Preparation, DFT calculations, docking studies, antioxidant, and anticancer properties of new pyrazole and pyridine derivatives.

Seven novel pyrazole derivatives (4a-g) and four novel starting compounds incorporating substituted pyridine moieties were synthesized successfully. Cell viability assay for the tested compounds was performed, and the inhibitory concentrationlogarithmic 50 (LogIC50 ) values of the compounds were calculated after a 24-h treatment. Four of the examined compounds (3d, 3g, 4f, and 4g) showed comparable cytotoxic activity against CaCo-2 compared to the standard drug docetaxel at 0.1 and 1 µM concentrations. Although the LogIC50  of docetaxel was -0.678 µM for CaCo-2 cells at 24 h, the LogIC50 values of compounds were -0.794, -0.567, -0.657, and -0.498 µM, respectively. Five of the compounds (2d, 2g, 3d, 3g, and 4e) showed comparable cytotoxic activity against MCF-7 at 0.1 µM concentration compared to docetaxel (p < 0.05). Docking studies revealed the compounds have a good affinity to the active site of the human topoisomerase II ß enzyme. The antioxidant capacities of all compounds were determined using both 1,1-diphenyl-2-picrylhydrazyl and metal chelation methods. Although the compounds did not show significant antioxidant activity, relatively effective are compounds 3c, 3d, and 3g, which are hydrazine derivatives with approximately 50% antioxidant activity of standard antioxidants at concentrations of 62.5 and 125 µg/ml.

Synthesis of new 7-amino-3,4-dihydroquinolin-2(1H)-one-peptide derivatives and their carbonic anhydrase enzyme inhibition, antioxidant, and cytotoxic activities.

Six new monopeptides, seven new dipeptides, and two deprotected monopeptide dihydroquinolinone conjugates were prepared by the benzothiazole-mediated method and their structures were confirmed by nuclear magnetic resonance, mass, infrared spectroscopy, and elemental analysis methods. The human carbonic anhydrase (hCA) I and hCA II enzyme inhibition activities of the compounds were determined using the stopped-flow instrument. The synthesized peptide-dihydroquinolinone conjugates 2, 3, 6, 10, 13, and 15 showed inhibition against the hCA II enzyme in the range of 15.7-65.7 µM. However, none of the compounds showed inhibition of hCA I at a concentration of 100 µM. The antioxidant activities of the compounds were also examined using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging method at concentrations of 12.5-125 µg/ml, but when compared with the standard antioxidant compounds α-tocopherol and butylated hydroxyanisole (BHA), weak antioxidant activities were detected. The cytotoxic effects of four compounds against the A549 and BEAS-2B cell lines were also investigated. Among the compounds studied, compound 7 was found to be most effective, with the IC50 values on the A549 cells for 48 and 72 h being 26.87 and 9.979 µg/ml, respectively, and the IC50 values on the BEAS-2B cells being >100 µg/ml. None of the tested compounds showed antimicrobial activity in the concentration range (800-1.56 µg/ml) studied.

The Association Between Medicaid Expansion and Diabetic Ketoacidosis Hospitalizations.

Background and objective Diabetic ketoacidosis (DKA) is a potentially fatal complication of uncontrolled diabetes and remains a significant source of morbidity and mortality even though it is considered preventable. Diabetes is a chronic illness that requires constant monitoring and regular check-ups. Delaying or foregoing necessary diabetes care due to a lack of health insurance can result in severe complications. The Affordable Care Act (ACA) Medicaid expansion is intended to increase access to healthcare and improve health outcomes. This study aimed to examine the relationship between the ACA Medicaid expansion and hospitalizations with DKA. Methods This retrospective cross-sectional study used discharge records from 2010 to 2017 for hospitals in Texarkana, located on the border of Texas and Arkansas. The study employed a difference-in-differences method. Patients from Arkansas, which expanded Medicaid in 2014, constituted the treatment group, while those from Texas, which did not adopt the expansion, were the control group. A triple difference methodology was used to compare the impact of the expansion on patients with different socioeconomic backgrounds. The main outcome measure was DKA per 1000 discharges. Results A total of 89,184 inpatient discharges from Texarkana hospitals were analyzed; 43,286 patients were from Arkansas (48.54%) and 45,898 (51.46%) were from Texas. Even though DKA cases increased from pre-expansion (2010-2013) to post-expansion (2014-2017) period among patients from Arkansas (by a mean of 4.33) and Texas (by a mean of 8.28), the increase was milder among Arkansas patients with an adjusted decrease of 4.17 per 1000 discharges (95% CI: -5.04 to -3.31; p<0.001), implying a 42% lower risk of hospitalizations with DKA compared to the baseline averages. The triple difference analysis suggested that the decrease in incidences was more pronounced for patients from low-income areas with an adjusted decrease of 13.47 per 1000 discharges (95% CI: -22.45 to -4.49; p=0.003). Conclusions Based on our findings, Medicaid expansion decreases hospitalizations with DKA, presumably due to better monitoring and care of diabetes made possible by increasing access to healthcare among individuals with low incomes.

Association between first-line monotherapy with metformin and the risk of atrial fibrillation (AMRAF) in patients with type 2 diabetes.

BACKGROUND: Type 2 diabetes (T2D) has a strong association with atrial fibrillation (AF) which increases risk of thromboembolic events, heart failure, and frequent hospitalizations. Metformin is the first-line medication for T2D with proposed anti-inflammatory, pro-metabolic, and cardio-protective benefits. Our objective was to investigate if initial therapy with metformin is associated with reduced incidence of AF in comparison to other non-insulin anti-hyperglycemic agents in patients with newly diagnosed T2D. METHODS: This retrospective cohort analysis included adults with a new diagnosis of T2D who were started on monotherapy (except insulin) between 2007 and 2017, without prior anti-hyperglycemic agent use, history of arrhythmias, or estimated GFR (eGFR) ≤ 30 ml/min. A multivariate analysis was performed using a fine-gray regression competing risk analysis to control for confounding variables after which pooled hazard ratios and 95 % confidence intervals were reported. Patients were followed until the end of study date, development of AF, addition of more anti-hyperglycemic agents, or death, whichever occurred first. RESULTS: Among 4584 metformin initiators compared to 1080 non-metformin monotherapy initiators, 10-year cumulative incidence of AF in metformin group was 5.2 % as compared to 8.1 % with other agents which was not statistically significant. Competing risk analysis did not demonstrate reduced rates of AF with metformin use (HR 0.92, 95 % CI 0.69 to 1.21; P = 0.55). Increased age and the presence of congestive heart failure were associated with significantly higher risk of AF in both groups (HR: 1.29, 95 % CI: 1.21 to 1.37; P ≤ 0.001; HR: 2.73, 95 % CI: 1.62 to 4.61; P ≤ 0.001, respectively). CONCLUSION: Initiation of metformin as a first line monotherapy for T2D, when compared to other non-insulin monotherapies, was not associated with decreased risk of developing AF in this retrospective observational study.

Use of Preoperative Imaging in Primary Hyperparathyroidism.

CONTEXT: Preoperative imaging is performed routinely to guide surgical management in primary hyperparathyroidism, but the optimal imaging modalities are debated. OBJECTIVE: Our objectives were to evaluate which imaging modalities are associated with improved cure rate and higher concordance rates with intraoperative findings. A secondary aim was to determine whether additive imaging is associated with higher cure rate. DESIGN, SETTING, AND PATIENTS: This is a retrospective cohort review of 1485 adult patients during a 14-year period (2004-2017) at an academic tertiary referral center that presented for initial parathyroidectomy for de novo primary hyperparathyroidism. MAIN OUTCOME MEASURES: Surgical cure rate, concordance of imaging with operative findings, and imaging performance. RESULTS: The overall cure rate was 94.1% (95% confidence interval, 0.93-0.95). Cure rate was significantly improved if sestamibi/single-photon emission computed tomography (SPECT) was concordant with operative findings (95.9% vs. 92.5%, P = 0.010). Adding a third imaging modality did not improve cure rate (1 imaging type 91.8% vs. 2 imaging types 94.4% vs. 3 imaging types 87.2%, P = 0.59). Despite having a low number of cases (n = 28), 4-dimensional (4D) CT scan outperformed (higher sensitivity, specificity, positive predictive value, negative predictive value) all imaging modalities in multiglandular disease and double adenomas, and sestamibi/SPECT in single adenomas. CONCLUSIONS: Preoperative ultrasound combined with sestamibi/SPECT were associated with the highest cure and concordance rates. If pathology was not found on ultrasound and sestamibi/SPECT, additional imaging did not improve the cure rate or concordance. 4D CT scan outperformed all imaging modalities in multiglandular disease and double adenomas, and sestamibi/SPECT in single adenomas, but these findings were underpowered.

Noninsulin Diabetes Therapies in Older Adults.

Diabetes risk increases with age due to changes in ß-cell function and increased insulin resistance and is one of the most common chronic medical conditions in the elderly. Diabetes management in this population requires a multidisciplinary, patient-centric approach due to wide heterogeneity in patients' health and functional capacities. Meticulous assessment of each patient before formulating a regimen and thorough patient education are keys to success in achieving glycemic goals, which should be individualized. Lifestyle modification is recommended for every patient.

Outcomes of Pancreatic Islet Allotransplantation Using the Edmonton Protocol at the University of Chicago.

OBJECTIVE: The aim of this study was to assess short-term and long-term results of the pancreatic islet transplantation using the Edmonton protocol at the University of Chicago. MATERIALS AND METHODS: Nine patients underwent pancreatic islet cell transplantation using the Edmonton Protocol; they were followed up for 10 years after initial islet transplant with up to 3 separate islet infusions. They were given induction treatment using an IL-2R antibody and their maintenance immunosuppression regimen consisted of sirolimus and tacrolimus. RESULTS: Nine patients received a total of 18 islet infusions. Five patients dropped out in the early phase of the study. Greater than 50% drop-out and noncompliance rate resulted from both poor islet function and recurrent side effects of immunosuppression. The remaining 4 (44%) patients stayed insulin free with intervals for at least over 5 years (cumulative time) after the first transplant. Each of them received 3 infusions, on average 445 000 islet equivalent per transplant. Immunosuppression regimen required multiple adjustments in all patients due to recurrent side effects. In the long-term follow up, kidney function remained stable, and diabetic retinopathy and polyneuropathy did not progress in any of the patients. Patients' panel reactive antibodies remained zero and anti-glutamic acid decarboxylase 65 antibody did not rise after the transplant. Results of metabolic tests including hemoglobin A1c, arginine stimulation, and mixed meal tolerance test were correlated with clinical islet function. CONCLUSIONS: Pancreatic islet transplantation initiated according to Edmonton protocol offered durable long-term insulin-free glycemic control in only highly selected brittle diabetics providing stable control of diabetic neuropathy and retinopathy and without increased sensitization or impaired renal function. Immunosuppression adjustments and close follow-up were critical for patient retention and ultimate success.