Use of real-world evidence data to evaluate the comparative effectiveness of second-line type 2 diabetes medications on chronic kidney disease

AbstractChronic kidney disease (CKD) is a common complication of type 2 diabetes mellitus (T2DM). Approximately one-third of patients with T2DM also have CKD. In clinical trial studies, several anti-diabetic medications (ADM) show evidence of preventing the progression of CKD. Biguanides (e.g., metformin) are widely accepted as the first line medication. However, the comparativeness effectiveness of second line ADMs on CKD outcomes in T2DM is unclear. In addition, results from clinical trials may not generalize into routine clinical practice. In this study, we aimed to investigate the association of second line ADMs with incident CKD and CKD hospitalization in T2DM patients using real-world data from electronic health records. Our study found that treatment with sodium-glucose cotransporter 2 (SGLT-2) inhibitors was significantly associated with a lower risk of CKD incidence in both primary analysis (hazard ratio, 0.43; 95% CI, [0.22;0.87]; p-value,0.02) (SU) as a second-line ADM. Treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor was significantly associated with lower CKD incidence (hazard ratio, 0.7; 95% CI, [0.53;0.96]; p-value, 0.03) and lower CKD hospitalization events (hazard ratio, 0.6; 95% CI, [0.37; 0.96]; p-value, 0.04) in the primary analysis. However, both associations were not significant in the sensitivity analysis. We did not observe significant association between use of GLP-1, TZD, insulin and CKD incidence or hospitalization compared to use of SU as the second-line ADM.</jats:p

Focal Injection of Ethidium Bromide as a Simple Model to Study Cognitive Deficit and Its Improvement

Introduction: Memory and cognitive impairments are some of devastating outcomes of Multiple Sclerosis (MS) plaques in hippocampus, the gray matter part of the brain. The present study aimed to evaluate the intrahippocampal injection of Ethidium Bromide (EB) as a simple and focal model to assess cognition and gray matter demyelination. Methods: Thirty Wistar rats were divided into three groups: control group, which received saline, as solvent of EB, into the hippocampus and two experimental groups, which received 3 &muL of EB into the hippocampus, and then, were evaluated 7 and 28 days after EB injection (n=10 in each group), using a 5-day protocol of Morris Water Maze (MWM) task as well as Transmission Electron Microscopy (TEM) assay. Results: Seven days after EB injection, the behavioral study revealed a significance increase in travelled distance for platform finding in the experimental group compared to the control group. In addition, the nucleus of oligodendrocyte showed the typical clumped chromatin, probably attributed to apoptosis, and the myelin sheaths of some axons were unwrapped and disintegrated. Twentyeight days after EB injection, the traveled distance and the time spent in target quadrant significantly decreased and increased, respectively in experimental groups compared to the control group. Also, TEM micrographs revealed a thin layer of remyelination around the axons in 28 days lesion group. Discussion: While intracerebral or intraventricular injection of EB is disseminated in different parts of the brain and can affect the other motor and sensory systems, this model is confined locally and facilitates behavioral study. Also, this project could show improvement of memory function subsequent to the physiological repair of the gray matter of the hippocampus

Association Between Metabolic Syndrome Inflammatory Biomarkers and COVID-19 Severity

AbstractContextMetabolic syndrome (MetS) is associated with increased risk of severe COVID-19. MetS inflammatory biomarkers share similarities with those of COVID-19, yet this association is poorly explored.ObjectiveBiomarkers of COVID-19 patients with and without MetS, the combination of diabetes, hypertension, obesity, and/or dyslipidemia, were analyzed to identify biological predictors of COVID-19 severity.MethodsIn this prospective observational study, at a large academic emergency department in Boston, Massachusetts, clinical and proteomics data were analyzed from March 24 to April 30, 2020. Patients age ≥18 with a clinical concern for COVID-19 upon arrival and acute respiratory distress were included. The main outcome was severe COVID-19 as defined using World Health Organization COVID-19 outcomes scores ≤4, which describes patients who died, required invasive mechanical ventilation, or required supplemental oxygen.ResultsAmong 155 COVID-19 patients, 90 (58.1%) met the definition of MetS and 65 (41.9%) were identified as Control. The MetS cohort was more likely to have severe COVID-19 compared with the Control cohort (OR 2.67 [CI 1.09-6.55]). Biomarkers, including CXCL10 (OR 1.94 [CI 1.38-2.73]), CXCL9 (OR 1.79 [CI 1.09-2.93]), HGF (OR 3.30 [CI 1.65-6.58]), and IL6 (OR 2.09 [CI 1.49-2.94]) were associated with severe COVID-19. However, when stratified by MetS, only CXCL10 (OR 2.39 [CI 1.38-4.14]) and IL6 (OR 3.14 [CI 1.53-6.45]) were significantly associated with severe COVID-19.ConclusionsMetS-associated severe COVID-19 is characterized by an immune signature of elevated levels of CXCL10 and IL6. Clinical trials targeting CXCL10 or IL6 antagonism in this population may be warranted.</jats:sec

Abstract MP08: Using Electronic Health Record Data To Link Families: The Pythonic Relationship Inference From The Electronic Health Record Algorithm

Introduction: Intergenerational patterns are an important part of understanding disease, but much of the family-based research can be costly or biased. Emergency contacts in electronic health records (EHR) can be used to link family members using a population that is more representative of a community than traditional family cohort studies. Hypothesis: Creating family trees using emergency contacts will result in robust data that can be used in intergenerational research. Methods: We revised a published algorithm: relationship inference from the electronic health record (RIFTEHR). Our version, pythonic RIFTEHR (P-RIFTEHR) was run on 8/5/21 in the Northwestern Medicine Electronic Data Warehouse (NMEDW) on approximately 3.7 million individuals and was validated using the existing link between children born at NM hospitals and their mothers as the gold-standard. As proof-of-concept, we modeled the association between parent and child obesity using logistic regression. Results: The P-RIFTEHR algorithm matched 1,427,622 individuals in 500,408 families. The median family size is 2, the largest family is approximately 300 persons, and 115 families span four generations or more. Of the EDW-linked mother-child pairs, all matching pairs in P-RIFTEHR were correctly identified as mother-child, resulting in 100% sensitivity. Children are two times more likely to be obese if a parent is obese (OR: 2.01; 95% CI: 1.94, 2.09). This association persists after adjustment (OR: 2.19; 95% CI: 2.10, 2.28) and in mixed models nesting children within parents (OR: 2.70; 95% CI: 2.56, 2.85). Conclusions: P-RIFTEHR works well in a large, diverse population in an integrated health system. Our obesity results are consistent with the literature, including a 2017 meta-analysis by Wang, et al, showing a strong parent-child obesity association (pooled OR: 2.22; 95% CI: 2.09, 2.36). While the information used in the EHR can be completely deidentified, privacy concerns will be addressed before these data are more widely available for research. </jats:p

How does the impact of a community trial on cardio-metabolic risk factors differ in terms of gender and living area? Findings from the Isfahan healthy heart program

Objective: To assess the impact of gender and living area on cardiovascular risk factors in the context of a comprehensive lifestyle intervention program. Design: Data from independent sample surveys before (2000--2001) and after (2007) a community trial, entitled the Isfahan Healthy Heart Program (IHHP) were used to compare differences in the intervention area (IA) and reference area (RA) by gender and living area. Setting: The interventions targeted the population living in Isfahan and Najaf-Abad counties as IA and Arak as RA. Participants: Overall, 12 514 individuals who were more than 19 years of age were studied at baseline, and 9570 were studied in postintervention phase. Interventions: Multiple activities were conducted in connection with each of the four main strategies of healthy nutrition, increasing physical activity, tobacco control, and coping with stress. Main Outcomes: Comparing serum lipids levels, blood pressure, blood glucose and obesity indices changes between IA and RA based on sex and living areas during the study. Results: In IA, while the prevalence of hypertension declined in urban and rural females (P < 0.05). In IA, the prevalence of hypercholesterolemia and hypertriglyceridemia decreased in both females and males of urban and rural areas except for hypercholesterolemia in rural males (P < 0.01). In RA, the significant changes include both decrease in the hypercholesterolemia among rural males (P < 0.001) and hypertriglyceridemia in urban females (P < 0.01), while hypertriglyceridemia was significantly increased in rural females (P < 0.01). Conclusions: This comprehensive community trial was effective in controlling many risk factors in both sexes in urban and rural areas. These findings also reflect the transitional status of rural population in adopting urban lifestyle behaviors

How does the impact of a community trial on cardio-metabolic risk factors differ in terms of gender and living area? Findings from the Isfahan healthy heart program

Objective: To assess the impact of gender and living area on cardiovascular risk factors in the context of a comprehensive lifestyle intervention program. Design: Data from independent sample surveys before (2000--2001) and after (2007) a community trial, entitled the Isfahan Healthy Heart Program (IHHP) were used to compare differences in the intervention area (IA) and reference area (RA) by gender and living area. Setting: The interventions targeted the population living in Isfahan and Najaf-Abad counties as IA and Arak as RA. Participants: Overall, 12 514 individuals who were more than 19 years of age were studied at baseline, and 9570 were studied in postintervention phase. Interventions: Multiple activities were conducted in connection with each of the four main strategies of healthy nutrition, increasing physical activity, tobacco control, and coping with stress. Main Outcomes: Comparing serum lipids levels, blood pressure, blood glucose and obesity indices changes between IA and RA based on sex and living areas during the study. Results: In IA, while the prevalence of hypertension declined in urban and rural females (P < 0.05). In IA, the prevalence of hypercholesterolemia and hypertriglyceridemia decreased in both females and males of urban and rural areas except for hypercholesterolemia in rural males (P < 0.01). In RA, the significant changes include both decrease in the hypercholesterolemia among rural males (P < 0.001) and hypertriglyceridemia in urban females (P < 0.01), while hypertriglyceridemia was significantly increased in rural females (P < 0.01). Conclusions: This comprehensive community trial was effective in controlling many risk factors in both sexes in urban and rural areas. These findings also reflect the transitional status of rural population in adopting urban lifestyle behaviors

Using electronic health record data to link families: an illustrative example using intergenerational patterns of obesity

AbstractObjectiveElectronic health record (EHR) data are a valuable resource for population health research but lack critical information such as relationships between individuals. Emergency contacts in EHRs can be used to link family members, creating a population that is more representative of a community than traditional family cohorts.Materials and MethodsWe revised a published algorithm: relationship inference from the electronic health record (RIFTEHR). Our version, Pythonic RIFTEHR (P-RIFTEHR), identifies a patient’s emergency contacts, matches them to existing patients (when available) using network graphs, checks for conflicts, and infers new relationships. P-RIFTEHR was run on December 15, 2021 in the Northwestern Medicine Electronic Data Warehouse (NMEDW) on approximately 2.95 million individuals and was validated using the existing link between children born at NM hospitals and their mothers. As proof-of-concept, we modeled the association between parent and child obesity using logistic regression.ResultsThe P-RIFTEHR algorithm matched 1 157 454 individuals in 448 278 families. The median family size was 2, the largest was 32 persons, and 247 families spanned 4 generations or more. Validation of the mother–child pairs resulted in 95.1% sensitivity. Children were 2 times more likely to be obese if a parent is obese (OR: 2.30; 95% CI, 2.23–2.37).ConclusionP-RIFTEHR can identify familiar relationships in a large, diverse population in an integrated health system. Estimates of parent–child inheritability of obesity using family structures identified by the algorithm were consistent with previously published estimates from traditional cohort studies.</jats:sec

Mutant IDH1 and seizures in patients with glioma.

ObjectiveBecause the d-2-hydroxyglutarate (D2HG) product of mutant isocitrate dehydrogenase 1 (IDH1mut) is released by tumor cells into the microenvironment and is structurally similar to the excitatory neurotransmitter glutamate, we sought to determine whether IDH1mut increases the risk of seizures in patients with glioma, and whether D2HG increases the electrical activity of neurons.MethodsThree WHO grade II-IV glioma cohorts from separate institutions (total N = 712) were retrospectively assessed for the presence of preoperative seizures and tumor location, WHO grade, 1p/19q codeletion, and IDH1mut status. Rat cortical neurons were grown on microelectrode arrays, and their electrical activity was measured before and after treatment with exogenous D2HG, in the presence or absence of the selective NMDA antagonist, AP5.ResultsPreoperative seizures were observed in 18%-34% of IDH1 wild-type (IDH1wt) patients and in 59%-74% of IDH1mut patients (p &lt; 0.001). Multivariable analysis, including WHO grade, 1p/19q codeletion, and temporal lobe location, showed that IDH1mut was an independent correlate with seizures (odds ratio 2.5, 95% confidence interval 1.6-3.9, p &lt; 0.001). Exogenous D2HG increased the firing rate of cultured rat cortical neurons 4- to 6-fold, but was completely blocked by AP5.ConclusionsThe D2HG product of IDH1mut may increase neuronal activity by mimicking the activity of glutamate on the NMDA receptor, and IDH1mut gliomas are more likely to cause seizures in patients. This has rapid translational implications for the personalized management of tumor-associated epilepsy, as targeted IDH1mut inhibitors may improve antiepileptic therapy in patients with IDH1mut gliomas