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Cardiovascular and Metabolic Risk
Incretin-Based Therapies and Diabetic Retinopathy: Real-World Evidence in Older U.S. Adults
Tiansheng Wang1,
Jin-Liern Hong1,
Emily W. Gower1,
Virginia Pate1,
Seema Garg2,
John B. Buse3 and
Til Stürmer1⇑
1Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC
2Department of Ophthalmology, University of North Carolina School of Medicine, Chapel Hill, NC
3Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
Corresponding author: Til Stürmer, til.sturmer{at}post.harvard.edu.
Diabetes Care 2018 Sep; 41(9): 1998-2009. https://doi.org/10.2337/dc17-2285
Suppl Material
OBJECTIVE Recent large trials yield conflicting results on the association between incretin-based therapies (IBTs) and diabetic retinopathy (DR). We examined whether IBTs increase DR risk compared with other antihyperglycemics.
RESEARCH DESIGN AND METHODS We implemented an active comparator, new-user cohort design using a nationwide 20% random sample of fee-for-service U.S. Medicare beneficiaries aged 65 years or older with Parts A, B, and D coverage between 2007 and 2015. We identified the following cohorts without prior treatment for retinopathy: dipeptidyl peptidase 4 inhibitors (DPP4i) versus sulfonylureas (SU), DPP4i versus thiazolidinediones (TZD), glucagon-like peptide-1 receptor agonists (GLP1RA) versus long-acting insulin (LAI), and GLP1RA versus TZD. Primary outcome was advanced diabetic retinopathy requiring treatment (ADRRT), defined as a procedure code for retinopathy treatment. Incident diabetic retinopathy (IDR), identified by a diagnosis code, was a secondary outcome. We estimated propensity scores to balance confounders and adjusted hazard ratios (95% CI) using weighted Cox proportional hazards models.
RESULTS We identified 213,652 eligible patients. During a median duration of 0.58 to 0.87 years across comparisons, with a rate from 6.0 to 12.8 per 1,000 person-years, IBTs were not associated with increased ADRRT or IDR risk. The adjusted hazard ratios (95% CI) for ADRRT were 0.91 (0.79–1.04) by comparing DPP4i to SU (n = 39,292 and 87,073); 0.91 (0.75–1.11), DPP4i to TZD (n = 51,410 and 22,231); 0.50 (0.39–0.65), GLP1RA to LAI (n = 9,561 and 82,849); and 0.75 (0.53–1.06), GLP1RA to TZD (n = 10,355 and 27,345).
CONCLUSIONS Our population-based cohort study of older U.S. adults with diabetes suggests that IBTs used for approximately 1 year do not increase the DR risk.
Incretin-based therapies (IBTs), including glucagon-like peptide-1 receptor agonists (GLP1RA) and dipeptidyl peptidase 4 inhibitors (DPP4i), control blood glucose by potentiation of incretin receptor signaling (1). Safety concerns regarding IBTs have focused on pancreatitis (2), pancreatic cancer (3), medullary thyroid cancer (1), and heart failure (4,5). Recent cardiovascular trials have led to concerns that IBTs may increase the risk of diabetic retinopathy (DR) compared with placebo. The Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) reported a significantly higher rate of retinopathy complications with the GLP1RA semaglutide (14.9 vs. 8.6 events/1,000 person-years over 2.1 years of treatment; hazard ratio [HR] 1.76 [95% CI 1.11–2.78]) (6). The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial showed a statistically nonsignificant higher incidence of retinopathy complications with another GLP1RA, liraglutide (6 vs. 5 events/1,000 person-years over a median 3.8 years of treatment; HR 1.15 [0.87–1.52]) (7). The Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS) study showed patients on DPP4i sitagliptin had a higher retinopathy frequency (2.8% vs. 2.2%, median follow-up of 3.0 years) (8), whereas the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial showed no increased retinopathy frequency in patients on GLP1RA exenatide (2.9% vs. 3.2%, median follow-up of 3.2 years) (9). The low retinopathy frequency in TECOS and EXSCEL trials could be explained by the absence of systematic examinations; none of the published trials systematically assessed retinopathy complications. Therefore, we conducted this large active comparator, new-user (ACNU) cohort study to examine whether the use of IBTs, as compared with therapeutic alternatives, is associated with an increased risk of DR.
Research Design and Methods
Medicare provides medical coverage for the U.S. population aged 65 years and older. The University of North Carolina (UNC) has access to longitudinal claims data for a 20% random sample of all fee-for-service Medicare beneficiaries with Parts A (inpatient), B (outpatient physician services), and D (dispensed prescription drugs) coverage for at least 1 month from January 2007 to September 2015. The study protocol was registered in the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP) electronic register of studies (www.encepp.eu/encepp/viewResource.htm?id=17777) and approved by the UNC institutional review board.
The eligible population consisted of Medicare enrollees aged 65 years or older with at least 12 months of continuous enrollment in Medicare Parts A, B and D and without Health Maintenance Organization coverage before initiation and during follow-up. We identified all new users of a therapy of interest based on the first dispensing of a prescription in a given drug class after a 12-month washout for that drug class. Patients entered the cohort on the date of dispensing of the first prescription. As we obtained prescription data (Part D) starting from 1 January 2007, thus the earliest index date was 1 January 2008. As IBTs are typically second-line therapies (10) and the DR risk increases with increased diabetes duration (11), it is necessary to compare IBTs with drugs used at a similar stage of diabetes (12). Using an active comparator study design helps to mitigate bias by only selecting individuals with an indication for initiating a second-line antidiabetes treatment, identifying individuals at a similar point in their disease management and ensuring only adverse events after drug initiation are evaluated (12). We identified new users of the following comparisons, DPP4i versus sulfonylureas (SU), DPP4i versus thiazolidinediones (TZD), GLP1RA versus long-acting insulin (LAI), and GLP1RA versus TZD, and we excluded new users who took the other drug in the 12 months prior to initiation. Thus, the number of participants and events for a specific drug class varied across comparisons. Given these antihyperglycemia agents are primarily indicated for diabetes treatment (10), we did not restrict cohorts to those with a diagnosis code for diabetes. As early detection can reduce DR progression and prevent vision loss, patients with diabetes in the U.S. are recommended to have an eye exam at least every 2 years (10,11). As only patients with diabetes who had an eye exam could receive eye disease diagnoses or codes for specific treatments, we required cohort participants to have at least one eye examination in the 12 months prior to the index date. We identified eye examinations using Current Procedural Terminology (CPT) codes (Supplementary Table 1) and excluded patients with blindness and low vision (ICD-9-CM 369.XX), retinopathy treatment (described below), or vitrectomy before the index date. As current guidelines recommend treatment only for severe DR (12), we did not exclude patients with a DR diagnosis (ICD-9-CM 362.0X) without treatment. Last, as patients with congestive heart failure are less likely to initiate TZD (4), we excluded patients with a diagnosis of congestive heart failure in the 12 months prior to the first prescription when comparing IBTs to TZD.
DR Outcome
Our primary outcome was advanced diabetic retinopathy requiring treatment (ADRRT) as a proxy for incident retinopathy severe enough to require treatment (in patients without retinopathy at cohort entry) and worsening of preexisting retinopathy requiring incident treatment (in patients with DR but no retinopathy treatment at cohort entry). We used CPT and Healthcare Common Procedure Coding System (HCPCS) code to identify these treatments (Supplementary Table 1) (11). The primary definition was based on receipt of one of the following procedures with a DR or diabetes diagnosis code on the same claim: 1) photocoagulation (CPT 67228, 67210), 2) vitrectomy (CPT 67036, 67038–67042), and 3) intravitreal injection (CPT 67028) of anti–vascular endothelial growth factor agents (ranibizumab, aflibercept, or bevacizumab) or corticosteroid (triamcinolone, dexamethasone, or fluocinolone). Because medication-specific codes were not available immediately after U.S. Food and Drug Administration approval and bevacizumab lacks a code specific to ocular use (13), we also included claims for intravitreal injection of unclassified/miscellaneous drug codes. To minimize miscoding or misclassification bias, we required all HCPCS drug codes to be jointly used with an intravitreal injection CPT code. As some of these therapies are approved to treat age-related macular degeneration (AMD) (13), we excluded treatments with the following AMD diagnosis codes, ICD-9-CM 362.50, 362.52, 362.42, or 362.43. To capture untreated retinopathy (11), we defined our secondary outcome as incident diabetic retinopathy (IDR), identified by diagnosis ICD-9-CM 362.0X. When assessing IDR, patients with DR at baseline were excluded.
Follow-up started at the first prescription and ended with the earliest of the following events: 1) 30 days after treatment discontinuation (the date of last prescription plus a 90-day grace period), 30 days after switching to or adding the comparator drug class, or 30 days after the end of Medicare Part D enrollment, whichever came first; 2) end of enrollment for Medicare Parts A or B; 3) death; 4) end of study (30 September 2015); or 5) a claim for retinopathy treatment (for secondary outcomes analyses, a claim with a retinopathy diagnosis). We used the first DR treatment date to define the outcome date (first DR diagnosis for secondary outcome). Our primary analysis was as treated (Supplementary Fig. 1), using follow-up based on actual exposure to the initial antihyperglycemia treatment. Patients were defined as exposed to the initial treatment until treatment changed, including index drug class discontinuation or switching to or addition of a drug from the alternative class in the comparison. Treatment discontinuation was defined as no refills within a period equal to the prescribed duration of the last filled prescription plus a 90-day grace period (14). In the SUSTAIN-6 trial, increased retinopathy events with semaglutide occurred within the first 2 months (7). The mechanisms for incretin-associated DR complications are not clear, but one theory is that it results from a rapid glycemic control (15). Thus, we assumed treatment-related retinopathy would occur soon after treatment initiation. To account for the time required between noticing ocular disturbances and receiving an eye exam (the "latency" period), we considered retinopathy events within 30 days after treatment changes to be related to the initial treatment.
We examined a variety of baseline characteristics for each cohort, defined based on claims during the 12 months prior to the index prescription (Table 1). These covariates included demographics, diabetes severity, comorbidities, comedications, health care utilization, and socioeconomic status (16). To control for factors that may influence the decision to prescribe a given treatment, we estimated propensity scores (PS) for each patient in each comparison using these variables. We did not use PS for the comparison on three groups simultaneously (DPP4i, SU, and TZD group and GLP1RA, TZD, and LAI group), as IBT initiators in each comparison are not the same population. To directly compare the estimates across two comparator groups for each of the IBTs, we standardized the covariate distribution of comparator initiators to the covariate distribution of IBT initiators using standardized mortality/morbidity ratio (SMR) weights [PS/(1 − PS)] (17). SMR weighting creates comparator cohorts with the same covariate distribution as in the IBT cohorts, as evinced by standardized differences of covariates close to zero after weighting.
Patient characteristics of IBT and comparator initiators*
We calculated crude incidence by dividing the number of patients with the outcome by the total amount of observation time for each exposure group, with CIs based on the Poisson distribution. We constructed SMR-weighted (adjusted) Kaplan-Meier curves to compare the cumulative incidence of ADRRT (18). We fit Cox proportional hazards models in the PS-weighted populations to estimate HRs and 95% CIs for DR associated with the use of IBTs versus comparators.
Secondary Analyses
Approximately 10% of fee-for-service Medicare beneficiaries initiating the drugs of interest had CPT II codes for HbA1c, blood pressure, and cholesterol categories (Table 1). These patients were likely seen by providers who participated in programs such as Healthcare Effectiveness Data and Information Set performance measurement in the accountable care organizations or the Physician Quality Reporting System, which require physicians to regularly report these clinical measures to Centers for Medicare & Medicaid Services (19,20). We performed 20 multiple imputations for these clinical measures to control for confounding using fully conditional specification with logistic regression (21,22), then estimated adjusted HRs balancing measured and imputed covariates in each of the 20 imputed data sets using PS weighting, and then pooled the results across the imputations. We then stratified by HbA1c tertiles (<7% [53 mmol/mol], 7–9% [53–75 mmol/mol], and >9% [75 mmol/mol]). To assess whether the risk varied with duration of use, we estimated separate HRs for the first 6 months, 6–12 months, and after 12 months. Additionally, we evaluated whether the risk varied across patients with and without preexisting untreated DR, hypertension, and use of ACE inhibitors or angiotensin receptor blockers (ARBs) at cohort entry and the risk for each individual IBT.
Sensitivity Analyses
To assess the robustness of estimated DR risk, we performed several sensitivity analyses. First, we changed the latency period from 30 days to 0, 60, 90, and 180 days. Second, we performed an analysis based on initial treatment (Supplementary Fig. 2), ignoring treatment changes during follow-up. This approach mimics the intention-to-treat analysis in a randomized trial. The follow-up ends with the earliest of the following events: 3 years after initiation, death, end of enrollment for Medicare Parts A or B, end of study (30 September 2015), or a retinopathy treatment claim. Third, we modified our primary outcome to require a DR diagnosis in the primary, secondary, or tertiary position within the procedure claim. Fourth, as some patients with diabetes undergo eye exams less frequently than recommended (22) and only patients who had an eye exam could receive treatment for retinopathy, we excluded patients without an eye exam after cohort entry, recognizing this introduces selection bias. Fifth, as intensive use of insulin has an "early worsening" effect on retinopathy (23), we censored patients receiving LAI during follow-up when compared to SU or TZD. Sixth, we censored patients when they received medications that may induce or worsen (24,25) or slow retinopathy progression (fenofibrate [11]) (Supplementary Table 2). The third through sixth sensitivity analyses were based on our primary analysis (as treated, 30-day latency period). Seventh, we conducted analysis using multivariable-adjusted Cox regression. Last, we assessed our secondary outcome, IDR, using as-treated analysis with different latency periods (0, 30, 60, 90, and 180 days).
We identified 213,652 eligible patients from 487,057 initiators of at least one drug of interest, including 126,365 initiators for the DPP4i versus SU comparison, 73,641 initiators for DPP4i versus TZD comparison, 92,410 initiators for GLP1RA versus LAI comparison, and 37,700 initiators for GLP1RA versus TZD comparison (Supplementary Fig. 3). The median duration from last eye exam to index date was about 120 days with interquartile range from 50 to 221 days: DPP4i vs. SU 117 (49–214) vs. 122 (51–221), DPP4i vs. TZD 119 (50–217) vs. 116 (48–218), GLP1RA vs. LAI 120 (50–220) vs. 122 (51–221), and GLP1RA vs. TZD 118 (49–216) vs. 116 (49–216). We present the crude and weighted baseline covariate distributions in Table 1. The mean age ranged between 72.5 and 76.9 years, 38.8% to 42.3% were men, and the frequency of preexisting retinopathy ranged from 10.7% (GLP1RA initiators) to 14.2% (LAI initiators). Overall, the prevalence of comorbidities was similar in the comparison cohorts except LAI initiator cohort, who was more likely to have diabetes complications, cardiovascular diseases, chronic obstructive pulmonary disease, and chronic kidney disease compared with the GLP1RA cohort. In the third column of each comparison in Table 1, we present PS-weighted covariate distributions for the comparator drug initiators. The virtually identical distribution of the covariates in IBT initiators and the PS-weighted comparator initiators shows that we were able to balance all measured covariates and, thus, remove confounding by these covariates. The standardized differences before and after weighting are presented in Supplementary Tables 3 and 4. In the small subset of patients with information on categories of HbA1c, blood pressure, and LDL cholesterol, the distribution of these clinical measures was similar between IBTs and comparators, except that the LAI initiator cohort was more likely to have a higher HbA1c level (>9% [75 mmol/mol]) compared with the GLP1RA initiator cohort. The distribution of clinical covariates was well balanced by PS weighting after multiple imputation.
IBTs and ADRRT
In Table 2, we present results of the primary as-treated analysis for ADRRT risk. Among the eight cohorts, the median treatment duration ranged from 0.58 to 0.87 years, the crude incidence of ADRRT ranged from 6.0 to 12.8 events per 1,000 person-years, and the average incidence was 8.7 per 1,000 person-years. After adjusting for confounding, DPP4i was not associated with a risk of ADRRT when compared to SU (HR 0.91 [95% CI 0.79–1.04]) or TZD (0.91 [0.75–1.11]), and GLP1RA was not associated with increased risk when compared to TZD (0.75 [0.53–1.06]) but showed a decreased risk compared to LAI (0.50 [0.39–0.65]). We present weighted Kaplan-Meier curves for IBTs and comparators in Fig. 1. The curves are similar except for the GLP1RA versus LAI comparisons, in which LAI was associated with a higher risk of ADRRT.
Crude and adjusted HRs for ADRRT associated with use of IBTs compared with therapeutic alternatives*
SMR-weighted Kaplan-Meier plots of ADRRT. A: DPP4i vs. SU cohort. HR 0.91 (95% CI 0.79–1.04). B: DPP4i vs. TZD cohort. HR 0.91 (95% CI 0.75–1.11). C: GLP1RA vs. LAI cohort. HR 0.50 (95% CI 0.39–0.65). D: GLP1RA vs. TZD cohort. HR 0.75 (95% CI 0.53–1.06). SMR weights create a pseudo-population of the untreated (comparators: SU, TZD, or LAI), which has the same covariate distribution as the treated (IBT). Every patient receiving IBT has a weight of 1, whereas every patient in the comparator group is weighted by PS/(1 − PS). The risks on the y-axis were obtained by a SMR-weighted Cox model (weighting comparator drug initiators by the PS odds [PS/(1 − PS)]). HR treats comparators as reference, and adjusted HR <1 indicates a lower risk for IBT.
The results for analysis based on multiple imputation for missing clinical measures (Supplementary Table 5) and subsequent analysis (Supplementary Table 6) stratified by HbA1c are consistent with primary results. When stratified by duration and preexisting retinopathy (Table 3) and baseline hypertension and ACE inhibitor/ARB treatment (Supplementary Table 7), the HRs of ADRRT did not differ meaningfully and the CIs widely overlap. We, therefore, refrained from statistical testing for interactions. When stratified by individual IBT, both exenatide and liraglutide showed a lower risk compared with LAI, and only exenatide showed a lower risk compared with TZD (Supplementary Table 8).
Crude and adjusted HRs for ADRRT associated with use of IBTs compared with therapeutic alternatives according to duration of use and preexisting retinopathy at cohort entry*
Overall, results of sensitivity analyses for ADRRT were consistent with our primary analysis (Supplementary Tables 9–15). However, we observed a decreased risk in the GLP1RA versus TZD comparison using a 180-day latency period (HR 0.68 [95% CI 0.50–0.93]) (Supplementary Table 9) or initial treatment analysis (0.75 [0.58–0.98]) (Supplementary Table 10). Our analyses for secondary outcome, IDR, also suggested similar results, except for a slightly lower risk for GLP1RA compared with TZD (e.g., HR 0.85 [0.75–0.97] using a 30-day latency period) (Supplementary Table 16).
Our study is the first large, population-based study to examine the effect of IBTs on the risk of DR among older adults with type 2 diabetes. Our results suggested that, compared with therapeutic alternatives, initiating IBTs is not associated with an increased risk of DR. Similar results were observed for DPP4i and GLP1RA, and, overall, the results were consistent across secondary and sensitivity analyses.
Unmeasured Confounding
Because some risk factors for DR may not be well captured in claims data (26), we mainly rely on the ACNU study design to reduce the potential for unmeasured confounding by indication. This study approach is a proven, effective method for minimizing the risk of confounding by indication. For example, in our previous study on cancer incidence among patients initiating insulin with glargine versus human NPH insulin (27), the strongest predictor of the need for insulin in patients with type 2 diabetes, BMI, had no influence on the choice of insulin because both cohorts in the ACNU design were candidates for either drug, thereby effectively removing unmeasured confounding that could be associated with differences in BMI between cohorts.
In this study, Table 1 presents evidence that treatment choice between IBTs and comparator was not meaningfully affected by measured markers of diabetes severity, including codes for neuropathy and nephropathy and broad categories of HbA1c levels, except for the GLP1RA versus LAI comparison. This finding is further evidence that if none of the measured risk factors for DR affect the choice between initiating these drug classes, it is unlikely that other unmeasured risk factors that would impact our study outcomes also influence treatment choice.
Additionally, we performed multiple imputation of key diabetes measures to further control for unmeasured confounding. Using this approach is statistically valid even though we have approximately 90% of missing data for the categories of HbA1c, blood pressure, and LDL cholesterol because the proportion of variables with missing data are small (4 out of 50 variables) and the size of the validation study (i.e., those with HbA1c, blood pressure, and LDL cholesterol values) is large (several hundred patients in each category) (28,29). The HRs changed slightly after multiple imputation for these clinical measures, indicating HbA1c had little effect on treatment choice except for GLP1RA versus insulin (both true and imputed clinical measures were not balanced for this comparison). However, as we only have broad HbA1c categories and have no separate category for very high HbA1c (e.g., >12% [108 mmol/mol]), there might be residual confounding by HbA1c, especially in our highest category (>9% [75 mmol/mol]).
IBT and Retinopathy Risk
As both albiglutide and dulaglutide were approved in 2014 in the U.S. (30,31), the majority of GLP1RA cohorts are exenatide and liraglutide initiators. GLP1RA therapies were not associated with an increased DR risk compared with therapeutic alternatives in our study, which is in line with the results of the EXSCEL (9) and LEADER trials (7). A few possible reasons may explain the inconsistency between our results and the significant findings in the SUSTAIN-6 (6) and TECOS (8) trials. First, the cardiovascular trials either did not assess DR (7–9) or grade DR severity (6) at baseline. Although randomization tends to minimize bias related to preexisting retinopathy, due to the relatively small numbers in these trials, it is possible that, by chance, the degree of retinopathy was not matched between the two arms (32). Second, it is possible that the effect of semaglutide on retinopathy truly exists, and the risk of DR differs across the class of GLP1RA, whereas our cohorts do not include semaglutide. Third, our study was limited to the elderly Medicare population and may not reflect outcomes in younger patients in trials who may have a lower risk of retinopathy. Last, the real-world adherence and persistence to treatment is typically lower (14) than trials, and the median duration for treatment in our cohorts ranged from 0.58 to 0.87 years.
GLP1RA was associated with a lower risk for DR (both ADRRT and IDR) compared with LAI and with a lower risk of IDR compared with TZD. Although results adjusting for HbA1c based on multiple imputation and subgroup analysis did not change much from primary analysis, residual confounding could not completely be ruled out. However, it is also possible that GLP1RA truly reduces the retinopathy risk. Topical administration of either GLP1RA (33) or DPP4i (34) prevents retinal neurodegeneration in mice. Further, the rapid glycemic control when initiating LAI is associated with early worsening of DR (23,35–37), which could contribute to this finding. TZD's effects on macular edema (24,38) may contribute to the observed GLP1RA's lower risk of IDR as well, although evidence has been conflicting (38,39). DPP4i shows a trend (statistically insignificant) of decreased risk of DR (both ADRRT and IDR), which could be explained by the observed preclinical beneficial effect on the retina (34).
Our study has several strengths. With data that are representative of U.S. older adults, our large observational cohort study is the first real-world evidence designed to assess the effect of IBTs on degree of DR severity. Our ACNU design comparing IBT initiators with patients initiating a guideline-recommended clinical alternative both reduces the potential for unmeasured confounding by indication and provides a clinically appropriate comparison. We systemically assessed the potential for residual confounding and used rigorous statistical adjustment to minimize remaining imbalances between treatment cohorts compared.
We used several methods to minimize detection bias, recognizing that patients who do not have eye exams cannot have severe DR diagnosed or treatments applied. First, we required baseline eye exams within the year before cohort entry, and our data showed that the duration between last eye exam and index date was well balanced between IBTs and comparators. Second, as other eye conditions may evoke greater attention from eye care professionals, leading to earlier detection and treatment of DR, we systematically evaluated and balanced baseline eye diseases. Third, we used Medicare's low-income subsidy as a surrogate marker for socioeconomic risk factors for DR diagnosis (16). Last, in a sensitivity analysis, we also restricted the analysis to patients with an eye exam after cohort entry, with results consistent with the primary analysis.
Our study has limitations. First, we had no information on diabetes duration, and data on measures of glycemic control were available for only a small proportion of the population. However, we used surrogate measures of diabetes duration and glycemic control including age, diabetes complications, number of hyperglycemia diagnoses, and number of hospitalizations due to diabetes. The well-balanced covariates and the available clinical measures suggest our ACNU design removed unmeasured confounding except for in the GLP1RA versus LAI comparison. We also performed multiple imputation for missing clinical data and conducted several stratified analyses to minimize the risk that unmeasured confounding is responsible for our results.
Second, our algorithm for detection of the outcome has not been validated previously. However, we identified our primary outcome by treatments, which are specialist procedures that would be provided only by an ophthalmologist. Furthermore, for cases identified with an intravitreal injection procedure code (67028), we required that it be used jointly with a HCPCS drug code to minimize miscoding of treatments and excluded patients with specific forms of AMD that are treated by intravitreal injections. Therefore, it is unlikely that patients that met our disease definition (with diagnosis of diabetes or DR and received retinopathy treatment) did not receive treatment for retinopathy. A highly specific outcome definition minimizes bias in the HR, even in the presence of nonperfect sensitivity (40). Reassuringly, our sensitivity analysis that modified the outcome definition to be more specific (with DR diagnosis and evidence of receiving retinopathy treatments) produced results that were consistent with those of our primary analysis.
Last, we only assessed short-term IBT use, as the real-world adherence is low (14). The short follow-up in this study may impair the potential for detecting differences with long-term use of these drugs. Long-term specific studies with systematic grading of DR and consideration of significant clinical variables such as diabetes duration, HbA1c, and hypertension are urgently needed.
Our population-based, ACNU cohort study of older U.S. adults with diabetes suggests that the real-world use of IBTs over an average of less than 1 year does not increase the risk of DR compared with alternatives.
Funding and Duality of Interest. This work was supported by a grant from Novo Nordisk. The sponsor had no role in analysis, drafting, or the decision to submit this manuscript. J.-L.H. is currently an employee of Takeda. V.P. receives salary support from R01 AG056479 and R01 HL118255 and the National Center for Advancing Translational Sciences, National Institutes of Health (NIH) (UL1TR002489). S.G. is supported by the Diabetic Retinopathy Clinical Research Network, NIH (U10EY018817-03, U10EY014229-07, U10EY014231-09, EY14231, EY14269, and EY14229) and serves on the clinical advisory board for Welch Allyn. J.B.B. is supported by NIH (UL1TR001111). He has received contracted consulting fees, paid to his institution, and travel support from Adocia, AstraZeneca, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia Therapeutics, Lexicon, Metavention, NovaTarg, Novo Nordisk, Sanofi, Senseonics, and vTv Therapeutics and grant support from AstraZeneca, Boehringer Ingelheim, Johnson & Johnson, Lexicon, Novo Nordisk, Sanofi, Theracos, and vTv Therapeutics. He holds stock options in Mellitus Health and PhaseBio and has served on the board of the AstraZeneca HealthCare Foundation. T.S. receives investigator-initiated research funding and support from the National Institute on Aging as a principal investigator (R01/R56 AG023178 and R01 AG056479) and from NIH as co-investigator (R01 CA174453, R01 HL118255, and R21-HD080214). He also receives salary support as director of the Comparative Effectiveness Research Strategic Initiative, North Carolina Translational and Clinical Sciences Institute; from the UNC Clinical and Translational Science Award (UL1TR002489); and as director of the Center for Pharmacoepidemiology (current members are GlaxoSmithKline, UCB BioSciences, Merck, and Shire). He also receives research support from pharmaceutical companies (Amgen and AstraZeneca) to the Department of Epidemiology, UNC. He does not accept personal compensation of any kind from any pharmaceutical company. He owns stock in Novartis, Roche, BASF, AstraZeneca, and Novo Nordisk. The database infrastructure used for this project was funded by the Pharmacoepidemiology Gillings Innovation Lab (PEGIL) for the population-based evaluation of drug benefits and harms in older U.S. adults (GIL200811.0010); the Center for Pharmacoepidemiology, Department of Epidemiology, UNC Gillings School of Global Public Health; the Comparative Effectiveness Research Strategic Initiative of UNC's Clinical and Translational Science Award (UL1TR002489); the Cecil G. Sheps Center for Health Services Research, UNC; and the UNC School of Medicine. No other potential conflicts of interest relevant to this article were reported.
Author Contributions. T.W. did the statistical analysis and wrote the first draft of the manuscript. T.W. and J.-L.H. developed the protocol. T.W., J.-L.H., J.B.B., and T.S. were involved in data review and interpretation. T.W., J.-L.H., E.W.G., and S.G. participated in the design of the study. T.W., E.W.G., S.G., J.B.B., and T.S. contributed to critical revision of the manuscript for important intellectual content. J.-L.H. carried out initial analysis. V.P. oversaw and supported programing. J.B.B. and T.S. conceived and designed the study. All authors approved the final version of the manuscript. T.W. and T.S. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this study were presented in abstract form at the 77th Scientific Sessions of the American Diabetes Association, San Diego, CA, 9–13 June 2017, and at the 33rd International Conference on Pharmacoepidemiology and Therapeutic Risk Management, Montreal, Canada, 26–30 August 2017.
This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc17-2285/-/DC1.
Received November 1, 2017.
Accepted May 28, 2018.
© 2018 by the American Diabetes Association.
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Drucker DJ,
Sherman SI,
Gorelick FS,
Bergenstal RM,
Sherwin RS,
Buse JB
. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care 2010;33:428–433pmid:20103558
Egan AG,
Blind E,
Dunder K, et al
. Pancreatic safety of incretin-based drugs--FDA and EMA assessment. N Engl J Med 2014;370:794–797pmid:24571751
Gokhale M,
Buse JB,
Gray CL,
Pate V,
Marquis MA,
Stürmer T
. Dipeptidyl-peptidase-4 inhibitors and pancreatic cancer: a cohort study. Diabetes Obes Metab 2014;16:1247–1256pmid:25109825
Gilbert RE,
Krum H
. Heart failure in diabetes: effects of anti-hyperglycaemic drug therapy. Lancet 2015;385:2107–2117pmid:26009231
Jonsson Funk M, et al
. No increased risk of cardiovascular events in older adults initiating dipeptidyl peptidase-4 inhibitors vs therapeutic alternatives. Diabetes Obes Metab 2017;19:970–978pmid:28195389
Marso SP,
Bain SC,
Consoli A, et al.; SUSTAIN-6 Investigators
. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375:1834–1844pmid:27633186
Daniels GH,
Brown-Frandsen K, et al.; LEADER Steering Committee; LEADER Trial Investigators
. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–322pmid:27295427
Green JB,
Bethel MA,
Armstrong PW, et al.; TECOS Study Group
. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:232–242pmid:26052984
EXSCEL Study Group
Holman RR,
Mentz RJ, et al.
l.; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2017;377:1228–1239pmid:28910237
. Pharmacologic approaches to glycemic treatment. Sec. 8. In Standards of Medical Care in Diabetes—2017. Diabetes Care 2017;40:S64–S74pmid:27979895
Solomon SD,
Chew E,
Duh EJ, et al
. Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care 2017;40:412–418pmid:28223445
Lund JL,
Richardson DB,
. The active comparator, new user study design in pharmacoepidemiology: historical foundations and contemporary application. Curr Epidemiol Rep 2015;2:221–228pmid:26954351
Parikh R,
Ross JS,
Sangaralingham LR,
Adelman RA,
Shah ND,
Barkmeier AJ
. Trends of anti-vascular endothelial growth factor use in ophthalmology among privately insured and Medicare Advantage patients. Ophthalmology 2017;124:352–358pmid:27890437
Carls GS,
Tuttle E,
Tan RD, et al
. Understanding the gap between efficacy in randomized controlled trials and effectiveness in real-world use of GLP-1 RA and DPP-4 therapies in patients with type 2 diabetes. Diabetes Care 2017;40:1469–1478pmid:28801475
Varadhan L,
Humphreys T,
Hariman C,
Walker AB,
Varughese GI
. GLP-1 agonist treatment: implications for diabetic retinopathy screening. Diabetes Res Clin Pract 2011;94:e68–e71pmid:21906831
Martinell M,
Dorkhan M,
Stålhammar J,
Storm P,
Groop L,
Gustavsson C
. Prevalence and risk factors for diabetic retinopathy at diagnosis (DRAD) in patients recently diagnosed with type 2 diabetes (T2D) or latent autoimmune diabetes in the adult (LADA). J Diabetes Complications 2016;30:1456–1461pmid:27593902
Sato T,
Matsuyama Y
. Marginal structural models as a tool for standardization. Epidemiology 2003;14:680–686pmid:14569183
Cole SR,
Hernán MA
. Adjusted survival curves with inverse probability weights. Comput Methods Programs Biomed 2004;75:45–49pmid:15158046
National Committee for Quality Assurance. The Healthcare Effectiveness Data and Information Set (HEDIS) measures. Available from http://www.ncqa.org/hedis-quality-measurement/hedis-measures. Accessed 10 April 2018
Bagley B. Measuring for Medicare: the Physician Quality Reporting Initiative. Available from https://www.aafp.org/fpm/2007/0600/p37.pdf. Accessed 10 April 2018
Rubin DB
. Multiple Imputation for Nonresponse in Surveys. Hoboken, NJ, John Wiley & Sons, 2004
Silva PS,
Aiello LP
. Telemedicine and eye examinations for diabetic retinopathy: a time to maximize real-world outcomes. JAMA Ophthalmol 2015;133:525–526pmid:25742322
The Diabetes Control and Complications Trial Research Group
. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch Ophthalmol 1998;116:874–886pmid:9682700
Makri OE,
Georgalas I,
Georgakopoulos CD
. Drug-induced macular edema. Drugs 2013;73:789–802pmid:23640687
Nencini C,
Barberi L,
Runci FM,
Micheli L
. Retinopathy induced by drugs and herbal medicines. Eur Rev Med Pharmacol Sci 2008;12:293–298pmid:19024212
Stürmer T,
Glynn RJ,
Rothman KJ,
Avorn J,
Schneeweiss S
. Adjustments for unmeasured confounders in pharmacoepidemiologic database studies using external information. Med Care 2007;45(Suppl. 2):S158–S165pmid:17909375
Zhou H, et al
. Cancer incidence among those initiating insulin therapy with glargine versus human NPH insulin. Diabetes Care 2013;36:3517–3525pmid:23877991
Wahl S,
Boulesteix AL,
Zierer A,
Thorand B,
van de Wiel MA
. Erratum to: Assessment of predictive performance in incomplete data by combining internal validation and multiple imputation. BMC Med Res Methodol 2016;16:170pmid:27919231
Sterne JA,
White IR,
Carlin JB, et al
. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ 2009;338:b2393pmid:19564179
U.S. Food and Drug Administration. Drugs@FDA: FDA approved drug products. Tanzeum Albiglutide. Available from https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125431. Accessed 17 October 2017
U.S. Food and Drug Administration. Drugs@FDA: FDA approved drug products. Trulicity Dulaglutide. Available from https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125469. Accessed 17 October 2017
Simó R,
Hernández C
. GLP-1R as a target for the treatment of diabetic retinopathy: friend or foe? Diabetes 2017;66:1453–1460pmid:28533296
Hernández C,
Bogdanov P,
Corraliza L, et al
. Topical administration of GLP-1 receptor agonists prevents retinal neurodegeneration in experimental diabetes. Diabetes 2016;65:172–187pmid:26384381
Solà-Adell C, et al
. Topical administration of DPP-IV inhibitors prevents retinal neurodegeneration in experimental diabetes. Diabetologia 2017;60:2285–2298pmid:28779212
Arun CS,
Pandit R,
Taylor R
. Long-term progression of retinopathy after initiation of insulin therapy in type 2 diabetes: an observational study. Diabetologia 2004;47:1380–1384pmid:15309288
The Kroc Collaborative Study Group
. Diabetic retinopathy after two years of intensified insulin treatment. Follow-up of the Kroc Collaborative Study. JAMA 1988;260:37–41pmid:2898025
Lauritzen T,
Frost-Larsen K,
Larsen HW,
Deckert T
. Two-year experience with continuous subcutaneous insulin infusion in relation to retinopathy and neuropathy. Diabetes 1985;34(Suppl. 3):74–79pmid:4018423
Idris I,
Warren G,
Donnelly R
. Association between thiazolidinedione treatment and risk of macular edema among patients with type 2 diabetes. Arch Intern Med 2012;172:1005–1011pmid:22688528
Gower EW,
Lovato JF,
Ambrosius WT, et al.; ACCORD Study Group
. Lack of longitudinal association between thiazolidinediones and incidence and progression of diabetic eye disease: the ACCORD Eye study. Am J Ophthalmol 2018;187:138–147pmid:29275147
Chubak J,
Pocobelli G,
Weiss NS
. Tradeoffs between accuracy measures for electronic health care data algorithms. J Clin Epidemiol 2012;65:343–349.e2pmid:22197520
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My name is Emma Clare and I am a Healer and Reiki Master practicing in South Warrington, Cheshie.
I believe that harnessing Universal Love we can feel wonderful benefits. In my healing treatments I channel Divine and Angelic Love.
Divine and Angelic Love is all around us and if we can open ourselves up to this great power wonderful things can happen. Love can heal.


Available for the first time in English, The Island of Second Sight is a masterpiece of world literature, first published in Germany in 1953 and hailed by Thomas Mann as "one of the greatest books of the twentieth century." Set on Mallorca in the 1930s in the years leading up to World War II, it is the fictionalized account of the time spent there by author--writing as Vigoleis, his alter-ego--and his wife, Beatrice, lured to the island by Beatrice's dying brother, who, as it turns out not dying at all but broke and ensnared by the local prostitute.
Pursued by both the Nazis and Spanish Francoists, Vigoleis and Beatrice embark on a series of the most unpredictable and surreal adventures in order to survive. Low on money, the couple seeks shelter in a brothel for the military, serves as tour guides to groups of German tourists, and befriends such literary figures Robert Graves and Harry Kessler, as well as the local community of smugglers, aristocrats, and exiled German Jews. Vigoleis with his inventor hat on even creates a self-inflating brassiere. Then the Spanish Civil War erupts, presenting new challenges to their escape plan. Throughout, Vigoleis is an irresistibly engaging narrator; by turns amusing, erudite, naughty, and always utterly entertaining.
Drawing comparisons to Don Quixote and The Man Without Qualities, The Island of Second Sight is a novel of astonishing and singular richness of language and purpose; the story is picaresque, the voice ironic, the detail often hilarious, yet it is a work of profound seriousness, with an anti-war, anti-fascist, humanistic attitude at its core. With a style ranging from the philosophical to the grotesque, the colloquial to the arcane, The Island of Second Sight is a literary tour de force.
The Island of Second Sight ePub (Adobe DRM) can be read on any device that can open ePub (Adobe DRM) files.


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Newark Academy teen actors welcome Cathy Renna
By Editor on October 18, 2018 Comments Off on Newark Academy teen actors welcome Cathy Renna
LIVINGSTON, NJ — Newark Academy's Arts Department presents "The Laramie Project" as this year's fall drama on Nov. 1, 2 and 3 at 7 p.m. "The Laramie Project" is based on the true story of Matthew Shepard, a gay University of Wyoming student who, in October 1998, was beaten to death in Laramie, Wyo. The murder was denounced as a hate crime and brought attention to the lack of hate crime laws in various states, including Wyoming.
On Oct. 16, almost 20 years from when play director Moises Kaufman and members of the Tectonic Theater Project interviewed the people in Laramie, Cathy Renna, a longtime media activist and communications expert on LGBTQ issues who continues to work closely with the Shepard family and the Matthew Shepard Foundation, will join NA students at rehearsal and discuss the presentation of characters and how the students are portraying them.
Renna was an advocate working for the Gay and Lesbian Alliance Against Defamation in 1998 and played a central role in shaping the media coverage after the horrific event unfolded. She was in Laramie right after the public was made aware of Shepard's death, as well as for the events that followed, including the trials of the perpetrators.
"We first staged this challenging play back in 2002, and now we are bringing it back to the NA stage in honor of the 20th anniversary of Matthew Shepard's death," Newark Academy Arts Department Chair Elaine Brodie said.
For more information on the show at Newark Academy, visit www.onthestage.com/show/newark-academy/the-laramie-project-6070.
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I was honored to attend CERAWeek, and this is really the most impressive interview, conducted last month, that I have ever seen. Kaeser and Yergin explain how our world is actually in a state of nasty competition despite the success of "Globalism". Mr Kaeser states the the issue at hand is the redistribution of wealth. He expands by saying that climate change is not really a great issue because the technology to solve that problem already exists. The question is, how is the wealth going to be distributed internationally?
My only divergence from his statements is on Nationalism. What is wrong with saying, "Americans for American jobs" or "Take care of your own citizens first"? The overarching theme of the interview is a positive stance on "Globalism" – which I am against.
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UM-Flint Alumnus Reflects on a Life of Liberal Arts
UM-Flint English Language Program Hosts Brazilian Medical Students
UM-Flint Theatre Students Bring 'Big Love' to the Stage
By UM-Flint News On January 27, 2017 10:59 am
A scene from UM-Flint Theatre's BIG LOVE.
What does "love" mean? Student actors, and their director Janet Haley, will explore this question in BIG LOVE, the second production of the UM-Flint theatre season. The play opens on January 27 and runs through February 4, 2017. It is a contemporary revision of one of the western world's oldest plays, The Suppliant Women by Aeschylus.
"This piece is so unlike what people may think what a 'play' is," said Haley. "[It] features song, dance, poetic language, gorgeous costumes, and a stunning scenic landscape. BIG LOVE examines and celebrates love, in all its manifestations."
More Than Just Love
BIG LOVE is the story of fifty brides on the run from arranged marriages—and what happens when they take refuge in an island villa with their fifty grooms in pursuit.
"It's called BIG LOVE for a reason. These characters have real epiphanies about themselves and the world. It's not a romantic comedy, a little romp in Italy, it's not Under the Tuscan Sun," noted Haley. "This play is giving our students a wide and diverse set of opportunities to be involved in—it's a very diverse composite of character perspectives, gender and sexual identities, age and experience range."
Make-up, costume, and hair for the UM-Flint Theatre production of BIG LOVE.
Layla Meillier, a Geneseee Early College student, English major, and Women's & Gender Studies minor, agrees. "Since I often study gender and communication," she said, "I have been thinking a lot about traditions and binary stereotyping and how this show enforces and challenges gender roles."
Meillier has found herself exploring themes of the play in her own life: "love in a large sense and how it manifests and conquers. Romantic love, sister love, humanity love. I have a sister and I think about how I would do anything for her when justifying the plot and text."
Computer Science major and actor Matthew Statson added, "Every character in this show searches for a 'comfortable' state that they might find in another person. It's important to remember that no matter what our intentions or goals are in life, how we accomplish it and treat others in the process may be the most important thing than actually achieving the overall goal."
A Collaborative Work
The staging and movement sequences of BIG LOVE were devised in collaboration with the student company and students hold leadership positions on the production team as Dance Captain, Fight Captain, Stage Manager, and Costume Designer, among others.
"It's a highly collaborative endeavor," said Haley. "[The students] were inventing, creating, and devising something together as a group. That's different than there being a script that tells you all of the words to say and where you are in space. This collaborative way of working ultimately helps our students learn how to have confidence in their ideas, to risk, to experiment, to research, to test. To know that not everything is going to be the right answer; it's kind of scientific. They are going in to try stuff—as you would in a lab—and some of it's not going to work, and we're okay with that, and we're going to keep trying things. Because whatever doesn't work puts us one step closer to discovering what will work."
Set and stage construction for UM-Flint Theatre's BIG LOVE.
The production style also reinforces lessons of effective communication and listening, respect for others' points of view and values, and a willingness to try new things. "I think this helps their citizenship skills," noted Haley, "their personal responsibility. We talk about teamwork a lot, it's a pretty complex thing."
Meillier appreciates the intense experience. "I have gained so much from this production," she said. "I have made so many friends and deepened my understanding of theatre. This piece has opened my mind to so much newness. I have been challenged in frequently incredible ways."
Both cast and crew members believe BIG LOVE will appeal to a wide audience.
"Love is such a universal entertainer," said Meillier. "Many in this community will be able to relate to what we have created no matter their sexuality or gender identity/expression. So much is considered and presented to the audience, every character is working from a different place and it is difficult to see clearly who may be in the wrong. [Playwright] Charles Mee really gets you to think about your values and reaccess your ideas of good and bad."
Added Statson, "In the extremes that this show goes to explain how love affects people, we hope it shines a light in your own life on where love hits you, and what you choose to do with that."
BIG LOVE is recommended for ages 18 and up. Mature content and strong language. Strobe lights. Stage violence. Running time is approximately 100 minutes with no intermission.
Tickets are available by calling (810) 237-6520 or at the UM-Flint Theatre Box office (buy ahead or at the door). Show times start promptly as stated below, please arrive early to purchase tickets.
UM-Flint Theatre Performances of Big Love:
Friday, January 27, 2017, 7:30 p.m.
Saturday, January 28, 2017, 7:30 p.m.
Sunday, January 29, 2017, 2:00 p.m.
Friday, February 3, 2017, 7:30 p.m.
Saturday, February 4, 2017, 7:30 p.m.
Sunday, February 5, 2017, 2:00 p.m.
The UM-Flint Theatre is located at 303 E. Kearsley Street, Flint, MI 48502. Free parking is available. For full details, visit the UM-Flint Theatre & Dance Department at umflint.edu/theatredance.
Women's & Gender Studies


A seasoned cover musician in the South of England, playing across the UK and internationally as a solo performer, duo, trio or full band.
From old songs to new to fast to slow, I use my vast experience to gauge the crowd and put my own spin on things to create a memorable experience for the audience - be it wedding, corporate event, party or pub.
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Please get in touch to talk to me directly (via the CONTACT TOM button at the top of the page) for bookings and enquires.


This exhibit demonstrates how a simple but powerful message combined with a comprehensive integrated campaign strategy can secure real success.
In her fifth blog for SOFII, Lucy asks if 'fun-raising' could be the key to boosting your fundraising and shares some fantastic interactive campaigns from both the charity and the corporate sectors.
This is a good example of how different types of fundraising can work alongside one another to create a successful campaign with a broad appeal.
In this innovative exhibit, a partnership between Citigroup and YMCA Singapore demonstrates the power of youth.
'Recession? What recession? It all goes to show that good fundraising still works, recession or not.' How a tiny congregation in rural England raised the huge sum needed to restore their splendid church.
An inspirational initiative from Riverside School designed to encourage India's young people to come up with solutions to the sub-continent's great challenges.
This highly professional multi-media campaign from Bosnia shows that inspirational and innovative fundraising can succeed anywhere.
SOFII doesn't have many rules but this exhibit nevertheless breaks a few of them, in that it focuses not on a charity/nonprofit but on a commercial sponsor. Still, it's a colourful, creative idea very well executed and several charities benefited rather significantly from it. It strikes us as a sound win-win situation, a good example of both commerce/charity partnership and of charities working together.
Fundraising is at its best when it mobilises large numbers of people to take action for a cause that will bring about change. This exhibit demonstrates how to reposition an event that is 'tired' and make it work on multiple levels.
UNICEF scores for children through forming a valuable, useful partnership. Together UNICEF and the Barcelona football club will use this power in numerous ways to further the cause of children.


Television's Community follows the shenanigans of a diverse group of traditional and nontraditional community college students: Jeff Winger, a former lawyer; Britta Perry, a feminist; Abed Nadir, a pop culture enthusiast; Shirley Bennett, a mother; Troy Barnes, a former jock; Annie Edison, a naïve overachiever; and Pierce Hawthorne, an old-fashioned elderly man. There are also Benjamin Chang, the maniacal Spanish teacher, and Craig Pelton, the eccentric dean of Greendale Community College, along with well-known guest stars who play troublemaking students, nutty professors and frightening administrators.
This collection of fresh essays familiarizes readers not only with particular characters and popular episodes, but behind-the-scenes aspects such as screenwriting and production techniques. The essayists explore narrative theme, hyperreality, masculinity, feminism, color blindness, civic discourse, pastiche, intertextuality, media consciousness, how Community is influenced by other shows and films, and how fans have contributed to the show.
Ann-Gee Lee is an assistant professor of English at the University of Arkansas-Fort Smith. She teaches first-year writing courses and upper-division rhetoric courses. She lives in Fort Smith.


DRIVEU offers the best solution for your Goodwood Horse racing day out from Dorset & Hampshire, so if you're looking for a quality and reliable minibus hire with driver service to take you to Goodwood Racecourse for a day out from Dorset or Hampshire, then look no further, as you're in the right place.
Positives: I do have no hesitation in recommending This company.
Going to Goodwood Racecourse for a horse racing day out is a really fun day out. Horse racing is actioned packed during the race, the atmosphere becomes electric as the horses come to the finish line with everyone cheering home the horse they picked.
Going to the Goodwood races doesn't have to be expensive either, you don't have to bet loads of money to enjoy the races, you can have a pound bet on each race, with a typical race meeting holding around 8 races, that equals £8 stake money, and if you back a winner, you could even come out in front.
Most racecourses like Goodwood have areas to watch the horse racing indoors and outdoors, with places to eat, places to drink and be merry, all in all, it makes for a really great day out for everyone in the group.
You may find that other companies are often only really interested in the transportation aspect, but we at DRIVEU Minibus Hire Dorset & Hampshire are far more concerned with your overall travel experience, that is why we take an interest in the journey and activities that you are planning on doing and the events you want to attend like Goodwood, and always try to go the extra mile.


We are very grateful for a gifts from the William F. and Linda C. Roemer Charitable Foundation and from Joan Francis.
We believe God will multiply their generosity far beyond our chronological lives.
2. Instruct your broker to transfer X number of shares of Y Company to our broker. We'll provide our account information and number.
3. Expect completion within five business days of instructing your broker. We will send you a tax receipt as soon as the transaction is completed.


McDonald's announced its unveiling of a newly-designed restaurant at Clark and Ontario streets in Chicago that will serve as the brand's flagship restaurant. Showcasing a one-of-a-kind modern, environmentally-friendly design and enhanced customer experience with self-order kiosks, table service, mobile order and payment, and delivery, the 19,000-square-foot restaurant was constructed with sustainability, green spaces, and energy conservation in mind. Read more here.
The global fast food giant also announced the return of the McGold Card, which will grant a lucky few free McDonald's for life. Read more here.
Following the launch of the first Kosher McDonald's outside of Israel twenty years ago, a new kosher fast food stand will open in Buenos Aires, The Times of Israel reports. The stand, named Bocasher, will open in the Boca Juniors' Bombonera stadium, and is believed to be the first kosher fast food stand at a soccer stadium in Latin America. Read more here.
According to a report by Bloomberg, Zume Inc., a startup that makes and delivers fresh pizzas with the help of robots, is drawing interest from the SoftBank Group Corp. who is in talks with them to invest up to USD$750 million. Zume, which owns a patent for delivery trucks capable of cooking food while it's en route to customers, is operated in part by robots and have ovens that fire up on demand, via a remote cloud signal. Read more here.
Shares of pizza giant Papa John's International Inc. fell by 7%, hitting a near four-year low, a day after the U.S. chain lowered its current-quarter forecast blaming its ongoing tussle with the chain's founder, Reuters reports. The pizza company also reported that its second-quarter comparable sales fell 6.1% in North America, predicting that it would continue to slip for the coming months. Read more here.


The events took place in the auditorium of the Madrid Bar Association, together with the WISTA MED CONFERENCE, in addition to the X Anniversary of WISTA SPAIN.
Capt. Antonio M. Padrón gave the conference "The IMO Maritime Ambassadors Program: Educating the Next Generation", also explaining the progress of the "Boarding Program for Maritime Cadets" -which has already 60 embarked- in which WISTA SPAIN, and many of its members, actively collaborate.
Pilotage as Service of General Interest.
What's behind a tuna tin?
Port Terminals and Port Authorities: Allies or Enemies?
The Women's International Shipping & Trading Association (WISTA), which members are women with outstanding trajectories and responsibility in the maritime industry, is present in more than 40 countries.


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World War II Airman Laid to Rest
The remains of 1st Lt. John E. Terpning, a World War II bomber pilot who had been missing in action since 1944, were laid to rest with full military honors on Wednesday at Arlington National Cemetery. Terpning, of Mount Prospect, Ill., was a B-24D pilot who, together with nine crewmates, went missing during a bombing mission on May 7, 1944, in Nadzab, Papua New Guinea, according to the March 29 Pentagon announcing the identification of his remains. The bomber had experienced mechanical issues prior to takeoff, states the release. The War Department in 1946 declared Terpning and his crewmembers to be presumed dead. Recovery efforts began in 1973 with the discovery of the crash site and human remains in mountainous terrain near Nadzab. Technology at the time prevented the identification of the individual crew members so the crew was buried as a group at Arlington in 1974. In April 2008, a US team recovered wreckage and additional human remains at the crash site. Forensic scientists subsequently used dental records and mitochondrial DNA to help identify Terpning's remains.
Last SLUFF Bows Out
Last crew member of Enola Gay has died.
Last Crew Member of the B-29 Enola Gay Has Died
The last surviving crew member of the Enola Gay, the B-29 Superfortress that dropped the atomic bomb on Hiroshima, Japan, to accelerate the end of World War II, has died. Theodore Van Kirk died July 28 at a nursing home in Stone Mountain, Ga. He was 93. Van Kirk, known as "Dutch," was the navigator in the Enola Gay crew, led by Col. Paul Tibbets, who commanded the 509th Composite Bomb Group, which was formed to conduct the atomic bomb missions. Flying from an airfield on the captured Japanese Island of Tinian, the crew dropped the 9,000-pound weapon, called "Little Boy," over Hiroshima early on Aug. 6, 1945. Three days later, another B-29 from the 509th dropped a second atomic bomb on Nagasaki. Japan surrendered Aug. 15. Van Kirk always supported the atomic bombings for avoiding an invasion of Japan that could have killed hundreds of thousands of allied troops and Japanese.
Enola Gay crewmembers (l-r) Maj. Theodore Van Kirk, Col. Paul Tibbets Jr., and Maj. Thomas Ferebee. File photo.
Retired Col George E. "Bud" Day Dies
Retired Col. George E. "Bud" Day, a Medal of Honor recipient who spent nearly six years as a prisoner of war in Vietnam, died on July 27 in Shalimar, Fla., following a long illness. He was 88. "I owe my life to Bud, and much of what I know about character and patriotism," said Sen. John McCain (R-Ariz.), who was Day's cellmate in captivity in Hanoi. "He was the bravest man I ever knew," said McCain. Day's funeral service is scheduled for Thursday in Fort Walton Beach, Fla., with burial at Barrancas National Cemetery in Pensacola, Fla., according to press reports. A native of Sioux City, Iowa, Day was born on Feb. 24, 1925. He served as a marine in World War II and then became an Air Force pilot during the Korean War. On Aug. 26, 1967, the North Vietnamese shot down Day's F-100 Super Sabre during a dangerous forward air control mission. He endured extreme hardship and torture in captivity. On March 14, 1973, Day regained his freedom. After recuperating, he returned to active flying status. He then retired from active duty in 1977 as the most decorated officer in the service's history and went on to practice law in Florida, becoming a crusader for veterans' issues. Day chronicled his Vietnam War experiences in the 1989 book Return with Honor.
Doolittle Raider Thomas Griffin Dies
Doolittle Raider Thomas Griffin Dies: Retired Maj. Thomas C. Griffin, one of the Doolittle Raiders who, along with 79 other airmen, carried out a daring bombing attack on Tokyo on April 18, 1942, died in his sleep in a veterans' hospital in Cincinnati on Feb. 26, Cincinnati.com. He was 96. Griffin, a native of Green Bay, Wisc., served as navigator on aircraft No. 9, one of the 16 B-25 bombers under the command of then-Lt. Col. Jimmy Doolittle that took off from the deck of the carrier USS Hornet in the Pacific Ocean to bomb Tokyo on that spring day in 1942, just four months after Japan's strike on Pearl Harbor. Griffin, then a lieutenant, bailed out with his crewmates over China after the raid and made his way back to allied lines. Eventually returning to combat, he later spent 22 months as a prisoner of war in Germany after his airplane was shot down in July 1943. Griffin's death leaves four surviving Doolittle Raiders: retired Lt. Col. Richard Cole, co-pilot on aircraft No. 1; retired Lt. Col. Bob Hite, co-pilot on aircraft No. 16; retired Lt. Col. Edward Saylor, engineer on aircraft No. 15; and retired MSgt. David Thatcher, engineer-gunner on aircraft No. 7. Those four are scheduled to gather in mid-April in Fort Walton Beach, Fla., for the Doolittle Raiders' 71st reunion.
George Vujnovich Dies.
Architect of Daring World War II Rescue Dies: George Vujnovich, the World War II OSS agent who orchestratedOperation Halyard, the largest ever escape of American airmen from behind enemy lines, has died, according to press reports. He died on April 24 of natural causes at his home in New York City, reported the Associated Press on Wednesday (via the Detroit Free Press). He was 96. The Pittsburgh native, born to Serbian immigrants, devised a plan in 1944 to rescue hundreds of US airmen who bailed out over Serbia on bombing missions against the Axis-held Ploesti oil fields in Romania. Working with Serbian guerrilla fighter Draza Mihailovich, leader of the Chetniks,Vujnovich and his OSS team built a makeshift mountaintop airfield from which US cargo aircraft ferried some 512 airmen to freedom between August and December 1944, In October 2010, Vujnovich received a Bronze Star Medal for his heroic service.
Thirty Seconds over Dayton.
Thirty Seconds over Dayton: One of the largest gatherings of B-25 Mitchell bombers assembled since World War II will mark the 70th anniversary of the daring Doolittle bombing raid on Tokyo during commemoration events in Dayton, Ohio, next Wednesday, according to event organizers. The National Museum of the US Air Force plans to reopen a normally closed runway specifically for the B-25s to take off from one-by-one and then fly in formation over the Dayton area and the museum just prior to the Doolittle Raiders' memorial service at the museum. Twenty-one B-25s are expected to participate. Eighty airmen in 16 B-25s took off from deck of the USS Hornet on April 18, 1942, in the surprise raid that struck a symbolic blow to Japan and buoyed American morale at a crucial time early in the war. The five surviving Doolittle Raiders are expected to attend the memorial service and other reunion events. They are (each retired): Lt. Col. Richard Cole, Lt. Col. Robert Hite, Lt. Col. Edward Saylor, Maj. Thomas Griffin and SSgt. David Thatcher. (Dayton report by Rob Bardua)
Flying Tiger Reunion
Flying Tigers Reunion: Past and present members of the Flying Tigers gathered at MacDill AFB, Fla., earlier this month for the latest in the series of reunions held since 1947. This year, five of the surviving original Flying Tigers pilots attended. So did some of the maintainers, intelligence, and medical staff who supported them when they flew P-40 Warhawks in defense of China against Imperial Japan during World War II. "It's an honor to meet with these generations of warriors," said Col. Ronald Stuewe, commander of the 23rd Fighter Group at Moody AFB, Ga., an A-10C unit that carries on the Flying Tigers name and shark's teeth nose art. "I've looked up to these guys since I was a little boy, so to actually meet them and hear their stories is truly, truly humbling," said Capt. Matthew Cichowski, a Moody A-10 pilot. (Tampa by SrA. Brigitte N. Brantley)
Remains of WWII Airmen Identified
Remains of WWII Airmen Identified: The DOD POW/Missing Personnel Office identification of the remains of four airmen, part of a 10-man B-17 crew lost in the Pacific in 1943. The airmen were on a bombing mission over Papau New Guinea in their B-17 Naughty but Nice on June 26, 1943, when the bomber was hit by antiaircraft fire and ultimately shot down by a Japanese fighter aircraft. The four airmen were: 1st Lt. William J. Sarsfield of Philadelphia; 2nd Lt. Charles E. Trimingham of Salinas, Calif.; TSgt. Robert L. Christopherson of Blue Earth, Minn.; and TSgt. Leonard A. Gionet of Shirley, Mass. Their remains are to be buried as a group in a single casket at Arlington National Cemetery. Previously, DOD had identified other members of the crew that perished in the crash: 2nd Lt. Herman Knott, 2nd Lt. Francis G. Peattie, SSgt. Henry Garcia, SSgt. Robert E. Griebel, and SSgt. Pace P. Payne—all of whom were buried individually in 1985. A 10th airman, 2nd Lt. Jose L. Holguin, was the only survivor and was held as a prisoner of war until 1945.
Last of the Piston Engineers retires
Last of the Piston Engineers: CMSgt. Michael Reinert, the Air Force's last piston-engine flight engineer, retired this week from the Missouri Air National Guard's 139th Airlift Wing at Rosecrans ANG Base. Reinert joined the service in 1970 and embarked on Operation Creek Party—the Air Guard's first sustained overseas commitment—as a KC-97 Stratotanker and C-97 Stratofreighter flight engineer. During two-week rotations to Rhein-Main AB, Germany, Reinert helped refuel fighter aircraft, allowing USAF's then-limited KC-135 fleet to focus on operations in Southeast Asia. The historic Creek Party effort, which took place between 1967 and 1977, "established a template for overseas deployments by the Air Guard" in support of Total Force operations, explained Charles Gross, ANG history program director at the Air Guard Readiness Center at JB Andrews, Md. When the Air Force scrapped the KC-97L, Reinert retrained on the C-130. (by MSgt. Mike Smit
The Navy took delivery of PCU California (SSN 781) from Huntington Ingalls Industries – Newport News Shipbuilding (HII–NNS), Aug. 7.
B-58 Designer Robert Widmer Dies
B-58 Designer Robert Widmer Dies: Robert H. Widmer, the aeronautical engineer who designed the Air Force's first operational supersonic bomber, the Convair B-58 Hustler, died in Fort Worth, Tex., at age 95. Widmer died June 20, 2011. Born on May 17, 1916, in Hawthorne, N.J., Widmer received an aeronautical engineering degree from Rensselaer Polytechnic Institute in Troy, N.Y., and then earned a master's degree at the California Institute of Technology in Pasadena CA, before joining Convair at its headquarters in San Diego. He later transferred to the company's aircraft factory in Fort Worth TX, where he established the design and engineering department. He worked at Fort Worth well into his 80s, as the company became General Dynamics, then Lockheed, and then Lockheed Martin. Among his accomplishments, Widmer also played instrumental roles in developing the F-111, F-16, and Tomahawk cruise missile.
Last China Burma "Hump" reunion
They braved the highest mountains in the world, terrible weather, Japanese fighters, and routine equipment malfunction to supply troops during World War II. This month they met for the last time. The pilots who flew the notorious "Hump," airlifting supplies over the Himalayas from India to allied forces in China, have met up every year since 1946. With the average Hump pilot now 90 years old and with only six attending this year's reunion at JB Charleston, S.C., the decision was made that it would be their final gathering. Nonetheless, still spry and animated, enjoyed the fellowship at this year's gathering. "Every time we meet, the Himalaya Mountains get higher, the weather gets worse, and there are more Japanese fighters," joked 91 year-old-pilot Tex Rankin.
Last World War I veteran dies
New kit from Alpine Division Scale Models, L.L.C.
Doolittle Raider Dies
Christmas Drop
VA information
Allen Dale June, Code Talker, Dies at 91
New Ship for the US Navy
UPS Store Branson, MO
USS Denver Arrives in Inchon for Anniversary of Historical Landing
Medal of Honor for CMSgt Richard L. Etchberger
Maj. Gen. William Eubank Dies
9-11-2010 OERM Swap Meet
Harvey Girls Orange Empire Railway Museum
Lt. Gen. David Deptula retiring
Black Bark Mine and Shaft
SSN 779 New Mexico commissioned
USS Sampson (DDG-102) help Tao Fong Shan Christian Center
WASP Women's Airforce Service Pilots
Alcoa 50,000-Ton Forging Press
Big River Train Town Hannibal , MO
LeRoy O. King Jr. 1921 - 2009
US ARMY MARKSMANSHIP UNIT
Sierra Division Summer Picnic
ECHO METAL WORKS
NMRA Information
Future NMRA National Conventions
Doc Blanchard Fighter Pilot and Heisman Trophy winner dies
Lt. Gen. William O. Senter dies
Great Train Show check it out in 2010.
Mt. Wilson Toll Road
Orange Empire Railway Museum Swap Meet and Meeting
U.S. Army Band Schedule
US Army receives new locomotives
1962 Vintage C-130 retired.
WWII Airman Finally gets his DFC
Old Town Brass Band schedule 2009
Doolittle Radiers
The Harvey Girls Historical Society at Orange Empire Railway Museum , Perris CA
Join the Southern Pacific Hist. & Tech. Soc.
CNC Cutting, Milling & Conventional
The Scenic Mt. Lowe Railway Historical Committee
USDA Forest Service Los Angeles River Ranger District
Retired Brig. Gen. Gustav E. Lundquist passes
Pacific Northwest Truck Museum
Coal to liquid fuel
Olde Town Brass Band Schedule for 2008
Canadian Fighter Jets plug hole in US Air Defences NORAD
NMRA Convention July 13-19, 2008 Manufactures Tour
Napa Valley Wine Train in Town
Trainfest November 10-11 ,2007 Milwaukee Wisconsin
Grand Opening of J.B Hobbies
October 28, 2007 Travel Throught Union Station Los Angeles CA
Calico Ghost Town Narrow Gauge Railroad
Brookville Equipment Corp.
Famed Flying Tiger Tex Hill Dies
The Nevada State Railroad Museum
Earthquake Recovery in Peru
Raptors in Alaska
Cover the Cars
Directions to the Illinois Railway Museum
Legendary fighter pilot Gen. Robin Olds dies
Chicago Fire Department Green Lights
Pilot in Doolittle Raid Dies
2007 USAF Outstanding Airmen
Air Force Airman's Creed
Ohio Firefighter Bikes for Burn Survivors
Baskin-Robbins Scoops for Firefighters
I watched the flag pass by one day.
Lt. Col. Chase Nielsen service held March 28, 2007
Train Show at Anaheim Conventation Center 1-6 & 7, 2007
Personal Products needed for Wounded at Walter Reed
Partners in Preservation
Bamberger Bullet 127 at Orange Empire Railway Museum
Cal Poly's Little Love Affair With Steam
Amboy is purchased by a new investor!
17th Annual Stater Bros. Route 66 Rendezvous® Presented by Firestone,
American Forest & Paper Association
Rail Car Builder Moving to Philadelphia Naval Yard
Kit #71 Hobby Shop 2 story. light green sides
Laws Railroad Museum and Historical Site, Bishop, California
Air Compressor Sales and Service in Southern California
"Railfest 2006
Building A 'Lift-Bridge Module' for a traction layout
Used Eyeglasses and old greeting cards collected by LADWP
Great Hobby Shop in Rancho Palos Verdes, California
Membership Open Southern California
New Web Site for Alpine Division Scale Models


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