Defining a Patient Population With Cirrhosis: An Automated Algorithm With Natural Language Processing.

OBJECTIVES: The objective of this study was to use natural language processing (NLP) as a supplement to International Classification of Diseases, Ninth Revision (ICD-9) and laboratory values in an automated algorithm to better define and risk-stratify patients with cirrhosis. BACKGROUND: Identification of patients with cirrhosis by manual data collection is time-intensive and laborious, whereas using ICD-9 codes can be inaccurate. NLP, a novel computerized approach to analyzing electronic free text, has been used to automatically identify patient cohorts with gastrointestinal pathologies such as inflammatory bowel disease. This methodology has not yet been used in cirrhosis. STUDY DESIGN: This retrospective cohort study was conducted at the University of California, Los Angeles Health, an academic medical center. A total of 5343 University of California, Los Angeles primary care patients with ICD-9 codes for chronic liver disease were identified during March 2013 to January 2015. An algorithm incorporating NLP of radiology reports, ICD-9 codes, and laboratory data determined whether these patients had cirrhosis. Of the 5343 patients, 168 patient charts were manually reviewed at random as a gold standard comparison. Positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity of the algorithm and each of its steps were calculated. RESULTS: The algorithm's PPV, NPV, sensitivity, and specificity were 91.78%, 96.84%, 95.71%, and 93.88%, respectively. The NLP portion was the most important component of the algorithm with PPV, NPV, sensitivity, and specificity of 98.44%, 93.27%, 90.00%, and 98.98%, respectively. CONCLUSIONS: NLP is a powerful tool that can be combined with administrative and laboratory data to identify patients with cirrhosis within a population.

Comparison of the safety, tolerability, and pharmacokinetic profile of a single oral dose of pitavastatin 4 mg in adult subjects with severe renal impairment not on hemodialysis versus healthy adult subjects.

Pitavastatin is a novel statin recently approved in the United States as an adjunctive therapy with diet to reduce elevated total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, and triglycerides and to increase high-density lipoprotein cholesterol. This open-label study enrolled 16 subjects as follows: group A: 8 adult subjects with severe renal impairment who were not on hemodialysis (estimated glomerular filtration rate of 15-29 mL/min/1.73 m2) and group B: 8 healthy adult subjects (estimated glomerular filtration rate ≥80 mL/min/1.73 m2). On day 1, the subjects received a single oral dose of pitavastatin 4 mg and remained in the clinic on days 1-3 for safety and pharmacokinetic assessments. Comparing group A with group B, the geometric mean ratio of AUC(0-inf) for pitavastatin was 1.36 (90% confidence interval, 0.88-2.11). For Cmax, the corresponding ratio was 1.18 (90% confidence interval, 0.68-2.02). There were no severe treatment-emergent adverse events (AEs), serious AEs, deaths, or treatment-emergent AEs leading to study drug discontinuation. A single dose of pitavastatin 4 mg was safe and well tolerated by the subjects in this study with severe renal impairment, who were not on hemodialysis.

Vasoactive response of isolated pulpal arterioles to endothelin-1.

The vasoactive effect of endothelin-1 applied intraluminally or extraluminally was studied in vitro in isolated perfused porcine pulpal arterioles using a microperfusion system. Pulpal arterioles (outer diameter, 94.2 +/- 2.8 microm, n = 12) were cannulated and perfused at a constant flow rate in an environment-controlled bath on the stage of an inverted microscope. The vessel diameters were measured online. Both intraluminal and extraluminal application of endothelin-1 (10(-16) M to 10(-8) M) induced dose-dependent constrictions, reaching 82.3 +/- 1.7% (n = 12) and 70.5 +/- 1.3% (n = 12) at 10(-8) M, respectively. Nifedipine reversed endothelin-1-induced constriction dose-dependently at 10(-7) M and above. These data demonstrate that endothelin-1 induces calcium-dependent vasoconstriction in porcine pulpal arterioles, with extraluminal application more potent, which seems to reflect the possible modulation of vascular endothelium in the control of vascular tone.

Tissue oxygen tension and blood-flow changes in rat incisor pulp with graded systemic hyperoxia.

The role of oxygen in the regulation of the pulpal microcirculation is unknown. This investigation is aimed to measure tissue oxygen tension and blood-flow changes in the pulp of rat lower incisors during graded systemic hyperoxia, and to determine the response of the pulpal vasculature to various oxygen tensions. Twenty-four Sprague-Dawley rats were anaesthetized and artificially ventilated with the appropriate gas mixture. Recessed oxygen-sensitive microelectrodes were used to measure pulpal tissue oxygen tension via a small access cavity filled with saline on the labial surface of the incisor. A laser Doppler flowmeter was used to record pulpal blood-flow. Inspired oxygen was increased stepwise from 20 to 100% in 20% steps. Systemic blood-gas concentrations were measured at each step. Systemic arterial oxygen tension at 100% oxygen ventilation reached 481.2 +/- 30.7% of the baseline at 20% oxygen breathing (n=21). Pulpal tissue oxygen tension did not change significantly whereas pulpal blood-flow fell dose-dependently to 74.6 +/- 5.0% at 100% oxygen ventilation (n=21). Systemic hyperoxia, therefore, induces a significant reduction in pulpal blood-flow whereas pulpal tissue oxygen tension remains relatively stable, indicating an oxygen-dependent local regulatory mechanism.

Role of occlusion in endodontic management: report of two cases.

The two clinical cases reported demonstrate that traumatic occlusion can play a role in the initiation and progression of pulp and periradicular inflammation. The symptom of persistent pain did not subside after the commencement of endodontic treatment. Traumatic occlusion was identified in both cases to be the main cause and hence occlusal adjustment was performed. This resulted in the gradual resolution of the symptoms. The findings suggest that occlusal trauma is often overlooked in the diagnosis and management of endodontic diseases.

Steady-state pharmacokinetics of darunavir/ritonavir and pitavastatin when co-administered to healthy adult volunteers.

BACKGROUND: The treatment of hyperlipidaemia in human immunodeficiency virus (HIV)-infected patients has become increasingly important. However, treatment options are limited because of the drug-drug interaction between certain statins and HIV medications metabolized by cytochrome P450 (CYP) enzymes. OBJECTIVES: The primary objective was to investigate the steady-state pharmacokinetics of pitavastatin when co-administered with darunavir/ritonavir. The secondary objective was to investigate the steady-state pharmacokinetics of both darunavir and ritonavir when co-administered with pitavastatin. METHODS: This was a single-centre, open-label, multi-dose, fixed-sequence study in HIV seronegative healthy volunteers. Pitavastatin 4 mg was administered once daily on days 1-5 and on days 12-16, and darunavir 800 mg/ritonavir 100 mg once daily on days 6-16. Pharmacokinetic blood sampling was performed on days 5, 11 and 16. No significant interaction was concluded if the 90 % confidence intervals (CIs) of the geometric mean ratios (GMRs) for total exposure [i.e. the area under the plasma concentration-time curve over a dosing interval at steady state (AUC(0-τ))] and for peak exposure [i.e. the maximum plasma concentration (C(max))] of the two treatments were within the 80-125 % range. RESULTS: Twenty-eight subjects (mean age 30.5 years) were enrolled, and pharmacokinetic data were available for 27 subjects. For pitavastatin, the GMRs and 90 % CIs for the AUC(0-τ) and C(max) ratios with co-administration were 0.74 (0.69-0.80) and 0.96 (0.84-1.09), respectively. For both darunavir and ritonavir, the 90 % CIs for the AUC(0-τ) and C max ratios were within 80-125 % with pitavastatin co-administration. No significant safety issues were reported. CONCLUSION: Darunavir/ritonavir decreased total exposure to pitavastatin by 26 %, while peak exposures were similar. Pitavastatin did not influence the pharmacokinetics of darunavir or ritonavir. There is limited interaction between pitavastatin and darunavir/ritonavir.

Effects of steady-state lopinavir/ritonavir on the pharmacokinetics of pitavastatin in healthy adult volunteers.

OBJECTIVES: Pitavastatin, a statin recently approved in the United States, has a potential benefit of reduced risk of cytochrome P450 (CYP)-mediated drug-drug interaction due to minimal metabolism by the CYP system. The primary objective was to investigate pharmacokinetic (PK) effects of lopinavir/ritonavir 400 mg/100 mg twice daily on pitavastatin 4 mg when coadministered. DESIGN: This was an open-label one-arm study. METHOD: Pitavastatin 4 mg was administered once daily (days 1-5 and days 20-24). Lopinavir/ritonavir 400 mg/100 mg was administered twice daily (days 9-24). Plasma samples for PK assessments were collected on days 5, 19, and 24. Plasma concentrations of analytes were determined by liquid chromatography with tandem mass spectrometric detection methods. RESULTS: PK data were available for 23 of 24 subjects enrolled. For pitavastatin, area under the concentration time curve (AUC0-τ) and maximum concentration (C(max)) were 136.8 ± 52.9 ng·h(-1)·mL(-1) and 58.6 ± 30.4 ng/mL, respectively, when given alone, versus 113.9 ± 53.8 ng·h(-1)·mL(-1) and 58.2 ± 32.7 ng/mL when combined with lopinavir/ritonavir. The geometric mean ratio for AUC(0-τ) for pitavastatin with lopinavir/ritonavir versus pitavastatin alone was 80.0 (90% confidence interval: 73.4 to 87.3) and C(max) was 96.1 (90% confidence interval: 83.6 to 110.4). Median T(max) of pitavastatin was approximately 0.5 hours for both treatments. The PK effect of pitavastatin on lopinavir/ritonavir was minimal. No significant safety issues were reported. CONCLUSIONS: The effect on exposures when pitavastatin and lopinavir/ritonavir are coadministered was minimal. Concomitant use of pitavastatin and lopinavir/ritonavir was safe and well tolerated in healthy adult volunteers.

Effect of pitavastatin vs. rosuvastatin on international normalized ratio in healthy volunteers on steady-state warfarin.

OBJECTIVE: Statins have been shown to impact international normalized ratio (INR) when coadministered with warfarin. The aim of this study was to assess the effect of pitavastatin compared with rosuvastatin on steady-state pharmacodynamics (PD) of warfarin by measuring INR in healthy adult subjects. METHODS: Subjects received oral doses of warfarin 5 mg once daily on days 1 through 3. The dose was titrated on days 4 through 9 to reach a steady-state INR of 1.5 to 2.2. Warfarin was continued on days 10 through 21 and pitavastatin 4 mg or rosuvastatin 40 mg was administered once daily on days 14 through 22. After a 14-day washout period, the process was repeated with the alternate statin. STUDY NUMBER: NK-104-4.03US. RESULTS: For pitavastatin, mean INR changed from 1.73 ± 0.18 (n = 42) on day 14 before starting statin dosing, to 1.78 ± 0.29 (n = 42) on day 22 at treatment end; the difference in INR was not significant (p = 0.219). For rosuvastatin, mean INR increased significantly from 1.74 ± 0.20 (n = 43) at baseline to 1.90 ± 0.30 (n = 43) at treatment end (p < 0.001). Rosuvastatin caused a significantly greater increase in INR than pitavastatin (p < 0.001). CONCLUSION: Steady-state INR during warfarin treatment did not change significantly when pitavastatin 4 mg was added to the regimen, while a significant increase was observed when rosuvastatin 40 mg was added. The effect of rosuvastatin on INR was significantly larger than the effect of pitavastatin. This study is limited because it was done in healthy volunteers. Further studies in patient populations are needed to better understand the clinical significance of the results.