Clinical Pharmacokinetics and Population Pharmacokinetic Analysis of Voriconazole in Transplant Patients

Transplant patients at high risk of invasive mold infections receive voriconazole for prophylaxis. Large variability in voriconazole exposure with a fixed dosing regimen was observed. Low exposure of voriconazole predisposes patients for infection. High concentrations are associated with toxicity.The objectives are to characterize the pharmacokinetics of voriconazole in transplant patients, to identify factors associated with the variability in the pharmacokinetics, and to develop adequate dosing guidelines for transplant patients.Liver, lung and pediatric bone marrow transplant (BMT) patients were enrolled. Multiple blood samples were collected within one dosing interval (totally 75 full pharmacokinetic profiles). Voriconazole plasma concentrations were measured using HPLC. Non-compartmental analysis was performed using WinNonlin. Population pharmacokinetic models were developed using NONMEM. Covariate models were built using a forward addition and reverse removal approach. Precision of parameter estimation was evaluated by bootstrapping. Adequate dosing regimens were developed using Monte Carlo simulations.There was a good correlation between AUCo-∞ and trough voriconazole plasma concentrations. Bioavailability of voriconazole is substantially reduced in lung transplant and BMT patients during the early post-transplant period. Pharmacokinetics of voriconazole is significantly associated with postoperative time, liver function and CYP2C19 genotype in liver transplant patients. Pharmacokinetics of voriconazole is significantly associated with postoperative time and cystic fibrosis in lung transplant patients. Pharmacokinetics of voriconazole is significantly associated with liver function in BMT patients. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability than non-CF patients. Donor characteristics had no significant correlation with pharmacokinetics of voriconazole in liver transplant patients. Bioavailability of voriconazole is similar between lung transplant and BMT patients. Compared to liver and lung transplant patients, BMT patients had significantly higher clearance and significantly lower volume of distribution.In conclusion, weight-adjusted or fixed dosing regimens resulted in highly variable exposure of voriconazole in liver transplant, lung transplant and BMT patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), voriconazole dose can be individualized based on trough concentrations. Population analysis demonstrated inadequacy of oral administration of voriconazole and adequacy of intravenous administration during the first few post-operative days, followed by oral doses for optimal drug exposure

Extendable chord for improved helicopter rotor performance

Extendable blade sections are investigated as a method for reducing rotor power and improving helicopter performance. A validated helicopter power prediction method, based on an elastic beam model is utilized. The static extendable chord can deliver a rather small power reduction in hover, and significant power savings at high speed flight, however, the cruise power is increased. In hover, the active chord is best deployed in the middle part of the blade, and just inboard of the tip at high speed flight. The increase in chord length can lead to power savings at high speed flight but the benefits decrease in other speeds. The 1/rev dynamically extendable chord can lead to an overall power reduction over the speed range of a helicopter. The best deployment location is at the blade tip, which is different from the statically extendable chord. It is best extended out in the retreating side, and retracted back in the advancing. The power reduction by the 1/rev dynamically extendable chord increases with the increase in the length of the chord extension and take-off weight of the helicopter. Generally, a lower harmonic extendable chord can save more power than one actuated at higher harmonics. The dynamic chord can reduce more power than the corresponding static chord

Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials

Background: The aim of this study was to determine correlations between progression-free survival (PFS) and the objective response rate (ORR) with overall survival (OS) in glioblastoma and to evaluate their potential use as surrogates for OS. Method Published glioblastoma trials reporting OS and ORR and/or PFS with sufficient detail were included in correlative analyses using weighted linear regression. Results: Of 274 published unique glioblastoma trials, 91 were included. PFS and OS hazard ratios were strongly correlated; R2 = 0.92 (95% confidence interval [CI], 0.71–0.99). Linear regression determined that a 10% PFS risk reduction would yield an 8.1% ± 0.8% OS risk reduction. R2 between median PFS and median OS was 0.70 (95% CI, 0.59–0.79), with a higher value in trials using Response Assessment in Neuro-Oncology (RANO; R2 = 0.96, n = 8) versus Macdonald criteria (R2 = 0.70; n = 83). No significant differences were demonstrated between temozolomide- and bevacizumab-containing regimens (P = .10) or between trials using RANO and Macdonald criteria (P = .49). The regression line slope between median PFS and OS was significantly higher in newly diagnosed versus recurrent disease (0.58 vs 0.35, P = .04). R2 for 6-month PFS with 1-year OS and median OS were 0.60 (95% CI, 0.37–0.77) and 0.64 (95% CI, 0.42–0.77), respectively. Objective response rate and OS were poorly correlated (R2 = 0.22). Conclusion: In glioblastoma, PFS and OS are strongly correlated, indicating that PFS may be an appropriate surrogate for OS. Compared with OS, PFS offers earlier assessment and higher statistical power at the time of analysis

Rapamycin With Antiretroviral Therapy in AIDS-Associated Kaposi Sarcoma: An AIDS Malignancy Consortium Study

The mammalian target of rapamycin (mTOR) is activated in Kaposi sarcoma (KS) and its inhibitor, rapamycin, has induced KS regression in transplant-associated KS. This study aimed to evaluate rapamycin's safety and toxicity in HIV-infected individuals with KS receiving antiretroviral therapy (ART), investigate rapamycin interactions with both protease inhibitor (PI)-containing and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing ART regimens, and assess clinical and biological endpoints including KS response and mTOR-dependent signaling

Global Analysis of DNA Methylation by Methyl-Capture Sequencing Reveals Epigenetic Control of Cisplatin Resistance in Ovarian Cancer Cell

Cisplatin resistance is one of the major reasons leading to the high death rate of ovarian cancer. Methyl-Capture sequencing (MethylCap-seq), which combines precipitation of methylated DNA by recombinant methyl-CpG binding domain of MBD2 protein with NGS, global and unbiased analysis of global DNA methylation patterns. We applied MethylCap-seq to analyze genome-wide DNA methylation profile of cisplatin sensitive ovarian cancer cell line A2780 and its isogenic derivative resistant line A2780CP. We obtained 21,763,035 raw reads for the drug resistant cell line A2780CP and 18,821,061reads for the sensitive cell line A2780. We identified 1224 hyper-methylated and 1216 hypomethylated DMRs (differentially methylated region) in A2780CP compared to A2780. Our MethylCap-seq data on this ovarian cancer cisplatin resistant model provided a good resource for the research community. We also found that A2780CP, compared to A2780, has lower observed to expected methylated CpG ratios, suggesting a lower global CpG methylation in A2780CP cells. Methylation specific PCR and bisulfite sequencing confirmed hypermethylation of PTK6, PRKCE and BCL2L1 in A2780 compared with A2780CP. Furthermore, treatment with the demethylation reagent 5-aza-dC in A2780 cells demethylated the promoters and restored the expression of PTK6, PRKCE and BCL2L1

Dynamic Extendable Chord to Improve Helicopter Rotor Performance

Extendable blade sections are investigated as a method for reducing rotor power and improving helicopter performance. A validated helicopter power prediction method, based on an elastic beam model is utilized. The static extendable chord can deliver a rather small power reduction in hover, and significant power savings at high speed flight, however, the cruise power is increased. In hover, the active chord is best deployed in the middle part of the blade, and just inboard of the tip at high speed flight. The increase in chord length can leads to power savings at high speed flight but the benefits decrease in other speeds. The 1/rev dynamically extendable chord can lead to an overall power reduction over the speed range of a helicopter. The best deployment location is the blade tip, which is different from the statically extendable chord. It is best extended out in the retreating side and retract back in the advancing. The power reduction by the 1/rev dynamically extendable chord increases with the increase in the length of the chord extension and take-off weight of the helicopter. Generally, a lower harmonic extendable chord can save more power than one actuated at higher harmonics. The dynamic chord can reduce more power than the corresponding static chord

Pennaticoxita tauricornuta Jiao & Bu 2016, sp. nov.

<i>Pennaticoxita tauricornuta</i> Jiao & Bu, sp. nov. <p>Diagnosis. The species is different from other species of the tribe Brachineurini by the aedeagus dorsally with a pair of horn-shaped prominences on the sub-apex, and each prominence approximately as long as gonostylus.</p> <p> Description. Adult. Body colour yellow brown, length 1.00– 1.10 mm (<i>n</i> = 6). Wing length (measured from the base) 1.40–1.50 mm (<i>n</i> = 6), width 0.50–0.60 mm (<i>n</i> = 6).</p> <p>Head (Figs 1–2). Eye bridge 8 facets long in the middle of vertex. Palpus sparsely setose, with palpiger and 3 segments, last two segments longer than first one (Fig. 1). Antenna with 10 flagellomeres; pedicel subglobular, smaller than scape, both densely covered with setae ventrally; node of all flagellomeres subcylindrical, a little broadened subbasally, neck of all flagellomeres a little shorter; each node with 2 horizontal, appressed, band-shaped circumfila, subapically and subbasally respectively linked by two similar longitudinal circumfila, and 2 whorls of long, strong and irregular setae, one subbasal and one subapical; first and second flagellomeres fused; third male flagellomere (Fig. 2) with the node 1.30–1.40 times as long as wide and the neck 4.10–4.20 times as long as wide, 0.90–0.95 times length of node.</p> <p> Thorax (Figs 3–4). Wing (Fig. 3) hyaline, 2.45–2.50 times as long as wide. Vein Sc weak, C, R 1 and R 5 strong; vein R 1 joining vein C at basal 2/5, with one pore near the distal; vein R 5 bent a little backward, joining vein C at wing apex, with one pore at basal 1/3; vein Cu not forked and bent backward, vein CuP parallel with Cu. Legs densely covered with narrow scales and sparse setae. Tarsal claw (Fig. 4) toothed on all legs; empodium shorter than tarsal claw; pulvillus cylindrical.</p> <p>Abdomen. Each tergite and sternite densely covered uniformly with scales. First through sixth tergites developed and strip-shaped, with an irregular but mostly single, posterior row of setae, with several pairs of lateral setae, and with one anterior of trichoid sensilla; first tergite much shorter than second tergite; seventh and eighth tergites both reduced to one strongly sclerotized, latitudinal and linear band with several scattered setae; second through eighth sternites covered with many scattered lateral and central setae, with one anterior pair of closely set trichoid sensilla; second sternite divided latitudinally into two bands, respectively with one single, anterior row of setae and one single, posterior row of setae; third through seventh sternites sub-rectangular with an irregular but mostly single, posterior row of setae; seventh sternite shorter than sixth; eighth sternite crescent, much shorter and much narrower than seventh.</p> <p>Male genitalia (Figs 5–6). Gonocoxite much slender, having a wing-shaped dorsal lobe approximately as long as 3/4 length of gonocoxite, and having mediobasal lobes undeveloped, only with four closely set setae, all inserted in a sub-frustoconical prominence; gonostylus slender, gradually tapered from base to apex, approximately as long as 3/5 length of gonocoxite, covered with a few setae and dense microtrichiae, with a short setae located apically on the inner side, toothed apically; cerci separated deeply and widely with a U-shaped depression forming two broad, semicircular lobes with a few long lateral setae; hypoproct a little longer than cerci, emarginated widely with a U-shaped depression forming two digitiform lobes; aedeagus sub-conical, approximately half the length of gonocoxite, dorsally with a pair of horn-shaped prominences on the sub-apex, each prominence approximately as long as gonostylus and covered with long setae.</p> <p>Female genitalia. Unknown.</p> <p> Holotype ♂. China, Guangxi, Shangsi, Nanping, Milü (21.55°N, 107.43°E; elev. 770 m), 3–5.IV.2002, leg. Huaijun Xue, Malaise trap (NKUCecid. No. BCA001). Paratypes. 2♂, same data as holotype (NKUCecid. No. BCA002–003); 2♂, China, Yunnan, Jingdong, Wuliang Mountain, Manwan (24.4°N, 100.8°E; elev. 1150 m), 30–31. V.2001, leg. Jun Li, Malaise trap (NKUCecid. No. BCA004-005); 1♂, 28–29. V.2001, <i>ibid</i>., (elev. 1200 m; NKUCecid. No. BCA006). All type specimens are deposited in NKUM.</p> <p>Distribution. China (Guangxi, Yunnan)</p> <p> Etymology. The species name <i>tauricornuta</i> means the aedeagus dorsally with a pair of horn-shaped prominences on the sub-apex.</p>Published as part of <i>Jiao, Kelong, Han, Peijin, Wang, Yuanhong & Bu, Wenjun, 2016, General review of the tribe Brachineurini (Diptera: Cecidomyiidae) with description of Pennaticoxita tauricornuta gen. & sp. nov. from China, pp. 307-314 in Zoological Systematics 41 (3)</i> on pages 311-313, DOI: 10.11865/zs.201633, <a href="http://zenodo.org/record/5365140">http://zenodo.org/record/5365140</a&gt