ZYBT1, a potent, irreversible Bruton's Tyrosine Kinase (BTK) inhibitor that inhibits the C481S BTK with profound efficacy against arthritis and cancer.

Bruton's tyrosine kinase (BTK) plays a central and pivotal role in controlling the pathways involved in the pathobiology of cancer, rheumatoid arthritis (RA), and other autoimmune disorders. ZYBT1 is a potent, irreversible, specific BTK inhibitor that inhibits the ibrutinib-resistant C481S BTK with nanomolar potency. ZYBT1 is found to be a promising molecule to treat both cancer and RA. In the present report we profiled the molecule for in-vitro, in-vivo activity, and pharmacokinetic properties. ZYBT1 inhibits BTK and C481S BTK with an IC50 of 1 nmol/L and 14 nmol/L, respectively, inhibits the growth of various leukemic cell lines with IC50 of 1 nmol/L to 15 µmol/L, blocks the phosphorylation of BTK and PLCγ2, and inhibits secretion of TNF-α, IL-8 and IL-6. It has favorable pharmacokinetic properties suitable for using as an oral anti-cancer and anti-arthritic drug. In accordance with the in-vitro properties, it demonstrated robust efficacy in murine models of collagen-induced arthritis (CIA) and streptococcal cell wall (SCW) induced arthritis. In both models, ZYBT1 alone could suppress the progression of the diseases. It also reduced the growth of TMD8 xenograft tumor. The results suggested that ZYBT1 has high potential for treating RA, and cancer.

Effect of Financial Bonus Size, Loss Aversion, and Increased Social Pressure on Physician Pay-for-Performance: A Randomized Clinical Trial and Cohort Study.

Importance: Despite limited effectiveness of pay-for-performance (P4P), payers continue to expand P4P nationally. Objective: To test whether increasing bonus size or adding the behavioral economic principles of increased social pressure (ISP) or loss aversion (LA) improves the effectiveness of P4P. Design, Setting, and Participants: Parallel studies conducted from January 1 to December 31, 2016, consisted of a randomized clinical trial with patients cluster-randomized by practice site to an active control group (larger bonus size [LBS] only) or to groups with 1 of 2 behavioral economic interventions added and a cohort study comparing changes in outcomes among patients of physicians receiving an LBS with outcomes in propensity-matched physicians not receiving an LBS. A total of 8118 patients attributed to 66 physicians with 1 of 5 chronic conditions were treated at Advocate HealthCare, an integrated health system in Illinois. Data were analyzed using intention to treat and multiple imputation from February 1, 2017, through May 31, 2018. Interventions: Physician participants received an LBS increased by a mean of $3355 per physician (LBS-only group); prefunded incentives to elicit LA and an LBS; or increasing proportion of a P4P bonus determined by group performance from 30% to 50% (ISP) and an LBS. Main Outcomes and Measures: The proportion of 20 evidence-based quality measures achieved at the patient level. Results: A total of 86 physicians were eligible for the randomized trial. Of these, 32 were excluded because they did not have unique attributed patients. Fifty-four physicians were randomly assigned to 1 of 3 groups, and 33 physicians (54.5% male; mean [SD] age, 57 [10] years) and 3747 patients (63.6% female; mean [SD] age, 64 [18] years) were included in the final analysis. Nine physicians and 864 patients were randomized to the LBS-only group, 13 physicians and 1496 patients to the LBS plus ISP group, and 11 physicians and 1387 patients to the LBS plus LA group. Physician characteristics did not differ significantly by arm, such as mean (SD) physician age ranging from 56 (9) to 59 (9) years, and sex (6 [46.2%] to 6 [66.7%] male). No differences were found between the LBS-only and the intervention groups (adjusted odds ratio [aOR] for LBS plus LA vs LBS-only, 0.86 [95% CI, 0.65-1.15; P = .31]; aOR for LBS plus ISP vs LBS-only, 0.95 [95% CI, 0.64-1.42; P = .81]; and aOR for LBS plus ISP vs LBS plus LA, 1.10 [95% CI, 0.75-1.61; P = .62]). Increased bonus size was associated with a greater increase in evidence-based care relative to the comparison group (risk-standardized absolute difference-in-differences, 3.2 percentage points; 95% CI, 1.9-4.5 percentage points; P < .001). Conclusions and Relevance: Increased bonus size was associated with significantly improved quality of care relative to a comparison group. Adding ISP and opportunities for LA did not improve quality. Trial Registration: ClinicalTrials.gov Identifier: NCT02634879.

Impact of emergency physician-provided patient education about alternative care venues.

OBJECTIVES: Interventions that focus on educating patients appear to be the most effective in directing healthcare utilization to more appropriate venues. We sought to evaluate the effects of mailed information and a brief scripted educational phone call from an emergency physician (EP) on subsequent emergency department (ED) utilization by low-risk adults with a recent treat-and-release ED visit. STUDY DESIGN: Patients were randomized into 3 groups for post-ED follow-up: EP phone call with mailed information, mailed information only, and no educational intervention. Each intervention group was compared with a set of matched controls. METHODS: We undertook this study in 6 EDs within an integrated healthcare delivery system. Overall, 9093 patients were identified; the final groups were the phone group (n = 609), mail group (n = 771), and matched control groups for each (n = 1827 and n = 1542, respectively). Analysis was stratified by age (<65 and ≥65 years). Patients were educated about available venues of care delivery for their future medical needs. The primary outcome was the rate of 6-month ED utilization after the intervention compared with the 6-month utilization rate preceding the intervention. RESULTS: Compared with matched controls, subsequent ED utilization decreased by 22% for patients 65 years or older in the phone group (P = .04) and by 27% for patients younger than 65 years in the mail group (P = .03). CONCLUSIONS: ED utilization subsequent to a low-acuity ED visit decreased after a brief post-ED education intervention by an EP explaining alternative venues of care for future medical needs. Response to the method of communication (phone vs mail) varied significantly by patient age.

Preclinical evaluation of saroglitazar magnesium, a dual PPAR-α/γ agonist for treatment of dyslipidemia and metabolic disorders.

1. Saroglitazar, a novel peroxisome proliferator-activated receptor (PPAR) agonist, regulates lipid and glucose metabolism. The objective of this report is to provide a preclinical evaluation (in vitro/in vivo) of ADME properties of saroglitazar. In vitro studies included determination of permeability, metabolic stability, plasma protein binding, CYP reaction phenotyping and CYP inhibitory liability. In vivo studies included oral bioavailability and pharmacokinetic assessment in mouse, rat and dog. The excretion of saroglitazar was determined in rats. Exploratory metabolism of saroglitazar was evaluated using in vitro and in vivo samples. 2. Saroglitazar was metabolically more stable in human liver microsomes as compared to rat and dog liver microsomes, highly protein bound (98-99.6%) with high Caco2 permeability (104 nm/s) with <2 efflux ratio. In vitro metabolism in rat, dog and human liver microsomes revealed three putative metabolites corresponding to di-hydroxylation, mono-oxygenation and dehydrogenation moieties. 3. Oral bioavailability was 100%, 72% and 47% in mouse, rat and dog, respectively. The intravenous clearance and volume of distribution of saroglitazar were 3.6, 8.5 and 6.9 mL/min/kg and 1.3, 4.8 and 1.8 L/kg for mouse, rat and dog, respectively. The elimination half-life of saroglitazar ranged between 6 and 15 h. Saroglitazar appeared to be eliminated via hepatobiliary route with negligible renal excretion.

Supplementation of vitamin E, selenium and increased energy allowance mitigates the transition stress and improves postpartum reproductive performance in the crossbred cow.

Dairy cow undergoes tremendous physiological challenges during the transition period leading to negative energy balance (NEBAL), impaired immunity and oxidative stress that ultimately compromises the postpartum fertility. Accordingly, we investigated the effects of antioxidant supplementation and increased energy allowance on transition stress and fertility of crossbred cow. Advanced pregnant crossbred cows (n = 26) of 2-4 parity and lactation potential of >10 L/day were divided into two equal groups (n = 13 cows/group). Cows were fed diets either (i) supplemented with vitamin E (80 IU/kg DM), Selenium (Se; 0.3 mg/kg DM) and increased energy allowance in the form of 20% additional concentrate (TRT) or (ii) basal diet without any supplementation as control (CON). Vitamin E and Se were supplemented with wheat flour bolus from -4 to 8 week of calving whereas energy allowance was increased from 2 to 8 week of calving on daily basis to individual animal (where 0 is day of calving). Blood samples were collected on weekly interval from -4 to 8 week of calving. Oxidative stress was assessed by estimation of malondialdehyde (MDA), total antioxidant capacity (TAC), superoxide dismutase (SOD) and catalase (CAT). Immunity level was assessed via estimation of phagocytic activity (PA) of granulocytes and lymphocyte proliferation assay (LPA). Postpartum fertility was assessed by interval to first postpartum estrus (day) and pregnancy rate. Cows in TRT had a significantly lower MDA, higher TAC and decreased activity of SOD and CAT than that of CON (P < 0.05). Phagocytic activity increased at -1, 0 and 3-8 weeks postpartum (P < 0.05) while LPA showed difference (P < 0.05) at parturition, week 4 and 8 postpartum. Marked improvement in the fertility was recorded in terms of early resumption of postpartum estrus (P < 0.001) and higher pregnancy rate (P < 0.05).

Consensus on Management of Deep Vein Thrombosis with Emphasis on NOACs (Non-Vitamin K Antagonist Oral Anticoagulants): Recommendations from Inter-Disciplinary Group of Indian Experts.

It is estimated that around 2.5 lac patients are identified as having an acute venous thrombo-embolic event in India annually. This includes patients with deep vein thrombosis and pulmonary embolism, and is estimated to result in more than 3.7 lacs deaths each year in European countries. The 'Consensus on Management of Deep Vein Thrombosis with Emphasis on NOACs (Non-Vitamin K Antagonist Oral Anticoagulants): Recommendations from Inter-Disciplinary Group of Indian Experts' position paper was developed to assist clinicians and institutions with an evidence-based approach to the diagnosis and treatment of acute deep vein thrombosis patients. Key to the evaluation of patients with suspected deep vein thrombosis is the use of the clinician's clinical evaluation with the help of pre-test probability tools as well as judicious use of objective diagnostic tests. Our hope is that we have supplemented clinicians' clinical acumen, and assisted them and their health systems in developing best practice approaches to this ever-interesting population of patients. The Deep Vein Thrombosis Consensus Working Group welcomes your inputs on how improvements might be made on this paper in the future.

Protective effect of Tribulus terrestris linn on liver and kidney in cadmium intoxicated rats.

Administration of cadmium (Cd) significantly increased the peroxidation markers such as malondialdehyde and protein carbonyls along with significant decrease in antioxidant markers such as super oxide dismutase and reduced glutathione in liver and kidney tissues. Cadmium also caused a significant alteration in hepatic and renal functional markers in serum viz. total protein, albumin, alanine transaminase, blood urea nitrogen and creatinine. Prominent pathological changes observed in liver were severe vascular and sinusoidal congestion with diffuse degenerative changes and mononuclear infiltration into peripheral areas, while the kidney showed vascular and glomerular congestion, cloudy swelling of tubular epithelium. Coadministration of ethonolic extract of T. terrestris or vitamin E along with Cd significantly reversed the Cd induced changes along with significant reduction in Cd load.

Discovery of inhibitors of plasminogen activator inhibitor-1: structure-activity study of 5-nitro-2-phenoxybenzoic acid derivatives.

Two novel series of 5-nitro-2-phenoxybenzoic acid derivatives are designed as potent PAI-1 inhibitors using hybridization and conformational restriction strategy in the tiplaxtinin and piperazine chemo types. The lead compounds 5a, 6c, and 6e exhibited potent PAI-1 inhibitory activity and favorable oral bioavailability in the rodents.

A model for integrating independent physicians into accountable care organizations.

The Affordable Care Act encourages the formation of accountable care organizations as a new part of Medicare. Pending forthcoming federal regulations, though, it is unclear precisely how these ACOs will be structured. Although large integrated care systems that directly employ physicians may be most likely to evolve into ACOs, few such integrated systems exist in the United States. This paper demonstrates how Advocate Physician Partners in Illinois could serve as a model for a new kind of accountable care organization, by demonstrating how to organize physicians into partnerships with hospitals to improve care, cut costs, and be held accountable for the results. The partnership has signed its first commercial ACO contract effective January 1, 2011, with the largest insurer in Illinois, Blue Cross Blue Shield. Other commercial contracts are expected to follow. In a health care system still dominated by small, independent physician practices, this may constitute a more viable way to push the broader health care system toward accountable care.

Facilitating follow-up after emergency care using an appointment assignment system.

Many emergency department (ED) patients require urgent follow-up in primary care. The most effective way to help patients obtain their needed after-visit care is to secure the appointment on their behalf prior to their departure from the ED. This study describes the development, implementation, and outcomes of an appointment assignment system that facilitates patient follow-up at two community hospitals in an integrated healthcare system. This patient-centered system resulted in a high rate of compliance and a very low rate of unscheduled ED recidivism. Improving access in this manner will likely strengthen the continuum of care, improve quality, and increase patient satisfaction.

Frequency, risk, and cost of gout-related episodes among the elderly: does serum uric acid level matter?

OBJECTIVE: We examined the association between serum uric acid (SUA) level and the frequency, risk, and cost of gout flares among the elderly. METHODS: Data were extracted from the Integrated Healthcare Information Services claims database (1999-2005). Patients were included if they had gout, were aged 65 years and older and had both medical and pharmacy benefits, and electronic laboratory data. Patients with gout and gouty episodes were identified using algorithms based on ICD-9-CM codes and medications. Logistic regression and negative binomial regressions were used to study the relationship between SUA concentration and the annual frequency and one-year risk of gout episodes. Generalized linear models were used to examine the direct healthcare costs associated with gout episodes in the 30 days following each episode. RESULTS: Elderly patients with gout (n = 2237) with high (6-8.99 mg/dl) and very high (> 9 mg/dl) SUA concentrations were more likely to develop a flare within 12 months compared to patients with normal (< 6 mg/dl) SUA levels (OR 2.1, 95% CI 1.7-2.6; OR 3.4, 95% CI 2.6-4.4, respectively). In multivariate regressions, the average annual number of flares increased by 11.9% (p < 0.001) with each unit-increase in SUA level above 6 mg/dl (p < 0.001). Among patients with very high SUA levels, average adjusted total healthcare and gout-related costs per episode were $2,555 and $356 higher, respectively, than those of patients with normal SUA levels (both p < 0.001). CONCLUSION: Higher SUA levels are associated with increased frequency and risk of gout episode, and with higher total and gout-related direct healthcare costs per episode.

Disease-related and all-cause health care costs of elderly patients with gout.

BACKGROUND: Gout is a common cause of inflammatory arthritis in the United States, and its prevalence has increased in recent decades, especially among older adults. Older adults with gout are of particular interest because they tend to experience higher rates of tophi, an advanced stage of gout, than do younger patients. OBJECTIVE: For older adults with gout to (1) assess health care utilization and costs from a third-party payer perspective; (2) evaluate health care costs related to tophi; and (3) explore the relationship between elevated serum uric acid (UA) level, an indicator of disease control, and health care utilization. METHODS: Data were extracted from the Integrated Healthcare Information Services (IHCIS) claims database (1999-2005), which includes approximately 40 private health plans in the United States for approximately 13 million beneficiaries, about 4% of whom are aged 65 years or older. Patients were included in the study if they: (1) had 2 diagnoses of gout (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code of 274.xx) on separate medical claims or 1 gout diagnosis plus at least 1 gout-related pharmacy claim (i.e., allopurinol, probenecid, colchicines, or sulfinpyrazone); (2) were at least 65 years old at the first diagnosis date (study index date); and (3) had 1 year of continuous eligibility both before and after the study index date. A comparison sample of elderly members without gout was selected using a 1:1 match to gout patients based on age, gender, and geographic region. Individuals in the comparison group also had 1 year of continuous eligibility both before and after the study index date, defined as the same index date as the respective matched gout patient. Patients with possible tophi were identified from at least 1 medical claim with an ICD-9-CM code 274.8x (274.81=gouty tophi of the ear; 274.82 = gouty tophi of other sites except ear; 274.89 = gout with other specified manifestations) during the 12-month study period following the study index date. Additionally, a subgroup of gout patients with at least 1 serum UA measure was selected. Patients were divided into 3 groups according to their serum UA level on the earliest test date (serum UA index date): low (< 6 mg per dL), moderate-high (6-8.99 mg per dL), and very high (> or = 9 mg per dL). Health care utilization was categorized into inpatient services, outpatient services, emergency room services, other medical services, and use of prescription drugs. Medical services were classified by the place of service indicated in the claim. Medical services costs and pharmacy costs were defined as the amount paid to the provider plus member cost share (e.g., deductible, copayment). Two types of costs were assessed in the analysis: total all-cause health care costs and gout-related costs, defined as costs associated with a claim with a primary or secondary diagnosis of gout (ICD-9-CM code 274.xx). Differences in total all-cause health care costs were calculated by comparing (1) gout patients and gout-free members during the 12-month period following the study index date; (2) gout patients with and without tophi during the 12-month period following the study index date; and (3) gout patients across the 3 serum UA categories during the 12-month period following the serum UA index date. Multivariate regression analyses were used to control for patients' baseline demographics, prior comorbidities indicated by the Deyo-Charlson Comorbidity Index, and number of medications used during the 12 months prior to the study index date. RESULTS: Over the 7 years of claims data through 2005, there were 11,935 gout patients aged 65 years or older. The sample had an average age of 71.4 years and was predominantly male (73.5%). In the 12 months following the study index date, the mean unadjusted per-patient gout-related health care cost was $876 (standard deviation $3,373) in 2005 dollars, 5.9% of the total all-cause health care cost of $14,734 (SD $27,401) for gout patients. Unadjusted total 12-month all-cause health care cost for the gout-free members was $9,219 (SD $20,186). After statistical adjustment for comorbidities, the difference in total 12-month all-cause health care costs between gout patients and gout-free members was $3,038 (P < 0.001). A diagnosis suggesting possible tophi was found in 2.0% (n = 240) of gout patients in the sample. After statistical adjustment for comorbidities, the difference in total 12-month all-cause health care costs between gout patients with and without tophi was $5,501 (P < 0.001), and the difference in total adjusted 12-month gout-related costs between patients with and without tophi was $1,710 (P < 0.001). Among the 2,237 (18.7%) patients with at least 1 serum UA measure, 28.3% had a low serum UA level, 52.4% had a moderate-high serum UA level, and 19.3% had a very high serum UA level. For patients with low, moderate-high, and very high serum UA levels, regression-adjusted gout-related costs in the 12 months following the serum UA index date represented, respectively, 2.9%, 2.7%, and 3.9% of total regression-adjusted health care costs. The group with a very high serum UA level had significantly higher regression-adjusted total 12-month all-cause health care costs and gout-related costs compared with those with a low serum UA level ($3,103 and $276 higher, respectively). CONCLUSIONS: Elderly patients with a diagnosis of gout have higher all-cause health care utilization and costs compared with matched elderly patients without a diagnosis of gout. Gout-related costs represent about 6% of total health care costs in elderly patients with gout. Very high serum UA levels (i.e., > or = 9 mg per dL) and diagnoses suggesting possible tophi are associated with increased utilization and costs in elderly gout patients.

Design, synthesis, and biological evaluation of substituted-N-(thieno[2,3-b]pyridin-3-yl)-guanidines, N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidines, and N-(1H-indol-3-yl)-guanidines.

Sulfonylureas stimulate insulin secretion independent of the blood glucose concentration and therefore cause hypoglycemia in type 2 diabetic patients. Over the last years, a number of aryl-imidazoline derivatives have been identified that stimulate insulin secretion in a glucose-dependent manner. In the present study, we have developed three series of substituted N-(thieno[2,3-b]pyridin-3-yl)-guanidine (2a-l), N-(1H-pyrrolo[2,3-b]pyridin-3-yl)-guanidine (3a-l), and N-(1H-indol-3-yl)-guanidine (4a-l) as new class of antidiabetic agents. In vitro glucose-dependent insulinotropic activity of test compounds 2a-l, 3a-l, and 4a-l was evaluated using RIN5F (Rat Insulinoma cell) based assay. All the test compounds showed concentration-dependent insulin secretion, only in presence of glucose load (16.7mmol). Some of the test compounds (2c, 3c, and 4c) from each series were found to be equipotent to BL 11282 (standard aryl-imidazoline), which indicated that the guanidine group acts as a bioisostere of imidazoline ring system.

Synthesis and antibacterial activity of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine quinolones.

Synthesis and antibacterial activity of a number of substituted 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine quinolones is reported. The antibacterial activities were evaluated in standard in vitro MIC assay method. Some of the compounds showed in vitro (MIC) antibacterial activity comparable to those of Gatifloxacin, Ciprofloxacin, and Sparfloxacin.

Outpatient management of deep venous thrombosis: 2 models of integrated care.

OBJECTIVE: To describe and evaluate the impact, effectiveness, and safety of 2 models of outpatient deep venous thrombosis (DVT) management. STUDY DESIGN: Observational health-records survey conducted in 2 community hospitals using a comparative design. METHODS: The model centered around the emergency department (ED) was studied from April 15, 1997, through December 31, 1999; the decentralized model was studied from July 15, 2002, through March 15, 2004. The effect of the decentralized model on processes of care was determined by comparing the percentages of patients who were managed by office-based primary care providers under the 2 models. Two-week clinical outcomes also were compared, including symptomatic pulmonary embolism, symptomatic progression of index DVT, new DVT, major bleeding, minor bleeding, and death. RESULTS: During the study periods, 187 and 254 outpatients were enrolled in the ED-centered model and the decentralized model, respectively. Under the ED-centered model, 17 (22.1%) of 77 patients who presented to the primary care providers' offices on weekdays before 1:30 PM (on-hours) were managed exclusively within the clinic setting. Under the decentralized model, 78 (91.8%) of 85 patients who presented on-hours were managed within the clinics--a difference of 69.7 absolute percentage points (95% confidence intervals, 58.7%, 80.7%; P < .001). The models had comparable 2-week clinical outcomes. CONCLUSIONS: The decentralized model for outpatient DVT management allowed more primary care clinic patients to receive their initial care exclusively in the clinic setting. There was no significant difference between the models in short-term effectiveness of therapy and patient safety.