OBJECTIVE:Mean blood glucose (MBG) over 2-3 months is a strong predictor of HbA(1c) (A1C) levels. Glucose instability, the variability of blood glucose levels comprising the MBG, and biological variation in A1C (BV) have also been suggested as predictors of A1C independent of MBG. To assess the relative importance of MBG, BV, and glucose instability on A1C, we analyzed patient data from the Diabetes Control and Complications Trial (DCCT).RESEARCH DESIGN AND METHODS:A glucose profile set and sample for A1C were collected quarterly over the course of the DCCT from each participant (n = 1,441). The glucose profile set consisted of seven samples, one each drawn before and 90 min after breakfast, lunch, and dinner and one before bedtime. MBG and glucose instability (SD of blood glucose [SDBG]) were calculated as the arithmetic mean and SD of glucose profile set samples for each visit, respectively. A statistical model was developed to predict A1C from MBG, SDBG, and BV, adjusted for diabetes duration, sex, treatment group, stratum, and race.RESULTS:Data from 32,977 visits were available. The overall model was highly statistically significant (log likelihood = -41,818.75, likelihood ratio chi2[7] = 7,218.71, P > chi2 = 0.0000). MBG and BV had large influences on A1C based on their standardized coefficients. SDBG had only 1/14 of the impact of MBG and 1/10 of the impact of BV.CONCLUSIONS:MBG and BV have a large influence on A1C, whereas SDBG is relatively unimportant. Consideration of BV as well as MBG in the interpretation of A1C may enhance our ability to monitor diabetes management and predict complications.

Problem: The Glycosylation Gap (GGAP) based on fructosamine (F) measurement and the Hemoglobin Glycation Index (HGI) based on mean blood glucose (MBG) are two indices of between-individual differences in glycated hemoglobin (HbA1c) adjusted for glycemia. We sought to simultaneously compare GGAP with HGI and other estimates of glycemia. Methods: HbA1c, F, and MBG level were obtained at a clinic visit from 62 patients with Type I diabetes. GGAP and HGI were calculated from the data as previously described. The variables were compared by correlation analysis. The concordance of patient classification by GGAP and HGI was compared by weighted kappa test. Results: The mean HbA1c= 11.1 +/- 2.7%, F = 372.0 +/- 136.6 mol/l, MBG = 186.5 +/- 58.4 mg/dl, HGI = 0.0 +/- 2.0, and GGAP = 0.0 +/- 1.9. MBG, HbA1c, and F were all highly correlated with each other. The HGI and GGAP were highly correlated (r = .73, P < .0001) and similar in both magnitude and direction. There was good agreement between HGI and GGAP classifications of patients into high, moderate, and low glycation groups (P < .0075). Conclusions: GGAP and MBG give similar information regarding between-patient differences in HbA1c among patients with diabetes. Thus, biological variation in HbA1c is not an artifact of variability in glucose measurements comprising the MBG. Individual patient factors influence the intracellular glycation of HbA1c in addition to the effect of extracellular glycemia, which is manifested as a between-individual biological variation in HbA1c. (c) 2005 Elsevier Inc. All rights reserved.

OBJECTIVE—We hypothesized that biological variation in HbA1c, distinct from variation attributable to mean blood glucose (MBG), would predict risk for microvascular complications in the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS—A longitudinal multiple regression model was developed from MBG and HbA1c measured in the 1,441 DCCT participants at quarterly visits. A hemoglobin glycation index (HGI = observed HbA1c - predicted HbA1c) was calculated for each visit to assess biological variation based on the directional deviation of observed HbA1c from that predicted by MBG in the model. The population was subdivided by thirds into high-, moderate-, and low-HGI groups based on mean participant HGI during the study. Cox proportional hazard analysis compared risk for development or progression of retinopathy and nephropathy between HGI groups controlled for MBG, age, treatment group, strata, and duration of diabetes. RESULTS—Likelihood ratio and t tests on HGI rejected the assumption that HbA1c levels were determined by MBG alone. At 7 years’ follow-up, patients in the high-HGI group (higher-than-predicted HbA1c) had three times greater risk of retinopathy (30 vs. 9%, P < 0.001) and six times greater risk of nephropathy (6 vs. 1%, P < 0.001) compared with the low-HGI group. CONCLUSIONS—Between-individual biological variation in HbA1c, which is distinct from that attributable to MBG, was evident among type 1 diabetic patients in the DCCT and was a strong predictor of risk for diabetes complications. Identification of the processes responsible for biological variation in HbA1c could lead to novel therapies to augment treatments directed at lowering blood glucose levels and preventing diabetes complications.

Nosocomial pneumonia in trauma patients is a significant source of resource utilization and mortality. We have previously described increased rates of pneumonia in male trauma patients in a single institution study. In that study, female trauma patients had a lower incidence of postinjury pneumonia but a higher relative risk for mortality when they did develop pneumonia. We sought to investigate the hypothesis that male trauma patients have an increased incidence of postinjury pneumonia in a separate population-based dataset. Prospective data were collected on 30,288 trauma patients (26,231 blunt injuries, 4057 penetrating injuries) admitted to all trauma centers (n = 26) in Pennsylvania over 24 months (January 1996 to December 1997). Gender differences in pneumonia were determined for the entire dataset. A second analysis examined all blunt injury patients and excluded all patients with a hospital length of stay less than 24 h, eliminating patients who expired early after admission. In trauma patients with minor injury (ISS < 15), there was no significant difference between male and female patients in the rate of postinjury pneumonia (male 1.37%, female 1.11%). In the moderate-injury group (ISS > 15), male trauma patients had a significantly increased incidence of postinjury pneumonia (ISS 15-30, male 8.85%, female 6.45%; ISS > 30, male 24.35%, female 17.30%). Logistic regression analysis of blunt trauma patients revealed that gender, ISS, injury type, admission Revised Trauma Score (RTS), admission respiratory rate, history of cardiac disease, and history of cancer were all independent predictors of pneumonia. Trauma patients with nosocomial pneumonia had a significantly higher mortality rate (P < 0.001) than patients without pneumonia. There was no gender-specific difference in mortality among pneumonia patients. Male gender is significantly associated with an increased incidence of postinjury pneumonia. In contrast to our initial study, there was no gender difference in postinjury pneumonia mortality rates identified in this population-based study.

Metformin lowers blood glucose by reducing hepatic glucose output and improving insulin sensitivity without requiring an increase in circulating insulin concentration. We hypothesized that metformin could be used adjunctively with insulin to improve glycemic control in type 1 diabetes mellitus (DM). We conducted a 6-month open-label pilot study in 10 adolescents and young adults with type 1 DM, 19.1 +/- 3.4 years, 4 males, 6 females, and body mass index 26.3 +/- 3.1 kg/m2. Patients started metformin at a dose of 250 mg b.i.d.; the dose was increased until blood glucose was within an optimal target range or a maximum of 2,500 mg/d was reached. Insulin dose was reduced as needed to prevent hypoglycemia. Seven patients had an average decrease in HbA(1c) of 11% from pretreatment. These responders had no change in insulin dose, BMI or lipid levels during the study. Three patients had no improvement of HbA(1c) on therapy. We conclude that some patients with type 1 DM will have improved glycemic control on adjunctive metformin therapy. Evaluation of the long-term benefit and safety of adjunctive therapy in patients with type 1 DM is warranted.

BACKGROUND:Women usually have lower mortality rates than men do at any age. This pattern is observed for most causes of death from chronic diseases. Significant controversy still exists about gender differences in outcomes in trauma. We previously reported no differences in in-hospital mortality based on gender in a large single-institution study (n= 18,892) that had a significant limitation in that it was not population based. This current study was performed to validate our earlier findings in a separate, statewide, population-based dataset of trauma victims.STUDY DESIGN:Prospective data were collected on 22,332 trauma patients (18,432 blunt, 3,900 penetrating) admitted to all trauma centers (n = 26) in Pennsylvania over 24 months (January 1996 to December 1997). Gender differences in in-hospital mortality were determined for the entire dataset and for the subsets of blunt and penetrating injury patients. A second analysis examined all blunt injury patients and excluded all patients with a hospital length of stay of less than 24 hours, eliminating patients who expired soon after admission. The null hypothesis was that female gender is protective in trauma outcomes.RESULTS:Multiple logistic regression analysis identified age (odds ratio [OR] 1.03, confidence interval [CI] 1.02 to 1.03), Injury Severity Score (OR 1.06, CI 1.05 to 1.06), non-Caucasian race (OR 1.72, CI 1.39 to 2.15), blunt injury type (OR 0.327, CI 0.26 to 0.41), and Revised Trauma Score (OR 0.44, CI 0.41 to 0.47) as independent predictors of in-hospital mortality in trauma. Preexisting diseases, including cardiac disease (OR 1.53, CI 1.12 to 2.09) and malignancy (OR 4.08, CI 1.64 to 10.17), were also identified as independent predictors of in-hospital mortality in trauma. Female gender was not associated with decreased mortality (OR 0.83, CI 0.67 to 1.03, p = 0.093). A second multiple regression analysis in blunt trauma patients admitted for longer than 24 hours (which eliminated early deaths and patients with minor injuries) determined that in-hospital mortality was not significantly different in male or female blunt trauma patients stratified by Injury Severity Score and age. The same factors that were predictive of in-hospital mortality in the total dataset were also significant in this secondary analysis.CONCLUSIONS:These population-based data confirm that female gender does not adversely affect in-hospital mortality in trauma when patients are appropriately stratified for other variables, including Injury Severity Score and age, that do significantly affect outcomes.

BACKGROUND Admission systemic inflammatory response syndrome (SIRS) score has been previously reported to be an accurate predictor of infection and outcome in trauma. However, the data were limited to the first 7 days of admission. Our objective in this follow-up study was to prospectively evaluate the utility of daily SIRS scores in the second and third week of admission as compared with the first week in prediction of nosocomial infection and outcome in high-risk trauma patients. METHODS Prospective data were collected on 1,277 consecutive trauma patients admitted during a 28-month period to the intensive care unit. SIRS scores were calculated daily for the first week and every other day for the following 2 weeks. Patients were categorized into SIRS occurring "early" (week 1), "middle" (week 2), and "late" (week 3). Centers for Disease Control and Prevention guidelines were used for the diagnosis of infection. Multivariate linear and logistic regression analyses were utilized for statistical analyses, controlling for the covariates of age, Injury Severity Score, and admission Glasgow Coma Scale score. RESULTS The trauma cohort included patients with blunt injuries (84%) and penetrating injuries (16%). The mean age was 43 +/- 21 years with an overall mortality of 14.7%. Nosocomial infection developed in 580 (45.4%) of the study patients (respiratory site most common) with a total of 1,001 infections (some patients with multiple infections). SIRS (defined as SIRS score >/=2) was common, with 92.4% of patients manifesting SIRS at admission. SIRS was most prevalent during the first week postinjury (91% of patients manifesting SIRS), decreasing to 69% and 50% during postinjury weeks 2 and 3. SIRS was more common in patients who acquired nosocomial infections compared with noninfected patients. Logistic regression analysis confirmed that patients with "middle" SIRS during week 2 (odds ratio [OR] 17.62, confidence interval [CI] 12.95-23.97, p < 0.0001, receiver operating characteristic [ROC] 0.83) and "late" SIRS during week 3 (OR18.12, CI 12.71-25.84, p < 0.0001, ROC 0.81) had significantly greater risk for nosocomial infection compared with patients with "early" SIRS during week 1 (OR 4.55, CI 2.57-8.06, p < 0.0001, ROC 0.65) postinjury. CONCLUSION SIRS is predictive of nosocomial infection in trauma through postinjury day 21. Nosocomial infection should be considered as a treatable cause of SIRS in trauma patients, and early diagnostic interventions should be initiated to evaluate for potential causes.

The beneficial impact of β blockade after an acute myocardial infarction (AMI) is clear, but β-adrenergic blockers differ in multiple characteristics, including lipophilicity and selectivity. The impact of these factors on the effects of β blockade is unknown. We therefore compared the effects of different β blockers on mortality after AMI. Charts of 201,752 patients with AMI were abstracted by the Cooperative Cardiovascular Project, a quality assurance program sponsored by the Health Care Financing Administration. Of the 69,338 patients prescribed β blockers, we compared mortality of patients receiving different β-adrenergic blockers using the Cox proportional-hazards model accounting for multiple factors that might influence survival. The mortality rates of the 2 selective agents, metoprolol and atenolol, were virtually identical (13.5% and 13.4% 2-year mortality, respectively). Compared with metoprolol, patients discharged on propranolol had a slightly increased mortality (15.9% 2-year mortality), which may be related to undetected differences at baseline. Survival with all of the drugs was superior to the 23.9% 2-year mortality seen in patients not receiving β blockers. Beta blockade overall was associated with a 40% improvement in survival. Although the use of β blockade after AMI has major prognostic importance, the present study suggests that the specific β blocker chosen will have little influence on mortality.

BACKGROUNDRecent studies have documented that the systemic inflammatory response syndrome (SIRS) score is a useful predictor of outcome in critical surgical illness. The duration and severity of SIRS are associated with posttrauma multiple organ dysfunction and mortality. We sought to determine whether the severity of SIRS at admission is an accurate predictor of mortality and length of stay (LOS) in trauma patients.METHODSProspective data of 4,887 trauma admissions to a Level I trauma center over a 18-month period (January 1997 to July 1998) were analyzed. Patients were stratified by age and Injury Severity Score (ISS), and a SIRS severity score (1 to 4) was calculated at admission (1 point for each component present: fever or hypothermia, tachypnea, tachycardia, and leukocytosis). The SIRS score was evaluated as an independent predictor of mortality and LOS by chi2 and multivariate logistic regression.RESULTSTrauma patients (n = 4,887, 83% blunt injuries, 72% male) had the following characteristics: 73.1% were age 18 to 45 years, 17.5% were age 46 to 65 years, and 9.4% were age > or =66 years; 77.7% had ISS less than 15, 18.8% had ISS 16 to 29, and 3.5% had ISS greater than 29. Analysis of variance adjusting for age and ISS determined that SIRS score of 2 was a significant predictor of LOS. Furthermore, the relative risk of death increased significantly with SIRS score of 2 when age and ISS were held constant.CONCLUSIONLogistic regression analysis confirmed that a SIRS score of 2 was a significant independent predictor of increased mortality and LOS in trauma patients. These data suggest that admission SIRS scoring in trauma patients is a simple tool that may be used as a predictor of outcome and resource utilization.

BACKGROUND AND PURPOSE Genetic enzyme variation and vitamin intake are important determinants of blood homocyst(e)ine levels. The prevalence of common genetic polymorphisms influencing homocyst(e)ine levels varies by race, and vitamin intake varies by socioeconomic status. Therefore, we examined the effect of vitamin intake, race, and socioeconomic status on the association of homocyst(e)ine with stroke risk. METHODS All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. One hundred sixty-seven cases of first ischemic stroke among women aged 15 to 44 years were compared with 328 controls identified by random-digit dialing from the same region. Risk factor data were collected by standardized interview and nonfasting phlebotomy. Plasma homocyst(e)ine was measured by high-performance liquid chromatography and electrochemical detection. RESULTS Blacks and whites did not differ in median homocyst(e)ine levels, nor did race modify the association between homocyst(e)ine and stroke. After adjustment for cigarettes per day, poverty status, and regular vitamin use, a plasma homocyst(e)ine level of >/=7.3 micromol/L was associated with an odds ratio for stroke of 1.6 (95% CI, 1.1 to 2.5). CONCLUSIONS The association between elevated homocyst(e)ine and stroke was independent not only of traditional vascular risk factors but also of vitamin use and poverty status. The degree of homocyst(e)ine elevation associated with an increased stroke risk in young women is lower than that previously reported for middle-aged men and the elderly and was highly prevalent, being present in one third of the control group.

PURPOSE: To determine the distribution and correlates of elevated total homocyst(e)ine (tHcy) concentration in a population of premenopausal black and white women.METHODS: Data from the Stroke Prevention in Young Women Study (N = 304), a population-based study of risk factors for stroke in women aged 15-44 years of age, were used to determine the distribution and correlates of elevated tHcy in black (N = 103) and white women (N = 201).RESULTS: The mean tHcy level for the population was 6.58 mu mol/L (range 2.89-26.5 mu mol/L). Mean tHcy levels increased with age, cholesterol level, alcohol intake, and number of cigarettes smoked tall: (p < 0.05). There were no race differences (mean tHcy 6.72 mu mol/L among blacks and 6.51 mu mol/L among whites; p = 0.4346). Regular use of multivitamins and increasing education was associated with significant reductions in tHcy concentration. Approximately 13% of the sample had elevated tHcy levels, defined as a tHcy concentration greater than or equal to 10.0 mu mol/L. Multivariate-adjusted correlates of elevated tHcy included education > 12 vs. less than or equal to 12 (odds ratio [OR] = 0.4, 95% confidence interval [CI] = 0.2-0.8); smoking greater than or equal to 20 cigarettes/day vs. nonsmokers (OR = 2.8, 95% CI = 1.1-7.3); and the regular use of multivitamins (OR = 0.4, 95% CI = 0.2-0.9).CONCLUSIONS: These results suggest that a substantial proportion of healthy young premenopausal women have tHcy levels that increase their risk for vascular disease. A number of potentially modifiable behavioral and environmental factors appear to be significantly related to elevated tHcy levels in young women.

Background and Purpose —Platelet glycoprotein IIb/IIIa (GpIIb-IIIa), a membrane receptor for fibrinogen and von Willebrand factor, has been implicated in the pathogenesis of acute coronary syndromes but has not been previously investigated in relation to stroke in young adults. Methods —We used a population-based case-control design to examine the association of the GpIIIa polymorphism P1A2 with stroke in young women. Subjects were 65 cerebral infarction cases (18 patients with and 47 without an identified probable etiology) 15 to 44 years of age from the Baltimore-Washington region and 122 controls frequency matched by age from the same geographic area. A face-to-face interview for vascular disease risk factors and a blood sample for the P1A2 allele and serum cholesterol were obtained from each participant. Logistic regression was used to estimate the odds ratio for one or more P1A2 alleles after adjustment for other risk factors. Results —Among cases and controls, the prevalence rates of one or more P1A2 alleles were 21% and 22% among blacks and 36% and 28% among whites, respectively. This genotype was significantly associated with hypertension only in black control subjects but otherwise not with any of the established vascular risk factors. The adjusted odds ratio for cerebral infarction of one or more P1A2 alleles was 1.1 (confidence interval [CI], 0.6 to 2.3) overall, 0.5 (CI, 0.1 to 7.1) among blacks, and 1.4 (CI, 0.5 to 3.7) among whites. For the cases with an identified probable etiology, the corresponding odds ratios were 3.0 (CI, 0.9 to 10.4) overall, 0.7 (CI, 0.1 to 7.1) among blacks, and 12.8 (CI, 1.2 to 135.0) among whites. Conclusions —No association was found between the P1A2 polymorphism of GpIIIa and young women with stroke. However, subgroup analyses showed that the P1A2 polymorphism of GpIIIa appeared to be associated with stroke risk among white women, particularly those with a clinically identified probable etiology for their stroke. Further work with an emphasis on stroke subtypes and with multiracial populations is warranted.

BACKGROUNDLong-term administration of beta-adrenergic blockers to patients after myocardial infarction improves survival. However, physicians are reluctant to administer beta-blockers to many patients, such as older patients and those with chronic pulmonary disease, left ventricular dysfunction, or non-Q-wave myocardial infarction.METHODSThe medical records of 201,752 patients with myocardial infarction were abstracted by the Cooperative Cardiovascular Project, which was sponsored by the Health Care Financing Administration. Using a Cox proportional-hazards model that accounted for multiple factors that might influence survival, we compared mortality among patients treated with beta-blockers with mortality among untreated patients during the two years after myocardial infarction.RESULTSA total of 34 percent of the patients received beta-blockers. The percentage was lower among the very elderly, blacks, and patients with the lowest ejection fractions, heart failure, chronic obstructive pulmonary disease, elevated serum creatinine concentrations, or type 1 diabetes mellitus. Nevertheless, mortality was lower in every subgroup of patients treated with beta-blockade than in untreated patients. In patients with myocardial infarction and no other complications, treatment with beta-blockers was associated with a 40 percent reduction in mortality. Mortality was also reduced by 40 percent in patients with non-Q-wave infarction and those with chronic obstructive pulmonary disease. Blacks, patients 80 years old or older, and those with a left ventricular ejection fraction below 20 percent, serum creatinine concentration greater than 1.4 mg per deciliter (124 micromol per liter), or diabetes mellitus had a lower percentage reduction in mortality. Given, however, the higher mortality rates in these subgroups, the absolute reduction in mortality was similar to or greater than that among patients with no specific risk factors.CONCLUSIONSAfter myocardial infarction, patients with conditions that are often considered contraindications to beta-blockade (such as heart failure, pulmonary disease, and older age) and those with nontransmural infarction benefit from beta-blocker therapy.

A polymorphism associated with a thermolabile variant (C677T) of the enzyme methylenetetrahydrofolate reductase has been associated with both elevated total homocysteine (tHcy) levels and risk for cardiovascular disease. Data from the Stroke Prevention in Young Women Study were used to determine the prevalence of the C677T genotype and to assess whether environmental factors modified the association between genotype and tHcy concentration. The C677T genotype prevalence was 80% -/-, 20% +/-, and 0% +/+ among 46 African-American women; and 39% -/-, 53% +/-, and 8% +/+ among 77 white women (P < 0.01). There was a trend toward higher tHcy levels in African-American women with the +/- genotype when compared with the -/- genotype (6.9 mumol/L vs 5.3 mumol/L respectively, p = 0.10); no association was found among the white women (6.0 mumol/L, -/-; 4.5 mumol/L, +/-; and 6.2 mumol/L, +/+; p = 0.67). Among African American women, those who smoked and were +/- genotype had the highest tHcy levels (8.0 mumol/L); while among white women, those who smoked and were -/- had the highest tHcy levels (8.1 mumol/L). Despite being hampered by a limited sample size, the thermolabile allele is significantly less common among African-American than white women. The association between genotype and tHcy concentration is influenced by smoking and multivitamin use.