Does the Encounter Type Matter When Defining Diabetes Complications in Electronic Health Records?

BACKGROUND: Electronic health records (EHRs) and claims records are widely used in defining type 2 diabetes mellitus (T2DM) complications across different types of health care encounters. OBJECTIVE: This study investigates whether using different EHR encounter types to define diabetes complications may lead to different results when examining associations between diabetes complications and their risk factors in patients with T2DM. RESEARCH DESIGN: The study cohort of 64,855 adult patients with T2DM was created from EHR data from the Research Action for Health Network (REACHnet), using the Surveillance Prevention, and Management of Diabetes Mellitus (SUPREME-DM) definitions. Incidence of coronary heart disease (CHD) and stroke events were identified using International Classification of Diseases (ICD)-9/10 codes and grouped by encounter types: (1) inpatient (IP) or emergency department (ED) type, or (2) any health care encounter type. Cox proportional hazards regression was used to estimate associations between diabetes complications (ie, CHD and stroke) and risk factors (ie, low-density lipoprotein cholesterol and hemoglobin A1c). RESULTS: The incidence rates of CHD and stroke in all health care settings were more than twice the incidence rates of CHD and stroke in IP/ED settings. The age-adjusted and multivariable-adjusted hazard ratios for incident CHD and stroke across different levels of low-density lipoprotein cholesterol and hemoglobin A1c were similar between IP/ED and all settings. CONCLUSION: While there are large variations in incidence rates of CHD and stroke as absolute risks, the associations between both CHD and stroke and their respective risk factors measured by hazard ratios as relative risks are similar, regardless of alternative definitions.

Patient reported outcome data from acromegaly patients treated with injectable somatostatin receptor ligands (SRLs) in routine clinical practice.

BACKGROUND: Acromegaly patients managed on Somatostatin receptor ligands (SRLs), the most common first-line pharmacotherapy for acromegaly, may still experience acromegaly symptoms such as headache, sweating, fatigue, soft tissue swelling, and joint pain, even those with normal IGF-1. Additionally, treatment with SRLs may cause injection site reactions and other side effects such as gastro-intestinal (GI) symptoms. This study utilized patient-reported outcome measures to examine the burden associated with acromegaly and its treatment for patients receiving a stable dose of long-acting SRLs in routine clinical practice. METHODS: US acromegaly patients on a stable dose of SRL seen by their treating healthcare provider in the past 12 months completed a one-time online survey including the Acro-TSQ, an acromegaly-specific tool for assessing symptom burden and treatment satisfaction and convenience. RESULTS: One hundred five patients were enrolled (mean age 49.9 years, 79.1% female). Patients experienced numerous symptoms, including > 80% who experienced joint pain, acro-fog, swelling of soft tissue, and fatigue/weakness. Many symptoms occurred constantly, while some occurred at the end of the injection cycle, even among those with IGF-1 < = 1.0 ULN. Injection site reactions were common. Patients were moderately satisfied with their current treatment; symptoms and side effects often affected daily activities. On average, patients reported > 3 acromegaly provider visits/year. CONCLUSIONS: Despite receiving a stable dose of SRL and regular visits with an acromegaly healthcare provider, US acromegaly patients in routine clinical practice, and even the subgroup with normal IGF-1, report significant burden of disease and treatment.

Observed discordance between outcomes reported by acromegaly patients and their treating endocrinology medical provider.

BACKGROUND: Acromegaly patients, even those with IGF-1 values within the normal range receiving somatostatin receptor ligands (SRLs), often suffer from significant symptoms. It is not known to what extent patients' medical providers are aware of the frequency and severity of acromegaly symptoms or level of treatment satisfaction with SRLs. This study sought to examine the concordance between outcomes reported by acromegaly patients treated with long-acting SRLs and those perceived by their medical provider. METHODS: US acromegaly patients on a stable dose of SRL and seen by their medical provider in the past year completed an online survey which included the Acro-TSQ. Their medical providers were interviewed about the perception of their patient's symptoms, level of control, and general health, and completed relevant portions of the Acro-TSQ. Concordance between patient and medical provider reported data was examined. RESULTS: Medical providers reported that their patients experienced acromegaly symptoms on a regular basis, however, there was poor agreement between patients and medical providers on the frequency, severity, and pattern of symptoms, as well as on the severity of injection site reactions and multiple domains of the Acro-TSQ, with patients generally reporting symptoms and injection site reactions more often and with higher severity than medical providers. CONCLUSIONS: Medical providers were aware that their patients who were receiving a stable dose of SRL regularly experienced acromegaly symptoms. Addressing discordance in patient- and medical provider-reported frequency and severity of acromegaly symptoms and injection site reactions by facilitating better communication may improve care of acromegaly patients.

Recombinant domain V of ß2-glycoprotein I inhibits the formation of atherogenic oxLDL/ß2-glycoprotein I complexes.

ß2-glycoprotein I (ß2-GPI) is a plasma protein that interacts with oxidized low-density lipoproteins (oxLDL) via ß2-GPI domain V to form oxLDL/ß2-GPI complexes, potential autoantigens promoting atherogenesis in patients with antiphospholipid syndrome (APS). Such a interaction would expose ß2-GPI domain I or/and IV, structures recognized by anti-ß2-GPI autoantibodies. IgG immune complexes with oxLDL/ß2-GPI complexes can interact with macrophages via Fcγ receptor, causing oxLDL/ß2-GPI endocytosis and foam cell formation, contributing to atherosclerosis. Here, we use recombinant domain V to study the interaction between oxLDL and ß2-GPI and hypothesized that domain V would interfere with this interaction thereby reducing oxLDL macrophage uptake and foam cell formation. The ß2-GPI domain V sequence was expressed by using the Pichia pastoris expression system to obtain recombinant domain V of ß2-GPI (P.rß2-GPI DV). ELISA tests demonstrated that P.rß2-GPI DV interacted with oxLDL via 7-ketocholesteryl-9-carboxynonanoate (oxLig-1), a negatively charged lipid moiety of oxLDL. The ω-carboxyl residue of oxLig-1 is required for the interaction. Serologic tests showed a significant increase in oxLDL and oxLDL/ß2-GPI levels in patients with APS (p < 0.05 compared to controls). P.rß2-GPI DV was able to bind oxLDL in high affinity and competitively inhibited native ß2-GPI (nß2-GPI) binding to free oxLDL as well as to oxLDL from the oxLDL/ß2-GPI complexes. These observations suggest that P.rß2-GPI DV may be used to inhibit the formation of the oxLDL/ß2-GPI complexes, a potential approach for reducing foam cell development and mitigating atherogenesis in patients with APS. The present work provides a new effective strategy to prevent the progression of atherothrombotic vascular complications in APS patients.

Simultaneous Interfacial Defect Passivation and Bottom-Up Excess PbI2 Management via Rubidium Chloride in Highly Efficient Perovskite Solar Cells with Suppressed Hysteresis.

In halide perovskite solar cells (PSCs), moderate lead iodide (PbI2) can enhance device efficiency by providing some passivation effects, but extremely active PbI2 leads to the current density-voltage hysteresis effect and device instability. In addition, defects distributed on the buried interface of tin oxide (SnO2)/perovskite will lead to the photogenerated carrier recombination. Here, rubidium chloride (RbCl) is introduced at the buried SnO2/perovskite interface, which not only acts as an interfacial passivator to interact with the uncoordinated tin ions (Sn4+) and fill the oxygen vacancy on the SnO2 surface but also converts PbI2 into an inactive (PbI2)2RbCl compound to stabilize the perovskite phase via a bottom-up evolution effect. These synergistic effects deliver a champion PCE of 22.13% with suppressed hysteresis for the W RbCl PSCs, in combination with enhanced environmental and thermal stability. This work demonstrates that the interfacial defect passivation and bottom-up excess PbI2 management using RbCl modifiers are promising strategies to address the outstanding challenges associated with PSCs.

Treatment Journey and Healthcare Resource Use Among Patients With Alcohol Use Disorder Who Initiated Extended-Release Naltrexone: An Analysis of Veterans Affairs Data.

Background: The US Department of Veterans Affairs, Department of Defense (VA/DoD) clinical guidelines recommend extended-release naltrexone (XR-NTX) as a treatment option for moderate-to-severe alcohol use disorder (AUD); however, contemporary real-world outcomes related to this guideline are lacking. This retrospective, observational, descriptive study examined treatment patterns and healthcare resource use (HCRU) among veterans with an AUD diagnosis who initiated XR-NTX. Methods: Veterans with incident AUD who initiated XR-NTX between 8/2014 and 11/2018 were identified. Treatment patterns and HCRU were assessed during the 1-year baseline period before and following XR-NTX initiation (the index date). Results: Of the 3665 VA patients (mean [SD] age: 46 [12.5] years; male: 89.7%; White: 76.9%) included in the study, time from AUD diagnosis to XR-NTX initiation was highly variable (mean [range]: 13.6 [0-50.5 months]). Patients received a mean [SD] of 6.8 [6.1] XR-NTX administrations; 44.4% received ⩾6. Mean [SD] time to XR-NTX discontinuation was 93.4 [75.7] days, and 31.3% of discontinuing patients resumed XR-NTX therapy. Of those who received other subsequent medications for AUD, 38.6% (acamprosate) to 47.8% (disulfiram) re-initiated XR-NTX. The proportion of patients with ⩾1 inpatient admissions decreased during follow-up compared with baseline (all-cause: 61.5% to 37.8%; AUD-related: 58.0%-35.4%); with a smaller decrease observed in emergency department (ED) visits. In contrast, more patients had ⩾1 outpatient visits during follow-up (all-cause: 97.5%-99.7%; AUD-related: 84.4%-92.7%). Compared with baseline, mean number of inpatient admissions and ED visits decreased during follow-up, while the number of outpatient visits increased for both all-cause and AUD-related care. Conclusions: Among VA patients with AUD who initiated XR-NTX, we observed reductions in all-cause and AUD-related acute care, and increases in outpatient care. This finding demonstrates a possible transition from acute, inpatient treatment to long-term, outpatient care that may reflect a reduction in disease severity. Additional research is warranted.

Pharmacologic properties of polyethylene glycol-modified Bacillus thiaminolyticus thiaminase I enzyme.

We have previously shown that the bacterial enzyme thiaminase 1 has antitumor activity. In an attempt to make thiaminase I a more effective pharmaceutical agent, we have modified it by adding polyethylene glycol (PEG) chains of various lengths. We were surprised to find that 5k-PEGylation eliminated thiaminase cytotoxic activity in all cell lines tested. Both native thiaminase and 5k-PEGylated thiaminase efficiently depleted thiamine from cell culture medium, and both could use intracellular phosphorylated thiamine as substrates. However, native enzyme more effectively depleted thiamine and thiamine diphosphate in RS4 leukemia cell cytosol, and native thiaminase depressed cellular respiration, whereas PEGylated thiaminase did not. Despite the lack of in vitro cytotoxicity, PEGylation markedly increased the in vivo toxicity of the enzyme. Pharmacokinetic studies revealed that the half-life of native thiaminase was 1.5 h compared with 34.4 h for the 5k-PEGylated enzyme. Serum thiamine levels were depleted by both native and 5k-PEGylated enzyme. Despite superior pharmacokinetics, 5k-PEGylated thiaminase showed no antitumor effect against an RS4 leukemia xenograft, in contrast to native thiaminase, which showed antitumor activity. PEGylation of thiaminase I has demonstrated that depression of mitochondrial function contributes, at least in part, to its anticancer activity. PEGylation also enhances plasma retention time, which increased its vivo toxicity and decreased its activity against a leukemia xenograft, the opposite of the desired effects. These studies suggest that the mechanism of anticancer cytotoxicity of thiaminase requires acute depression of cellular respiration, whereas systemic toxicity is related to the duration of extracellular thiamine depletion.

Low-thiamine diet increases mammary tumor latency in FVB/N-Tg(MMTVneu) mice.

We have previously described the down-regulation of thiamine transporter gene expression in breast cancer, and others have shown an epidemiologic relationship between obesity and breast cancer. To further explore the relationship of thiamine, fat, and breast cancer, we exposed FVB/N-Tg(MMTVneu)202Mul/J female mice to four diets that varied in fat and thiamine content (15 mice per group). The high-fat (HF) diet contained 60 % of calories from fat and the normal-fat (NF) diet contained 10 % of calories from fat. The normal-thiamine (NT) diet contained 6 mg thiamine per 4057 kcal and the low-thiamine (LT) diet contained 2 mg thiamine/4057 kcal. Tumor latency was 203 days from date of birth for the HF/NT group, 210 days for the HF/LT group, 225 days for the NF/NT group, and 295 days for the NF/LT group (p = 0.01). The time to endpoint of a mammary tumor volume > 1000 mm3 was 231 days for the HF/NT group, 238 days for the HF/LT group, 257 days for the NF/NT group, and undefined (>310 days) for the NF/LT group (p < 0.001). The high-fat groups were heavier than the normal-fat groups, and the low-thiamine group had a lower serum thiamine level than the normal-thiamine group. There were no differences in the number of pulmonary metastases between groups. This study demonstrates a potential role for dietary thiamine, and an interaction between thiamine and fat, in breast cancer progression.

Enhanced Hole Mobility and Decreased Ion Migration Originated from Interface Engineering for High Quality PSCs with Average FF beyond 80.

Perovskite solar cells (PSCs) have made significant progress in power conversion efficiency (PCE) by optimizing deposition method, composition, interface, etc. Although the two-step method demonstrates the advantage of being easy to operate, too much residual PbI2 not only forms defect centers, but affects the perovskite crystallization by arising more grain boundaries (GBs) due to the easy-to-crystallize nature of PbI2 . And GBs in polycrystalline perovskite usually provide main channel for ion migration, leading to accumulation of charges at the interface to form a barrier, thus reducing carrier mobility and resulting in degradation of perovskite devices. Here, an organic molecule N-(4-acetylphenyl)maleimide (N-APMI) is used to modify interface between perovskite and hole transport layer. X-ray photoelectron spectroscopy, scanning electron microscope, and nuclear magnetic resonance results show that ketone group (CO) in N-APMI forms a strong coordination with Pb2+ , which effectively reduces the residual amount of PbI2 nanoparticles on the perovskite surface, giving rise to improved crystallization of perovskite. Temperature-dependent current response demonstrates that ion migration is effectively suppressed, and hole mobility validly increases from 10.74 to 19.48 cm2 V-1 s-1 , leading to a champion fill factor (FF) of 82.5% (PCE 21.96%), and the maximum PCE of the device improves from 20.09% to 23.03%.

Prevalence of diabetes and impaired fasting glucose in Chinese adults, China National Nutrition and Health Survey, 2002.

INTRODUCTION: As a result of rapid economic development in China, the lifestyles and dietary habits of its people have been changing, and the rates of obesity, diabetes, and other chronic conditions have increased substantially. We report the prevalence of type 2 diabetes and impaired fasting glucose (IFG) and the association between diabetes and overweight and obesity in Chinese adults. We also compare the results with those from the US National Health and Nutrition Examination Survey, 1999-2002. METHODS: Data were from adults aged 20 years or older who participated in the China National Nutrition and Health Survey, 2002 (n = 47,729). Diabetes and IFG were defined by the American Diabetes Association 2009 criteria. We assessed the prevalence of diabetes, IFG, and overweight and obesity by sex, age, region of residence, and ethnicity. RESULTS: The prevalence of diabetes and IFG in Chinese adults was 2.7% and 4.9%, respectively. The prevalence of diabetes increased with age and body mass index. Men and women had a similar prevalence of diabetes, but men had a significantly higher prevalence of IFG. The prevalence of diabetes among Chinese who lived in urban areas was 2 to 3 times higher than the prevalence among those who lived in rural areas (3.9% for urban areas and 6.1% for large cities vs 1.9% for rural areas), and the prevalence of IFG was 1.5 to 2 times higher (6.1% and 8.1% vs 4.2%, respectively). The prevalence of diabetes among Chinese women and young (20-39 y) and middle-aged (40-59 y) adults who lived in large cities was similar to the prevalence of diabetes in the US population. CONCLUSION: The prevalence of diabetes and IFG was much higher in urban than rural areas, particularly in the large cities of China. Prevention must be emphasized among adults to reduce the future social and economic burden of diabetes in China.

Standardizing the haemoglobin glycation index.

AIMS: A high haemoglobin glycation index (HGI) is associated with greater risk for hypoglycaemia and chronic vascular disease. Standardizing how the HGI is calculated would normalize results between research studies and hospital laboratories and facilitate the clinical use of HGI for assessing risk. METHODS: The HGI is the difference between an observed HbA1c and a predicted HbA1c obtained by inserting fasting plasma glucose (FPG) into a regression equation describing the linear relationship between FPG and HbA1c in a reference population. We used data from the 2005-2016 U.S. National Health and Nutrition Examination Survey (NHANES) to identify a reference population of 18,675 diabetes treatment-naïve adults without self-reported diabetes. The reference population regression equation (predicted HbA1c = 0.024 FPG + 3.1) was then used to calculate the HGI and divide participants into low (<-0.150), moderate (-0.150 to <0.150) and high (≥0.150) HGI subgroups. Diabetes status was classified by OGTTs. RESULTS: As previously reported in multiple studies, a high HGI was associated with black race independent of diabetes status, and with older age, higher BMI and higher CRP in normal and prediabetic but not diabetic participants. The mean HGI was 0.6% higher in self-reported diabetic adults. The HGI was not associated with plasma insulin, HOMA-IR or 2 h OGTT in participants classified as normal, prediabetic or diabetic. CONCLUSIONS: The regression equation derived from this demographically diverse diabetes treatment-naïve adult NHANES reference population is suitable for standardizing how the HGI is calculated for both clinical use and in research to mechanistically explain population variation in the HGI and why a high HGI is associated with greater risk for chronic vascular disease.

The Effect of Proton Pump Inhibitor Use on the Course of Kidney Function in Patients with Chronic Kidney Disease Stages G3a to G4.

BACKGROUND: Proton pump inhibitors (PPI) are widely used and implicated in the progression of chronic kidney disease (CKD). We evaluated the relation between chronic PPI use in veterans with CKD G3a to G4 and the rate of decline in renal function. METHODS: We accessed the Veteran Affairs Informatics and Computing Infrastructure national database to evaluate the relation between chronic PPI use and rate of decline in renal function in veterans with CKD (eGFR <60 ml/min1.73 m2). We applied Propensity Score Matching to match the PPI group and the no-PPI control group on age, sex, race, and Charlson Comorbidity Index. The final sample included 1406 patients (age: 62.07±7.82, 62.02% Caucasian) in the PPI cohort with a median 4.7 years follow-up and 1425 patients (age: 65.45±6.58, 71.16% Caucasian) in the control cohort with a median 3.9 years follow-up. Kaplan-Meier curve and Cox regression were performed to analyze the associations of PPI use with dialysis, all-cause mortality, metabolic acidosis, and CKD progression. RESULTS: The PPI group had a significantly increased risk of CKD progression, dialysis and all-cause mortality (aHR, 1.83; 95% CI, 1.53 to 2.19; aHR, 1.84; 95% CI, 1.26 to 2.67; and aHR, 1.34; 95% CI, 1.08 to 1.65, respectively). The PPI cohort also had a trend for development of metabolic acidosis (aHR, 1.34; 95% CI, 0.998 to 1.80), although the difference was not statistically significant. CONCLUSIONS: The data suggest that chronic PPI use accelerates progression of kidney disease and is associated with increased mortality in CKD patients.

Glycemic control and risk factors for in-hospital mortality and vascular complications after coronary artery bypass grafting in patients with and without preexisting diabetes.

BACKGROUND: The purpose of this study was to investigate risk factors of in-hospital mortality and vascular complications after coronary artery bypass grafting (CABG), particularly the effect of different glycemic control levels on outcomes in patients with and without previous evidence of diabetes. METHODS: A total of 8682 patients with and without previous diabetes undergoing CABG were categorized into strict, moderate, and liberal glucose control groups according to their mean blood glucose control level <7.8 mmol/L, 7.8 to 10.0 mmol/L, and ≥10.0 mmoL/L after in-hospital CABG. RESULTS: The patients with previous diabetes had higher rates of in-hospital mortality (1.3% vs 0.4%, P < .001) and major complications (7.0% vs 4.8%, P < .001) than those without diabetes. Current diabetes was significantly associated with a higher risk of in-hospital mortality (odds ratio [OR] = 3.14, 95% confidence interval [CI] 1.87-5.27) and major complications (OR = 1.49, 95% CI 1.24-1.80), and smoking and higher low-density lipoprotein cholesterol (LDL-C) levels showed similar results. Among patients with previous diabetes, strict glucose control was significantly associated with an increased risk of in-hospital mortality (OR = 8.32, 95% CI 3.95-17.51) compared with moderate glucose control. Nevertheless, among non-previous diabetic patients with stress hyperglycemia, strict glucose control led to a lower risk of major complications (OR = 0.71, 95% CI 0.52-0.98). CONCLUSIONS: Diabetes status, smoking, and LDL-C levels were modifiable risk factors of both in-hospital mortality and major complications after CABG. Strict glucose control was associated with an increased risk of in-hospital mortality among patients with diabetes, whereas it reduced the risk of major complications among non-previous diabetic patients.

Racial and sex differences in the polymorphisms of the endocannabinoid receptor genes in obesity.

BACKGROUND: Obesity is a global epidemic and prevalence of obesity is higher in African Americans (AAs) compared to Caucasians. The endocannabinoid system (EC) and polymorphism in the endocannabinoid receptor type 1 (CNR1) gene 3813A/G and 4895A/G and in the fatty acid amide hydrolase (FAAH) are associated with obesity. The objective was to explore racial and sex differences in these polymorphisms and the biochemical abnormalities seen in obesity. METHODS: A cross-sectional study of 667 subjects (53.67% female; 49.18% AA; 69.72% were obese (body mass index [BMI] ≥30)) were screened for CNR1 3813, 4895 and FAAH 385 polymorphisms using a real-time polymerase chain reaction (PCR) system. RESULTS: Subjects with FAAH 385 polymorphisms were more likely to be obese (75.14% vs. 67.81, P = 0.046). There were no significant sex differences for CNR1 3813 and CNR1 4895; or between obese and control group. AAs had higher prevalence of CNR1 3813 (OR, 2.80, 95% CI, 1.95-4.04) and FAAH 385 (OR, 2.48, 95% CI, 1.82-3.38). Association between African American race and the three genotypes persisted after adjustment of all the variables (P < 0.001). CONCLUSION: FAAH 385 polymorphism is more likely seen in obese and in older subjects. AAs had higher prevalence of CNR1 3813 and FAAH 385 polymorphisms; and lower prevalence of CNR1 4895 polymorphism. These findings may explain some of the racial differences, but not the sex differences in the clinical expression of obesity.

Correction to: Novel Risk Engine for Diabetes Progression and Mortality in USA: Building, Relating, Assessing, and Validating Outcomes (BRAVO).

The original article can be found online.

Effect of metformin on neurodegenerative disease among elderly adult US veterans with type 2 diabetes mellitus.

OBJECTIVE: This study aimed to evaluate the association between metformin treatment and the risk of neurodegenerative disease (ND) among elderly adults with type 2 diabetes mellitus (T2DM). DESIGN/SETTING/PARTICIPANTS: This retrospective longitudinal cohort study examined the effects of the length of metformin exposure on ND among elderly US veterans with T2DM and insulin treatment using the Veterans Affairs electronic medical record database. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary clinical outcome was defined as diagnosis of ND including dementia, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and mild cognitive impairment during the follow-up period. The secondary clinical outcomes were separately measured by AD, PD, HD, dementia and mild cognitive impairment. RESULT: Adjusted by propensity score weight, a total of 5528 patients (mean age, 63.2±10.9 years; male, 98%; white, 60%) with a median follow-up of 5.2 years were selected. Those with ND or other mental disorders at baseline or who were on insulin for less than two-thirds of the study period were excluded. The incidence rate of ND was 11.48 per 1000 person-years among patients with metformin treatment, compared with 25.45 per 1000 person-years for those without metformin. Compared with no metformin use, 2-4 years and >4 years of metformin exposure were significantly associated with lower risk of ND (adjusted HR (aHR)=0.62, 95% CI 0.45 to 0.85; aHR=0.19, 95% CI 0.12 to 0.31, respectively), while metformin exposure in the first 2 years showed no significant influence. CONCLUSION: We conclude that long-term metformin therapy (>2 years) was associated with lower incidence of ND among elderly veterans with T2DM. We need to conduct a study with more representative population and more robust method for causal inferences. Further investigation into the mechanism involved is needed along with randomised trials to confirm a potential neuroprotective effect of metformin.

Comparative Effectiveness of Non-cisplatin First-line Therapies for Metastatic Urothelial Carcinoma: Phase 2 IMvigor210 Study Versus US Patients Treated in the Veterans Health Administration.

BACKGROUND: First-line treatments for cisplatin-ineligible patients with metastatic urothelial carcinoma (mUC) include carboplatin-based chemotherapy and checkpoint inhibitors such as atezolizumab (anti-PD-L1). OBJECTIVE: To compare overall survival (OS) among patients with mUC treated in the first-line setting with atezolizumab versus carboplatin-based chemotherapies (any carboplatin-based regimens or carboplatin-gemcitabine). DESIGN, SETTING, AND PARTICIPANTS: Cisplatin-ineligible patients with mUC from the phase 2 trial IMvigor210 (ClinicalTrials.gov NCT02951767) treated with atezolizumab and patients from the Veterans Health Administration (VHA) health care system (2006-2017, with IMvigor210 eligibility criteria applied using proxy measurements) treated according to normal clinical practice. INTERVENTIONS: IMvigor210 cohort 1 patients were treated with atezolizumab, and real-world VHA cohorts were treated with carboplatin-based regimens. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Entropy-balance weighting was applied to balance prespecified baseline patient characteristics. OS was analyzed using weighted Kaplan-Meier and Cox methods. RESULTS AND LIMITATIONS: The median OS was 15.0 mo with atezolizumab (n = 110), 12.1 mo with any carboplatin-based chemotherapy (n = 282), and 8.7 mo with carboplatin-gemcitabine (n = 120). An OS benefit occurred with atezolizumab versus carboplatin-based regimens after 9 mo (hazard ratio [HR] 0.43; p = 0.004) and with atezolizumab versus carboplatin-gemcitabine after 5 mo (HR 0.52; p = 0.005). Study limitations include a predominantly male VHA cohort and ≤24-mo follow-up. Adjustment for confounding, a potential limitation of nonrandomized studies, was limited by the availability of clinical measurements in the VHA data, which allowed for replication of IMvigor210 exclusions in the VHA cohorts. CONCLUSIONS: First-line atezolizumab for cisplatin-ineligible mUC may provide an OS benefit over carboplatin-based treatments after 5-9 mo, depending on the regimen. PATIENT SUMMARY: Many patients with metastatic urothelial carcinoma are ineligible for cisplatin-based chemotherapy. This study compared patients from a clinical trial receiving the immunotherapeutic agent atezolizumab with those in Veterans Health Administration clinical practice receiving carboplatin-based chemotherapy. Atezolizumab provided a survival benefit over chemotherapy after 5-9 mo.

Potent cytotoxicity of the phosphatase inhibitor microcystin LR and microcystin analogues in OATP1B1- and OATP1B3-expressing HeLa cells.

Microcystins are a family of cyclic peptides that are potent inhibitors of the protein phosphatase families PP1 and PP2A. Only three human proteins are thought to be able to mediate the hepatic uptake of microcystins (the organic anion-transporting polypeptides OATP1B1, OATP1B3, and OATP1A2), and the predominant hepatic expression of these transporters accounts for the liver-specific toxicity of microcystins. A significant obstacle in the study of microcystins as anticancer drugs is the requirement of specific transport proteins for cellular uptake. We report that OATP1B3 mRNA is up-regulated in non-small cell lung cancer tumors in comparison with normal control tissues. This finding led to the exploration of microcystins as potential anticancer agents. We have developed a HeLa cell model with functional OATP1B1 and OATP1B3 activity. Transiently transfected HeLa cells are over 1,000-fold more sensitive to microcystin LR than the vector-transfected control cells, showing that transporter expression imparts marked selectivity for microcystin cytotoxicity. In addition, microcystin analogues showed variable cytotoxicities in the OATP1B1- and OATP1B3-transfected cells, including two analogues with IC(50) values <1 nmol/L. Cytotoxicity of microcystin analogues seems to correlate to the inhibition of PP2A in these cells and induces rapid cell death as seen by chromatin condensation and cell fragmentation. These studies show that microcystin-induced phosphatase inhibition results in potent cytotoxicity when microcystin compounds can gain intracellular access and are a potent novel class of therapeutic agents for tumors expressing these uptake proteins.

Long-term outcomes associated with triple-goal achievement in patients with type 2 diabetes mellitus (T2DM).

AIMS: This study was designed to compare the risk of long-term health outcomes, including microvascular, macrovascular complications and mortality, across 4 cohorts: triple-goal, dual-goal, single-goal, and no-goal achievers. METHODS: A retrospective cohort of 53,120 patients with T2DM were identified (97.51% male, 61.49% whites) from the Veterans Affairs (VA) electronic medical records VISN 16 data warehouse (2004-2010). Propensity score weight (PSW) was used to balance demographic characteristics and complication history at baseline. The PSW adjusted hazard ratios (aHR) from Cox proportional hazard models were used to compare complications and all-cause mortality over an average of 4 years of follow-up. RESULTS: At baseline, 25.43% (13,507) patients achieved triple-goal, while 41.36% (21,972) and 26.37% (14,010) patients achieved dual-goal and single-goal, respectively. During the follow-up period, triple-goal achievement was associated with risk reductions of complications and all-cause mortality when compared to all other groups of achieving dual or single-goal. Across different combinations of dual-goal achievement, the cohort with LDL-C goal achievement had lower risk of complication events and mortality, compared to those that achieved other goals but failed to reach LDL-C goal. CONCLUSIONS: Achievement of triple-goal was associated with better health outcomes among veterans with T2DM compared to those that did not, while LDL-C has more weight of influence. Multi-faceted treatment strategies targeting hypertension, hyperglycemia and hyperlipidemia may improve health outcome in veterans with T2DM.

Novel Risk Engine for Diabetes Progression and Mortality in USA: Building, Relating, Assessing, and Validating Outcomes (BRAVO).

BACKGROUND: There is an urgent need to update diabetes prediction, which has relied on the United Kingdom Prospective Diabetes Study (UKPDS) that dates back to 1970 s' European populations. OBJECTIVE: The objective of this study was to develop a risk engine with multiple risk equations using a recent patient cohort with type 2 diabetes mellitus reflective of the US population. METHODS: A total of 17 risk equations for predicting diabetes-related microvascular and macrovascular events, hypoglycemia, mortality, and progression of diabetes risk factors were estimated using the data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (n = 10,251). Internal and external validation processes were used to assess performance of the Building, Relating, Assessing, and Validating Outcomes (BRAVO) risk engine. One-way sensitivity analysis was conducted to examine the impact of risk factors on mortality at the population level. RESULTS: The BRAVO risk engine added several risk factors including severe hypoglycemia and common US racial/ethnicity categories compared with the UKPDS risk engine. The BRAVO risk engine also modeled mortality escalation associated with intensive glycemic control (i.e., glycosylated hemoglobin < 6.5%). External validation showed a good prediction power on 28 endpoints observed from other clinical trials (slope = 1.071, R2 = 0.86). CONCLUSION: The BRAVO risk engine for the US diabetes cohort provides an alternative to the UKPDS risk engine. It can be applied to assist clinical and policy decision making such as cost-effective resource allocation in USA.