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Competing Interests: Declaration of competing interests There are no competing interests to disclose.

Competing Interests: Declaration of competing interests There are no competing interests to disclose.

Background: Elexacaftor-tezacaftor-ivacaftor has been shown to be safe and efficacious in people with cystic fibrosis and at least one F508del allele. Our aim was to identify a novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination capable of further increasing CFTR-mediated chloride transport, with the potential for once-daily dosing., Methods: We conducted two phase 2 clinical trials to assess the safety and efficacy of a once-daily combination of vanzacaftor-tezacaftor-deutivacaftor in participants with cystic fibrosis who were aged 18 years or older. A phase 2 randomised, double-blind, active-controlled study (VX18-561-101; April 17, 2019, to Aug 20, 2020) was carried out to compare deutivacaftor monotherapy with ivacaftor monotherapy in participants with CFTR gating mutations, following a 4-week ivacaftor monotherapy run-in period. Participants were randomly assigned to receive either ivacaftor 150 mg every 12 h, deutivacaftor 25 mg once daily, deutivacaftor 50 mg once daily, deutivacaftor 150 mg once daily, or deutivacaftor 250 mg once daily in a 1:1:2:2:2 ratio. The primary endpoint was absolute change in ppFEV 1 from baseline at week 12. A phase 2 randomised, double-blind, controlled, proof-of-concept study of vanzacaftor-tezacaftor-deutivacaftor (VX18-121-101; April 30, 2019, to Dec 10, 2019) was conducted in participants with cystic fibrosis and heterozygous for F508del and a minimal function mutation (F/MF genotypes) or homozygous for F508del (F/F genotype). Participants with F/MF genotypes were randomly assigned 1:2:2:1 to receive either 5 mg, 10 mg, or 20 mg of vanzacaftor in combination with tezacaftor-deutivacaftor or a triple placebo for 4 weeks, and participants with the F/F genotype were randomly assigned 2:1 to receive either vanzacaftor (20 mg)-tezacaftor-deutivacaftor or tezacaftor-ivacaftor active control for 4 weeks, following a 4-week tezacaftor-ivacaftor run-in period. Primary endpoints for part 1 and part 2 were safety and tolerability and absolute change in ppFEV 1 from baseline to day 29. Secondary efficacy endpoints were absolute change from baseline at day 29 in sweat chloride concentrations and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. These clinical trials are registered with ClinicalTrials.gov, NCT03911713 and NCT03912233, and are complete., Findings: In study VX18-561-101, participants treated with deutivacaftor 150 mg once daily (n=23) or deutivacaftor 250 mg once daily (n=24) had mean absolute changes in ppFEV 1 of 3·1 percentage points (95% CI -0·8 to 7·0) and 2·7 percentage points (-1·0 to 6·5) from baseline at week 12, respectively, versus -0·8 percentage points (-6·2 to 4·7) with ivacaftor 150 mg every 12 h (n=11); the deutivacaftor safety profile was consistent with the established safety profile of ivacaftor 150 mg every 12 h. In study VX18-121-101, participants with F/MF genotypes treated with vanzacaftor (5 mg)-tezacaftor-deutivacaftor (n=9), vanzacaftor (10 mg)-tezacaftor-deutivacaftor (n=19), vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=20), and placebo (n=10) had mean changes relative to baseline at day 29 in ppFEV 1 of 4·6 percentage points (-1·3 to 10·6), 14·2 percentage points (10·0 to 18·4), 9·8 percentage points (5·7 to 13·8), and 1·9 percentage points (-4·1 to 8·0), respectively, in sweat chloride concentration of -42·8 mmol/L (-51·7 to -34·0), -45·8 mmol/L (95% CI -51·9 to -39·7), -49·5 mmol/L (-55·9 to -43·1), and 2·3 mmol/L (-7·0 to 11·6), respectively, and in CFQ-R respiratory domain score of 17·6 points (3·5 to 31·6), 21·2 points (11·9 to 30·6), 29·8 points (21·0 to 38·7), and 3·3 points (-10·1 to 16·6), respectively. Participants with the F/F genotype treated with vanzacaftor (20 mg)-tezacaftor-deutivacaftor (n=18) and tezacaftor-ivacaftor (n=10) had mean changes relative to baseline (taking tezacaftor-ivacaftor) at day 29 in ppFEV 1 of 15·9 percentage points (11·3 to 20·6) and -0·1 percentage points (-6·4 to 6·1), respectively, in sweat chloride concentration of -45·5 mmol/L (-49·7 to -41·3) and -2·6 mmol/L (-8·2 to 3·1), respectively, and in CFQ-R respiratory domain score of 19·4 points (95% CI 10·5 to 28·3) and -5·0 points (-16·9 to 7·0), respectively. The most common adverse events overall were cough, increased sputum, and headache. One participant in the vanzacaftor-tezacaftor-deutivacaftor group had a serious adverse event of infective pulmonary exacerbation and another participant had a serious rash event that led to treatment discontinuation. For most participants, adverse events were mild or moderate in severity., Interpretation: Once-daily dosing with vanzacaftor-tezacaftor-deutivacaftor was safe and well tolerated and improved lung function, respiratory symptoms, and CFTR function. These results support the continued investigation of vanzacaftor-tezacaftor-deutivacaftor in phase 3 clinical trials compared with elexacaftor-tezacaftor-ivacaftor., Funding: Vertex Pharmaceuticals., Competing Interests: Declaration of interests AZU received grants from the Cystic Fibrosis Foundation and the CFF-Therapeutic Development Network for the present work; received payment or honoraria from Vertex Pharmaceuticals for presentations at CF Centers in UK; and participated in advisory boards for Vertex and Eloxx. VI received grant support from CF TDN for the present work; consulting fees from Mylan for CF—TOBI podhaler advisory board; and grant support from CFF for meeting attendance. PA received support from Vertex Pharmaceuticals for lectures, presentations, and materials; meeting attendance; and participation on data safety monitoring boards or advisory boards. MAM received payment from Vertex for the current work and personal fees for serving on an advisory board; grants from Vertex and from the German Ministry for Education and Research; consulting fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Sterna Biologicals, Enterprise Therapeutics, Antabio, and Abbvie; lecture fees from Boehringer Ingelheim, Arrowhead Pharmaceuticals, and Vertex Pharmaceuticals; travel reimbursement from Boehringer Ingelheim and Vertex Pharmaceuticals; personal fees for participation in an advisory board from Boehringer Ingelheim, Arrowhead Pharmaceuticals, Vertex Pharmaceuticals, Santhera, Enterprise Therapeutics, Antabio, Kither Biotech, Abbvie, and Pari; and serves as an ECFS Board member. EFM received grants and other payments or honoraria from Vertex; and support for meetings or travel from Menarini. BWR received payments from Vertex for the present work, and payments for a presentation in Vancouver, BC, Canada in 2019; and participated on data safety monitoring boards or advisory boards for CF Storm Clinical Trial, Vertex Pharmaceuticals, Janssen, Abbvie, and Insmed. SMR received support for a clinical trial; consulting fees on the design and conduct of clinical trials; support for meeting attendance and for his role as Co-Chair of the Next Generation Steering Committee; received grants or contracts from Novartis, TranslateBio, Galapagos–Abbvie, Synedgen–Synspira, Eloxx, Vertex Pharmaceuticals, and Ionis Astra Zenica; consulting fees from Novartis, Galapagos–Abbvie, Synedgen–Synspira, Vertex Pharmaceuticals, Renovion, Ionis, Cystetic Medicines, and Arcturus; support for meeting attendance from Vertex; has patents planned, issued or pending; serves as a Co-Chair of the Next Generation Steering Committee; and owns stock or stock options with Synedgen–Synspira and Renovion. RCR received clinical trial support and consulting fees from Vertex for the present work; grants from CFF, NIDDK, NHLBI, NICHD, and NIDCD; received consulting fees from Guidepoint Global, Gerson Lehrman Group, and Cystic Fibrosis Foundation; participated on a data safety monitoring or advisory board for NHLBI DSMB. JLT-C received personal consulting fees from Vertex for the present work; received grants from Vertex, Eloxx, and 4DMT for the conduct of a research trial; personal fees from Vertex, Insmed, and 4DMT for trial design consulting; personal fees from Vertex for non-branded speaking; and personal fees from AbbVie for her role as DMC Chair; served as the adult patient care representative to the CFF Board of Trustees, on the CF Foundation's Clinical Research Executive Committee, Clinical Research Advisory Board, and Racial Justice Working Group; as immediate past chair of the CF TDN's Sexual Health, Reproduction and Gender Research Working Group; on the scientific advisory board for Emily's Entourage; on the ATS Respiratory Health Awards Working Group; on the ATS Scientific Grant Review and Clinical Problems Assembly Programming Committees; and served as an associate editor for the Journal of Cystic Fibrosis. ET received payment for the present work and grants for doing clinical trials from Vertex Pharmaceuticals; received payment and reimbursement from Vertex for her role on a steering committee and for presentations at educational events. JB received funding from Vertex Pharmaceuticals for the present work. AH received funding from Vertex Pharmaceuticals for the present work; grant support from NIHR, CF Trust, CF Foundation, and Medical Research Council; payments for educational lectures from Vertex Pharmaceuticals and for an advisory board from Mylan; medical writing support from Vertex; served as Chair of the UK CF Clinical Trials Accelerator Platform and as a board member of the UK CF Medical Association. LMY received salary support from mgH TDN for clinical research activity for the present work. DW has patents planned, issued or pending. DW, LTW, CC, APM, NN, PRS, ST, FVG, and YX are Vertex employees and might own stocks or stock options. GM and CK have nothing to disclose. LV was a clinical pharmacology lead at Vertex during the conduct of this study and conducted PK data analysis for the present study., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

This short communication introduced a simple and sensitive LC-MS/MS method for therapeutic drug monitoring of digoxin in children with the lower limit of quantitation of 0.2 ng/mL based on 30 μL of plasma. The plasma sample was pretreated by one-step protein precipitation. Then the chromatographic separation was performed on a short C-18 column with a total run time of 2.4 min. The detection was achieved through multiple reaction monitoring using positive ionization mode on a triple quadrupole mass spectrometer. The linear range of digoxin in human plasma was among 0.2-6.4 ng/mL. The intra-day and inter-day accuracies of digoxin ranged from -6.0 % to 10.1 % and imprecisions were less than 8.8 %. The extraction recovery rate of digoxin in plasma samples was above 90 %. Matrix factor normalized by internal standard was within acceptance criteria. This method was fully verified and applied to determine the plasma digoxin concentrations of 43 pediatric patients. It is approved appropriate and practical for the therapeutic drug monitoring of digoxin in routine clinical laboratory practice, especially for children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Aims: Although ticagrelor exerts an antibacterial activity, its effect on infections in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI) is unclear. We aimed to assess whether ticagrelor and clopidogrel affect infections in these patients during hospitalization., Methods: A total of 2116 consecutive patients with STEMI undergoing PCI were divided into the ticagrelor (n = 388) and clopidogrel (n = 1728) groups. The primary outcome was infection onset. Secondary outcomes were in-hospital all-cause death and major adverse cardiovascular and cerebrovascular events (MACCE). Propensity score analyses were conducted to test the robustness of the results., Results: Infections developed in 327 (15.4%) patients. There was no significant difference in infection between both groups (ticagrelor vs. clopidogrel: 13.1% vs. 16.0%, p = 0.164). Patients in the ticagrelor group had lower rates of in-hospital all-cause death and MACCE than patients in the clopidogrel group. Multivariate logistic regression analysis determined that ticagrelor and clopidogrel had a similar preventive effect on infections during hospitalization (adjusted odds ratio [OR] = 1.20; 95% confidence interval [CI] = 0.80-1.78, p = 0.380). Compared to the patients treated with clopidogrel, patients treated with ticagrelor had a slightly lower risk of other outcomes, but no statistical difference. Propensity score analyses demonstrated similar results for infections and other outcomes., Conclusions: Compared with clopidogrel treatment, ticagrelor treatment did not significantly alter the risk of infections during hospitalization among STEMI patients undergoing PCI, but was associated with a slightly lower risk of in-hospital all-cause death and MACCE., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Tezacaftor/ivacaftor is a CFTR modulator approved to treat people with cystic fibrosis (pwCF) who are homozygous (F/F) or heterozygous for the F508del-CFTR mutation and a residual function mutation (F/RF). This randomized, double-blind, placebo-controlled Phase 3 study evaluated the efficacy, safety, tolerability, and pharmacokinetics (PK) of tezacaftor/ivacaftor in participants ≥12 years of age heterozygous for the F508del-CFTR mutation and a minimal function mutation (F/MF), which produces no CFTR protein or a protein unresponsive to tezacaftor/ivacaftor in vitro., Methods: Participants were randomized 1:1 to receive tezacaftor/ivacaftor or placebo for 12 weeks. The primary endpoint was the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV 1 ) between the tezacaftor/ivacaftor and placebo groups through week 12. Key secondary endpoints included absolute change from baseline in CF Questionnaire-Revised respiratory domain scores and the number of pulmonary exacerbations through week 12 and the absolute change from baseline in body mass index at week 12. A prespecified interim analysis (IA) for futility was conducted when approximately 50% of a planned enrollment of 300 participants reached week 12 of the study., Results: At the time of the IA, 83 participants were randomized to tezacaftor/ivacaftor and 85 to placebo; 165 participants completed treatment. The study failed to demonstrate that tezacaftor/ivacaftor significantly improved ppFEV 1 or any of the key secondary endpoints and was terminated for futility. The safety profile and PK parameters of tezacaftor/ivacaftor were similar to those reported in prior studies in participants ≥12 years of age with CF., Conclusions: Tezacaftor/ivacaftor did not show a clinically meaningful benefit in participants with F/MF genotypes but was generally safe and well tolerated, consistent with the safety profile reported in other Phase 3 studies (NCT02516410)., Competing Interests: Declaration of Competing Interest All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience LLC, which received funding from Vertex Pharmaceuticals Incorporated. Additional disclosures are as follows: DC, CAO, NA, and LTW are employees of Vertex Pharmaceuticals Incorporated and may own stock or stock options in Vertex Pharmaceuticals Incorporated. AM: Coordinator for the Vertex tezacaftor/ivacaftor clinical trial 661-107 and fees for their institution (Robert Debré Hospital, Paris, France) during the conduct of the study; participation in advisory boards and educational meetings with Vertex Pharmaceuticals Incorporated outside of the submitted work. CW: Income on a per-patient basis derived from pharmaceutical studies (Vertex Pharmaceuticals Incorporated and Boehringer-Ingelheim); research grant from Novo Nordisk Pharmaceuticals for the P/L-CF-IDEA study; Vertex Pharmaceuticals P/L honorarium to attend the CF International Advisory Board Meeting in February 2014; Vertex Pharmaceuticals P/L honorarium to attend CF Medical Advisory Board Meeting in Adelaide in April 2014; Novartis Pharmaceuticals P/L honorarium to present a symposium at the National Pediatric Congress in Lebanon in May 2014; Vertex Pharmaceuticals P/L return travel and honorarium for lecture & discussions at the European CF Conference in Gothenburg in June 2014; DKBmed, LLC honorarium to present symposium at the North American CF Conference Georgia in October 2014; Vertex Pharmaceuticals P/L honorarium to present as speaker in an educational meeting series in Brisbane and Sydney in April 2015; Vertex Pharmaceuticals P/L honorarium to attend the Vertex Steering Committee Meetings on the VX15-770-123 study in 2014; Vertex Pharmaceuticals P/L honorarium for Vertex Medical Advisory Board-Innovative endpoints in CF in August 2015; University of Miami honorarium for meeting attendance in 2015; Thorax honorarium for associate editor duties in Q3/Q4 2015; BMJ honorarium for work as a reviewer; Vertex Pharmaceuticals 2015 Chicago return flight and accommodation for work as investigator in lumacaftor study; Vertex Pharmaceuticals 2015–2017 honorarium for being a speaker at Vertex-sponsored educational meeting series in Australia; Vertex Pharmaceuticals 2016 Phoenix return flight and accommodation as investigator in the Next Gen study; Vertex Pharmaceuticals December 2016 honoraria for work as a speaker at a Vertex-sponsored educational meeting in Liverpool, UK; DKBmed eCF review issue honoraria in January 2017; Vertex Pharmaceuticals March 2017 honoraria for being a speaker at TSANZ meeting; Vertex Pharmaceuticals Incorporated 2014–2018 honorarium for acting as a consultant on the Vertex Orkambi 6-11 HTA Advisory Board, the Global Pediatric Advisory Committee, the Global Medical Advisory Board, and the VIA Grants Committee; Gilead Sciences Ltd. honorarium for meeting attendance on CF imaging; honorarium for In Vivo Academy Limited for webcast meeting attendance at ECFC 2018; Vertex Pharmaceuticals P/L honorarium to present as a speaker in an educational meeting at ECFC in Belgrade 2018; Vertex Pharmaceuticals Incorporated honorarium to attend the Next Gen Early Lifecycle Management Plan in London in 2018; Vertex Pharmaceuticals P/L to act as consultant and to render such services in the form of documents, advice, meetings, and conferences from October 2018 to present; Vertex Pharmaceuticals (Australia) P/L to attend as a steering committee member at the Medical Symposium Event (SHIFT 2019) in Perth in 2019; Vertex Pharmaceuticals P/L to attend the EU Real World Evidence steering committee in Amsterdam in 2019; Current board positions: International Advisory Board, Vertex Pharmaceuticals P/L; Associate Editor, Thorax; Associate Editor, Respirology. EK: Grants from Vertex Pharmaceuticals Incorporated during the conduct of the study; speaker honorarium and membership in scientific advisory board at Vertex Pharmaceuticals Incorporated outside the submitted work. HE: participated in an advisory board meeting with Vertex Pharmaceuticals Incorporated outside of the submitted work., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Antibiotics ingested in the human gut may create selective pressure to change the composition of the gut microbiota, which could adversely effect the immune system of the host. However, the occurrence and distribution of antibiotics in the human gut remains unclear. A total population of 180 individuals, across three Chinses regions with different economic development levels, including children, adults, and elders, were sampled in 2017. A total of 19 representative antibiotics, including both clinical and veterinary antibiotics, were investigated in human faeces. While clinical use and prescriptions were the main exposure pathways for children, environmental media were the exposure pathway to adults. In addition, significant differences (P < 0.05) in antibiotic residues in human faeces were observed amongst various economic development levels, where human faeces from underdeveloped areas were mostly associated with higher levels of antibiotics. This study first to investigate the occurrence and distribution of typical antibiotics in the faeces of a Chinese population and thereby provide a reference for the intensive study of the effects and mechanisms of antibiotics on human gut microbiota., (Copyright © 2019. Published by Elsevier B.V.)

Background: The efficacy, safety, and tolerability of lumacaftor and ivacaftor are established in patients aged 6 years and older with cystic fibrosis, homozygous for the F508del-CFTR mutation. We assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of lumacaftor and ivacaftor in children aged 2-5 years., Methods: In this multicentre, phase 3, open-label, two-part study, we enrolled children aged 2-5 years, weighing at least 8 kg at enrolment, with a confirmed diagnosis of cystic fibrosis who were homozygous for the F508del-CFTR mutation. Children received lumacaftor 100 mg and ivacaftor 125 mg (bodyweight <14 kg) or lumacaftor 150 mg and ivacaftor 188 mg (bodyweight ≥14 kg) orally every 12 h for 15 days in part A (to assess pharmacokinetics and safety) and for 24 weeks in part B (to assess safety, pharmacokinetics, pharmacodynamics, and efficacy). Children could participate in part A, part B, or both. Children were enrolled into part A at five sites in the USA and into part B at 20 sites in North America (USA, 17 sites; Canada, three sites). The primary endpoints of the study were the pharmacokinetics (part A) and safety (part B) of lumacaftor and ivacaftor; all analyses were done in children who received at least one dose of lumacaftor and ivacaftor. Secondary endpoints in part A were safety and pharmacokinetics of the metabolites of lumacaftor and ivacaftor, and in part B included pharmacokinetics in children who received at least one dose of lumacaftor and ivacaftor and absolute changes from baseline in sweat chloride concentration, growth parameters, and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02797132., Findings: The study was done from May 13, 2016, to Sept 8, 2017. 12 children enrolled in part A, 11 of whom completed the 15-day treatment period and enrolled in part B. 60 children enrolled in part B, 56 of whom completed the 24-week treatment period. Safety and pharmacokinetics were consistent with the well characterised safety profile of lumacaftor and ivacaftor. In part B, most children (59 [98%] of 60 children) had one or more treatment-emergent adverse events; most events were mild to moderate in severity. The most common adverse events were cough (38 [63%] of 60), vomiting (17 [28%]), pyrexia (17 [28%]), and rhinorrhoea (15 [25%]). Serious adverse events occurred in four children: infective pulmonary exacerbation of cystic fibrosis (n=2), gastroenteritis viral (n=1), and constipation (n=1). Three (5%) of 60 children discontinued treatment because of elevated serum aminotransferase concentrations. Mean sweat chloride concentrations decreased by 31·7 mmol/L, biomarkers of pancreatic function improved (fecal elastase-1 concentrations increased and serum immunoreactive trypsinogen concentrations decreased), and growth parameters increased at week 24., Interpretation: Lumacaftor and ivacaftor were generally safe and well tolerated in children aged 2-5 years with cystic fibrosis for 24 weeks. Efficacy findings also suggest that early intervention with lumacaftor and ivacaftor has the potential to modify the course of disease., Funding: Vertex Pharmaceuticals Incorporated., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

A novel synthetic route of producing ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) was developed through multiple reactions from cheap and readily-available cholic acid. The reaction conditions of the key elimination reaction of mesylate ester group were also investigated and optimized, including solvent, base and reaction temperature. In the straightforward synthetic route for preparation of UDCA and OCA, most of the reaction steps have high conversions with average yields of 94% and 92%, and overall yield up to 65% (7 steps) and 36% (11 steps) from cholic acid, respectively. This promising route offers economical and efficient strategies for potential large-scale production of UDCA and OCA., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Aims: Diabetes-associated osteoporosis is mainly caused by the formation and accumulation of advanced glycation end products (AGEs). Angiotensin II type 1 receptor blocker (ARB) has anabolic bone effects on the physicochemical properties of the bone in diabetes. We hypothesized that ARB could inhibit AGEs-induced deleterious effects., Main Methods: In this study, we chose seven-week-old Leprdb/Lepr+ (db/+) and Leprdb/Leprdb (db/db) mice. After 12 week intervention by irbesartan, the microarchitecture and mechanical strength of the bone of seven-week-old db/db mice were investigated systematically. Meanwhile, the molecular mechanisms of the osteoblasts were analyzed, after AGEs or irbesartan were added to the culture. Also, intracellular formation of reactive oxygen species (ROS) was measured with DCF fluorescence., Key Foundings: Results showed that 12-week irbesartan treatment could dramatically improve trabecular bone microarchitecture through increasing BV/TV (p = 0.003, +46.7%), Tb.N (p = 0.020, +52.0%), and decreasing that of Tb.Sp (p = 0.005, -21.2%) and SMI (p = 0.007, -26.4%), comparing with the db/db group. Irbesartan could also substantially raise biomechanical parameters including max load (p = 0.013, +20.7%), fracture load (p = 0.014, +70.5%), energy absorption (p = 0.019, +99.4%). Besides, it could inhibit AGEs-induced damage of cell proliferation and osteogenic differentiation of osteoblasts, as well as suppressing the activation of apoptosis caused by AGEs. Moreover, co-incubation with irbesartan could prevent the AGEs-induced increase of intracellular oxidative stress and RAGE expression in osteoblasts., Significance: In conclusion, this study suggested that irbesartan might play a protective role in diabetes-related bone damages by blocking the deleterious effects of AGEs/RAGE-mediated oxidative stress. This may provide a revolutionary benefits to therapy with irbesartan on diabetic osteoporosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Ivacaftor is generally safe and effective in patients aged 2 years and older who have cystic fibrosis and specific CFTR mutations. We assessed its use in children aged 12 to <24 months., Methods: The ARRIVAL study is a phase 3, single-arm, two-part, multicentre study. Eligible children were aged 12 to <24 months at enrolment and had a confirmed diagnosis of cystic fibrosis and a CFTR gating mutation on at least one allele and could participate in one or both parts of the study. Children received 50 mg (bodyweight 7 to <14 kg) or 75 mg (bodyweight ≥14 to <25 kg) ivacaftor orally every 12 h. In study part A, children received ivacaftor for 3 days plus one morning. In study part B, children received 24 weeks of treatment. Children were enrolled into part A at seven sites in Australia (one site), the UK (one), and the USA (five) and into part B at 13 sites in Australia (two sites), Canada (one), the UK (three), and the USA (seven). Primary endpoints were pharmacokinetics (part A) and safety (parts A and B) in children who received at least one dose of ivacaftor. Secondary endpoints in part B were pharmacokinetics in children who received at least one dose of ivacaftor and absolute change from baseline in sweat chloride concentration. We also explored changes in growth parameters and markers of pancreatic function. This study is registered with ClinicalTrials.gov, number NCT02725567., Findings: Children aged 12 to <24 months were enrolled between Aug 25, 2016, and Nov 1, 2017. Seven children were enrolled in part A, of whom five received 50 mg and two received 75 mg ivacaftor. All completed treatment. Of 19 children enrolled in part B, including one from part A, all received 50 mg ivacaftor and 18 completed treatment (one withdrew because of difficulty with blood draws). All children received at least one dose of ivacaftor. Pharmacokinetics indicated exposure was similar to that in children aged 2 to <6 years and adults. No children discontinued because of adverse events or safety findings. In part A, three (43%) of seven children had treatment-emergent adverse events, all of which were mild and deemed not to be or unlikely to be related to ivacaftor. By 24 weeks in part B, treatment-emergent adverse events had been reported in 18 (95%) of 19 children, of which most were mild or moderate and the most frequent was cough (14 [74%] children). Two children in part B had four serious adverse events: one had constipation (possibly related to ivacaftor), distal intestinal obstruction syndrome, and eczema herpeticum, and one had persistent cough, all needing hospital admission. In five (28%) of 18 children aspartate or alanine aminotransferase concentrations rose to more than three times the upper limit of normal (to more than eight times in two children with concurrent infections). At week 24, the mean absolute change from baseline in sweat chloride concentration was -73·5 (SD 17·5) mmol/L. Growth parameters for age were normal at baseline and at week 24. At week 24, concentrations of faecal elastase-1 had increased and concentrations of immunoreactive trypsinogen had decreased from baseline. Mean serum lipase and amylase were raised at baseline and rapidly decreased after treatment was started., Interpretation: Ivacaftor was generally safe and well tolerated in children aged 12 to <24 months for up to 24 weeks and was associated with rapid and sustained reductions in sweat chloride concentrations. Improvements in biomarkers of pancreatic function suggest that ivacaftor preserves exocrine pancreatic function if started early. The study is continuing in infants younger than 12 months., Funding: Vertex Pharmaceuticals Incorporated., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Clinically relevant antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in bioaerosols have become a greater threat to public health. However, few reports have shown that ARB and ARGs were found in the atmosphere. High-throughput sequencing applied to environmental sciences has enhanced the exploration of microbial populations in atmospheric samples. Thus, five nosocomial bioaerosols were collected, and the dominant microbial and pathogenic microorganisms were identified by high-throughput sequencing in this study. The results suggested that the dominant microorganisms at the genus level were Massilia, Sphingomonas, Methylobacterium, Methylophilus, Micrococcineae, and Corynebacterineae. The most abundant pathogenic microorganisms were Staphylococcus saprophyticus, Corynebacterium minutissimum, Streptococcus pneumoniae, Escherichia coli, Arcobacter butzleri, Aeromonas veronii, Pseudomonas aeruginosa, and Bacillus cereus. The relationship between microbial communities and environmental factors was evaluated with canonical correspondence analysis (CCA). Meanwhile, differences in the pathogenic bacteria between bioaerosols and dust in a typical hospital was investigated. Furthermore, cultivable Staphylococcus isolates with multi-drug resistance phenotype (>3 antibiotics) in the inpatient departments were much higher than those in the transfusion area and out-patient departments, possibly attributed to the dense usage of antibiotics in inpatient departments. The results of this study might be helpful for scientifically air quality control in hospitals., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The study of parathyroid hyperplasia with bone disease as a critical manifestation of chronic kidney disease-mineral and bone disorders (CKD-MBDs) is challenging due to the lack of a suitable research model. Here, we established a rat model with secondary hyperparathyroidism (SHPT) and bone disease induced by adenine and a high phosphorous diet and analyzed the skeletal characteristics. We performed blood analysis, emission computed tomography (ECT), dual energy X-ray absorptiometry (DEXA), micro-computed tomography (micro-CT), bone histomorphometry, and bone mechanical tests. The CKD rats with SHPT induced by adenine and a high phosphorus diet showed severe abnormalities in calcium and phosphorus metabolism and exhibited parathyroid hyperplasia. The bone mineral density (BMD) of femurs and lumbar vertebrae was significantly lower in the CKD rats than in the control (CTL) rats. The cortical and trabecular bone parameters of femurs showed significant bone loss. In addition, we found decreases in ultimate force, work to failure, stiffness, and elastic modulus in the CKD rats. In conclusion, our findings demonstrated that the CKD rats with SHPT induced by adenine and a high phosphorus diet may serve as a useful model for skeletal analysis in CKD with SHPT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Handan, a city within the North China Plain (NCP) region, is a typical city influenced by regional particulate matter (PM) pollution. One-year hourly semi-continuous observation was carried out in 2015 in Handan with the aim of identifying the chemical composition and variations in PM 2.5 . Moreover, the concentration of aerosol precursors, meteorological factors, and secondary transformations are considered. The results demonstrate that the annual average PM 2.5 concentration in Handan is 122.35μgm -3 , approximately 3.5 times higher than the Chinese National Ambient Air Quality Standard (NAAQS) (35μgm -3 ), and only 12days were below the guideline. As expected, PM concentrations are highest in winter, especially in December. In addition, we measure the concentrations of five species commonly found in PM, nitrate, sulfate, ammonium, inorganic carbon, and organic carbon. Of these, nitrate and sulfate account for the largest proportion of PM 2.5 ; during periods when the PM 2.5 concentration was below 400μgm -3 , nitrate dominates, while above this concentration, sulfate dominate. This is likely related to the nitrogen and sulfur oxidation ratios, which are in turn, especially the sulfur oxidation ratio, driven by high relative humidity (>60%). In addition, haze events are driven by other meteorological conditions, wind speed and direction, where low wind speeds from the south and southwest enable pollutant accumulation, which are infrequently interspersed with brief periods with high wind speeds that promote pollutant dispersal. Even though Handan is among the ten most polluted cities in China with regard to air pollution, few studies beyond model simulations have analyzed air pollutant concentrations in this city. Therefore, this study makes a significant contribution to understanding air pollution in Handan, which can further be used to improve our understanding of regional pollution in the highly populated North China Plain. These results have implications for the creation of policies and legislation, as well as other pollution control measures., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A simple, green and efficient extraction method named modified-solvent free microwave extraction (M-SFME) was employed for the extraction of essential oils (EOs) from Amomun tsao-ko. The process of M-SFME was optimized with the prominent preponderance of such higher extraction yield (1.13%) than those of solvent free microwave extraction (SFME, 0.91%) and hydrodistillation (HD, 0.84%) under the optimal parameters. Thirty-four volatile substances representing 95.4% were identified. The IC 50 values of EOs determined by DPPH radical scavenging activity and β-carotene/linoleic acid bleaching assay were 5.27 and 0.63mg/ml. Furthermore, the EOs exhibited moderate to potent broad-spectrum antimicrobial activity against all tested strains including five gram-positive and two gram-negative bacteria (MIC: 2.94-5.86mg/ml). In general, M-SFME is a potential and desirable alternative for the extraction of EOs from aromatic herbs, and the EOs obtained from A. tsao-ko can be explored as a potent natural antimicrobial and antioxidant preservative ingredient in food industry from the technological and economical points of view., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Aberrant transforming growth factor (TGF)-β signaling is involved in the pathogenesis of pulmonary arterial hypertension (PAH). We aimed to investigate the predictive value of the upstream ligand of TGF-β signaling (TGF-β1) on long-term mortality and the clinical characteristics of patients with idiopathic pulmonary arterial hypertension (IPAH) and heritable PAH (HPAH)., Methods and Results: Plasma TGF-β1 levels were measured in 151 IPAH and 65 HPAH patients retrospectively enrolled between January 2008 and March 2013, and compared to 61 healthy subjects. Data for mortality over time were obtained from hospital databases and from telephone follow-ups. The main outcome was all-cause death. Plasma TGF-β1 was significantly higher in IPAH/HPAH patients compared to control subjects (4.74 vs. 2.61ng/mL, respectively; P<0.001). Mean follow-up time was 3.4±1.8years, during which 86 patients died. ROC curves were utilized to determine TGF-β1 cutoff values. Compared to patients with TGF-β1 of <3.74ng/mL, heart function was significantly impaired (percentage of patients with WHO functional class III/IV, 51.4% vs. 65.5%, P=0.043) and mortality risk was elevated (P=0.009) for patients with TGF-β1>3.74ng/mL. However, the difference in mortality rate between patients with higher and lower TGF-β1 levels was only statistically significant for female patients (P=0.004), despite a similar trend for male patients. Multivariate analyses revealed that TGF-β1 (HR after log transformation base of 10: 2.623; 95%CI: 1.228-5.603; P=0.013) emerged as the independent predictor for all-cause mortality., Conclusion: High circulating levels of TGF-β1 were an independent predictor of a poor outcome for IPAH/HPAH patients., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Osteosarcoma is the most common primary malignant bone tumour in children and adolescents and is characterised by high malignant and metastatic potentials. However, the molecular mechanism underlying this invasiveness remains unclear. In this study, we determined that PD98059 and SP600125, the two mitogen-activated protein kinase (MAPK) family inhibitors, decreased the osteosarcoma cell U2OS-AEG-1 migration and invasion that was enhanced by astrocyte elevated gene-1 (AEG-1) in an in vitro wound-healing and Matrigel invasion assay independently of cell viability. These findings indicate that AEG-1 promoted osteosarcoma cell invasion is relevant to the MAPK pathways. The up-regulation of AEG-1 increased the levels of phosphor-c-Jun N-terminal kinase (JNK) and phosphor-c-Jun; however, there were no marked changes in the levels of phosphor-extracellular regulated kinase (ERK) 1/2 or phosphor-c-Fos due to the activation of AEG-1 in U2OS. SP600125 (a JNK inhibitor) decreased phosphor-c-Jun and MMP-2 in U2OS-AEG-1, while PD98059 (a ERK1/2 inhibitor) had no influence on the levels of phosphor-c-Jun or MMP-2 in U2OS-AEG-1. Further study revealed that the down-regulation of phosphor-c-Jun not only obviously decreased the MMP-2 protein level and the MMP-2 transcriptional activity that were up-regulated by AEG-1 in Western-blot and luciferase reporter assays, but also inhibited the migration and invasion abilities of the U2OS-AEG-1 cells, which suggests that AEG-1 mediated U2OS invasion at least partially via the JNK/c-Jun/MMP-2 pathway. Consistent with these observations, immunohistochemical (IHC) staining revealed that AEG-1 expression was associated with the protein levels of phosphor-c-Jun and MMP-2 in needle biopsy paraffin-embedded archival human osteosarcoma tissues. Taken together, our findings suggest that AEG-1 plays a crucial role in the aggressiveness of osteosarcoma via the JNK/c-Jun/MMP-2 pathway., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Mesenchymal stem cells (MSCs) are multi-potent with numerous mesenchymal-lineage differentiation potential and immunomodulatory capabilities. However, the immunoregulatory properties of MSCs are not clearly defined. The objective of the present study was to elucidate the role(s) of MSCs in IL-17 production and the subsequent effect(s) on neutrophil activation. We have demonstrated that human bone marrow-derived MSCs (BM-MSCs) instruct anti-CD3/anti-CD28 antibody-activated CD4(+) CD45RO(+) memory T cells, but not other CD4(+) subsets or CD8(+) T cells, to produce IL-17 after cell-cell contact. After the addition of IL-17, neutrophil phagocytic activity was increased. This is the first report on the ability of BM-MSCs to induce IL-17 production in memory CD4(+) T cells that, in turn, promotes enhanced phagocytic activity of neutrophils. These results suggest that MSCs regulate the functional activation of neutrophils via their role in modulating IL-17 from CD4(+) CD45RO(+) memory T cells., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

We report on a novel, non-invasive patient positioning system for radiosurgery of extracranial tumors. The system consisted of infrared cameras and reflective markers attached to the skin. Because localization accuracy is critical in radiosurgery, we performed a theoretical analysis of the accuracy of the system. A computer simulation program modeled errors in marker position, and was used to predict errors in targeting and study methods for minimizing errors. The use of redundant markers improved the overall accuracy of targeting. Experimental data was collected using a rigid torso phantom and correlated with theoretical results. The accuracy of the infrared system was compared with existing systems.

Bronchial carcinoid tumors (BCT) are the most frequent primary pulmonary neoplasms of childhood. Seventeen of 208 patients diagnosed as having BCT at the Massachusetts General Hospital were between 10 and 21 years of age. We reviewed our records of the 17 patients and 8 other pediatric cases and compared their findings with those of seven large series of adults. Distribution was equal between the sexes. The average age at diagnosis was 17 years; 4 patients were < or = 15 years old. The duration of symptoms prior to diagnosis varied from 2 weeks to 2.6 years, with a median duration of 8.5 months. In contrast to adults, no child was asymptomatic. The majority of children presented with wheezing and atelectasis in addition to the characteristic adult triad of cough, hemoptysis, and pneumonitis. Five patients presented with weight loss and one patient presented with hoarseness. One of the 17 pediatric patients presented with Cushing's syndrome and a functional BCT. Twelve of 14 patients were disease free for 9 months to 34 years after surgical resection. We conclude that BCT should be suspected in children with pneumonitis resistant to therapy, atelectasis, wheezing, and hemoptysis. Surgical resection will result in symptom-free recovery in the majority of cases in spite of low-grade malignancy.