Ethionamide Population Pharmacokinetic Model and Target Attainment in Multidrug-Resistant Tuberculosis

Ethionamide (ETA), an isonicotinic acid derivative, is part of the multidrug-resistant tuberculosis (MDR-TB) regimen. The current guidelines have deprioritized ETA because it is potentially less effective than other agents. Our aim was to develop a population pharmacokinetic (PK) model and simulate ETA dosing regimens in order to assess target attainment. This study included subjects from four different sites, including healthy volunteers and patients with MDR-TB. The TB centers included were two in the United States and one in Bangladesh. Patients who received ETA and had at least one drug concentration reported were included. The population PK model was developed, regimens with a total of 1,000 to 2,250 mg daily were simulated, and target attainment using published MICs and targets of 1.0-log kill and resistance suppression was assessed with the Pmetrics R package. We included 1,167 ethionamide concentrations from 94 subjects. The final population model was a one-compartment model with first-order elimination and absorption with a lag time. The mean (standard deviation [SD]) final population parameter estimates were as follows: absorption rate constant, 1.02 (1.11) h(-1); elimination rate constant, 0.69 (0.46) h(-1); volume of distribution, 104.16 (59.87) liters; lag time, 0.43 (0.32) h. A total daily dose of 1,500 mg or more was needed for >= 90% attainment of the 1.0-log kill target at a MIC of 1 mg/liter, and 2,250 mg/day led to 80% attainment of the resistance suppression target at a MIC of 0.5 mg/liter. In conclusion, we developed a population PK model and assessed target attainment for different ETA regimens. Patients may not be able to tolerate the doses needed to achieve the pre-defined targets supporting the current recommendations for ETA deprioritization

Finite Intersection Property and Dynamical Compactness

[EN] Dynamical compactness with respect to a family as a new concept of chaoticity of a dynamical system was introduced and discussed in Huang et al. (J Differ Equ 260(9):6800-6827, 2016). In this paper we continue to investigate this notion. In particular, we prove that all dynamical systems are dynamically compact with respect to a Furstenberg family if and only if this family has the finite intersection property. We investigate weak mixing and weak disjointness by using the concept of dynamical compactness. We also explore further difference between transitive compactness and weak mixing. As a byproduct, we show that the -limit and the -limit sets of a point may have quite different topological structure. Moreover, the equivalence between multi-sensitivity, sensitive compactness and transitive sensitivity is established for a minimal system. Finally, these notions are also explored in the context of linear dynamics.Wen Huang and Sergii Kolyada acknowledge the hospitality of the School of Mathematical Sciences of the Fudan University, Shanghai. Sergii Kolyada also acknowledges the hospitality of the Max-Planck-Institute fur Mathematik (MPIM) in Bonn, the Departament de Matematica Aplicada of the Universitat Politecnica de Valencia, the partial support of Project MTM2013-47093-P, and the Department of Mathematics of the Chinese University of Hong Kong. We thank the referees for careful reading and constructive comments that have resulted in substantial improvements to this paper. Wen Huang was supported by NNSF of China (11225105, 11431012); Alfred Peris was supported by MINECO, Projects MTM2013-47093-P and MTM2016-75963-P, and by GVA, Project PROMETEOII/2013/013; and Guohua Zhang was supported by NNSF of China (11671094).Huang, W.; Khilko, D.; Kolyada, S.; Peris Manguillot, A.; Zhang, G. (2018). 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Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Cultural Intelligence and Work–Family Conflict: A Moderated Mediation Model Based on Conservation of Resources Theory

This study aims to explore the influence mechanism of cultural intelligence on work&ndash;family conflict for Chinese expatriates in cross-cultural non-profit organizations. Drawing on conservation of resources theory, this longitudinal study (six-month time lag) is the first to examine cultural intelligence as an antecedent of work&ndash;family conflict. The study also examines the mediating role of work engagement and the moderating role of leader&ndash;member exchange (LMX) in the cultural intelligence and work&ndash;family conflict relationship. The sample comprises 206 expatriate Chinese language teachers working at 45 Confucius Institutes in the US, Canada, and Russia. Results show that cultural intelligence not only reduces work&ndash;family conflict but also promotes expatriates&rsquo; work engagement. The higher the work engagement, the higher the work&ndash;family conflict experienced by expatriates. LMX moderates not only the positive relationship between work engagement and work&ndash;family conflict but also the indirect effect of cultural intelligence on work&ndash;family conflict through work engagement. Thus, the indirect effect of cultural intelligence on work&ndash;family conflict through work engagement is stronger with low (compared to high) LMX. This study&rsquo;s findings provide implications for managers of cross-cultural non-profit organizations to better understand and solve expatriates&rsquo; work&ndash;family conflict problem