Timing of complementary food introduction and age at diagnosis of type 1 diabetes: the SEARCH nutrition ancillary study (SNAS).

The association between timing of complementary food introduction and age at diagnosis of type 1 diabetes was investigated among 1077 children in the SEARCH for Diabetes in Youth study. Age at diagnosis was 5 months earlier for children introduced to sugar-sweetened beverages (SSB) in the first 12 months of life compared with those who were not (9.0±0.2 vs 9.5±0.1; P=0.02) independent of human leukocyte antigen (HLA) risk status. Analyses stratified by HLA risk status found that children with a high-risk HLA genotype had an earlier age at diagnosis if they were introduced to fruit juice in the first year of life (mean age at diagnosis=9.3±0.1, 9.1±0.1 and 9.6±0.2 for introduction at ⩽6 months, between 7 and 11 months and ⩾12 months, respectively; P=0.04). Introduction of SSB in the first year of life may accelerate the onset of type 1 diabetes independent of HLA risk status.

Comparison of two waist circumference measurement protocols: the SEARCH for diabetes in youth study.

BACKGROUND: Reports comparing waist circumference (WC) measurements from young populations are scarce. OBJECTIVES: We compared two protocols for measuring waist circumference in a sample of youth with diabetes. METHODS: Participants were enrolled in the SEARCH for Diabetes in Youth Study (SEARCH). WC was measured at least twice by the National Health and Nutrition Examination Survey (NHANES) protocol and twice by the World Health Organization (WHO) protocol. Method-specific averages were used in these analyses. RESULTS: Among 6248 participants, the mean NHANES WC (76.3 cm) was greater than the mean WHO WC (71.9 cm). Discrepancies between protocols were greater for females than males, among older participants, and in those with higher body mass index (BMI). In both sexes and four age strata, the WCs using either method were highly correlated with BMI z-score. The within-method differences between the first and second measurements were similar for the two methods. CONCLUSIONS: These analyses do not provide evidence that one of these two methods is more reproducible or is a better indicator of obesity as defined by BMI z-scores.

Clinical review: Volkmann's ischaemic contracture.

INTRODUCTION: Volkmann's ischaemic contracture is a devastating condition with serious motor and sensory functional implications for the affected limb. This clinical review outlines acute compartment syndrome and Volkmann's ischaemic contracture, their presentation, evolution and current management. AIMS: This up-to-date clinical review is aimed at both specialist and non-specialist healthcare professionals who can play a key role in the early recognition of signs and symptoms to allow prevention of the condition. METHODS: No Cochrane reviews are currently available regarding Volkmann's ischaemic contracture. Medline, EMBASE and Scopus databases were searched using the MeSH terms 'Volkmann's ischaemic/ischemic contracture' and 'compartment syndrome'. Current guidelines were referred to. DISCUSSION: Prevention is essential regarding Volkmann's ischaemic contracture. This can be achieved through careful observation of patients sustaining high-risk extremity injuries, notably, children with supracondylar fractures of the humerus, and immediate decompression if signs and symptoms of a compartment syndrome are present. Increased awareness amongst doctors of compartment syndrome is fundamental and will allow early recognition, clinical diagnosis and subsequent fasciotomy.

Efficacy, safety and lack of immunogenicity of insulin aspart compared with regular human insulin for women with gestational diabetes mellitus.

AIM: The efficacy and safety of insulin aspart (IAsp), a rapid-acting human insulin analogue, were compared with regular human insulin (HI) as the bolus component of basal-bolus therapy for subjects with gestational diabetes mellitus (GDM). METHODS: In a randomized, parallel-group, open-labelled trial, 27 women with GDM (age 30.7 +/- 6.3 years, HbA(1c) < 7%) were randomized to receive IAsp (5 min before meal) or HI (30 min before meal). The trial period extended from diagnosis of GDM (18-28 weeks) to 6 weeks postpartum. RESULTS: Both treatment groups maintained good overall glycaemic control during the study (beginning and end of study HbA(1c)< or = 6%). During the meal test, mean glucose at week 6 (IAsp 4.2 +/- 0.57 mmol/l, HI 4.8 +/- 0.86 mmol/l) was slightly lower than at week 0 (IAsp 4.9 +/- 0.59 mmol/l, HI 5.1 +/- 0.36 mmol/l). However, change from baseline values for average glucose (IAsp -1.09 +/- 0.54 mmol/l, HI -0.54 +/- 0.74 mmol/l; P = 0.003) and C-peptide (IAsp -0.50 +/- 0.67 nmol/l, HI -0.30 +/- 0.70 nmol/l; P = 0.027) were significantly lower after IAsp treatment than HI treatment. No major hypoglycaemic events were reported during the study. Cross-reacting insulin antibody binding increased slightly from baseline in both treatments groups (end of study: IAsp 2.1 +/- 5.4%, HI 6.4 +/- 13.9%), whereas antibodies specific to IAsp or HI remained relatively low (< 1% binding). CONCLUSION: IAsp was more effective than HI in decreasing postprandial glucose concentrations. Duration of IAsp injection 5 min before a meal rather than 30 min prior to meals offers a more convenient therapy for subjects with GDM. Overall safety and effectiveness of IAsp were comparable to HI in pregnant women with GDM.

Pregnancy plasma glucose levels exceeding the American Diabetes Association thresholds, but below the National Diabetes Data Group thresholds for gestational diabetes mellitus, are related to the risk of neonatal macrosomia, hypoglycaemia and hyperbilirubinaemia.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is a risk factor for perinatal complications. In several countries, the criteria for the diagnosis of GDM have been in flux, the American Diabetes Association (ADA) thresholds recommended in 2000 being lower than those of the National Diabetes Data Group (NDDG) that have been in use since 1979. We sought to determine the extent to which infants of women meeting only the ADA criteria for GDM are at increased risk of neonatal complications. MATERIALS AND METHODS: In a multiethnic cohort of 45,245 women who did not meet the NDDG criteria and were not treated for GDM, we conducted nested case-control studies of three complications of GDM that occurred in their infants: macrosomia (birthweight >4,500 g, n = 494); hypoglycaemia (plasma glucose <2.2 mmo/l, n = 488); and hyperbilirubinaemia (serum bilirubin > or =342 micromol/l (20 mg/dl), n = 578). We compared prenatal glucose levels of the mothers of these infants and mothers of 884 control infants. RESULTS: Women with GDM by ADA criteria only (two or more glucose values exceeding the threshold) had an increased risk of having an infant with macrosomia (odds ratio OR = 3.40, 95% CI = 1.55-7.43), hypoglycaemia (OR = 2.61, 95% CI = 0.99-6.92) or hyperbilirubinaemia (OR = 2.22, 95% CI = 0.98-5.04). Glucose levels 1 h after the 100-g glucose challenge that exceeded the ADA threshold were particularly strongly associated with each complication. CONCLUSIONS/INTERPRETATION: These results lend support to the ADA recommendations and highlight the importance of the 1-h glucose measurement in a diagnostic test for GDM.

The combination oral and nutritional treatment of late-onset diabetes mellitus (CONTROL DM) trial results.

OBJECTIVE: To examine the effect of short-term improvements in glycaemic control on brachial artery endothelial function as a marker of cardiovascular health. METHODS: Persons with Type 2 diabetes who were poorly controlled on oral therapy were randomly assigned to monotherapy with repaglinide or combination therapy with repaglinide plus metformin. Brachial artery flow-mediated vasodilation was assessed by ultrasonography at randomization and following 16 weeks of therapy. The primary outcome was change in brachial artery endothelial function from baseline. Comparison of randomized groups was a secondary aim. RESULTS: Eighty-six participants were randomized, and 83 were followed to study completion. Post occlusion brachial artery vasodilation was 3.74% at baseline and 3.82% following 16 weeks of therapy (P = 0.77). The treatment effect was 0.08% (95% CI: -0.48%, 0.64%). No difference was seen between treatment groups (P = 0.69). Overall, A1C was reduced from 8.3% to 7.0%, with a greater reduction in the combination therapy group (from 8.4% to 6.7%) than in the monotherapy group (from 8.3% to 7.3%, p for difference between groups = 0.01). Statistically significant reductions were observed in fasting glucose, and plasminogen activator inhibitor-1. Statistically significant increases were observed for fasting insulin, uric acid, weight and BMI. CONCLUSIONS: Brachial artery endothelial function was not influenced by short-term improvements in glycaemic control. The CONTROL DM group was successful in lowering A1C. Future research should explore more intensive and longer-lasting improvements in glycaemic control on endothelial function. Some data previously published in abstract form (Diabetes 2001; 50 (Suppl. 2): A217).

Application of a propensity score to adjust for channelling bias with NSAIDs.

PURPOSE: To compare the relative risks of upper GI haemorrhage (UGIH) in users of Newer versus Older, non-specific NSAIDs when adjusted for channelling bias by regression on individual covariates, a propensity score and both. METHODS: Cohort study of patients prescribed NSAIDs between June 1987 and January 2000. Exposure to Newer and Older non-specific NSAIDs was identified, and risk factors evaluated for each patient. Results of multiple covariate analyses and the propensity scoring technique to assess potential channelling bias in comparisons between Newer and Older non-specific NSAIDs were compared. RESULTS: This study included 7.1 thousand patient years (tpy) exposure to meloxicam, 1.6 tpy exposure to coxibs, and 628 tpy exposure to Older non-specific NSAIDs. Patients receiving Newer NSAIDs were older, more likely to have a history of GI symptoms, and at higher risk for GI complications. Adjusting for these risk factors reduced the relative risks of UGIH on meloxicam and coxibs versus Older non-specific NSAIDs to 0.84 (95%CI 0.60, 1.17) and 0.36 (0.14, 0.97) respectively. CONCLUSIONS: Channelling towards high GI risk patients occurred in the prescribing of Newer NSAIDs. Propensity scores highlighted the markedly different risk profiles of users of Newer and Older non-specific NSAID. Correcting for channelling bias, coxib exposure, but not meloxicam exposure, was associated with less UGIH than Older non-specific NSAID exposure. In the present study, corrections made by regression on a propensity score and on individual covariates were similar.

Channelling of patients taking NSAIDs or cyclooxygenase-2-specific inhibitors and its effect on interpretation of outcomes.

When new drugs with improved safety or efficacy are introduced, they may be preferentially prescribed to specific populations of patients. Safety and efficacy may be underestimated if such channelling effects are not recognized. Meloxicam and cyclooxygenase (COX)-2-specific inhibitors were developed as safer alternatives to non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of osteoarthritis and rheumatoid arthritis. Studies of the use of meloxicam and COX-2-specific inhibitors demonstrate that both of these drugs are being prescribed to patients at increased risk of gastrointestinal adverse drug events. In the case of COX-2-specific inhibitors, this channelling appears to represent a prescribing pattern consistent with current recommendations. Subsequent analysis of the data, after adjusting for channelling bias, showed that the risk of gastrointestinal toxicity for meloxicam was similar to that for other NSAIDs, while COX-2-specific inhibitors reduced the risk of developing gastrointestinal adverse drug events by approximately 60%. These studies serve as examples of observed channelling bias and highlight the need for adjusting for channelling in order to provide a valid assessment of relevant outcomes for drugs likely to be preferentially prescribed to specific populations.

Channelling bias and the incidence of gastrointestinal haemorrhage in users of meloxicam, coxibs, and older, non-specific non-steroidal anti-inflammatory drugs.

BACKGROUND: Although clinical trial results suggest that meloxicam has less gastrointestinal toxicity than most other non-steroidal anti-inflammatory drugs (NSAIDs), in practice it has been associated with a large number of yellow card reports of gastrointestinal complications. AIMS: To estimate whether meloxicam and the coxibs, rofecoxib and celecoxib, have been channelled towards high risk patients, and to estimate the risk of hospitalisation for gastrointestinal haemorrhage associated with the use of these drugs, allowing for the effects of channelling. PATIENTS: Using the UK General Practice Research Database, this study included 7.1 thousand patient years (tpy) exposure to meloxicam, 1.6 tpy exposure to coxibs, and 628 tpy exposure to older non-specific NSAIDs. METHODS: Cohort study of patients who received a prescription for an NSAID between June 1987 and January 2001. Exposure to newer NSAIDs (meloxicam, rofecoxib, celecoxib) and to older non-specific NSAIDs was identified. Channelling was assessed on factors including: demographic variables; diagnosis of arthritis; history of NSAID use or gastrointestinal events, including gastrointestinal haemorrhage; and use of ulcer healing drugs. RESULTS: Most risk factors for gastrointestinal haemorrhage were more prevalent among patients prescribed the newer NSAIDs. Adjusting for these risk factors reduced the relative risks of gastrointestinal haemorrhage on meloxicam and coxibs versus older non-specific NSAIDs to 0.84 (95% confidence interval 0.60, 1.17) and 0.36 (0.14, 0.97), respectively. CONCLUSIONS: Channelling towards high risk gastrointestinal patients occurred in the prescribing of newer NSAIDs. After attempting to correct for channelling bias, coxib exposure, but not meloxicam exposure, was associated with a significantly lower risk of gastrointestinal haemorrhage than older non-specific NSAID exposure.

Intrauterine diabetic environment confers risks for type 2 diabetes mellitus and obesity in the offspring, in addition to genetic susceptibility.

Numerous studies have reported that offspring whose mothers had type 2 diabetes mellitus (DM) are more likely to develop type 2 DM, impaired glucose tolerance, and obesity at an early age than offspring whose fathers had DM. Exposure to the diabetic intrauterine environment has been shown to be an important risk factor for all these conditions. To what extent transmission of type 2 DM from mother to offspring is the effect of genetic inheritance and to what extent it is the long-term consequence of exposure to maternal hyperglycemia is still uncertain. There are, of course, interactions between the diabetic intrauterine environment and genetics. Several data in experimental animals as well as in humans suggest, however, that exposure of the fetus to the mother's DM confers a risk for type 2 DM and obesity that is above any genetically transmitted susceptibility. In the Pima Indian population much of the increase in childhood type 2 DM can be attributed to the diabetic intrauterine environment. This suggests that intensive glucose control during pregnancy might have extended beneficial effects, contributing to a decrease in the prevalence of childhood type 2 DM.

Family and genetic studies of indices of insulin sensitivity and insulin secretion in Pima Indians.

BACKGROUND: The present analyses were conducted to examine the extent to which insulin sensitivity and insulin secretion, assessed using simple indices derived from an oral glucose tolerance test, are influenced by genetic factors, and to assess whether these genetic factors overlap with those influencing susceptibility to type 2 diabetes in Pima Indians. METHODS: Indices calculated from fasting and 2-h post-load insulin (I(0), I(120)) and glucose (G(0), G(120)) concentrations included insulin sensitivity index [ISI(0)=10(4)/(I(0).G(0))] and corrected insulin response [CIR(120)=I(120)/[G(120).(G(120)-70 mg/dl)]]. Heritability (h(2)) was determined using variance components methods in 1421 non-diabetic individuals from 446 sibships. Among 595 individuals in 186 sibships, genome-wide quantitative trait linkage analyses of ISI(0) and CIR(120) were conducted and affected-sibling analyses of diabetic siblings stratified by prediabetic measurements of ISI(0) and CIR(120) were also performed. RESULTS: Both ISI(0) (h(2)=0.37+/-0.06) and CIR(120) (h(2)=0.25+/-0.07) were moderately heritable. Modest evidence for linkage with CIR(120) (logarithm of odds (LOD)=1.6) was observed on chromosome 1q in a region previously shown to have linkage with young-onset diabetes in Pimas. When diabetic siblings were stratified by CIR(120), evidence for linkage in this region was strongest (LOD=1.5) among those with a low CIR(120). Additional regions with modest evidence for linkage with ISI(0) were observed on chromosomes 9p (LOD=2.0) and 14p (LOD=1.7). CONCLUSIONS: The present analyses suggest that insulin sensitivity and insulin secretion are influenced by genetic factors in Pima Indians. The linkage analyses suggest that the putative diabetes-susceptibility gene on chromosome 1q affects insulin secretion. Published in 2001 by John Wiley & Sons, Ltd.

Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians.

OBJECTIVE: Markers of inflammation have recently been shown to be predictive of cardiovascular disease (CVD). Furthermore, the excess mortality in rheumatoid arthritis (RA), a disease characterized by chronic polyarthritis, is chiefly due to death from CVD. With this background, we studied the effect of inflammation, as reflected by the number of joints with soft tissue swelling, and rheumatoid factor (RF) seropositivity on CVD-related mortality. METHODS: Mortality rates and rate ratios for all-cause and CVD-related deaths were computed in a longitudinal, population-based cohort of Pima Indians in Arizona from 1965 through 1994. Repeated health examinations were performed, involving systematic assessment of the features of RA, cardiovascular risk factors, serum titers of RF, as well as mortality. The cohort comprised 4,120 subjects (1,861 men, 2,259 women) who were examined an average of 3.5 times during a mean followup of 14 years. RESULTS: During the followup period, 182 CVD-related deaths ocurred. The age- and sex-adjusted CVD-related mortality rates increased significantly with the presence of a higher number of joints with soft tissue swelling (Ptrend = 0.04), and were 2.07 (95% confidence interval [95% CI] 1.30-3.31) times as high in those subjects who had 2 or more swollen joints as in those who had none. There were no significant additional effects on CVD-related mortality when seropositivity for RF or a previous diagnosis of RA were considered. In age- and sex-adjusted proportional hazards analyses, which were controlled for possible confounders, the effect of swollen joints remained significant (mortality rate ratio 1.33, 95% CI 1.04-1.71 per category increase [no swollen joints, 1 swollen joint, at least 2 swollen joints]). CONCLUSION: Joint swelling is a significant risk factor for CVD-related death, independent of other known risk factors including a diagnosis of RA. This finding supports the hypothesis that inflammatory mechanisms are important for the development of CVD.

The effect of nonsteroidal anti-inflammatory drugs on the use of gastroprotective medication in people with arthritis.

OBJECTIVE: To estimate the incidence of gastroprotective medication use among users and nonusers of prescription nonsteroidal anti-inflammatory drugs (NSAIDs) who have arthritis. STUDY DESIGN: A retrospective cohort study. PATIENTS AND METHODS: We used the Protocare Sciences proprietary Managed Care Organization database, which contains data on more than 3 million lives, to identify 57,136 patients given an initial diagnosis of osteoarthritis (OA; International Classification of Disease, Ninth Revision, Clinical Modification [ICD-9-CM] codes: 715, 721.0, 721.3, or 721.9) or rheumatoid arthritis (RA; ICD-9-CM codes: 714.0, 714.1, 714.2, or 714.9); the diagnoses were made during inpatient or outpatient medical encounters occurring between October 1, 1993, and September 30, 1997. The duration of therapy was calculated as the sum of the total number of days of receipt of all prescriptions during the year. The prescribed daily dose was determined by multiplying the drug dose by the number of pills dispensed and the dividing the product by the number of days supplied, as noted in the pharmacy records. RESULTS: During the year after NSAID initiation, 27% of people with RA and 12% of those with OA were chronic NSAID users. NSAID users with RA were 4 times as likely as NSAID nonusers with RA to begin using a gastroprotective agent within the first year; NSAID users with OA were twice as likely as nonusers with OA to do so. CONCLUSION: The use of gastroprotective agents during the first year after NSAID initiation for the treatment of arthritis was greater than their use by those who did not take NSAIDs.

A framework for evaluating the clinical consequences of initial therapy with NSAIDs, NSAIDs plus gastroprotective agents, or celecoxib in the treatment of arthritis.

OBJECTIVE: The purpose of this study is to provide a framework for estimating the economic efficiency of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), concomitant gastroprotective agents (GPAs) to reduce the risk of NSAID toxicity, and celecoxib, a specific cyclo-oxygenase-2 inhibitor. Concomitant GPA therapies considered include one of the following: proton pump inhibitors (PPIs) plus NSAIDs, histamine H2 receptor antagonists (H2RAs) plus NSAIDs, misoprostol plus NSAIDs, and a single tablet formulation of diclofenac/misoprostol. DESIGN: The study employs a decision-tree framework to establish probabilities of upper gastrointestinal (GI) adverse events occurring over a 6-month time frame. Celecoxib clinical trial data are used to establish probabilities of upper GI events for celecoxib and NSAIDs, and published literature is used to predict upper GI events for the other concomitant therapies. Upper GI adverse events included in the decision-tree are as follows: GI discomfort, symptomatic ulcer, serious GI complications (with and without death), and anaemia with occult bleeding. MAIN OUTCOME MEASURES AND RESULTS: Clinical probabilities indicate celecoxib has significant tolerability and safety advantages compared with nonselective NSAIDs. Celecoxib also reduces the risk of GI adverse events to a similar or superior degree when compared with reductions observed with NSAIDs with concomitant GPAs. CONCLUSION: Use of celecoxib is expected to significantly reduce the economic costs of GI toxicity and its associated morbidity.

Birth weight as a predictor of type 2 diabetes mellitus: the U-shaped curve.

Recent findings have sparked intense interest in birth weight as a predictor of type 2 diabetes mellitus. In some populations, there is an inverse association between birth size and disease; however, in the Pima Indians, a population with very high rates of gestational diabetes, high birth weight and low birth weight are associated with diabetes. This results in a U-shaped curve with higher diabetes rates in both tails of the distribution. Similarly, there are reports of an inverse association between stature and prevalence of gestational diabetes, but, in California Latina women with gestational diabetes, there is a positive association between stature and glucose concentration. Could these disparate findings also represent the two ends of a U-shaped curve? The disparities are likely due to differences in the environment, both in utero and postnatally, that different groups experience.

Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships.

Intrauterine exposure to diabetes is associated with an excess of diabetes and obesity in the offspring, but the effects of intrauterine exposure are confounded by genetic factors. To determine the role of the intrauterine diabetic environment per se, the prevalence of diabetes and the mean BMI were compared in siblings born before and after their mother was recognized as having diabetes. Nuclear families in which at least one sibling was born before and one after the mother was diagnosed with type 2 diabetes were selected. Consequently, the siblings born before and after differed in their exposure to diabetes in utero. A total of 58 siblings from 19 families in which at least one sibling had diabetes were examined at similar ages (within 3 years). The risk of diabetes was significantly higher in siblings born after the mother developed diabetes than in those born before the mother's diagnosis of diabetes (odds ratio 3.7, P = 0.02). In 52 families, among 183 siblings without diabetes, the mean BMI was 2.6 kg/m2 higher in offspring of diabetic than in offspring of nondiabetic pregnancies (P = 0.003). In contrast, there were no significant differences in risk of diabetes or BMI between offspring born before and after the father was diagnosed with diabetes. Intrauterine exposure to diabetes per se conveys a high risk for the development of diabetes and obesity in offspring in excess of risk attributable to genetic factors alone.