An open-label, randomized, single intravenous dosing study to investigate the effect of fixed-dose combinations of tenofovir/lamivudine or atazanavir/ritonavir on the pharmacokinetics of remdesivir in Ugandan healthy volunteers (RemTLAR)

Background Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. Methods This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. Discussion This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. Trial registration ClinicalTrials.gov NCT04385719. Registered 13 May 2020.

Variations in breast cancer detection rates during mammogram-reading sessions: does experience have an impact?

Objectives: To examine whether radiologists’ performances are consistent throughout a reading session and whether any changes in performance over the reading task differ depending on experience of the reader. Methods: The performance of ten radiologists reading a test set of 60 mammographic cases without breaks was assessed using an ANOVA, 2 × 3 factorial design. Participants were categorized as more (≥2,000 mammogram readings per year) or less (<2,000 readings per year) experienced. Three series of 20 cases were chosen to ensure comparable difficulty and presented in the same sequence to all readers. It usually takes around 30 min for a radiologist to complete each of the 20-case series, resulting in a total of 90 min for the 60 mammographic cases. The sensitivity, specificity, lesion sensitivity, and area under the ROC curve were calculated for each series. We hypothesized that the order in which a series was read (i.e. fixed-series sequence) would have a significant main effect on the participants’ performance. We also determined if significant interactions exist between the fixed-series sequence and radiologist experience. Results: Significant linear interactions were found between experience and the fixed sequence of the series for sensitivity (F[1] =5.762, p = .04, partial η2 = .41) and lesion sensitivity. (F[1] =6.993, p = .03, partial η2 = .46). The two groups’ mean scores were similar for the first series but progressively diverged. By the end of the third series, significant differences in sensitivity and lesion sensitivity were evident, with the more experienced individuals demonstrating improving and the less experienced declining performance. Neither experience nor series sequence significantly affected the specificity or the area under the ROC curve. Conclusions: Radiologists’ performance may change considerably during a reading session, apparently as a function of experience, with less experienced radiologists declining in sensitivity and lesion sensitivity while more experienced radiologists actually improve. With the increasing demands on radiologists to undertake high-volume reporting, we suggest that junior radiologists be made aware of possible sensitivity and lesion sensitivity deterioration over time so they can schedule breaks during continuous reading sessions that are appropriate to them, rather than try to emulate their more experienced colleagues. Advances in knowledge: Less-experienced radiologists demonstrated a reduction in mammographic diagnostic accuracy in later stages of the reporting sessions. This may suggest that extending the duration of reporting sessions to compensate for increasing workloads may not represent the optimal solution for less-experienced radiologists.

A Feature-Independent Hyper-Heuristic Approach for Solving the Knapsack Problem

Recent years have witnessed a growing interest in automatic learning mechanisms and applications. The concept of hyper-heuristics, algorithms that either select among existing algorithms or generate new ones, holds high relevance in this matter. Current research suggests that, under certain circumstances, hyper-heuristics outperform single heuristics when evaluated in isolation. When hyper-heuristics are selected among existing algorithms, they map problem states into suitable solvers. Unfortunately, identifying the features that accurately describe the problem state—and thus allow for a proper mapping—requires plenty of domain-specific knowledge, which is not always available. This work proposes a simple yet effective hyper-heuristic model that does not rely on problem features to produce such a mapping. The model defines a fixed sequence of heuristics that improves the solving process of knapsack problems. This research comprises an analysis of feature-independent hyper-heuristic performance under different learning conditions and different problem sets.

Theta-phase dependent neuronal coding during sequence learning in human single neurons

The ability to maintain a sequence of items in memory is a fundamental cognitive function. In the rodent hippocampus, the representation of sequentially organized spatial locations is reflected by the phase of action potentials relative to the theta oscillation (phase precession). We investigated whether the timing of neuronal activity relative to the theta brain oscillation also reflects sequence order in the medial temporal lobe of humans. We used a task in which human participants learned a fixed sequence of pictures and recorded single neuron and local field potential activity with implanted electrodes. We report that spikes for three consecutive items in the sequence (the preferred stimulus for each cell, as well as the stimuli immediately preceding and following it) were phase-locked at distinct phases of the theta oscillation. Consistent with phase precession, spikes were fired at progressively earlier phases as the sequence advanced. These findings generalize previous findings in the rodent hippocampus to the human temporal lobe and suggest that encoding stimulus information at distinct oscillatory phases may play a role in maintaining sequential order in memory.

Integrating Production Planning with Truck-Dispatching Decisions through Reinforcement Learning While Managing Uncertainty

This paper presents a new truck dispatching policy approach that is adaptive given different mining complex configurations in order to deliver supply material extracted by the shovels to the processors. The method aims to improve adherence to the operational plan and fleet utilization in a mining complex context. Several sources of operational uncertainty arising from the loading, hauling and dumping activities can influence the dispatching strategy. Given a fixed sequence of extraction of the mining blocks provided by the short-term plan, a discrete event simulator model emulates the interaction arising from these mining operations. The continuous repetition of this simulator and a reward function, associating a score value to each dispatching decision, generate sample experiences to train a deep Q-learning reinforcement learning model. The model learns from past dispatching experience, such that when a new task is required, a well-informed decision can be quickly taken. The approach is tested at a copper–gold mining complex, characterized by uncertainties in equipment performance and geological attributes, and the results show improvements in terms of production targets, metal production, and fleet management.

An open-label, randomized, single intravenous dosing study to investigate the effect of fixed dose combinations of tenofovir/lamivudine or atazanavir/ritonavir on the pharmacokinetics of remdesivir in Ugandan healthy volunteers (RemTLAR)

Background: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate /lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. Methods: This is an open label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, Crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for seven days and a single 200mg remdesivir infusion administered over 60 minutes. Pharmacokinetic blood sampling will be performed relative to start of remdesivir infusion; predose (before start of remdesivir infusion) and 30 minutes after start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12 and 24 hours after end of remdesivir infusion. Discussion: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. Trial registration: ClinicalTrials.gov, ID:NCT04385719

An open-label, fixed-sequence study to evaluate the effect of encequidar (HM30181) an oral P-gp inhibitor, on the pharmacokinetics of dabigatran etexilate (a P-gp substrate) in healthy male volunteers.

e15060 Background: Oral co-administration of encequidar (a selective, minimally absorbed oral P-gp inhibitor) 12.9 mg with paclitaxel (a P-gp substrate) 205 mg/m2 for 3 consecutive days per week can achieve comparable AUC exposure to that of IV paclitaxel 80mg/m2 with a significantly lowered Cmax and has been demonstrated its improved tumor response with reduced neuropathy compared to IV paclitaxel 175 mg/m2 Q3W for the treatment of patients with metastatic breast cancer. Because of its pharmacology as an inhibitor of P-gp, encequidar may increase the bioavailability of orally administered drugs that are substrates of P-gp, such as dabigatran etexilate. Methods: To determine the effect of a therapeutic dose and regimen (3 once-daily 12.9 mg doses) of encequidar on the single dose PK of dabigatran etexilate, an open-label, fixed-sequence study was performed in 20 healthy male subjects. Participants received a single oral dose of dabigatran etexilate 75 mg on Day 1 of Treatment Period 1 (reference) and, after a washout period of at least 7 days, on Days 3, 17 and 31 of Treatment Period 2, after receiving once-daily oral doses 12.9 mg encequidar on Days 1 to 3 of Period 2. The PK sampling for determination of plasma concentrations of total and unconjugated dabigatran lasted up to 48 hours postdose of each dabigatran etexilate dosr. Results: Mean AUC and Cmax values for dabigatran were both increased ̃ 95% without changing t½ when dabigatran etexilate was administered 1 hour post the 3rd dose of 12.9 mg encequidar compared to when dabigatran etexilate was administered alone. When dabigatran etexilate was administered 2 weeks after encequidar administration, no apparent differences in dabigatran AUC or Cmax were detected compared to those of dabigatran etexilate alone. When administered 4 weeks after discontinuation of encequidar, dabigatran AUC and Cmax were both slightly lower than Reference dabigatran etexilate (̃ 25% lower for AUC and 34% lower for Cmax). Both unconjugated and total dabigatran PK data were analyzed and shown to be similar. Encequidar and dabigatran etexilate were well tolerated and had acceptable safety findings in this healthy subject population. Conclusions: Concomitant dosing of encequidar with dabigatran etexilate resulted in < 2-fold increase in exposure to dabigatran, which had abated by the time of the first re-test, 14 days after the last dose of encequidar. The observed changes do not warrant dose adjustment of dabigatran etexilate when administered with encequidar. Clinical trial information: ACTRN12618000791235.

Relative bioavailability of H3B-6545 tablets versus capsules and drug-drug interaction between H3B-6545 and pantoprazole.

e13022 Background: H3B-6545 is a selective, orally available, small molecule antagonist of the estrogen receptor (ER), covalently binding to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins. H3B-6545 demonstrated preliminary clinical antitumor activity in breasts cancer patients in phase 1b/2. Methods: This was an open-label phase 1 study to evaluate the relative bioavailability of H3B-6545 from a tablet formulation compared to capsules, and the effect of pantoprazole on the pharmacokinetics of H3B-6545, in healthy post-menopausal women. Subjects were randomized (1:1 ratio) to a combined crossover and fixed sequence 3 periods treatment: A single oral dose (SOD) of 450 mg H3B-6545 fasted on day 1 (capsules or tablets), followed by a 4-day washout; A SOD of 450 mg H3B-6545 fasted on day 5 (crossover formulation from the first period), followed by a 4-day washout; daily oral doses of 40 mg pantoprazole on days 9 to 15 with coadministration of a SOD of 450 mg H3B-6545 (tablets) on day 15. Results: A total of 16 subjects were enrolled and received at least one dose of H3B-6545 and 15 subjects completed all 3 periods. One subject assigned to the tablet/capsule treatment sequence withdrew from the study due to subject decision on day 13 (Period 3), following completion of Period 1 (H3B-6545 tablet) and Period 2 (H3B-6545 capsule). Following a SOD of H3B-6545 capsules alone, tablets alone, or tablets at steady-state QD of pantoprazole, H3B-6545 geometric mean Cmax was about 1070, 1120 and 1330 ng/mL, respectively, AUC was about 16600, 17500 and 18300 ng.h/mL, respectively, half-life was about 11.0, 11.0 and 10.2 hours, respectively, and the median Tmax was about 3.0, 4.0, and 2.0 hours post dose, respectively. The ratio (capsule/tablet) of Cmax and AUC was both about 0.95; steady-state pantoprazole QD increased H3B-6545 Cmax by 20% with no change in AUC. Nine subjects (56.3%) reported at least 1 TEAE during the study with constipation being the most common (43.8%); all TEAEs were mild in severity. There were no SAEs reported. Conclusions: Plasma PK of H3B-6545 is similar between tablets and capsules, and in the absence or presence of pantoprazole. Concurrent use of gastric acid reducers had a minimal effect on H3B-6545 exposure and was not considered clinically meaningful.

Signal Representations Via SIP p-frames and SIP Bessel Multipliers in Separable Banach Spaces

Digital signals are often modeled as functions in Banach spaces, such as the ubiquitous [Formula: see text] spaces. The frame theory in Banach spaces induces flexible representations of signals due to the robustness and redundancy of frames. Nevertheless, the lack of inner product in general Banach spaces limits the direct representations of signals in Banach spaces under a given basis or frame. In this paper, we introduce the concept of semi-inner product (SIP) [Formula: see text]-Bessel multipliers to extend the flexibility of signal representations in separable Banach spaces, where [Formula: see text]. These multipliers are defined as composition of analysis operator of an SIP-I Bessel sequence, a multiplication with a fixed sequence and synthesis operator of an SIP-II Bessel sequence. The basic properties of the SIP [Formula: see text]-Bessel multipliers are investigated. Moreover, as special cases, characterizations of [Formula: see text]-Riesz bases related to signal representations are given, and the multipliers for [Formula: see text]-Riesz bases are discussed. We show that SIP [Formula: see text]-Bessel multipliers for [Formula: see text]-Riesz bases are invertible. Finally, the continuity of SIP [Formula: see text]-Bessel multipliers with respect to their parameters is investigated. The results theoretically show that the SIP [Formula: see text]-Bessel multipliers offer a larger range of freedom than frames on signal representations in Banach spaces.