Background and ObjectiveSeveral features favor paracetamol (acetaminophen) administration by the intravenous rather than the oral route in the postoperative setting. This study compared the pharmacokinetics and bioavailability of oral and intravenous paracetamol when given with or without an opioid, morphine.MethodsIn this randomized, single-blind, parallel, repeat-dose study in healthy adults, subjects received four repeat doses of oral or intravenous 1000 mg paracetamol at 6-h intervals, and morphine infusions (0.125 mg/kg) at the 2nd and 3rd intervals. Comparisons of plasma pharmacokinetic profiles were conducted before, during, and after opioid co-administrations.ResultsTwenty-two subjects were included in the pharmacokinetic analysis. Observed paracetamol peak concentration (C max) and area under the plasma concentration-time curve over the dosing interval (AUC0–6) were reduced when oral paracetamol was co-administered with morphine (reduced from 11.6 to 7.25 µg/mL and from 31.00 to 25.51 µg·h/mL, respectively), followed by an abruptly increased C max and AUC0–6 upon discontinuation of morphine (to 13.5 µg/mL and 52.38 µg·h/mL, respectively). There was also a significantly prolonged mean time to peak plasma concentration (T max) after the 4th dose of oral paracetamol (2.84 h) compared to the 1st dose (1.48 h). However, pharmacokinetic parameters of paracetamol were not impacted when intravenous paracetamol was co-administered with morphine.ConclusionsMorphine co-administration significantly impacted the pharmacokinetics of oral but not intravenous paracetamol. The abrupt release of accumulated paracetamol at the end of morphine-mediated gastrointestinal inhibition following oral but not intravenous administration of paracetamol suggests that intravenous paracetamol provides a better option for the management of postoperative pain.ClinicalTrials.gov IdentifierNCT02848729.

Next-generation sequencing (NGS)-based HIV drug resistance (HIVDR) assays outperform conventional Sanger sequencing in scalability, sensitivity, and quantitative detection of minority resistance variants. Thus far, HIVDR assays have been applied primarily in research but rarely in clinical settings. One main obstacle is the lack of standardized validation and performance evaluation systems that allow regulatory agencies to benchmark and accredit new assays for clinical use. By revisiting the existing principles for molecular assay validation, here we propose a new validation and performance evaluation system that helps to both qualitatively and quantitatively assess the performance of an NGS-based HIVDR assay. To accomplish this, we constructed a 70-specimen proficiency test panel that includes plasmid mixtures at known ratios, viral RNA from infectious clones, and anonymized clinical specimens. We developed assessment criteria and benchmarks for NGS-based HIVDR assays and used these to assess data from five separate MiSeq runs performed in two experienced HIVDR laboratories. This proposed platform may help to pave the way for the standardization of NGS HIVDR assay validation and performance evaluation strategies for accreditation and quality assurance purposes in both research and clinical settings.

Purpose: To analyse interfraction setup using two different image guidance modalities for prostate and head-and-neck (H&N) cancer treatment.Materials and methods: Seventy-two prostate and 60 H&N cancer patients, imaged with kilovoltage cone beam computed tomography (KVCBCT) or megavoltage fan beam computed tomography (MVFBCT), were studied retrospectively. The daily displacements in mediolateral (ML), craniocaudal (CC) and anteroposterior (AP) dimensions were investigated. The setup errors were calculated to determine the clinical target volume to planning target volume (CTV-to-PTV) margins.Results: Based on 1,606 KVCBCT and 2,054 MVFBCT scans, average interfraction shifts in ML, CC and AP direction for H&N cases were 0?5 ± 1?5, 20?3 ± 2?0, 0?3 ± 1?7 mm using KVCBCT, 0?2 ± 1?9, 20?2 ± 2?4 and 0?0 ± 1?7 mm using MVFBCT. For prostate cases, average interfraction displacements were 20?3 ± 3?9, 0?2 ± 2?4, 0?4 ± 3?8 mm for MVFBCT and 20?2 ± 2?7, 20?6 ± 2?9, 20?5 ± 3?4 mm for KVCBCT. The calculated CTV-to-PTV margins, if determined by image-guided radiotherapy (IGRT) data, were 5?6 mm (H&N) and 7?8 mm (prostate) for MVFBCT, compared with 4?8 mm and 7?2 mm for KVCBCT. We observed no statistically significant difference in daily repositioning using KVCBCT and MVFBCT in early, middle and late stages of the treatment course. Conclusion:In the absence of IGRT, the CTV-to-PTV margin determined using IGRT data, may be varied for different imaging modalities for prostate and H&N irradiation.

Tablet hardness, a measure of the breaking force of a tablet, is based on numerous factors. These include the shape of the tablet and the mode of the application of force. For instance, when a pentagonal-shaped tablet was tested with a traditional hardness tester with flat platens, there was a large variation in hardness measurements. This was due to the propensity of vertices of the tablet to crush, referred to as an "improper break". This article describes a novel approach to measure the hardness of pentagonal-shaped tablets using modified platens. The modified platens have more uniform loading than flat platens. This is because they reduce loading on the vertex of the pentagon and apply forces on tablet edges to generate reproducible tablet fracture. The robustness of modified platens was assessed using a series of studies, which included feasibility and Gauge Repeatability & Reproducibility (R&R) studies. A key finding was that improper breaks, generated frequently with a traditional hardness tester using flat platens, were eliminated. The Gauge R&R study revealed that the tablets tested with novel platens generated consistent values in hardness measurements, independent of batch, hardness level, and day of testing, operator and tablet dosage strength.