Profiling antibody epitopes induced by mRNA-1273 vaccination and boosters.

Background: Characterizing the antibody epitope profiles of messenger RNA (mRNA)-based vaccines against SARS-CoV-2 can aid in elucidating the mechanisms underlying the antibody-mediated immune responses elicited by these vaccines. Methods: This study investigated the distinct antibody epitopes toward the SARS-CoV-2 spike (S) protein targeted after a two-dose primary series of mRNA-1273 followed by a booster dose of mRNA-1273 or a variant-updated vaccine among serum samples from clinical trial adult participants. Results: Multiple S-specific epitopes were targeted after primary vaccination; while signal decreased over time, a booster dose after >6 months largely revived waning antibody signals. Epitope identity also changed after booster vaccination in some subjects, with four new S-specific epitopes detected with stronger signals after boosting than with primary vaccination. Notably, the strength of antibody responses after booster vaccination differed by the exact vaccine formulation, with variant-updated mRNA-1273.211 and mRNA-1273.617.2 booster formulations inducing significantly stronger S-specific signals than a mRNA-1273 booster. Conclusion: Overall, these results identify key S-specific epitopes targeted by antibodies induced by mRNA-1273 primary and variant-updated booster vaccination.

Distinguishing features of long COVID identified through immune profiling.

Post-acute infection syndromes may develop after acute viral disease1. Infection with SARS-CoV-2 can result in the development of a post-acute infection syndrome known as long COVID. Individuals with long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions2-4. However, the biological processes that are associated with the development and persistence of these symptoms are unclear. Here 275 individuals with or without long COVID were enrolled in a cross-sectional study that included multidimensional immune phenotyping and unbiased machine learning methods to identify biological features associated with long COVID. Marked differences were noted in circulating myeloid and lymphocyte populations relative to the matched controls, as well as evidence of exaggerated humoral responses directed against SARS-CoV-2 among participants with long COVID. Furthermore, higher antibody responses directed against non-SARS-CoV-2 viral pathogens were observed among individuals with long COVID, particularly Epstein-Barr virus. Levels of soluble immune mediators and hormones varied among groups, with cortisol levels being lower among participants with long COVID. Integration of immune phenotyping data into unbiased machine learning models identified the key features that are most strongly associated with long COVID status. Collectively, these findings may help to guide future studies into the pathobiology of long COVID and help with developing relevant biomarkers.

Safety and Effectiveness of Rasburicase in the Control of Hyperuricemia in Pediatric Patients with Non-Hodgkin's Lymphoma and Acute Leukemia: An Open-Label, Single-Arm, Multi-center, Interventional Study.

INTRODUCTION: Despite rasburicase's proven efficiency in Caucasians, Japanese, and Koreans, studies evaluating the safety and effectiveness of rasburicase in Chinese pediatric patients with non-Hodgkin's lymphoma (NHL) and acute leukemia (AL) in particular are lacking. OBJECTIVE: The aim was to evaluate the safety and effectiveness of rasburicase in Chinese pediatric patients with NHL and AL. METHODS: In this phase IV, open-label, non-randomized, single-arm, multi-center, interventional study (NCT04349306), children newly diagnosed with NHL or AL who received 0.20 mg/kg/day of rasburicase were included. The primary objective was to assess the safety of rasburicase by the incidence of adverse events (AEs). The secondary objective was to determine the effectiveness of rasburicase in the control of hyperuricemia. RESULTS: Out of 50 patients, 25 reported a total of 76 treatment-emergent adverse events (TEAEs), including eight TEAEs of grade ≥ 3 in 12 patients. A drug-related serious AE was reported in one patient, and there was no incidence of death. The response rate in the intent-to-treat population was 100.0% (95% confidence interval 82.4-100.0) in patients (n = 19) with baseline uric acid level of > 8.0 mg/dL. Similarly, the response rate was 86.2% (n = 25) among 29 patients (60.4%) with baseline uric acid levels of ≤ 8.0 mg/dL. The maximum mean percentage decrease of plasma uric acid level in the overall patients was 96.9%. CONCLUSION: Rasburicase was well tolerated and effective in controlling hyperuricemia in Chinese pediatric patients with NHL and AL.

Impact of Type 2 Diabetes Duration on the Efficacy and Safety of Add-on Lixisenatide in Asian Individuals Receiving Basal Insulin: A Pooled Analysis.

INTRODUCTION: This analysis investigated the efficacy and safety of add-on lixisenatide by disease duration in Asian people with type 2 diabetes inadequately controlled with basal insulin ± oral antidiabetic drugs. METHODS: Data for Asian participants in the GetGoal-Duo 1, GetGoal-L, and GetGoal-L-C studies were pooled and categorized by diabetes duration: < 10 years (group 1), 10 to < 15 years (group 2), and ≥ 15 years (group 3). Efficacy and safety of lixisenatide versus placebo were evaluated by subgroup. The potential influence of diabetes duration on efficacy was examined using multivariable regression analyses. RESULTS: A total of 555 participants were included (mean age 53.9 years, 52.4% male). No significant differences in treatment effect between the duration subgroups were observed for the changes from baseline to 24 weeks in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), postprandial glucose (PPG), PPG excursion, body weight or body mass index, or the proportion of participants with HbA1c < 7% at 24 weeks (all P values for interaction > 0.1). Change in insulin dosage (U/day) was significantly different between subgroups (P = 0.038). Multivariable regression analysis showed participants in group 1 had a smaller change in body weight and basal insulin dose over the 24-week treatment period than participants in group 3 (P = 0.014 and 0.030, respectively) and were less likely to achieve an HbA1c < 7% than participants in group 2 (P = 0.047). No severe hypoglycemia was reported. A higher proportion of participants in group 3 versus the other groups had symptomatic hypoglycemia, for both lixisenatide and placebo, and T2D duration had a significant effect on hypoglycemia risk (P = 0.001). CONCLUSIONS: Lixisenatide improved glycemic control in Asian individuals regardless of diabetes duration, without increasing the risk of hypoglycemia. Individuals with longer disease duration had a greater risk of symptomatic hypoglycemia than individuals with shorter disease duration regardless of treatment. No additional safety concerns were observed. CLINICAL TRIAL REGISTRATION: GetGoal-Duo 1, ClinicalTrials.gov record NCT00975286; GetGoal-L, ClinicalTrials.gov record NCT00715624; GetGoal-L-C, ClinicalTrials.gov record NCT01632163.

Measuring Self-management Among People with Diabetes Mellitus: A Systematic Review of Patient-Reported Diabetes-Specific Instruments in English and Chinese.

INTRODUCTION: Effective behavioral management is critical for people with diabetes to achieve glycemic control. Many instruments have been developed to measure diabetes-specific self-management. This review aimed to retrieve existing self-management-related instruments and identify well-validated instruments suitable for clinical research and practice. METHODS: First, PubMed, Psych INFO, ERIC, and two Chinese databases (CNKI and Wanfang Data) were searched to identify existing instruments for self-management in diabetes systematically. Second, instruments were screened based on the pre-specified inclusion and exclusion criteria. Third, the psychometric property data of each included instrument were retrieved, and instruments with poor psychometric properties were excluded. Fourth, selected instruments were categorized into four categories: knowledge and health literacy, belief and self-efficacy, self-management behaviors, and composite scales. Finally, recommendations were made according to the application status and quality of the instruments. Instruments in English and Chinese were screened and summarized separately. RESULTS: A total of 406 instruments (339 English instruments and 67 Chinese instruments) were identified. Forty-three English instruments were included. Five focused on knowledge and literacy, 12 on belief and self-management perception-related constructs, 21 on self-management and behaviors, and 5 on composite measures. We further recommended 19 English scales with relatively good quality and are frequently applied. Twenty-five Chinese instruments were included, but none were recommended because of a lack of sufficient psychometric property data. CONCLUSION: Many English instruments measuring diabetes self-management have been developed and validated. Further research is warranted to validate instruments adapted or developed in the Chinese population.

Efficacy and safety of basal-first titration order in individuals with type 2 diabetes receiving short-term intensive insulin therapy: An exploratory analysis of BEYOND V.

AIMS: To present the results of an exploratory analysis of the BEYOND V study in which Chinese individuals with uncontrolled type 2 diabetes (T2D) received short-term intensive insulin therapy (SIIT) during study run-in (prior to randomization) using a basal-first insulin titration method. MATERIALS AND METHODS: This was exclusively an exploratory analysis of the 7- to 10-day run-in period of BEYOND V. Participants were hospitalized and had oral therapies withdrawn (except metformin). They received SIIT with once-daily insulin glargine and three-times-daily premeal insulin glulisine, titrated daily from a total starting dose of 0.4 to 0.5 units/kg/d, first adjusting insulin glargine to achieve fasting blood glucose (FBG) of 4.4 to 6.1 mmol/L (79 to 119 mg/dL), then insulin glulisine to achieve pre-meal blood glucose of 4.4 to 6.1 mmol/L. Key outcomes were the proportions of participants achieving FBG and 2-hour postprandial blood glucose (PBG) targets. RESULTS: Overall, 397 entered the run-in (mean 54.2 years, 235 males [59.2%]). At the end of SIIT, 374/396 participants (94.4%) had both FBG <7.0 mmol/L (<126 mg/dL) and 2-hour PBG <10 mmol/L (<180 mg/dL) and 282/396 (71.2%) had both FBG <6.1 mmol/L (<100 mg/dL) and 2-hour PBG <10 mmol/L. The mean first time taken to achieve FBG <7 mmol/L, 2-hour PBG <10 mmol/L, and both, was 4.35, 3.88, and 5.04 days, respectively. Hypoglycaemia occurred in 99 participants (24.9%). There was no severe hypoglycaemia. CONCLUSIONS: Titrating basal insulin first is an effective and safe method of SIIT in individuals with T2D, rapidly achieving target glucose levels with a relatively low rate of hypoglycaemia.

Influence of Baseline HbA1c and Antiplatelet Therapy on 1-Year Vein Graft Outcome.

Background: The influence of baseline HbA1c levels on vein graft outcomes post coronary artery bypass grafting (CABG) remains unclear. Objective: The purpose of this study was to assess the association between baseline HbA1c and 1-year vein graft patency, and the effects of antiplatelet therapy on the 1-year vein graft patency after CABG in patients with baseline HbA1c <6.5% vs ≥6.5%. Methods: We examined the subgroups with baseline HbA1c <6.5% vs ≥6.5% from the DACAB trial (NCT02201771), in which 500 patients were randomly allocated to receive ticagrelor plus aspirin (T+A), ticagrelor alone (T), or aspirin alone (A) for 1 year after CABG. The primary outcome was the vein graft patency (FitzGibbon grade A) at 1 year. Results: A total of 405 patients with available baseline HbA1c data were included in this subgroup analysis. Of them, there were 233 patients (678 vein grafts) with baseline HbA1c <6.5% and 172 patients (512 vein grafts) with baseline HbA1c ≥6.5%. Compared with the HbA1c <6.5% subgroup, the HbA1c ≥6.5% subgroup showed worse 1-year vein graft patency (adjusted odds ratio [OR] for nonpatency: 1.69, 95% confidence interval [CI]: 1.08-2.64). T+A showed higher vein graft patency than A in both HbA1c <6.5% (adjusted OR for nonpatency: 0.34, 95% CI: 0.15-0.75) and HbA1c ≥6.5% subgroups (adjusted OR for nonpatency: 0.45, 95% CI: 0.19-1.09), without an interaction effect (P for interaction = 0.335), whereas T did not show more significant improvement than A in both subgroups. Conclusions: In the DACAB trial, lower baseline HbA1c was associated with higher vein graft patency 1 year after CABG. T+A improved 1-year vein graft patency vs A, irrespective of baseline HbA1c.

Patient-reported outcome (PRO) instruments for disease severity and quality of life in patients with atopic dermatitis: a systematic review of English and Chinese literature.

Background: Many patient-reported outcome (PRO) on disease severity quality of life (QOL) have been developed for atopic dermatitis (AD) patients. However, none of them on the reliability and validity of the instruments was sufficient for their application in clinical studies. The objective of this study is to identify and assess the quality of recently developed PROs for disease severity and QOL in English and Chinese in AD patients. Methods: We conducted a systematic review of PROs for disease severity and QOL for AD from PubMed, Web of Science, PsycINFO and ERIC (English literatures), and CNKI and Wanfang Data (Chinese literatures) from September 2010 to December 2021 with string including "atopic dermatitis" and "scaling". All studies were screened by 2 reviewers. After being removed duplications, the studies developed the instruments for the AD patients, were reported by patients, and assessing the disease severity or QOL were included. Results: Twenty-six instruments were retrieved. Three single-item Numeric Rating Scale (NRS) and 8 multidimensional instruments assessing disease severity and 15 assessing QOL were found to be originally developed in English (n=23) or Chinese (n=3). After full assessment on the reliability and validity, 3 NRS and 9 multidimensional instruments were recommended. The 3 NRS were Peak Pruritus/Itch NRS, Skin Pain NRS and Sleep Disturbance (SD) NRS. The multidimensional instruments for disease severity included the Patient-Oriented Eczema Measure (POEM), the patient oriented-SCORAD (PO-SCORAD), and Atopic Dermatitis Symptom Score (ADSS), and the instruments for QOLs included Infant's Dermatology Quality of Life Index (IDQOL), Children's Dermatology Life Quality Index (CDLQI), Atopic Dermatitis Control Tool (ADCT), PROMIS® Itch Questionnaire Mood and Sleep (PIQ-MS), PROMIS-Sleep Disturbance (PROMIS-SD), and PROMIS-Sleep-Related Impairment (PROMIS-SRI) for QOL. However, none of the Chinese PROs either originally developed or adapted were fully validated. Discussion: Single-item NRS is a complement to multidimensional PROs in assessing the disease severity of AD. Quality of these instruments vary greatly and only a few instruments that meet the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) standards are recommended. Therefore, standardization of PROs is essential for developing new instruments, and for adapting a PRO in other populations with different culture and languages.

Predictors of HbA1c reduction and hypoglycemia in type 2 diabetes mellitus individuals switching from premixed to basal insulin: an exploratory analysis of optimization study.

OBJECTIVE: To identify population with type 2 diabetes mellitus (T2DM) who are more likely to benefit from switching to basal insulin (BI) treatment from premixed insulin. METHODS: This secondary analysis included data from a previously published study (Optimization: NCT00693771) which was a single-arm, multicenter, 16 weeks, phase IV study. The analysis included participants with T2DM inadequately controlled with premixed insulin plus oral hypoglycemic drugs (OADs) who switched to BI plus OADs. RESULTS: Among the 297 participants included for analysis, subjects with fasting C-peptide (FCP)>1.2 nmol/L group showed a trend for greater reduction in HbA1c [Least square mean difference (LSMD), -0.59; 95% confidence interval (CI), -0.98 to -0.21; p = 0.003] and FPG (LSMD, -1.36; 95% CI, -2.20 to -0.53; p = 0.002) than those with FCP ≤ 0.4 nmol/L. The baseline insulin glargine 100 U/mL (Gla-100) dose increased significantly in 0.4 to ≤ 1.2 nmol/L group with LS mean difference (SE) of 0.16 (0.01) U/kg/day (p = 0.008) compared to FCP ≤ 0.4 nmol/L group. When combined with Diabetes Treatment Satisfaction Questionnaire (DTSQ) score, participants with a C-peptide level of 0.4 to ≤1.2 nmol/L (OR, 4.05; 95% CI, 1.08 to 15.22; p = 0.039) had significantly higher odds of achieving HbA1c <7%. The number of participants experiencing documented symptomatic hypoglycaemia (≤3.9 mmol/L) was higher in the FCP ≤0.4 nmol/L group compared to those in 0.4 to ≤1.2 nmol/L FCP group at any time of the day (31.6 vs. 17.1%) and during night (00:00 ∼ 05:59) (17.1 vs. 7.5%). CONCLUSION: The findings from this study proposed that FCP is an important biomarker to identify T2DM participants who experience improved glucose control without compromising on hypoglycemia levels during switch from premixed insulin to BI. Participants especially with FCP levels >1.2 nmol/L may respond better in terms of HbA1c reduction without increased hypoglycemia risk compared to those with lower FCP values.

Influence of lipoproteins and antiplatelet agents on vein graft patency 1 year after coronary artery bypass grafting.

OBJECTIVE: It remains unclear whether aggressive low-density lipoprotein cholesterol (LDL-C) management (<1.8 mmol/L) can slow the process of vein graft stenosis. This study aimed to explore the impact of baseline LDL-C levels on vein graft patency in patients on ticagrelor with or without aspirin 1 year after coronary artery bypass grafting (CABG). METHODS: This was a post hoc analysis of the DACAB (Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery) trial (NCT02201771), a randomized controlled trial (ticagrelor + aspirin or ticagrelor vs aspirin) of patients undergoing CABG in China. The study subjects were stratified as LDL-low (baseline LDL-C <1.8 mmol/L, 148 patients with 430 vein grafts) versus LDL-high (baseline LDL-C ≥1.8 mmol/L, 352 patients with 1030 vein grafts). The primary outcome was the 1-year vein graft patency (Fitzgibbon grade A) assessed by coronary computed tomographic angiography or coronary angiography. RESULTS: Baseline/1-year LDL-C were 1.4/1.6 and 2.6/2.4 mmol/L in the LDL-low and LDL-high subgroups, respectively. Regardless of antiplatelet regimen, no significant inter-subgroup difference was observed for 1-year graft patency (LDL-low: 83.8% [359/430 grafts]; LDL-high: 82.3% [848/1030 grafts]; adjusted OR for non-patency [ORadj], 0.96; 95% confidence interval [CI], 0.62-1.50, P = .857). For both subgroups, the 1-year graft patency rates were greater with ticagrelor + aspirin versus aspirin (LDL-low: ORadj, 0.41; 95% CI, 0.17-0.97; LDL-high: ORadj, 0.38; 95% CI, 0.20-0.71; inter P = .679). CONCLUSIONS: In general, baseline LDL-C is not associated with 1-year vein graft patency after CABG. Regardless of the baseline LDL-C levels, ticagrelor + aspirin was superior to aspirin alone in maintaining vein graft patency. The primary factor causing early vein graft disease might not be atherosclerosis but thrombosis.

High-resolution epitope mapping and characterization of SARS-CoV-2 antibodies in large cohorts of subjects with COVID-19.

As Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to spread, characterization of its antibody epitopes, emerging strains, related coronaviruses, and even the human proteome in naturally infected patients can guide the development of effective vaccines and therapies. Since traditional epitope identification tools are dependent upon pre-defined peptide sequences, they are not readily adaptable to diverse viral proteomes. The Serum Epitope Repertoire Analysis (SERA) platform leverages a high diversity random bacterial display library to identify proteome-independent epitope binding specificities which are then analyzed in the context of organisms of interest. When evaluating immune response in the context of SARS-CoV-2, we identify dominant epitope regions and motifs which demonstrate potential to classify mild from severe disease and relate to neutralization activity. We highlight SARS-CoV-2 epitopes that are cross-reactive with other coronaviruses and demonstrate decreased epitope signal for mutant SARS-CoV-2 strains. Collectively, the evolution of SARS-CoV-2 mutants towards reduced antibody response highlight the importance of data-driven development of the vaccines and therapies to treat COVID-19.

Phase Ib study of patients with metastatic castrate-resistant prostate cancer treated with different sequencing regimens of atezolizumab and sipuleucel-T.

BACKGROUND: Combining an immune checkpoint inhibitor with a tumor vaccine may modulate the immune system to leverage complementary mechanisms of action that lead to sustained T-cell activation and a potent prolonged immunotherapeutic response in metastatic castration resistant prostate cancer (mCRPC). METHODS: Subjects with asymptomatic or minimally symptomatic mCRPC were randomly assigned in a 1:1 ratio to receive either atezolizumab followed by sipuleucel-T (Arm 1) or sipuleucel-T followed by atezolizumab (Arm 2). The primary endpoint was safety, while secondary endpoints included preliminary clinical activity such as objective tumor response and systemic immune responses that could identify key molecular and immunological changes associated with sequential administration of atezolizumab and sipuleucel-T. RESULTS: A total of 37 subjects were enrolled. The median age was 75.0 years, median prostate specific antigen (PSA) was 21.9 ng/mL, and subjects had a median number of three prior treatments. Most subjects (83.8%) had at least one treatment-related adverse event. There were no grade 4 or 5 toxicities attributed to either study drug. Immune-related adverse events and infusion reactions occurred in 13.5% of subjects, and all of which were grade 1 or 2. Of 23 subjects with Response Evaluation Criteria in Solid Tumors measurable disease, only one subject in Arm 2 had a partial response (PR) and four subjects overall had stable disease (SD) at 6 months reflecting an objective response rate of 4.3% and a disease control rate of 21.7%. T-cell receptor diversity was higher in subjects with a response, including SD. Immune response to three novel putative antigens (SIK3, KDM1A/LSD1, and PIK3R6) appeared to increase with treatment. CONCLUSIONS: Overall, regardless of the order in which they were administered, the combination of atezolizumab with sipuleucel-T appears to be safe and well tolerated with a comparable safety profile to each agent administered as monotherapy. Correlative immune studies may suggest the combination to be beneficial; however, further studies are needed. TRIAL REGISTRATION NUMBER: NCT03024216.

Lixisenatide is effective and safe as add-on treatment to basal insulin in Asian individuals with type 2 diabetes and different body mass indices: a pooled analysis of data from the GetGoal Studies.

INTRODUCTION: This analysis aims to investigate the efficacy and safety of once-daily lixisenatide add-on treatment to basal insulin in Asian individuals with type 2 diabetes, by baseline body mass index (BMI). RESEARCH DESIGN AND METHODS: Data from all Asian participants in the placebo-controlled GetGoal-Duo 1, GetGoal-L, and GetGoal-L-C Studies were pooled and categorized according to the following BMI subgroups:<25 kg/m2, 25-<30 kg/m2 and ≥30 kg/m2. Efficacy and safety of lixisenatide versus placebo were evaluated among BMI subgroups. Multivariable regression analyses were also conducted to explore the potential influence of BMI on efficacy outcomes after adjusting for baseline characteristics. RESULTS: 555 participants were included (mean age 53.9 years, 52.4% men). No significant differences in treatment effect between the BMI subgroups were observed for the changes from baseline to 24 weeks in glycated hemoglobin (HbA1c), fasting plasma glucose, postprandial glucose (PPG), PPG excursion, body weight, BMI, and basal insulin dose with lixisenatide, as well as the change in basal insulin dose at study endpoint and the proportion of participants achieving an HbA1c <7% at 24 weeks (all p values for interaction >0.15). In the multivariable regression analysis, participants in the lowest BMI group had a smaller reduction in body weight over the 24-week treatment period relative to the highest BMI group (p=0.023). CONCLUSIONS: This post hoc analysis indicates that lixisenatide improved glycemic control regardless of baseline BMI and was well tolerated in Asian individuals unable to achieve their HbA1c target on basal insulin±oral antidiabetic drugs.

Comparison of insulin glargine 300 U/mL versus glargine 100 U/mL on glycemic control and hypoglycemic events in East Asian patients with type 2 diabetes: A Patient-level meta-analysis of phase 3 studies.

AIMS: To evaluate efficacy and safety of Gla-300 with Gla-100 in a patient-level meta-analysis among large East Asian patients with type 2 diabetes mellitus (T2DM). METHODS: A patient level meta-analysis of three EDITION studies with similar design and endpoints were conducted over 6-months treatment period. The analysis included 547 patients treated with Gla-300 and 348 patients treated with Gla-100. RESULTS: Over 6-month treatment period, mean change in HbA1c was similar for Gla-300 [Least square (LS) mean, (SE): -1.13 (0.05) % and Gla-100: -1.14 (0.05) %], showing non-inferiority of Gla-300 to Gla-100 (LS mean difference: 0.02%, 95% CI: -0.08 to 0.11). Gla-300 was associated with reduced risk of hypoglycemic event (confirmed ≤ 3.9 mmol/L or severe) vs Gla-100 at any time of day or at night (00:00-05:59 h). The event rates of hypoglycemia were consistently lower with Gla-300 than Gla-100. Severe hypoglycemia was rare in both treatment groups. Weight gain was minimal in both treatment groups. CONCLUSION: Gla-300 provides comparable glycemic control to Gla-100 in East Asian patients with broad clinical spectrum of T2DM, with consistently less hypoglycemia at any time of the day and night.

Efficacy of once-daily glucagon-like peptide-1 receptor agonist lixisenatide as an add-on treatment to basal insulin in Asian and white adults with type 2 diabetes mellitus: An individual-level pooled analysis of phase III studies.

AIMS/INTRODUCTION: The prevalence and pathophysiological background of type 2 diabetes mellitus vary across ethnicities, and can affect treatment responses. Adding lixisenatide to basal insulin (BI) in type 2 diabetes mellitus patients has shown improvements in glycated hemoglobin (HbA1c) and postprandial glycemic (PPG) excursions, without increasing hypoglycemic events. We aim to compare the efficacy of lixisenatide in Asian and white patients inadequately controlled with basal insulin. MATERIALS AND METHODS: An individual-level pooled analysis of two multi-national phase III studies, GetGoal-L and GetGoal-L-C, was carried out to assess the efficacy of lixisenatide versus placebo as an add-on treatment to BI ± metformin in Asian and white patients with type 2 diabetes mellitus. Change in HbA1c, 2-h PPG and PPG excursion were analyzed, along with possible predictors of glycemic control. RESULTS: Pooled data showed that baseline characteristics were similar between Asian and white patients with the exception of bodyweight, body mass index and BI dose being higher in white patients. After 24 weeks, lixisenatide reduced HbA1c in both ethnic groups, with no statistically significant difference between the two groups (Asian patients least squares mean difference -0.49, 95% confidence interval -0.68 to - 0.30 and white patients least squares mean difference -0.45, 95% confidence interval -0.63 to - 0.26; P = 0.6287). Similarly, no significant difference was found in 2-h PPG reduction between both groups (least squares mean difference for Asian vs white patients: -3.37 vs -3.93; P = 0.3203). Treatment with lixisenatide contributed to HbA1c reduction of -0.56% after adjustment of baseline HbA1c level in Asian patients, and -0.41% in white patients. CONCLUSIONS: Adding lixisenatide to BI significantly reduced HbA1c and 2-h PPG levels in both Asian and white participants with type 2 diabetes mellitus. No differences in treatment effect were observed between the two populations.

Annual glycemic variations and risk of cancer among Chinese patients with type 2 diabetes mellitus: A population-based cohort study in Shanghai.

BACKGROUND: Long-term glycemic variation in diabetes patients may have contributed to cancer incidence. AIM: In this study we aimed at the association between annual glycemic variation and the risk of cancer in Chinese patients with type 2 diabetes mellitus (T2DM). METHODS: Subjects of this study were from an established population-based cohort of T2DM patients in Minhang District of Shanghai, China. Incident cancer were obtained from the Shanghai Cancer Registry. Glycemic variation was evaluated using the annual fasting glucose coefficient of variation (FG-CV), which was used as a time-dependent variable in a Cox regression model to estimate the associations with the cancer risk. Restricted cubic splines were used to explore potential non-linear associations. RESULTS: A total of 2,140 incident cancers (1100 men and 1040 women) were identified from the 46,202 diabetes patients during 12-year follow-up. The annual FG-CV remained significantly associated with an increased risk of cancer, even after adjusting for the annual mean FG level. A significant non-linear association was found in male T2DM patients, and a significant linear association in female patients. CONCLUSIONS: The positive association of the annual FG-CV with the risk of cancer in T2DM patients indicate the importance to stabilize the FG level.

Effect of ticagrelor with or without aspirin on vein graft outcome 1 year after on-pump and off-pump coronary artery bypass grafting.

BACKGROUND: In the present post hoc analysis of the DACAB trial, we evaluated the effects of ticagrelor with or without aspirin on 1-year vein graft outcomes after coronary artery bypass grafting (CABG) with and without cardiopulmonary bypass (CPB) (on-pump and off-pump). METHODS: The DACAB trial was a multicenter, randomized, open-label, parallel control study enrolling 500 patients with 1,460 vein grafts undergoing CABG. For current post-hoc study, all patients in the DACAB study were included in the analysis to compare the effects of different antiplatelet regimens under on/off pump. Patients were randomly assigned to 1 of 3 antiplatelet treatment regimens (ticagrelor plus aspirin, T + A; ticagrelor alone, T; or aspirin alone, A) within 24 hours after CABG, and were stratified into on-pump and off-pump subgroups. The primary outcome was 1-year vein graft patency rate. RESULTS: Totally 121 patients underwent on-pump CABG (39 with 121 vein grafts in T + A, 36 with 101 vein grafts in T, and 46 with 137 vein grafts in A) and 379 patients underwent off-pump CABG (129 with 336 vein grafts in T + A, 130 with 387 vein grafts in T, and 120 with 348 vein grafts in A). Compared with A, T + A showed a higher 1-year vein graft patency rate in both on-pump (adjusted OR for non-patency =0.62, 95% CI: 0.16-2.45) and off-pump (adjusted OR for non-patency =0.35, 95% CI: 0.20-0.62) subgroups, P interaction =0.647; whereas T did not in either on-pump (adjusted OR for non-patency = 0.92, 95% CI: 0.31-2.76) or off-pump (adjusted OR for non-patency =0.58, 95% CI: 0.34-1.00) subgroups, P interaction =0.430. CONCLUSIONS: In the DACAB trial, for patients underwent either on-pump or off-pump CABG, ticagrelor plus aspirin showed consistent benefit for achieving 1-year vein graft patency, with particular benefit being seen in the off-pump.

Autoantibody Landscape in Patients with Advanced Prostate Cancer.

PURPOSE: Autoantibody responses in cancer are of great interest, as they may be concordant with T-cell responses to cancer antigens or predictive of response to cancer immunotherapies. Thus, we sought to characterize the antibody landscape of metastatic castration-resistant prostate cancer (mCRPC). EXPERIMENTAL DESIGN: Serum antibody epitope repertoire analysis (SERA) was performed on patient serum to identify tumor-specific neoepitopes. Somatic mutation-specific neoepitopes were investigated by associating serum epitope enrichment scores with whole-genome sequencing results from paired solid tumor metastasis biopsies and germline blood samples. A protein-based immunome-wide association study (PIWAS) was performed to identify significantly enriched epitopes, and candidate serum antibodies enriched in select patients were validated by ELISA profiling. A distinct cohort of patients with melanoma was evaluated to validate the top cancer-specific epitopes. RESULTS: SERA was performed on 1,229 serum samples obtained from 72 men with mCRPC and 1,157 healthy control patients. Twenty-nine of 6,636 somatic mutations (0.44%) were associated with an antibody response specific to the mutated peptide. PIWAS analyses identified motifs in 11 proteins, including NY-ESO-1 and HERVK-113, as immunogenic in mCRPC, and ELISA confirmed serum antibody enrichment in candidate patients. Confirmatory PIWAS, Identifying Motifs Using Next-generation sequencing Experiments (IMUNE), and ELISA analyses performed on serum samples from 106 patients with melanoma similarly revealed enriched cancer-specific antibody responses to NY-ESO-1. CONCLUSIONS: We present the first large-scale profiling of autoantibodies in advanced prostate cancer, utilizing a new antibody profiling approach to reveal novel cancer-specific antigens and epitopes. Our study recovers antigens of known importance and identifies novel tumor-specific epitopes of translational interest.

Adherence to Dietary Recommendations among Long-Term Breast Cancer Survivors and Cancer Outcome Associations.

BACKGROUND: Adherence to dietary recommendations has been shown to be associated with reduced mortality in healthy populations. Little is known about the possible benefits of adherence to dietary recommendations among breast cancer survivors. METHODS: Dietary information was collected using food frequency questionnaires at the 5-year postdiagnosis survey in 3,450 5-year breast cancer survivors from the Shanghai Breast Cancer Survival Study. Adherence scores to Chinese Food Pagoda (CHFP)-2007, CHFP-2016, modified Dietary Approaches to Stop Hypertension (DASH), and Healthy Eating Index 2015 (HEI-2015) were created. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for total mortality and breast cancer-specific events according to adherence scores. RESULTS: Participants in the highest quartiles of CHFP-2007, CHFP-2016, and DASH had 25% to 34% lower risk of total mortality (HR, 0.66; 95% CI, 0.48-0.89 for CHFP-2007; HR, 0.75; 95% CI, 0.55-1.01 for CHFP-2016; HR, 0.66; 95% CI, 0.49-0.91 for DASH), and 36% to 40% lower risk of breast cancer-specific events (HR, 0.64; 95% CI, 0.44-0.93 for CHFP-2007; HR, 0.67; 95% CI, 0.45-0.99 for CHFP-2016; HR, 0.60; 95% CI, 0.40-0.90 for DASH) comparing with the lowest quartiles. Associations did not vary by known prognostic factors. HEI-2015 scores were not significantly associated with breast cancer outcomes. CONCLUSIONS: Higher adherence to CHFP and DASH dietary guidelines post-cancer diagnosis was associated with reduced risk of both overall death and breast cancer-specific recurrence or death among long-term breast cancer survivors. IMPACT: Our study highlights the importance of overall dietary quality among long-term breast cancer survivors.