Structural Similarities, in Relation with the Cross-Reactivity, of Hymenoptera Allergenic Dipeptidyl Peptidases IV-An Overall Comparison Including a New Dipeptidyl Peptidase IV Sequence from Vespa velutina.

(1) Background: Dipeptidyl Peptidases IV (DPPIVs), present in many organisms, are minor components in the venoms of Hymenoptera, where they have been identified as cross-reactive allergenic molecules. Considering that the structure of homologous DPPIVs is well characterized, we aimed to explain which regions have higher similarity among these proteins and present a comparison among them, including a new Vespa velutina DPPIV sequence. Moreover, two cases of sensitization to DPPIVs in wasp- and honeybee-sensitized patients are presented. (2) Methods: Proteomic analyses have been performed on the venom of the Asian hornet Vespa velutina to demonstrate the sequence of its DPPIV (allergen named Vesp v 3, with sequence accession number P0DRB8, and with the proteomic data available via ProteomeXchange with the identifier PXD046030). A comparison performed through their alignments and analysis of the three-dimensional structure showed a region with higher similarity among Hymenoptera DPPIVs. Additionally, ImmunoCAP™ determinations (including specific inhibition experiments), as well as IgE immunoblotting, are performed to demonstrate the allergenicity of Api m 5 and Ves v 3. (3) Results and Conclusions: The data presented demonstrate that the similarities among Hymenoptera DPPIVs are most likely localized at the C-terminal region of these enzymes. In addition, a higher similarity of the Vespa/Vespula DPPIVs is shown. The clinical cases analyzed demonstrated the allergenicity of Api m 5 and Ves v 3 in the sera of the allergic patients, as well as the presence of this minor component in the preparations used in venom immunotherapy.

Evaluating a unique enhanced recovery protocol in laparoscopic donor nephrectomy: A single center experience.

INTRODUCTION: Enhanced recovery after surgery (ERAS) protocols have been associated with a reduction in opioid consumption and a hastening in recovery in abdominal surgery. However, their impact on laparoscopic donor nephrectomy (LDN) has not been fully elucidated. The aim of this study is to evaluate opioid consumption and other relevant outcome measures before and after implementation of a unique LDN ERAS protocol. METHODS: 244 LDN patients were included in this retrospective cohort study. Forty-six underwent LDN prior to implementation of ERAS, whereas 198 patients received ERAS perioperative care. The primary outcome was daily oral morphine equivalent (OME) consumption averaged over the entire postoperative stay. Due to removal of preoperative oral morphine from the protocol partway through the study period, the ERAS group was further subdivided into morphine recipients and non-recipients for subgroup analysis. Secondary outcomes included the incidence of postoperative nausea and vomiting (PONV), length of stay, pain scores, and other relevant measures. RESULTS: ERAS donors consumed significantly fewer average daily OMEs than Pre-ERAS donors (21.5 vs. 37.6, respectively; p < .0001). There were no statistically significant differences in OME consumption between morphine recipients and non-recipients. The ERAS group experienced less PONV (44.4% requiring one or more rescue antiemetic postoperatively, vs. 60.9% of Pre-ERAS donors; p = .008). CONCLUSIONS: A protocol pairing lidocaine and ketamine with a comprehensive approach to preoperative PO intake, premedication, intraoperative fluid management and postoperative pain control is associated with reduced opioid consumption in LDN.

Pain Medicine Fellowship Video Interviews: A COVID-19 Trend or Here to Stay?

BACKGROUND: The COVID-19 pandemic ushered in a shift to a video format for pain medicine fellowship interviews for the 2021-2022 academic year, which represented a major change in the fellowship interview paradigm. OBJECTIVES: Our aim was to assess the experience of a video-only format in place of in-person interviews for Pain Medicine fellowship program directors and applicants after the 2020 fellowship interview season to determine the feasibility for continuation beyond COVID-19 travel restrictions. STUDY DESIGN: Survey via Qualtrics. SETTING: Academic pain medicine programs. METHODS: A consortium of program directors converged to discuss methods for determining the effectiveness and future direction of the video format for pain medicine fellowship interviews. Two surveys were formulated, one targeting pain medicine fellowship program directors and the other for candidates interviewing for the year 2021-2022. RESULTS: For applicants, 55 out of 170 responded for a response rate of 32.3%, and for program directors, 38 out of 95 responded for a response rate of 40%. Of the applicants, 45.7% stated that they would prefer video interviews, whereas 27.3% of program directors preferred video interviews. Savings of time and money were the most common reason for preferring video interviews. LIMITATIONS: The number of pain fellowship applicants invited was limited to those who interviewed at a subset of pain fellowships, which may not have been representative of all pain fellow applicants. CONCLUSIONS: The video format for pain medicine fellowship interviews was viewed positively by both candidates and program directors. We suspect that the video format alone or as a part of a hybrid model will become a routine method for the interview process in the future, given its time and cost benefits.

Standardisation of allergen products: 4. Validation of a candidate European Pharmacopoeia standard method for quantification of major grass pollen allergen Phl p 5.

BACKGROUND: The aim of the BSP090 project is the establishment of European Pharmacopoeia Chemical Reference Substances (CRSs) in combination with corresponding standard ELISA methods for quantification of major allergens in allergen products. Here, we present data of a Phl p 5-specific sandwich ELISA that proved suitable for the quantification of Phl p 5, one of the major Timothy grass (Phleum pratense) pollen allergens. METHODS: A Phl p 5-specific ELISA system was assessed with respect to accuracy, precision, inter-assay (within laboratory) and inter-laboratory variations, in a ring trial including 14 laboratories in Europe and the USA. Model samples containing recombinant Phl p 5a CRS as well as native grass pollen extracts were analysed. Each participant was instructed to perform at least one preliminary assay to familiarise with the protocol, followed by three independent assays. RESULTS: The candidate standard ELISA proved suitable to quantify recombinant and native Phl p 5 with satisfactory precision (93% of results within ±30% acceptance range). Inter-assay variation (max. GCV 24%) and especially inter-laboratory variation (max. GCV 13%) showed conclusive results. When assessing accuracy by means of recovery of recombinant spikes from a grass pollen extract matrix, similarly satisfactory spike recovery results were observed for the two spikes with higher concentrations (all within ±30% acceptance range), whereas recovery of the lowest concentration spike was slightly poorer with mean results of six laboratories exceeding acceptance range. CONCLUSIONS: Based on the collaborative study results, the assessed Phl p 5-specific immunoassay is appropriate to be proposed as European Pharmacopoeia standard method.

Purification and molecular characterization of phospholipase, antigen 5 and hyaluronidases from the venom of the Asian hornet (Vespa velutina).

The aim of this study was to purify potential allergenic components of Vespa velutina venom, the yellow legged Asian Hornet, and perform a preliminary characterization of the purified proteins. Starting from the whole venom of V.velutina, several chromatographic steps allowed to purify the phospholipase (named Vesp v 1), as well as the antigen 5 (Vesp v 5, the only allergenic component described as such so far). The two hyaluronidase isoforms found (Vesp v 2A and Vesp v 2B) cannot be separated from each other, but they are partially purified and characterized. Purity of the isolated proteins in shown by SDSPAGE, as well as by the results of the N-terminal sequencing. This characterization and nLC-MS/MS data provide most of the sequence for Vesp v 1 and Vesp v 5 (72 and 84% coverage, respectively), confirming that the whole sequences of the isolated natural components match with the data available in public transcriptomic databases. It is of particular interest that Vesp v 1 is a glycosylated phospholipase, a fact that had only described so far for the corresponding allergen components of Dolichovespula maculata and Solenopsis invicta. The availability of the complete sequences of Vespa velutina components permits comparison with homologous sequences from other Hymenoptera. These data demonstrate the higher similarity among the species of the genera Vespa and Vespula, in comparison to Polistes species, as it is especially observed with the hyaluronidases isoforms: the isoform Vesp v 2A only exists in the former genera, and not in Polistes; in addition, the most abundant isoform (Vesp v 2B) exhibits 93% sequence identity with the Ves v 2 isoform of Vespula vulgaris. Finally, the isolated components might be useful for improving the diagnosis of patients that could be allergic to stings of this invasive Asian hornet, as it has been the case of an improved diagnosis and treatment of other Hymenoptera-sensitized patients.

Phenotypes of Chronic Hepatitis B in Children From a Large North American Cohort.

OBJECTIVE: The aim of the study was to define chronic HBV phenotypes in a large, cohort of United States and Canadian children utilizing recently published population-based upper limit of normal alanine aminotransferase levels (ULN ALT), compared with local laboratory ULN; identify relationships with host and viral factors. BACKGROUND: Chronic hepatitis B virus (HBV) infection has been characterized by phases or phenotypes, possibly associated with prognosis and indications for therapy. METHODS: Baseline enrollment data of children in the Hepatitis B Research Network were examined. Phenotype definitions were inactive carrier: HBeAg-negative with low HBV DNA and normal ALT levels; immune-tolerant: HBeAg-positive with high HBV DNA but normal ALT levels; or chronic hepatitis B: HBeAg-positive or -negative with high HBV DNA and abnormal ALT levels. RESULTS: Three hundred seventy-one participants were analyzed of whom 274 were HBeAg-positive (74%). Younger participants were more likely be HBeAg-positive with higher HBV DNA levels. If local laboratory ULN ALT levels were used, 35% were assigned the immune tolerant phenotype, but if updated ULN were applied, only 12% could be so defined, and the remaining 82% would be considered to have chronic hepatitis B. Among HBeAg-negative participants, only 21 (22%) were defined as inactive carriers and 14 (14%) as HBeAg-negative chronic hepatitis B; the majority (61%) had abnormal ALT and low levels of HBV DNA, thus having an indeterminant phenotype. Increasing age was associated with smaller proportions of HBeAg-positive infection. CONCLUSIONS: Among children with chronic HBV infection living in North America, the immune tolerant phenotype is uncommon and HBeAg positivity decreases with age.

Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection.

BACKGROUND & AIMS: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America. METHODS: We collected data from the Hepatitis B Research Network-an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). RESULTS: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th-75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P<.0001), at risk alcohol use (OR, 2.27 vs none or moderate; P=.02), and higher FIB-4 values (OR, 1.85 per log2; P<.0001). Older age was associated with lower odds of an ALT flare (OR, 0.63 per 10 years; P=.004). Rate of decrease in level of HBV DNA by 1 log10 or more (59 vs 23 per 100 person-years for HB e antigen (HBeAg)-positive vs HBeAg-negative patients; P=.003) and HBeAg loss (47 vs 15 per 100 person-years; P=.002) were higher in patients with an ALT flare than in patients without, but the rate of HBsAg loss was similar (4 vs 2 per 100 person-years; P=.26). No hepatic decompensation, liver transplants, or deaths were observed in participants with ALT flares. CONCLUSION: In a large racially heterogeneous cohort of adults with chronic HBV infection, the cumulative incidence of severe ALT flares was low and associated with greater decreases in HBV DNA and loss of HBeAg, but not with loss of HBsAg.

Relationship Between Metabolic Syndrome, Alanine Aminotransferase Levels, and Liver Disease Severity in a Multiethnic North American Cohort With Chronic Hepatitis B.

OBJECTIVE: Metabolic syndrome (MS) is prevalent and is associated with adverse outcomes of liver disease. We evaluated the prevalence of MS and its influence on alanine aminotransferase (ALT) levels and fibrosis, as estimated by the aspartate aminotransferase-to-platelet ratio index (APRI), in a large, multiethnic North American cohort with chronic hepatitis B (HBV) infection. RESEARCH DESIGN AND METHODS: Adults with chronic HBV from 21 centers within the U.S. and Canada were evaluated at baseline and for up to 5 years (median 3.7 years) of follow-up. MS was defined as the presence of at least three of five criteria including waist circumference, blood pressure, glucose, triglyceride, and HDL levels. RESULTS: Analysis included 777 participants, of whom 171 (22%) had MS. Participants with MS (vs. those without MS) were older (median age 54.4 vs. 40.2 years), more often male (61% vs. 51%), and born in the U.S./Canada or had immigrated >20 years ago (60% vs. 43%). MS was not associated with ALT or APRI at baseline. Upon adjusted multivariable analysis of serial ALT values, ALT was significantly higher (mean 12%; P = 0.02) among those with MS at baseline and even higher (mean 19%; P = 0.003) among those with persistent MS compared with those with persistent absence of MS. MS was not associated with serial APRI on follow-up. CONCLUSIONS: MS was prevalent in this HBV cohort and was independently associated with higher ALT levels longitudinally. These findings highlight the importance of screening for MS and the potential for MS to influence ALT and its interpretation in the context of HBV treatment decisions.

Use of an electronic health record to identify prevalent and incident cardiovascular disease in type 2 diabetes according to treatment strategy.

BACKGROUND: The increasing use of electronic health records (EHRs) in clinical practice offers the potential to investigate cardiovascular outcomes over time in patients with type 2 diabetes (T2D). OBJECTIVE: To develop a methodology for identifying prevalent and incident cardiovascular disease (CVD) in patients with T2D who are candidates for therapeutic intensification of glucose-lowering therapy. METHODS: Patients with glycated hemoglobin (HbA1c) ≥7% (53 mmol/mol) while receiving 1-2 oral diabetes medications (ODMs) were identified from an EHR (2005-2011) and grouped according to intensification with insulin (INS) (n=372), a different class of ODM (n=833), a glucagon-like peptide receptor 1 agonist (GLP-1RA) (n=59), or no additional therapy (NAT) (n=2017). Baseline prevalence of CVD was defined by documented International Classification of Diseases Ninth Edition (ICD-9) codes for coronary artery disease, cerebrovascular disease, or other CVD with first HbA1c ≥7% (53 mmol/mol). Incident CVD was defined as a new ICD-9 code different from existing codes over 4 years of follow-up. ICD-9 codes were validated by a chart review in a subset of patients. RESULTS: Sensitivity of ICD-9 codes for CVD ranged from 0.83 to 0.89 and specificity from 0.90 to 0.96. Baseline prevalent (INS vs ODM vs GLP-1RA vs NAT: 65% vs 39% vs 54% vs 59%, p<0.001) and incident CVD (Kaplan-Meier estimates: 58%, 31%, 52%, and 54%, p=0.002) were greater in INS group after controlling for differences in baseline HbA1c (9.2±2.0% vs 8.3±1.2% vs 8.2±1.3% vs 7.7±1.1% (77 vs 67 vs 66 vs 61 mmol/mol), p<0.001) and creatinine (1.15±0.96 vs 1.10±0.36 vs 1.01±0.35 vs 1.07±0.45 mg/dL, p=0.001). CONCLUSIONS: An EHR can be an effective method for identifying prevalent and incident CVD in patients with T2D.

Diabetes and prediabetes in patients with hepatitis B residing in North America.

UNLABELLED: Diabetes is associated with liver disease progression and increased hepatocellular carcinoma risk, but factors associated with diabetes in patients with chronic hepatitis B virus (HBV) infection in North America are unknown. We aimed to determine factors predictive of diabetes and impaired fasting glucose (IFG) in a large HBV-infected multiethnic cohort. Adults with chronic HBV not receiving antiviral therapy were enrolled from 21 centers in North America. Diabetes was defined by history/medication use or fasting glucose≥126 mg/dL and IFG as fasting glucose 100-125 mg/dL. Of 882 patients included, 47.2% were female, 71.3% Asian, 83.7% foreign born, median age was 44 years, and median body mass index BMI 24.3 kg/m2. In this cohort, 26.0% were hepatitis B envelope antigen (HBeAg) positive, 43.9% had HBV DNA≥20,000 IU/mL, and 26.7% alanine aminotransferase (ALT)≥2× upper limit of normal (≥40 U/L women, ≥60 U/L men). Overall, 12.5% had diabetes and 7.8% IFG. The combined prevalence of diabetes or IFG was highest among blacks (36.7%) and those either born in the United States/Canada or foreign born with migration>20 years ago (25.5%). Obesity (odds ratio [OR]: 2.13), hyperlipidemia (OR, 4.13), hypertension (OR, 3.67), high ALT level (OR, 1.86), and family history of diabetes (OR, 3.43) were associated with diabetes. Factors associated with IFG were obesity (OR, 4.13) and hypertension (OR, 3.27), but also HBeAg positivity (OR, 0.39). Recent migration was negatively associated with diabetes among non-Asians (OR, 0.30). CONCLUSIONS: Diabetes is more prevalent in HBV-infected North American adults than the general population and is associated with known metabolic risk factors and liver damage, as determined by ALT levels. Among the foreign born, longer duration of North America residence predicted diabetes risk in non-Asians. These results highlight the opportunities for interventions to prevent diabetes especially among at-risk ethnic groups with HBV.

Triglyceride High-Density Lipoprotein Ratios Predict Glycemia-Lowering in Response to Insulin Sensitizing Drugs in Type 2 Diabetes: A Post Hoc Analysis of the BARI 2D.

Glycemic management is central in prevention of small vessel and cardiovascular complications in type 2 diabetes. With the plethora of newer medications and recommendations for a patient centered approach, more information is necessary to match the proper drug to each patient. We showed that BARI 2D, a five-year trial designed to compare two different glycemic treatment strategies, was suitable for assessing different responses according to different phenotypic characteristics. Treatment with insulin sensitizing medications such as thiazolidinediones and metformin was more effective in improving glycemic control, particularly in the more insulin resistant patient, when compared to the insulin provision strategy using insulin and or sulfonylureas. Triglyceride and high density lipoprotein ratio (TG/HDL-cholesterol ratio) was found to be a readily available and practical biomarker that helps to identify the insulin resistant patient. These results support the concept that not all medications for glycemic control work the same in all patients. Thus, tailored therapy can be done using phenotypic characteristics rather than a "one-size-fits-all approach."

Use of an Electronic Medical Record (EMR) to Identify Glycemic Intensification Strategies in Type 2 Diabetes.

BACKGROUND: Current treatment guidelines for type 2 diabetes (T2D) recommend individualized intensification of therapy for glycated hemoglobin (A1C) ≥ 7% in most patients. The purpose of this investigation was to explore the ability of an electronic medical record (EMR) to identify glycemic intensification strategies among T2D patients receiving pharmacologic therapy. METHODS: Patient records between 2005 and 2011 with documentation of A1C and active prescriptions for any diabetes medications were queried to identify potential candidates for intensification based on A1C ≥ 7% while on 1-2 oral diabetes medications (ODM). Patients with follow-up A1C values within 1 year of index A1C were grouped according to intensification with insulin, GLP-1 receptor agonists (GLP-1RA), a new class of ODM, or no intensification. Changes in A1C and continuation of intensification therapy were determined. RESULTS: A total of 4921 patients meeting inclusion criteria were intensified with insulin (n = 416), GLP-1RA (n = 68), ODM (n = 1408), or no additional therapy (n = 3029). Patients receiving insulin had higher baseline (9.3 ± 2.0 vs 8.3 ± 1.2 vs 8.3 ± 1.3 vs 7.6 ± 1.0%, P < .0001) and follow-up A1C (8.1 ± 1.6 vs 7.5 ± 1.2 vs 7.6 ± 1.3 vs 7.2 ± 1.1%, P < .0001) despite experiencing larger absolute A1C reductions (-1.2 ± 2.1 vs -0.8 ± 1.4 vs -0.7 ± 1.4 vs -0.3 ± 1.1%, P < .0001). Patients receiving GLP-1RA were more obese at baseline (BMI: 33.6 ± 7.1 vs 37.7 ± 6.1 vs 33.7 ± 6.8 vs 32.9 ± 7.1 kg/m(2), P < .0001) and follow-up (BMI: 33.9 ± 7.3 vs 36.6 ± 6.1 vs 33.8 ± 7.0 vs 32.4 ± 7.0 kg/m(2), P < .0001) despite experiencing more absolute weight reduction. Insulin was the most and GLP-1RA the least likely therapy to be continued. CONCLUSIONS: An EMR allows identification of prescribing practices and compliance with T2D treatment guidelines. Patients receiving intensification of glycemic medications had baseline A1C >8% suggesting that treatment recommendations are not being followed.

Determinants of successful glycemic control among participants in the BARI 2D trial: a post-hoc analysis.

OBJECTIVE: The BARI 2D trial compared insulin provision (IP) versus insulin sensitization (IS) for the primary outcome of total mortality in participants with T2DM and cardiovascular disease (CVD). In this analysis we examine baseline characteristics that are associated with successful long-term glycemic control. RESEARCH DESIGN AND METHODS: In a 2×2 factorial design, 2368 participants were randomized to either IP or IS therapy, and to either prompt revascularization with medical therapy or medical therapy alone. Successful long-term glycemic control (success) was defined by simultaneously meeting 1) a mean HbA1c level of <7.0% after each participant's third year of follow-up period, and 2) adherence with medications only from the assigned glycemic treatment arm during >80% of the BARI 2D follow-up. The association between baseline variables and success was determined using unadjusted and adjusted logistic regression models. RESULTS: 1917 participants (962 IP and 955 IS participants) had sufficiently long follow-up and data for this analysis. Among these IP and IS participants, 235 and 335 participants met both criteria of success, respectively (p<0.001). Those not on insulin at entry had higher odds of success (OR 2.25; CI 1.79-2.82) when treated with IS versus IP medications, irrespective of baseline HbA1c levels. Younger age, shorter duration of T2DM, and lower HbA1c at baseline were also each independently associated with higher success when treated with IS versus IP medications. CONCLUSION: Patients similar to those in the BARI 2D trial may have a higher chance of achieving success with IS versus IP medications if they are younger, have shorter duration of T2DM, have lower HbA1c levels, have moderate or strenuous physically activity, and are not on insulin. In contrast, increasing age, longer duration of T2DM, higher HbA1c, and insulin therapy are associated with increased chance of success if treated with IP medications.

Rosiglitazone and outcomes for patients with diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: Rosiglitazone improves glycemic control for patients with type 2 diabetes mellitus, but there remains controversy regarding an observed association with cardiovascular hazard. The cardiovascular effects of rosiglitazone for patients with coronary artery disease remain unknown. METHODS AND RESULTS: To examine any association between rosiglitazone use and cardiovascular events among patients with diabetes mellitus and coronary artery disease, we analyzed events among 2368 patients with type 2 diabetes mellitus and coronary artery disease in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. Total mortality, composite death, myocardial infarction, and stroke, and the individual incidence of death, myocardial infarction, stroke, congestive heart failure, and fractures, were compared during 4.5 years of follow-up among patients treated with rosiglitazone versus patients not receiving a thiazolidinedione by use of Cox proportional hazards and Kaplan-Meier analyses that included propensity matching. After multivariable adjustment, among patients treated with rosiglitazone, mortality was similar (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.58-1.18), whereas there was a lower incidence of composite death, myocardial infarction, and stroke (HR, 0.72; 95% CI, 0.55-0.93) and stroke (HR, 0.36; 95% CI, 0.16-0.86) and a higher incidence of fractures (HR, 1.62; 95% CI, 1.05-2.51); the incidence of myocardial infarction (HR, 0.77; 95% CI, 0.54-1.10) and congestive heart failure (HR, 1.22; 95% CI, 0.84-1.82) did not differ significantly. Among propensity-matched patients, rates of major ischemic cardiovascular events and congestive heart failure were not significantly different. CONCLUSIONS: Among patients with type 2 diabetes mellitus and coronary artery disease in the BARI 2D trial, neither on-treatment nor propensity-matched analysis supported an association of rosiglitazone treatment with an increase in major ischemic cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Favorable effects of insulin sensitizers pertinent to peripheral arterial disease in type 2 diabetes: results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

OBJECTIVE: The aim of this manuscript was to report the risk of incident peripheral arterial disease (PAD) in a large randomized clinical trial that enrolled participants with stable coronary artery disease and type 2 diabetes and compare the risk between assigned treatment arms. RESEARCH DESIGN AND METHODS: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial randomly assigned participants to insulin sensitization (IS) therapy versus insulin-providing (IP) therapy for glycemic control. Results showed similar 5-year mortality in the two glycemic treatment arms. In secondary analyses reported here, we examine the effects of treatment assignment on the incidence of PAD. A total of 1,479 BARI 2D participants with normal ankle-brachial index (ABI) (0.91-1.30) were eligible for analysis. The following PAD-related outcomes are evaluated in this article: new low ABI≤0.9, a lower-extremity revascularization, lower-extremity amputation, and a composite of the three outcomes. RESULTS: During an average 4.6 years of follow-up, 303 participants experienced one or more of the outcomes listed above. Incidence of the composite outcome was significantly lower among participants assigned to IS therapy than those assigned to IP therapy (16.9 vs. 24.1%; P<0.001). The difference was significant in time-to-event analysis (hazard ratio 0.66 [95% CI 0.51-0.83], P<0.001) and remained significant after adjustment for in-trial HbA1c (0.76 [0.59-0.96], P=0.02). CONCLUSIONS: In participants with type 2 diabetes who are free from PAD, a glycemic control strategy of insulin sensitization may be the preferred therapeutic strategy to reduce the incidence of PAD and subsequent outcomes.

Evaluation of the effect of pollution and fungal disease on Pinus radiata pollen allergenicity.

BACKGROUND: Pollutants and other stressing factors like mold infection might increase the production of pathogen-related proteins in plants. Since this is invoked as one of the causes for the high prevalence of allergic diseases in developed countries, we aimed to determine the potential effect of environmental pollution, with or without mold infection of the trees, on the allergenic potency of pine pollen (Pinus radiata). METHODS: Pine pollen samples were recovered from three selected areas: low polluted (A), highly polluted (B) and highly polluted and infected with fungi (Spheropsis sapinea) (C). The allergenic potency of pollen from areas A, B or C were compared in vivo in 35 pine pollen-allergic patients by skin prick test and specific IgE (sIgE) quantification. Pollen was also analyzed in vitro by SDS-PAGE immunoblotting, RAST inhibition and cDNA-AFLP (amplified fragment length polymorphism) to compare differences in proteins and mRNA expression. RESULTS: The allergenic potency measured by prick test, sIgE and RAST inhibition was greater in pollen A, which was exposed to smaller amounts of NO(x), PM(10) and SO(2) but greater amounts of O(3). No differences were found in IgE-binding bands in immunoblotting or densitometry of the bands. In cDNA-AFLP, three homologous transcript-derived fragments were expressed in samples B only, with an expressed sequence tag related with stress-regulated gene expression. CONCLUSIONS: A greater allergenic potency, in terms of skin tests and sIgE, is observed in pine pollen coming from unpolluted areas. We consider that this fact might be related to a higher exposure to ozone, resulting in a greater expression of allergenic proteins.

Ankle-brachial index and cardiovascular outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial.

BACKGROUND: Peripheral arterial disease increases cardiovascular risk in many patient populations. The risks associated with an abnormal ankle-brachial index (ABI) in patients with type 2 diabetes and stable coronary artery disease have not been well described with respect to thresholds and types of cardiovascular events. METHODS: We examined 2,368 patients in the BARI 2D trial who underwent ABI assessment at baseline. Death and major cardiovascular events (death, myocardial infarction and stroke) during follow-up (average 4.3 years) were assessed across the ABI spectrum and by categorized ABI: low (≤0.90), normal (0.91-1.3), high (>1.3), or noncompressible. RESULTS: A total of 12,568 person-years were available for mortality analysis. During follow-up, 316 patients died, and 549 had major cardiovascular events. After adjustment for potential confounders, with normal ABI as the referent group, a low ABI conferred an increased risk of death (relative risk [RR] 1.6, CI 1.2-2.2, P = .0005) and major cardiovascular events (RR 1.4, CI 1.1-1.7, P = .004). Patients with a high ABI had similar outcomes as patients with a normal ABI, but risk again increased in patients with a noncompressible ABI with a risk of death (RR 1.9, CI 1.3-2.8, P = .001) and major cardiovascular event (RR 1.5, CI 1.1-2.1, P = .01). CONCLUSIONS: In patients with coronary artery disease and type 2 diabetes, ABI screening and identification of ABI abnormalities including a low ABI (<1.0) or noncompressible artery provide incremental prognostic information.

The prevalence and predictors of an abnormal ankle-brachial index in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

OBJECTIVE: To examine ankle-brachial index (ABI) abnormalities in patients with type 2 diabetes and coronary artery disease (CAD). RESEARCH DESIGN AND METHODS: An ABI was obtained in 2,240 patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. ABIs were classified as: normal, 0.91-1.3; low, ≤ 0.9; high, >1.3; or noncompressible artery (NC). Baseline characteristics were examined according to ABI and by multivariate analysis. RESULTS ABI was normal in 66%, low in 19%, and high in 8% of patients, and 6% of patients had NC. Of the low ABI patients, 68% were asymptomatic. Using normal ABI as referent, low ABI was independently associated with smoking, female sex, black race, hypertension, age, C-reactive protein, diabetes duration, and lower BMI. High ABI was associated with male sex, nonblack race, and higher BMI; and NC artery was associated with diabetes duration, higher BMI, and hypertension. CONCLUSIONS: ABI abnormalities are common and often asymptomatic in patients with type 2 diabetes and CAD.