Pre-specified Time Research Articles

Bioequivalence Study of Bedaquiline Fumarate Tablets in Healthy Chinese Subjects.

Bedaquiline fumarate tablets are a novel oral antimycobacterial drug. This study assessed the bioequivalence of a generic bedaquiline fumarate tablet compared to a reference tablet under fasting (n=44) and fed (n=24) conditions. Conducted as a single-center, randomized, open-label, 2-sequence, crossover trial, 68 participants were randomly assigned to receive a 100-mg dose of either the test or reference tablet, with a 42-day washout period between doses. Blood samples were collected at prespecified time points from 0 hour (before administration) to 984 hours after administration. Plasma concentrations of bedaquiline were measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry method. Safety was monitored throughout the study. Key pharmacokinetic parameters included maximum plasma concentration, area under the plasma concentration-time curve (AUC) from 0 to 72 hours, AUC from time 0 to the last measurable concentration, AUC from 0 to 336 hours, and AUC from time 0 to infinity. The 90% confidence intervals for the geometric mean ratios of the test/reference formulations for maximum plasma concentration, AUC from 0 to 72 hours, AUC from 0 to 336 hours, AUC from time 0 to the last measurable concentration, and AUC from time 0 to infinity fell within the bioequivalence acceptance range of 80%-125%. confirming bioequivalence between the 2 formulations in healthy Chinese volunteers. Moreover, a high-fat diet can significantly elevate the exposure of bedaquiline. No serious adverse events occurred, and both formulations were well tolerated across all participants.

Acute dose-dependent effects and self-guided titration of continuous N,N-dimethyltryptamine infusions in a double-blind placebo-controlled study in healthy participants.

N,N-dimethyltryptamine (DMT) is a serotonergic psychedelic that is known for its short-lasting effects when administered intravenously. Several studies have investigated the administration of intravenous boluses or combinations of a bolus and a subsequent continuous infusion. However, data on dose-dependent acute effects and pharmacokinetics of continuous DMT infusions are lacking. We used a double-blind, randomized, placebo-controlled, crossover design in 22 healthy participants (11 women, 11 men) who received placebo and DMT (0.6, 1.2, 1.8, and 2.4 mg/min) over an infusion duration of 120 min. We also tested a self-guided titration scheme that allowed participants to adjust the DMT dose rate at prespecified time points to achieve their desired level of subjective effects. Outcome measures included subjective effects, autonomic effects, adverse effects, plasma hormone concentrations, and pharmacokinetics up to 3 h after starting the infusion. DMT infusions exhibited dose-proportional pharmacokinetics and rapidly induced dose-dependent subjective effects that reached a plateau after 30 min. A ceiling effect was observed for "good drug effect" at 1.8 mg/min. The 2.4 mg/min dose of DMT induced greater anxious ego dissolution than the 1.8 mg/min dose and induced significant anxiety compared with placebo. We observed moderate acute tolerance to acute effects of DMT. In the self-guided titration session, the participants opted for moderate to strong psychedelic effects, comparable in intensity to the 1.8 mg/min DMT dose rate in the randomized dosing sessions. These results may assist with dose finding for future DMT research and demonstrate that acute subjective effects of DMT can be rapidly adjusted through dose titration.

Adaptive practical prescribed-time control for uncertain nonlinear systems with time-varying parameters

In this paper, adaptive practical prescribed-time (PPT) control is proposed for a class of uncertain nonlinear systems with time-varying parameters and unmodeled dynamics. By constructing a novel time-varying scaling function and utilizing nonlinear mapping, the PPT control is successfully resolved. The dynamical uncertainties resulting from unmodeled dynamics are estimated by employing an auxiliary available signal, and the unknown continuous terms are handled by the aid of radial basis function neural networks (RBFNNs). A novel adaptive control method is developed by introducing the compensating signals and dynamic surface control as well as practical prescribed-time control. All the signals involved are proved to be semi-globally uniformly ultimately bounded, and the tracking error could enter the pre-specified convergence region within a pre-specified time. The robotic manipulator system is used to demonstrate the effectiveness of the proposed control approach.

Allowing ad libitum sleep during overnight polysomnography affects Multiple Sleep Latency Test results in patients being assessed for hypersomnolence.

The Multiple Sleep Latency Test (MSLT) is a key diagnostic component in the diagnosis of central disorders of hypersomnolence. Due to time constraints, it is common practice to wake patients at a standard time from overnight polysomnography (PSG) prior to the MSLT. This has the potential to influence MSLT results due to sleep deprivation. We describe the impact of allowing ad libitum sleep on the night prior to the MSLT in patients being assessed for hypersomnolence. A total of 580 consecutive patients undergoing PSG/MSLT for assessment of hypersomnolence were analyzed: 290 either side of a change in laboratory protocol that allowed patients ad libitum sleep during the PSG, rather than being woken at a prespecified time. Baseline characteristics, PSG and MSLT results were compared between the groups. Groups were similar at baseline, other than there being more females in the ad libitum group. After adjusting for confounding variables, patients allowed ad libitum sleep had later sleep offset time (+58.7 minutes; P < .001), longer PSG total sleep time (+47.8 minutes; P < .001), longer MSLT mean sleep latency (+1.3 minutes; P = .002), and 23% fewer MSLT with mean sleep latency less than 8 minutes (P = .004) when compared with patients who were woken at a standard time. The common practice of waking patients from their PSG at a standard time has the potential to curtail sleep and affect MSLT results by reducing mean sleep latency. Patients being assessed for hypersomnolence should be allowed ad libitum sleep during the PSG on the night prior to their MSLT. Frenkel S, Amaranayake A, Molesworth C, Orellana L, Southcott AM. Allowing ad libitum sleep during overnight polysomnography affects Multiple Sleep Latency Test results in patients being assessed for hypersomnolence. J Clin Sleep Med. 2024;20(12):1937-1943.

Intraoperative Frontal EEG Alpha Power is Associated with Post-Operative Mortality and Other Adverse Outcomes.

With estimated global post-operative mortality rates at 1-4% leading to approximately 3-12 million deaths per year, an urgent need exists for reliable measures of perioperative risk. Existing approaches suffer from poor performance, place a high burden on clinicians to gather data, or do not incorporate intraoperative data. Prior work demonstrated that intraoperative anesthetics induce prefrontal EEG oscillations in the alpha band (8-12Hz) that correlate with post-operative cognitive outcomes. We analyzed a retrospective cohort of 1,081 patients undergoing surgery with general anesthesia at Massachusetts General Hospital with intraoperative EEG recordings. The association between EEG alpha power and adverse outcomes were characterized using statistical models that were fitted on propensity weighted data. Our primary outcome was post-operative mortality, measured from date of surgery to date of death or last follow-up. Secondary outcomes included mortality within pre-specified time windows (30-days, 90-days, 180-days, and 1-year), hospital and PACU lengths of stay, discharge to long-term care, and 30-day hospital readmission. Alpha power was associated with mortality risk (HR = 0.92, 95% CI:[ 0.85, 0.99], p=0.039). Within specified time windows, alpha power was associated with 30-day mortality (OR = 0.81, 95% CI: [0.66, 0.95], p=0.010), 90-day mortality (OR = 0.68, 95% CI: [0.55, 0.79], p<0.001), 180-day mortality (OR = 0.75, 95% CI: [0.66, 0.83], p<0.001), and 1-year mortality (OR = 0.85, 95% CI: [0.79, 0.91], p<0.001). Additionally, alpha power was associated with discharge to long-term care (OR = 0.91, 95% CI: [0.86, 0.96], p<0.001). We did not find significant associations among alpha power and 30-day readmission and hospital or PACU lengths of stay. Intraoperative EEG alpha power is independently associated with post-operative mortality and adverse outcomes, suggesting it could represent a broad measure of post-operative physical resilience and provide clinicians with a low-burden, personalized measure of post-operative risk.

Oxygen Delivery and Consumption in Patients Who Are Comatose After Out-of-Hospital Cardiac Arrest Are Affected by Blood Pressure Target.

In the management of patients resuscitated from out-of-hospital cardiac arrest, a primary goal is to restore sufficient oxygen delivery (DO2) to meet demands in oxygen consumption (VO2). This post hoc analysis of the BOX (Blood Pressure and Oxygen Targets) study included adult patients who were comatose and experienced out-of-hospital cardiac arrest from a presumed cardiac cause, who were randomized to a mean arterial blood pressure (MAP) target of 63 mm Hg (MAP63) or 77 mm Hg (MAP77) and a Restrictive PaO2 target of 9 to 10 kPa versus a Liberal target of 13 to 14 kPa in a 2×2 factorial design. A pulmonary artery catheter was inserted following randomization. DO2 and VO2 were calculated as: DO2=cardiac output × arterial oxygen content, and VO2= cardiac output × arteriovenous oxygen difference. Of 789 patients, 730 (92.5%) were included in this substudy. A total of 362 patients were randomized to MAP77, and 368 to MAP63, 368 to a liberal Pao2 target, and 362 to a restrictive target. At all prespecified time points, DO2 in MAP77 was higher compared with MAP63, with a cumulative treatment effect of 203 L (95% CI, 132-274) O2 after 36 hours. VO2 was higher in MAP77 after 36 hours, with a cumulative treatment effect of 21.9 L (95% CI, 5.8-38) O2, compared with the MAP63 group. Targeting a MAP of 77 mm Hg resulted in an overall increase in DO2 and a smaller increase in VO2 compared with a MAP target of 63 mm Hg. A higher Pao2 target did not result in any difference in DO2 or VO2.

Assessment of pharmacokinetic and pharmacodynamic interactions between zavegepant and sumatriptan: A phase 1, randomized, placebo-controlled study in healthy adults.

To evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) interactions between zavegepant and sumatriptan in healthy adults. Zavegepant is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist administered as a nasal spray approved in the United States for the acute treatment of migraine. Triptans, including sumatriptan, are a different class of drugs for acute migraine treatment and are associated with a risk of increased blood pressure (BP). Hence, it is important to study the drug-drug interactions between zavegepant and sumatriptan due to potential coadministration in clinical settings. This was a Phase 1, single-center, partially blind, randomized, placebo-controlled, single-arm study. Eligible participants were males aged ≥ 18 and ≤ 40 years or females aged ≥ 18 and ≤ 50 years. On Day 1, participants received sumatriptan 2 × 6 mg subcutaneous injections (1 h apart) and were then randomized (6:1 ratio) to receive zavegepant 2 × 10 mg nasal spray (1 in each nostril) or placebo on Days 2 and 3. On Day 4, zavegepant or placebo was coadministered with sumatriptan after the second sumatriptan injection. BP, PK, and safety were evaluated at pre-specified time points. Forty-two participants enrolled in the study received at least one dose of any treatment and were included in the safety analyses. Forty-one participants who completed the study were included in the BP and PK analyses. The mean (standard deviation) time-weighted average (TWA) of mean arterial pressure (MAP [sumatriptan+ zavegepant 87.2 (6.8) vs. sumatriptan 86.9 (6.0)]), diastolic BP (DBP [sumatriptan + zavegepant 72.3 (6.8) vs. sumatriptan 72.1 (6.2)]), and systolic BP (SBP [sumatriptan + zavegepant 116.8 (10.2) vs. sumatriptan 116.2 (8.6)]) did not change following zavegepant and sumatriptan coadministration on Day 4 compared to sumatriptan alone on Day 1. Statistical comparisons of the TWA of MAP, DBP, and SBP between sumatriptan and zavegepant coadministration and sumatriptan alone were similar; the differences observed were 0.04 mmHg for MAP (90% confidence interval [CI]: -0.69, 0.77 mmHg), 0.00 mmHg for DBP (90% CI: -0.76, 0.76 mmHg), and 0.33 mmHg for SBP (90% CI: -0.97, 1.63 mmHg). Sumatriptan PK after sumatriptan and zavegepant coadministration versus sumatriptan alone was similar; the comparison ratios were 102.5% (90% CI: 100.7%, 104.2%) for AUC0-inf and 104.1% (90% CI: 98.0%, 110.6%) for Cmax. A small difference in zavegepant PK exposure after sumatriptan and zavegepant coadministration versus zavegepant alone was not considered clinically relevant: the comparison ratios were 112.4% (90% CI: 103.4%, 122.3%) for AUC0-24 and 96.7% (90% CI: 88.9%, 105.2%) for Cmax. Overall, 90% (38/42) of participants experienced ≥ 1 treatment-emergent adverse event that was mild or moderate in severity. All treatments were generally safe and well tolerated. Coadministration of zavegepant with sumatriptan was safe and without PD or PK interactions in healthy adults.

Semi-parametric sensitivity analysis for trials with irregular and informative assessment times.

Many trials are designed to collect outcomes at or around pre-specified times after randomization. If there is variability in the times when participants are actually assessed, this can pose a challenge to learning the effect of treatment, since not all participants have outcome assessments at the times of interest. Furthermore, observed outcome values may not be representative of all participants' outcomes at a given time. Methods have been developed that account for some types of such irregular and informative assessment times; however, since these methods rely on untestable assumptions, sensitivity analyses are needed. We develop a sensitivity analysis methodology that is benchmarked at the explainable assessment (EA) assumption, under which assessment and outcomes at each time are related only through data collected prior to that time. Our method uses an exponential tilting assumption, governed by a sensitivity analysis parameter, that posits deviations from the EA assumption. Our inferential strategy is based on a new influence function-based, augmented inverse intensity-weighted estimator. Our approach allows for flexible semiparametric modeling of the observed data, which is separated from specification of the sensitivity parameter. We apply our method to a randomized trial of low-income individuals with uncontrolled asthma, and we illustrate implementation of our estimation procedure in detail.

Protocol for a clinically annotated biorepository of samples from Australian immune-compromised patients to investigate the host–microbiome interaction

IntroductionThe human gut microbiota has the potential to modulate the outcomes of several human diseases. This effect is likely to be mediated through interaction with the host immune system. This...

Gamma Lindley distribution in acceptance sampling plans in terms of truncated life tests with an application to industrial data

Acceptance sampling plans (ASP) are needed in areas where 100% inspection is impractical or expensive. They help ensure product quality meets requirements, reduce inspection costs, and prevent nonconforming goods from reaching customers. The ASP that are well-planned offer an efficient and dependable way to maintain quality control in manufacturing procedures and supply chains. The Gamma Lindley distribution (GaLD) is used to design acceptance sampling plans in this study when the life test is truncated at a pre-specified (pre-determined) time. The mean is used as the quality parameter. The smallest sample size is required to guarantee that the desired life mean is reached at the risk of the particular consumer. In addition to the producer's risk, the operating characteristic values of the sample plans are presented. In order to evaluate the suggested sampling plans, a real data from the first failure of 20 electric carts utilized for internal transportation and delivery in a big manufacturing facility is provided.

Distributed Output-Feedback Asymptotic Consensus Tracking for High-Order Multiagent Systems With Quantized Input.

This article is devoted to distributed adaptive asymptotic consensus tracking control based on output feedback for the uncertain high-order multiagent systems with input quantization. Compared with the output-feedback canonical form, the system takes unmeasured states-dependent nonlinearities into account and also includes unknown parameters and quantized input. The improved K -filters with one dynamic gain are constructed to dispose the unmeasured states-dependent nonlinearities and estimate the unknown states. Then, the novel recursive control strategy with the aid of new first-order dynamic parameter filters is proposed, which is able to effectively counteract the filter errors and steer the consensus tracking errors to zero asymptotically with low design complexity. Moreover, the new funnel variable combined with prespecified time performance function is first introduced, which can predefine practical transition time and maximum overshoot of consensus error. Finally, simulation results are presented to illustrate the validity and superiority of the proposed scheme.

Rail journey cost calculator for Great Britain

Accessibility of different places, such as hospitals or areas with jobs, is important in understanding transportation systems, urban environments, and potential inequalities in what services and opportunities different people can reach. Often, research in this area is framed around the question of whether people living in an area are able to reach certain destinations within a prespecified time frame. However, the cost of such journeys, and whether they are affordable, is often omitted or not considered to the same level. Here, we present a Python package and an associated data set which allows to analyse the cost of train journeys in Great Britain. We present the original data set we used to construct this, the Python package we developed to analyse it, and the output data set which we generated. We envisage our work to allow researchers, policy makers, and other stakeholders, to investigate questions around the cost of train journeys, any geographical or social inequalities arising from this, and how the transport system could be improved.

Bioequivalence and Safety of Generic Glecaprevir/Pibrentasvir Compared to a Branded Product: A Randomized, Crossover Study in Healthy Volunteers.

This was an open-label, randomized, single-dose, 2-period, crossover clinical trial with an adaptive design to evaluate the bioequivalence and comparative pharmacokinetics of generic glecaprevir/pibrentasvir versus the brand name product in healthy White male and female volunteers under fed conditions. Safety profiles were also assessed. A total of 56 healthy adult volunteers were enrolled and randomly assigned in a 1:1 ratio to receive a single dose of either the generic or reference formulation. After a 7-day washout period, subjects received the alternate product. Blood samples were collected at pre-specified time points up to 48hours post-dosing. Plasma concentrations of glecaprevir and pibrentasvir were determined using a validated high-performance liquid chromatography-tandem mass spectrometry method. The geometric mean ratios of the test to the reference formulation for maximum plasma concentration (Cmax) and area under the concentration-time curve from drug administration to the last measurable concentration (AUC0-t) fell within the predefined bioequivalence range of 80%-125%. Both formulations demonstrated comparable pharmacokinetic profiles for glecaprevir and pibrentasvir, and can be considered bioequivalent. No adverse events were reported, and both formulations were well tolerated by all participants.

EXPRESS: Wait for Free: A Consumption-Decelerating Promotion for Serialized Digital Media

Promotions for digital goods have typically focused on enticing users to hasten their consumption. Here, we investigate a novel deceleration-incentivizing promotional policy, “Wait For Free” (WFF), applied to serialized digital content – sequences of interconnected episodes – monetized via episode-level paywalls. Specifically, customers can sample early episodes of promoted series for free, and can continue to do so by waiting a pre-specified time; or for those unwilling to wait, by paying. WFF can draw users to start viewing a promoted series, and generate revenue through two sources: impatient users opting to pay to consume the next episode immediately; and additional users continuing through to paid-only episodes at the end. We analyze large-scale viewership data from a platform that enacted WFF for digital comics. A comic-level Difference-in-Differences (DiD) analysis provides robust evidence that WFF boosts paid viewership for the promoted series, and the degree of lift varies by user type and over time. A more granular episode-level analysis incorporating inter-comic spillovers and promotional lift heterogeneity suggests that WFF can boost net-of-cannibalization revenue at the platform level: specifically, the model-optimized set of promoted comics performs roughly 18% better than the firm-enacted one and 25% better than the no-promotion baseline; furthermore, WFF and paid-only episodes each receive nontrivial degrees of lift, 70% and 59% respectively.

Cardiac remodelling during pregnancy in women with congenital heart disease and systemic left ventricle.

Women with congenital heart disease (CHD) are at risk of pregnancy-related adverse outcomes (PRAO). The purpose of this study was to assess temporal changes in cardiac structure and function (cardiac remodelling) during pregnancy, and the association with PRAO in women with CHD. Retrospective study of pregnant women with CHD and serial echocardiograms (2003-2021). Cardiac structure and function were assessed at pre-specified time points: prepregnancy, early pregnancy, late pregnancy, and postnatal period. PRAO was defined as the composite of maternal cardiovascular, obstetric, and neonatal complications. The study comprised 81 women with CHD (age, 29 ± 5 years). Compared to the baseline echocardiogram, there was a relative increase in right ventricular systolic pressure (RVSP) (relative change 13 ± 5%, P < 0.001, in early pregnancy; and 18 ± 5%, P < 0.001, in late pregnancy). There was a relative decrease in right ventricle free wall strain (RVFWS) (relative change -11 ± 3%, P < 0.001, in late pregnancy; and -11 ± 4%, P = 0.003, in postnatal period), and a relative decrease in RVFWS/RVSP (relative change, -10 ± 5%, P = 0.02 in early pregnancy, -26 ± 7%, P < 0.001, in late pregnancy, and -14 ± 5%, P < 0.001, in postnatal period). Baseline right ventricular to pulmonary arterial (RV-PA) coupling, and temporal change in RV-PA coupling were associated with PRAO, after adjustment for maternal age and severity of cardiovascular disease. Women with CHD had a temporal decrease in RV systolic function and RV-PA coupling, and these changes were associated with PRAO. Further studies are required to delineate the aetiology of deterioration in RV-PA coupling during pregnancy, and the long-term implications of right heart dysfunction observed in the postnatal period.

Three-dimensional line-of-sight-angle-constrained leader-following cooperative interception guidance law with prespecified impact time

To address the problem of multi-missile cooperative interception against maneuvering targets at a prespecified impact time and desired Line-of-Sight (LOS) angles in Three-Dimensional (3D) space, this paper proposes a 3D leader-following cooperative interception guidance law. First, in the LOS direction of the leader, an impact time-controlled guidance law is derived based on the fixed-time stability theory, which enables the leader to complete the interception task at a prespecified impact time. Next, in the LOS direction of the followers, by introducing a time consensus tracking error function, a fixed-time consensus tracking guidance law is investigated to guarantee the consensus tracking convergence of the time-to-go. Then, in the direction normal to the LOS, by combining the designed global integral sliding mode surface and the second-order Sliding Mode Control (SMC) theory, an innovative 3D LOS-angle-constrained interception guidance law is developed, which eliminates the reaching phase in the traditional sliding mode guidance laws and effectively saves energy consumption. Moreover, it effectively suppresses the chattering phenomenon while avoiding the singularity issue, and compensates for unknown interference caused by target maneuvering online, making it convenient for practical engineering applications. Finally, theoretical proof analysis and multiple sets of numerical simulation results verify the effectiveness, superiority, and robustness of the investigated guidance law.

Reasons for non-feasibility of therapeutic drug monitoring of oral targeted therapies in oncology – an analysis of the closed cohorts of a multicentre prospective study

BackgroundTherapeutic drug monitoring (TDM) – performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets – could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible.MethodsWe evaluated drug cohorts from the Dutch Pharmacology Oncology Group – TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed.ResultsFor 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort.ConclusionsAlthough TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.

On Estimating the Feasible Solution Space of Multi-objective Testing Resource Allocation

The multi-objective testing resource allocation problem (MOTRAP) is concerned on how to reasonably plan the testing time of software testers to save the cost and improve the reliability as much as possible. The feasible solution space of a MOTRAP is determined by its variables (i.e., the time invested in each component) and constraints (e.g., the pre-specified reliability, cost, or time). Although a variety of state-of-the-art constrained multi-objective optimisers can be used to find individual solutions in this space, their search remains inefficient and expensive due to the fact that this space is very tiny compared to the large search space. The decision maker may often suffer a prolonged but unsuccessful search that fails to return a feasible solution. In this work, we first formulate a heavily constrained MOTRAP on the basis of an architecture-based model, in which reliability, cost, and time are optimised under the pre-specified multiple constraints on reliability, cost, and time. Then, to estimate the feasible solution space of this specific MOTRAP, we develop theoretical and algorithmic approaches to deduce new tighter lower and upper bounds on variables from constraints. Importantly, our approach can help the decision maker identify whether their constraint settings are practicable, and meanwhile, the derived bounds can just enclose the tiny feasible solution space and help off-the-shelf constrained multi-objective optimisers make the search within the feasible solution space as much as possible. Additionally, to further make good use of these bounds, we propose a generalised bound constraint handling method that can be readily employed by constrained multi-objective optimisers to pull infeasible solutions back into the estimated space with theoretical guarantee. Finally, we evaluate our approach on application and empirical cases. Experimental results reveal that our approach significantly enhances the efficiency, effectiveness, and robustness of off-the-shelf constrained multi-objective optimisers and state-of-the-art bound constraint handling methods at finding high-quality solutions for the decision maker. These improvements may help the decision maker take the stress out of setting constraints and selecting constrained multi-objective optimisers and facilitate the testing planning more efficiently and effectively.

Baseline Lung Allograft Dysfunction After Bilateral Lung Transplantation Is Associated With an Increased Risk of Death: Results From a Multicenter Cohort Study.

A prior single-center, retrospective cohort study identified baseline lung allograft dysfunction (BLAD) as a risk factor for death in bilateral lung transplant recipients. In this multicenter prospective cohort study, we test the association of BLAD with death in bilateral lung transplant recipients, identify clinical risk factors for BLAD, and assess its association with allograft injury on the molecular level. This multicenter, prospective cohort study included 173 bilateral lung transplant recipients that underwent serial pulmonary function testing and plasma collection for donor-derived cell-free DNA at prespecified time points. BLAD was defined as failure to achieve ≥80% predicted for both forced expiratory volume in 1 s and forced vital capacity after lung transplant, on 2 consecutive measurements at least 3 mo apart. BLAD was associated with increased risk of death (hazard ratio, 1.97; 95% confidence interval [CI], 1.05-3.69; P = 0.03) but not chronic lung allograft dysfunction alone (hazard ratio, 1.60; 95% CI, 0.87-2.95; P = 0.13). Recipient obesity (odds ratio, 1.69; 95% CI, 1.15-2.80; P = 0.04) and donor age (odds ratio, 1.03; 95% CI, 1.02-1.05; P = 0.004) increased the risk of developing BLAD. Patients with BLAD did not demonstrate higher log10(donor-derived cell-free DNA) levels compared with no BLAD (slope [SE]: -0.0095 [0.0007] versus -0.0109 [0.0007]; P = 0.15). BLAD is associated with an increased risk of death following lung transplantation, representing an important posttransplant outcome with valuable prognostic significance; however, early allograft specific injury on the molecular level does not increase the risk of BLAD, supporting further mechanistic insight into disease pathophysiology.

Neoadjuvant pembrolizumab plus chemotherapy/adjuvant pembrolizumab for early-stage triple-negative breast cancer: quality-of-life results from the randomized KEYNOTE-522 study.

In KEYNOTE-522 (NCT03036488), neoadjuvant pembrolizumab plus chemotherapy and then adjuvant pembrolizumab significantly improved pathological complete response and event-free survival vs neoadjuvant chemotherapy in early-stage triple-negative breast cancer (TNBC). We report patient-reported outcomes (PROs) from KEYNOTE-522. Patients were randomized 2:1 to neoadjuvant pembrolizumab 200 mg or placebo every 3 weeks, plus 4 cycles of paclitaxel plus carboplatin and then 4 cycles of doxorubicin (or epirubicin) plus cyclophosphamide. After surgery, patients received adjuvant pembrolizumab or placebo for up to 9 cycles. European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific Quality of Life Questionnaire (EORTC QLQ-BR23) were prespecified secondary objectives. Between-group differences in least squares (LS) mean change from baseline (day 1 of cycle 1 in both neoadjuvant and adjuvant phases) to the prespecified latest time point with at least 60% completion and at least 80% compliance were assessed using a longitudinal model (no alpha error assigned). Week 21 (neoadjuvant phase) and week 24 (adjuvant phase) were the latest time points at which completion/compliance rates were ≥60%/80%. In the neoadjuvant phase, between-group differences (pembrolizumab plus chemotherapy [n = 762] vs placebo plus chemotherapy [n = 383]) in LS mean change from baseline to week 21 in QLQ-C30 global health status/quality of life (GHS/QoL), emotional functioning, and physical functioning were -1.04 (95% confidence interval = -3.46 to 1.38), -0.69 (95% CI = -3.13 to 1.75), and -2.85 (95% CI = -5.11 to -0.60), respectively. In the adjuvant phase, between-group differences (pembrolizumab [n = 539] vs placebo [n = 308]) in LS mean change from baseline to week 24 were -0.41 (95% CI = -2.60 to 1.77), -0.60 (95% CI = -2.99 to 1.79), and -1.57 (95% CI = -3.36 to 0.21). No substantial differences in PRO assessments were observed between neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab vs neoadjuvant placebo plus chemotherapy in early-stage TNBC. ClinicalTrials.gov, NCT03036488.