from 4649 subjects at entry and 6267 subjects at year 2. At entry, the aggregate length, number of cores, and mean length of cores differed significantly among regions. Aggregate length was longest in biopsies from Australia, and number of cores was highest from South America. At year 2, each region collected the protocol-required 10 cores, and aggregate length and mean length of cores were greater than for entry biopsies; site variance was reduced for all factors. CONCLUSIONS: There were significant differences in aggregate length, number of cores, and mean length of cores among regions at study entry. After investigator training by the study sponsor and use of a central laboratory for standardized processing, year 2 biopsies showed an increase in all 3 quality factors when compared with entry biopsies. Variance in biopsy quality can be reduced by investigator training and standardization of collection and processing, thereby optimizing detection of cancer. Biopsy quality may be a useful comparative measure in urologic practice.