Derivation and validation of a noninvasive prediction tool to identify pulmonary hypertension in patients with IPF: Evolution of the model FORD.

BACKGROUND: The administration of inhaled prostanoids to patients with pulmonary hypertension (PH) related to idiopathic pulmonary fibrosis (IPF) and other fibrotic lung diseases improves functional outcomes. Selection of patients with IPF at risk for concomitant PH to undergo right heart catheterization (RHC) remains challenging. We sought to develop a clinical prediction tool based on common noninvasive parameters to identify PH in patients with IPF. METHODS: A prediction model based on noninvasive parameters was derived from patients enrolled in the ARTEMIS-IPF randomized, placebo-controlled clinical trial. Predictor variables were tested for association with the presence of PH diagnosed based on RHC. The derived multivariable logistic regression model and associated point-score index were then externally validated in a real-world cohort of patients with IPF. RESULTS: Of the 481 patients included in the ARTEMIS-IPF study, 9.8% (N = 47) were diagnosed with PH related to IPF. Four variables were associated with PH and were included in the final model: forced vital capacity/diffusing capacity for carbon monoxide ratio (F), oxygen saturation nadir during 6-minute walk test (6MWT) (O), race (R), and distance ambulated during 6MWT (D). A model containing continuous predictors (FORD calculator) and a simple point-score system (FORD index) performed similarly well in the derivation cohort (area under the curve [AUC]: 0.75 and 0.75, respectively) and validation cohort (AUC: 0.69 and 0.69, respectively). CONCLUSIONS: The FORD models are simple, validated tools incorporating noninvasive parameters that can be applied to identify patients at risk of PH related to IPF who may benefit from invasive testing.

Advance in the sulfur-based electron donor autotrophic denitrification for nitrate nitrogen removal from wastewater.

In the field of wastewater treatment, nitrate nitrogen (NO3--N) is one of the significant contaminants of concern. Sulfur autotrophic denitrification technology, which uses a variety of sulfur-based electron donors to reduce NO3--N to nitrogen (N2) through sulfur autotrophic denitrification bacteria, has emerged as a novel nitrogen removal technology to replace heterotrophic denitrification in the field of wastewater treatment due to its low cost, environmental friendliness, and high nitrogen removal efficiency. This paper reviews the advance of reduced sulfur compounds (such as elemental sulfur, sulfide, and thiosulfate) and iron sulfides (such as ferrous sulfide, pyrrhotite, and pyrite) electron donors for treating NO3--N in wastewater by sulfur autotrophic denitrification technology, including the dominant bacteria types and the sulfur autotrophic denitrification process based on various electron donors are introduced in detail, and their operating costs, nitrogen removal performance and impacts on the ecological environment are analyzed and compared. Moreover, the engineering applications of sulfur-based electron donor autotrophic denitrification technology were comprehensively summarized. According to the literature review, the focus of future industry research were discussed from several aspects as well, which would provide ideas for the application and optimization of the sulfur autotrophic denitrification process for deep and efficient removal of NO3--N in wastewater.

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.

Importance: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

Periodically reversing electrocoagulation technique for efficient removal of short-chain perfluoroalkyl substances from contaminated groundwater around a fluorochemical facility.

Widespread distributions of short-chain perfluoroalkyl substances (PFASs) has been recognized as a crucial environmental issue. However, multiple treatment techniques were ineffective due to their high polarity and mobility, contributing to a never-ending existence in the aquatic environment ubiquitously. The present study revealed potential technique of periodically reversing electrocoagulation (PREC) to perform efficient removal of short-chain PFASs including experimental factors (in the conditions of 9 V for voltage, 600 r/min of stirring speed, 10 s of reversing period, and 2 g/L of NaCl electrolyte), orthogonal experiments, actual application, and removal mechanism. Accordingly, based upon the orthogonal experiments, the removal efficiencies of perfluorobutane sulfonate (PFBS) in simulated solution could achieve 81.0% with the optimal parameters of Fe-Fe electrode materials, addition of 665 µL H2O2 per 10 min, and pH at 3.0. The PREC was further applied for treating the actual groundwater around a fluorochemical facility, consequently the removal efficiencies for typical short-chain perfluorobutanoic acid (PFBA), perfluoropentanoic acid (PFPeA), perfluorohexanoic acid (PFHxA), PFBS, and perfluoropentane sulfonate (PFPeS) were 62.5%, 89.0%, 96.4%, 90.0%, and 97.5%, respectively. The other long-chain PFASs contaminants had superior removal with the removal efficiencies up to 97%-100%. In addition, a comprehensive removal mechanism related to electric attraction adsorption for short-chain PFASs could be verified through the morphological analysis of ultimate flocs composition. The oxidation degradation was further revealed as the other removal mechanism by suspect and nontarget screening of intermediates formed in simulated solution, as well as density functional theory (DFT) calculation theory. Moreover, the degradation pathways about one CF2O molecule or CO2 eliminated with one C atom removed in PFBS by ·OH generated from the PREC oxidation process were further proposed. As a result, the PREC would be a promising technique for the efficient removal of short-chain PFASs from severely contaminated water bodies.

Simultaneous removal of multiple PFAS from contaminated groundwater around a fluorochemical facility by the periodically reversing electrocoagulation technique.

Increasing attentions have been paid on widespread contaminations of perfluoroalkyl substances (PFAS). Particularly, simultaneous occurrence of multiple PFAS in the aquatic environments globally has been recognized as a crucial emerging issue. The present study aimed to perform simultaneous removal of multiple PFAS contaminations from groundwater around a fluorochemical facility based upon the technique of periodically reversing electrocoagulation (PREC). Accordingly, the experiments were implemented on the best conditions, actual application, and removal mechanism in the process of PREC with Al-Zn electrodes. Consequently, 1 mg/L synthetic solution of ten PFAS could be eliminated ideally during the initial 10 min, under the optimal conditions involving voltage at 12 V, pH at 7.0, and electrolyte with NaCl. The maximum removal rates of perfluorobutanoic acid (PFBA), perfluorobutane sulfonate (PFBS), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonate (PFOS) were 90.9%, 91.0%, 99.7%, and 100%, respectively. The PREC performed a significant improvement for the wide scope of PFAS removal with the levels ranging from 10 µg/L to 100 mg/L. In addition, the optimized PREC technique was further applied to remove various PFAS contaminations from the natural groundwater samples underneath the fluorochemical facility, subsequently generating the removal efficiencies in the range between 31.3% and 99.9%, showing the observable advantages compared with other removal techniques for the actual application. Finally, the mechanism of PFAS removal was mainly related to enmeshment and synergistic bridging adsorption, together with oxidation degradation that determined by potential formation of short-chain PFAS in the PREC process. As a result, the PREC technique would be a promising technique for the efficient removal of multiple PFAS contaminations simultaneously from natural water bodies.

Target analysis and suspect screening of per- and polyfluoroalkyl substances in paired samples of maternal serum, umbilical cord serum, and placenta near fluorochemical plants in Fuxin, China.

The levels of legacy per- and polyfluoroalkyl substances (PFASs) have been growing in the environmental matrices and blood of residents living around the fluorochemical industrial park (FIP) in Fuxin of China over the past decade. Although some recent studies have reported occurrence of novel PFAS alternatives in biotic and abiotic matrices near fluorochemical facilities worldwide, little is known about novel PFAS congeners in maternal sera, umbilical cord sera, and placentas from the female residents close to the FIP and their related health risks. In this study, 50 paired samples of maternal and cord serum as well as placenta were derived from Fuxin pregnant women at delivery, and 21 target analytes of legacy PFASs in all the samples were analyzed via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), revealing that PFBS, PFBA, and PFOA were the dominant PFAS contaminants observed in the whole samples. Based upon the suspect screening through high-resolution mass spectrometry (HRMS), 49 novel PFASs assigned to 11 classes were further identified in the Fuxin samples, of which, 20 novel congeners in 4 classes were reported in human blood and placentas for the first time. Moreover, the coefficients for mother-placenta transfer (Rm/p), placenta-newborn transfer (Rp/n), and mother-newborn transfer (Rm/n) of legacy PFASs could be calculated with median values of 1.7, 1.1, and 2.0, respectively, and Rm/p, Rp/n, and Rm/n for each novel PFAS identified were also estimated with the median values of 0.9, 1.2, and 0.8 individually. Accordingly, novel PFASs contributed 90% of all the legacy and novel PFASs in maternal sera and even occupied 96% of the whole PFASs in both placentas and cord sera. In addition, significant associations were determined among the neonate birth outcomes and serum concentrations of thyroid hormone, sex hormone, and glucocorticoid, together with the levels of certain legacy and novel PFASs in cord sera.

Bioaccumulation of perfluoroalkyl substances in greenhouse vegetables with long-term groundwater irrigation near fluorochemical plants in Fuxin, China.

The levels of perfluoroalkyl substances (PFASs) have been growing progressively in the groundwater beneath a fluorochemical industrial park (FIP) in Fuxin of China recently, however, little information is available about whether long-term irrigation with local groundwater could have a potential effect on the bioaccumulation of PFASs in greenhouse vegetables near the FIP. In the present study, groundwater, soil, and vegetable samples were collected from Fuxin with five sampling campaigns during a period of 40 days, and ten target analytes of PFASs in all the samples were analyzed via high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). As the dominant PFAS contaminants, perfluorooctanoic acid (PFOA) and perfluorobutane sulfonate (PFBS) in groundwater samples were determined with the maximum levels of 2.47 and 32.4 µg L-1, respectively. Furthermore, perfluorobutanoic acid (PFBA), PFOA, and PFBS were the major PFASs in greenhouse samples of soil (up to 6.1, 6.8, and 46 ng g dry weight (dw)-1), tomato (up to 87, 1.7, and 13 ng g dw-1), and cucumber (up to 63, 2.6, and 15 ng g dw-1), which were significantly correlated with those in groundwater samples, indicating PFAS contaminations could be introduced into soil and vegetables in the greenhouse through long-term groundwater irrigation. In addition, all the levels of three main PFAS analytes in soil and vegetables presented an overall increasing trend over the period of vegetable growth. The bioaccumulation efficiencies for PFAS contaminants from soil to vegetables were negatively associated with the carbon chain length in PFASs. According to the reference dose (RfD) for PFBA, PFOA, and PFBS from the Minnesota Department of Health (MDH), daily intakes of those three analytes by rural residents in Fuxin were lower than the respective RfD via consumption of greenhouse tomatoes and cucumbers so far. However, long-term surveillance would be focused on greenhouse vegetables near the Fuxin FIP to prevent potential health risks of local residents from increasing PFAS contaminations.

The Relative Bioavailability, Food Effect, and Drug Interaction With Omeprazole of Momelotinib Tablet Formulation in Healthy Subjects.

Momelotinib is a potent and selective small-molecule inhibitor of JAK1/2 that is under investigation for the treatment of myeloproliferative neoplasms. In a phase 1/2 study in myelofibrosis patients, once-daily dosing of a 300-mg momelotinib capsule was selected for further development based on a favorable benefit:risk profile. A tablet formulation was recently developed for further clinical evaluation. In this study, the relative bioavailability of the tablet formulation versus the initial capsule formulation and the effect of food and omeprazole on the pharmacokinetics of a single-dose momelotinib tablet were evaluated in healthy subjects. The momelotinib tablet, 200 mg, provided plasma exposure equivalent to the 300-mg capsule. Plasma exposure of momelotinib increased less than dose-proportionally from 100 to 800 mg. Food intake modestly increased Cmax (38% and 28% increase for low- and high-fat meals, respectively) and AUCinf (16% and 28% increase for low- and high-fat meals, respectively) for the momelotinib tablet. Omeprazole reduced the exposure of the momelotinib tablet by 36% for Cmax and 33% for AUCinf . Neither the food effect nor the omeprazole effect on momelotinib exposure was considered clinically meaningful because of the safety and efficacy profile of momelotinib.

A phase 2 study of momelotinib, a potent JAK1 and JAK2 inhibitor, in patients with polycythemia vera or essential thrombocythemia.

Momelotinib is a potent inhibitor of JAK1 and JAK2 that demonstrated efficacy in patients with primary and secondary myelofibrosis. This phase 2, open-label, randomized study evaluated the efficacy and safety of oral once-daily momelotinib (100mg and 200mg) for the treatment of polycythemia vera (PV) and essential thrombocythemia (ET). The primary endpoint for PV was overall response rate (ORR), defined as the proportion of patients with hematocrit <45%, white blood cell count <10×109/L, platelet count ≤400×109/L, and resolution of palpable splenomegaly, each lasting ≥4 weeks. The definition of ORR for ET excluded the hematocrit component. A total of 39 patients (28 PV, 11 ET) were enrolled, with 28 patients receiving ≥12 weeks of treatment. The study was terminated due to limited efficacy. Two patients (ORR 5.1%) met the primary efficacy endpoint (both PV 200mg). Predose plasma levels of momelotinib were stable over time. A total of 31 (79.5%) patients experienced momelotinib-related adverse events (AEs), the most frequent being headache (23.1%), dizziness (18.0%), somnolence (15.4%), nausea (15.4%), and fatigue (15.4%). Three patients experienced serious AEs (7.7%), with 1 considered related to momelotinib (dyspnea). Peripheral neuropathy occurred in 7 (17.9%) patients (4 PV, 3 ET).

Pharmacokinetics, Pharmacodynamics, and Safety of Entospletinib, a Novel pSYK Inhibitor, Following Single and Multiple Oral Dosing in Healthy Volunteers.

BACKGROUND AND OBJECTIVES: Entospletinib is a selective, reversible, adenosine triphosphate-competitive small-molecule spleen tyrosine kinase (SYK) inhibitor that blocks B cell receptor-mediated signaling and proliferation in B lymphocytes. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of entospletinib in a double-blind, single/multiple ascending dose study in healthy volunteers. METHODS: In sequential cohorts, 120 subjects received entospletinib (25-1200 mg; fasted) as single or twice-daily oral doses for 7 days. Along with pharmacokinetics, the study assessed functional inhibition of ex vivo anti-immunoglobulin E-stimulated CD63 expression on basophils and pervanadate-evoked phosphorylated SYK (pSYK) Y525. Safety and tolerability were assessed throughout the study. RESULTS: Entospletinib was generally well-tolerated over a 48-fold dose range. Adverse events (AEs) were generally mild to moderate, with no AE-driven study drug discontinuations noted. Entospletinib displayed a median plasma half-life of 9-15 h; entospletinib exposures reached a plateau at ≥600 mg twice daily (likely due to solubility-limited absorption) and provided >90% CD63 inhibition at peak concentrations and >60% inhibition at trough concentrations (corresponding pSYK inhibition of >70 and >50%). CONCLUSION: The overall safety, pharmacokinetics, and pharmacodynamics profiles of entospletinib support further clinical evaluation.

Correlation between T2* (T2 star) relaxation time and cervical intervertebral disc degeneration: An observational study.

PURPOSE: To demonstrate the potential benefits of T2 relaxation time of intervertebral discs (IVDs) regarding the detection and grading of degenerative disc disease using 3.0-T magnetic resonance imaging (MRI) in a clinical setting. MATERIALS AND METHODS: Cervical sagittal T2-weighted, T2 relaxation MRI was performed at 3.0-T in 61 subjects, covering discs C2-3 to C6-7. All discs were morphologically assessed based on the Pfirrmann grade, and regions of interests (ROIs) were drawn over the T2 mapping. Receiver operating characteristic (ROC) analysis was performed among grades to determine the cut-off values. RESULTS: Cervical intervertebral discs (IVDs) of patients were commonly determined to be at Pfirrmann grades III to V. The nucleus pulposus (NP) values did not differ significantly between sexes at the same anatomic level (P > 0.05). In the NP, the T2 values tended to decrease with increasing grade (P < 0.000), and a significant difference was found in the T2 values between grades I to V (P < 0.05). T2 values based on disc degeneration level classification were as follows: grade I (>30 milliseconds), grade II (24.55-29.99 milliseconds), grade III (21.65-24.54 milliseconds), grade IV (18.35-21.64 milliseconds), and grade V (<18.34 milliseconds). CONCLUSION: Our standardized method of region-specific quantitative T2 relaxation time evaluation seems capable of characterizing different degrees of disc degeneration quantitatively. The T2 values obtained in these cervical IVDs may serve as baseline values for future T2 measurements in both healthy and degenerated cervical discs.

Pulmonary hypertension in idiopathic pulmonary fibrosis with mild-to-moderate restriction.

The clinical course of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) is not known except in advanced disease.488 subjects in a placebo-controlled study of ambrisentan in IPF with mild-moderate restriction in lung volume, underwent right heart catheterisation (RHC) at baseline and 117 subjects (24%) had repeated haemodynamic measurements at 48 weeks. The subjects were categorised into a) World Health Organization (WHO) Group 3 PH (PH associated with pulmonary disease), n=68 (14%); b) WHO Group 2 PH (PH associated with left-sided cardiac disease), n=25 (5%); c) no PH but elevated pulmonary artery wedge pressure (PAWP), n=21 (4%); and d) no PH but without elevation of PAWP, n=374 (77%). The WHO Group 3 PH subjects had a lower diffusion capacity, 6MWD and oxygen saturation compared to the subjects with no PH. There was no significant change in mean pulmonary arterial pressure with ambrisenten or placebo after 12 months. Subjects with IPF associated with WHO Group 3 PH had impaired gas exchange and exercise capacity compared to patients without PH. An additional 9% of the subjects had haemodynamic evidence of subclinical left-ventricular dysfunction. Pulmonary artery pressures remained stable over 1 year in the majority of the cohort.

Aztreonam for inhalation solution in patients with non-cystic fibrosis bronchiectasis (AIR-BX1 and AIR-BX2): two randomised double-blind, placebo-controlled phase 3 trials.

BACKGROUND: The clinical benefit of inhaled antibiotics in non-cystic fibrosis bronchiectasis has not been established in randomised controlled trials. We aimed to assess safety and efficacy of aztreonam for inhalation solution (AZLI) in patients with non-cystic fibrosis bronchiectasis and Gram-negative bacterial colonisation. METHODS: AIR-BX1 and AIR-BX2 were two double-blind, multicentre, randomised, placebo-controlled phase 3 trials, which included patients aged 18 years or older who had bronchiectasis and history of positive sputum or bronchoscopic culture for target Gram-negative organisms. Patients were randomly assigned to receive either AZLI or placebo (1:1). Randomisation was done without stratification and the code was generated by a Gilead designee. In both studies, two 4-week courses of AZLI 75 mg or placebo (three-times daily; eFlow nebulizer) were each followed by a 4-week off-treatment period. Primary endpoint was change from baseline Quality of Life-Bronchiectasis Respiratory Symptoms scores (QOL-B-RSS) at 4 weeks. These trials are registered with ClinicalTrials.gov, numbers are NCT01313624 for AIR-BX1 and NCT01314716 for AIR-BX2. FINDINGS: We recruited participants from 47 ambulatory clinics for AIR-BX1 and 65 ambulatory clinics for AIR-BX2; studies were done between April 25, 2011, and July 1, 2013. In AIR-BX1, of the 348 patients screened, 134 were randomly assigned to receive AZLI and 132 to receive placebo. In AIR-BX2, of the 404 patients screened, 136 were randomly assigned to receive AZLI and 138 to receive placebo. The difference between AZLI and placebo for adjusted mean change from baseline QOL-B-RSS was not significant at 4 weeks (0.8 [95% CI -3.1 to 4.7], p=0.68) in AIR-BX1, but was significant (4.6 [1.1 to 8.2], p=0.011) in AIR-BX2. The 4.6 point difference in QOL-B-RSS after 4 weeks in AIR-BX2 was not deemed clinically significant. In both studies, treatment-related adverse events were more common in the AZLI group than in the placebo group, as were discontinuations from adverse events. The most commonly reported treatment-emergent adverse events were dyspnea, cough, and increased sputum. Each was more common for AZLI-treated than for placebo-treated patients, but the incidences were more balanced in AIR-BX2. INTERPRETATION: AZLI treatment did not provide significant clinical benefit in non-cystic fibrosis bronchiectasis, as measured by QOL-B-RSS, suggesting a continued need for placebo-controlled studies to establish the clinical benefit of inhaled antibiotics in patients with this disorder. FUNDING: Gilead Sciences.

Diagnosis of idiopathic pulmonary fibrosis with high-resolution CT in patients with little or no radiological evidence of honeycombing: secondary analysis of a randomised, controlled trial.

BACKGROUND: Present guidelines for the diagnosis of idiopathic pulmonary fibrosis require histological confirmation of surgical lung biopsy samples when high-resolution CT images are not definitive for usual interstitial pneumonia. We aimed to assess the predictive value of high-resolution CT in a cohort of patients with suspected idiopathic pulmonary fibrosis from a previous randomised trial. METHODS: ARTEMIS-IPF was a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial of ambrisentan for adults aged 40-80 years with well-defined idiopathic pulmonary fibrosis and 5% or less honeycombing on high-resolution CT. In December, 2010, an interim analysis showed lack of efficacy and the trial was stopped. In the present follow-on analysis, we assessed patients who were screened for ARTEMIS-IPF who underwent high-resolution CT as part of screening and surgical lung biopsy as part of standard clinical care. A radiologist and a pathologist from a central panel independently assessed anonymised CT scans and biopsy samples. We calculated the positive and negative predictive value of high-resolution CT (classified as usual interstitial pneumonia, possible usual interstitial pneumonia, and inconsistent with usual interstitial pneumonia) for confirmation of histological patterns of usual interstitial pneumonia. This study is registered with ClinicalTrials.gov, number NCT00768300. FINDINGS: 315 (29%) of 1087 consecutively screened patients in ARTEMIS-IPF had both high-resolution CT and surgical lung biopsy samples. 108 of 111 patients who met high-resolution CT criteria for usual interstitial pneumonia had histologically confirmed usual interstitial pneumonia (positive predictive value 97·3%, 95% CI 92·3-99·4), as did 79 of 84 patients who met high-resolution CT criteria for possible usual interstitial pneumonia (94·0%, 86·7-98·0). 22 of 120 patients had an inconsistent high-resolution CT pattern for usual interstitial pneumonia that was histologically confirmed as not or possible usual interstitial pneumonia (negative predictive value 18·3%, 95% CI 11·9-26·4). INTERPRETATION: In the appropriate clinical setting, for patients with possible usual interstitial pneumonia pattern on high resolution CT, surgical lung biopsy sampling might not be necessary to reach a diagnosis of idiopathic pulmonary fibrosis if high-resolution CT scans are assessed by experts at regional sites familiar with patterns of usual interstitial pneumonia and management of idiopathic interstitial pneumonia. FUNDING: Gilead Sciences.

Quantitative T2 magnetic resonance imaging compared to morphological grading of the early cervical intervertebral disc degeneration: an evaluation approach in asymptomatic young adults.

OBJECTIVE: The objective of this study was to evaluate the efficacy of quantitative T2 magnetic resonance imaging (MRI) for quantifying early cervical intervertebral disc (IVD) degeneration in asymptomatic young adults by correlating the T2 value with Pfirrmann grade, sex, and anatomic level. METHODS: Seventy asymptomatic young subjects (34 men and 36 women; mean age, 22.80±2.11 yr; range, 18-25 years) underwent 3.0-T MRI to obtain morphological data (one T1-fast spin echo (FSE) and three-plane T2-FSE, used to assign a Pfirrmann grade (I-V)) and for T2 mapping (multi-echo spin echo). T2 values in the nucleus pulposus (NP, n = 350) and anulus fibrosus (AF, n = 700) were obtained. Differences in T2 values between sexes and anatomic level were evaluated, and linear correlation analysis of T2 values versus degenerative grade was conducted. FINDINGS: Cervical IVDs of healthy young adults were commonly determined to be at Pfirrmann grades I and II. T2 values of NPs were significantly higher than those of AF at all anatomic levels (P<0.000). The NP, anterior AF and posterior AF values did not differ significantly between genders at the same anatomic level (P>0.05). T2 values decreased linearly with degenerative grade. Linear correlation analysis revealed a strong negative association between the Pfirrmann grade and the T2 values of the NP (P = 0.000) but not the T2 values of the AF (P = 0.854). However, non-degenerated discs (Pfirrmann grades I and II) showed a wide range of T2 relaxation time. T2 values according to disc degeneration level classification were as follows: grade I (>62.03 ms), grade II (54.60-62.03 ms), grade III (<54.60 ms). CONCLUSIONS: T2 quantitation provides a more sensitive and robust approach for detecting and characterizing the early stage of cervical IVD degeneration and to create a reliable quantitative in healthy young adults.

Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression.

We evaluated whether lysyl oxidase-like 2 (LOXL2), which promotes cross-linking of collagen in pathological stroma, was detectable in serum from idiopathic pulmonary fibrosis (IPF) patients, and assessed its relationship with IPF disease progression. Patients from the ARTEMIS-IPF (n=69) and the Genomic and Proteomic Analysis of Disease Progression in IPF (GAP) (n=104) studies were analysed. Baseline serum LOXL2 (sLOXL2) levels were compared with baseline clinical and physiological surrogates of disease severity, and the association with IPF disease progression was assessed using a classification and regression tree (CART) method. sLOXL2 correlated weakly with forced vital capacity and carbon monoxide diffusion capacity (r -0.24-0.05) in both cohorts. CART-determined thresholds were similar: ARTEMIS-IPF 800 pg·mL(-1) and GAP 700 pg·mL(-1). In ARTEMIS-IPF, higher sLOXL2 (>800 pg·mL(-1)) was associated with increased risk for disease progression (hazard ratio (HR) 5.41, 95% CI 1.65-17.73). Among GAP subjects with baseline spirometric data (n=70), higher sLOXL2 levels (>700 pg·mL(-1)) were associated with more disease progression events (HR 1.78, 95% CI 1.01-3.11). Among all GAP subjects, higher sLOXL2 levels were associated with increased risk for mortality (HR 2.28, 95% CI 1.18-4.38). These results suggest that higher sLOXL2 levels are associated with increased risk for IPF disease progression. However, due to multiple limitations, these results require validation.

Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by formation and proliferation of fibroblast foci. Endothelin-1 induces lung fibroblast proliferation and contractile activity via the endothelin A (ETA) receptor. OBJECTIVE: To determine whether ambrisentan, an ETA receptor-selective antagonist, reduces the rate of IPF progression. DESIGN: Randomized, double-blind, placebo-controlled, event-driven trial. (ClinicalTrials.gov: NCT00768300). SETTING: Academic and private hospitals. PARTICIPANTS: Patients with IPF aged 40 to 80 years with minimal or no honeycombing on high-resolution computed tomography scans. INTERVENTION: Ambrisentan, 10 mg/d, or placebo. MEASUREMENTS: Time to disease progression, defined as death, respiratory hospitalization, or a categorical decrease in lung function. RESULTS: The study was terminated after enrollment of 492 patients (75% of intended enrollment; mean duration of exposure to study medication, 34.7 weeks) because an interim analysis indicated a low likelihood of showing efficacy for the end point by the scheduled end of the study. Ambrisentan-treated patients were more likely to meet the prespecified criteria for disease progression (90 [27.4%] vs. 28 [17.2%] patients; P = 0.010; hazard ratio, 1.74 [95% CI, 1.14 to 2.66]). Lung function decline was seen in 55 (16.7%) ambrisentan-treated patients and 19 (11.7%) placebo-treated patients (P = 0.109). Respiratory hospitalizations were seen in 44 (13.4%) and 9 (5.5%) patients in the ambrisentan and placebo groups, respectively (P = 0.007). Twenty-six (7.9%) patients who received ambrisentan and 6 (3.7%) who received placebo died (P = 0.100). Thirty-two (10%) ambrisentan-treated patients and 16 (10%) placebo-treated patients had pulmonary hypertension at baseline, and analysis stratified by the presence of pulmonary hypertension revealed similar results for the primary end point. LIMITATION: The study was terminated early. CONCLUSION: Ambrisentan was not effective in treating IPF and may be associated with an increased risk for disease progression and respiratory hospitalizations. PRIMARY FUNDING SOURCE: Gilead Sciences.

Discovery of INCB8761/PF-4136309, a Potent, Selective, and Orally Bioavailable CCR2 Antagonist.

We report the discovery of a new (S)-3-aminopyrrolidine series of CCR2 antagonists. Structure-activity relationship studies on this new series led to the identification of 17 (INCB8761/PF-4136309) that exhibited potent CCR2 antagonistic activity, high selectivity, weak hERG activity, and an excellent in vitro and in vivo ADMET profile. INCB8761/PF-4136309 has entered human clinical trials.

Discovery of INCB3284, a Potent, Selective, and Orally Bioavailable hCCR2 Antagonist.

We report the identification of 13 (INCB3284) as a potent human CCR2 (hCCR2) antagonist. INCB3284 exhibited an IC50 of 3.7 nM in antagonism of monocyte chemoattractant protein-1 binding to hCCR2, an IC50 of 4.7 nM in antagonism of chemotaxis activity, an IC50 of 84 µM in inhibition of the hERG potassium current, a free fraction of 58% in protein binding, high selectivity over other chemokine receptors and G-protein-coupled receptors, and acceptable oral bioavailability in rodents and primates. In human clinical trials, INCB3284 exhibited a pharmacokinetic profile suitable for once-a-day dosing (T 1/2 = 15 h).

Discovery of INCB3344, a potent, selective and orally bioavailable antagonist of human and murine CCR2.

Rational design based on a pharmacophore of CCR2 antagonists reported in the literature identified lead compound 9a with potent inhibitory activity against human CCR2 (hCCR2) but moderate activity against murine CCR2 (mCCR2). Modification on 9a led to the discovery of a potent CCR2 antagonist 21 (INCB3344) with IC(50) values of 5.1 nM (hCCR2) and 9.5 nM (mCCR2) in binding antagonism and 3.8 nM (hCCR2) and 7.8 nM (mCCR2) in antagonism of chemotaxis activity. INCB3344 exhibited >100-fold selectivity over other homologous chemokine receptors, a free fraction of 24% in human serum and 15% in mouse serum, and an oral bioavailability of 47% in mice, suitable as a tool compound for target validation in rodent models.