Concurrent Control Research Articles

Increasing Utilization of Extended Criteria Donor Hearts for Transplantation: The OCS Heart EXPAND Trial

BackgroundExtended criteria donor (ECD) hearts available with donation after brain death (DBD) are underutilized for transplantation due to limitations of cold storage. ObjectivesThis study evaluated use of an extracorporeal perfusion system on donor heart utilization and post-transplant outcomes in ECD DBD hearts. MethodsIn this prospective, single-arm, multicenter study, adult heart transplant recipients received ECD hearts using an extracorporeal perfusion system if hearts met study criteria. The primary outcome was a composite of 30-day survival and absence of severe primary graft dysfunction (PGD). Secondary outcomes were donor heart utilization rate, 30-day survival, and incidence of severe PGD. The safety outcome was the mean number of heart graft–related serious adverse events within 30 days. Additional outcomes included survival through 2 years benchmarked to concurrent nonrandomized control subjects. ResultsA total of 173 ECD DBD hearts were perfused; 150 (87%) were successfully transplanted; 23 (13%) did not meet study transplantation criteria. At 30 days, 92% of patients had survived and had no severe PGD. The 30-day survival was 97%, and the incidence of severe PGD was 6.7%. The mean number of heart graft–related serious adverse events within 30 days was 0.17 (95% CI: 0.11-0.23). Patient survival was 93%, 89%, and 86% at 6, 12, and 24 months, respectively, and was comparable with concurrent nonrandomized control subjects. ConclusionsUse of an extracorporeal perfusion system resulted in successfully transplanting 87% of donor hearts with excellent patient survival to 2 years post-transplant and low rates of severe PGD. The ability to safely use ECD DBD hearts could substantially increase the number of heart transplants and expand access to patients in need. (International EXPAND Heart Pivotal Trial [EXPANDHeart]; NCT02323321; Heart EXPAND Continued Access Protocol; NCT03835754)

Leveraging external control data in the design and analysis of neuro-oncology trials: Pearls and perils.

Randomized controlled trials have been the gold standard for evaluating medical treatments for many decades but they are often criticized for requiring large sample sizes. Given the urgent need for better therapies for glioblastoma, it has been argued that data collected from patients treated with the standard regimen can provide high-quality external control data to supplement or replace concurrent control arm in future glioblastoma trials. In this article, we provide an in-depth appraisal of the use of external control data in the context of neuro-oncology trials. We describe several clinical trial designs with particular attention to how external information is utilized and address common fallacies that may lead to inappropriate adoptions of external control data. Using 2 completed glioblastoma trials, we illustrate the use of an assessment tool that lays out a blueprint for assembling a high-quality external control data set. Using statistical simulations, we draw caution from scenarios where these approaches can fall short on controlling the type I error rate. While this approach may hold promise in generating informative data in certain settings, this sense of optimism should be tampered with a healthy dose of skepticism due to a myriad of design and analysis challenges articulated in this review. Importantly, careful planning is key to its successful implementation.

The Kidney Not Taken: Single-Kidney Use in Deceased Donors.

The nonuse rate for kidneys recovered from deceased donors is increasing, rising to 27% in 2023. In 10% of these cases, 1 kidney is transplanted but the mate kidney is not. We conducted a retrospective, single-center cohort study from December 2001 to May 2023 comparing single kidneys transplanted at our center (where the contralateral kidney was not used) to kidneys where both were transplanted separately, at least 1 of which was at our center. We performed 395 single deceased-donor kidney transplants in which the mate kidney was not transplanted. Primary reasons for mate kidney nonuse were as follows: no recipient located or list exhausted (33.4%), kidney trauma or injury or anatomic abnormalities (18.7%), biopsy findings (16.7%), and poor renal function (13.7%). Mean donor and recipient ages were 51.5 ± 14.2 and 60 ± 12.6 years, respectively. Mean kidney donor profile index was 73% ± 22%, and 104 donors (26.3%) had kidney donor profile index >85%. Mean cold ischemia was 25.6 ± 7.4 hours, and 280 kidneys (70.7%) were imported. Compared with 2,303 concurrent control transplants performed at our center, primary nonfunction or thrombosis (5.1% single vs 2.8% control) and delayed graft function (35.4% single vs 30.1% control) were greater with single-kidney use (both p < 0.05). Median patient and death-censored graft survival were shorter in the single group (11.6 vs 13.5 years, p = 0.03 and 11.6 vs 19 years, p = 0.003), although the former was at least double median survival on the waiting list. In patients with functioning grafts in the single-kidney group, 1-year mean serum creatinine was 1.77 ± 0.8 mg/dL and estimated glomerular filtration rate was 44.8 ± 20 mL/min/1.73 m 2 . These findings suggest that many mate kidneys are being inappropriately rejected, given the acceptable outcomes that can be achieved by transplanting the single kidney in appropriately selected recipients.

3D BIOMIMETIC CONSTRUCTS STEER STEM CELL COMMITMENT BY SYNERGISTIC MODULATION OF BIOPHYSICAL CUES AND GROWTH FACTOR SIGNALLING

Tendon diseases are prevalent health concerns for which current therapies present limited success, in part due to the intrinsically low regenerative ability of tendons. Therefore, tissue engineering presents a potential to improve this outcome. Here, we hypothesize that a concurrent control over both biophysical and biochemical stimuli will boost the tenogenic commitment of stem cells, thus promoting regeneration. To achieve this, we combine molecularly imprinted nanoparticles (MINPs), which act as artificial amplifiers for endogenous growth factor (GF) activity, with bioinspired anisotropic hydrogels2 to manufacture 3D tenogenic constructs. MINPs were solid phase-imprinted using a TGF-β3 epitope as template and their affinity for the target was assessed by SPR and dot blot. Magnetically-responsive microfibers were produced by cryosectioning electrospun meshes containing iron oxide nanoparticles. The constructs were prepared by encapsulating adipose tissue-derived stem cells (ASCs), microfibers, and MINPs within gelatin hydrogels, while aligning the microfibers with an external magnetostatic field during gelation. This allows an effective modulation of hydrogel fibrillar topography, mimicking the native tissue's anisotropic architecture. Cell responses were analyzed by multiplex immunoassay, quantitative polymerase chain reaction, and immunocytochemistry. MINPs showed an affinity for the template comparable to monoclonal antibodies. Encapsulated ASCs acquired an elongated shape and predominant orientation along the alignment direction. Cellular studies revealed that combining MINPs with aligned microfibers increased TGF-β signaling via non-canonical Akt/ERK pathways and upregulated tendon-associated gene expression, contrasting with randomly oriented gels. Immunostaining of tendon-related proteins presented analogous outcomes, corroborating our hypothesis.Our results thus demonstrate that microstructural cues and biological signals synergistically direct stem cell fate commitment, suggesting that this strategy holds potential for improving tendon healing and might be adaptable for other biological tissues. The proposed concept highlights the GF-sequestering ability of MINPs which allows a cost-effective alternative to recombinant GF supplementation, potentially decreasing the translational costs of tissue engineering strategies.Acknowledgements: The authors acknowledge the funding from the European Union's Horizon 2020 under grant No. 772817; from FCT/MCTES for scholarships PD/BD/143039/2018 &amp; COVID/BD/153025/2022 (S.P.B.T.), and PD/BD/129403/2017 (S.M.B.), co-financed by POCH and NORTE 2020, under the Portugal 2020 partnership agreement through the European Social Fund, for contract 2020.03410.CEECIND (R.M.A.D.) and project 2022.05526.PTDC; and from Xunta de Galicia for grant ED481B2019/025 (A.P.).

Concurrent Learning-Based Adaptive Control of Underactuated Robotic Systems With Guaranteed Transient Performance for Both Actuated and Unactuated Motions.

With the wide applications of underactuated robotic systems, more complex tasks and higher safety demands are put forward. However, it is still an open issue to utilize "fewer" control inputs to satisfy control accuracy and transient performance with theoretical and practical guarantee, especially for unactuated variables. To this end, for underactuated robotic systems, this article designs an adaptive tracking controller to realize exponential convergence results, rather than only asymptotic stability or boundedness; meanwhile, unactuated states exponentially converge to a small enough bound, which is adjustable by control gains. The maximum motion ranges and convergence speed of all variables both exhibit satisfactory performance with higher safety and efficiency. Here, a data-driven concurrent learning (CL) method is proposed to compensate for unknown dynamics/disturbances and improve the estimate accuracy of parameters/weights, without the need for persistency of excitation or linear parametrization (LP) conditions. Then, a disturbance judgment mechanism is utilized to eliminate the detrimental impacts of external disturbances. As far as we know, for general underactuated systems with uncertainties/disturbances, it is the first time to theoretically and practically ensure transient performance and exponential convergence speed for unactuated states, and simultaneously obtain the exponential tracking result of actuated motions. Both theoretical analysis and hardware experiment results illustrate the effectiveness of the designed controller.

Switched Concurrent Learning Adaptive Control for Treadmill Walking Using a Lower Limb Hybrid Exoskeleton

Switched Concurrent Learning Adaptive Control for Treadmill Walking Using a Lower Limb Hybrid Exoskeleton

A proof-of-concept rat toxicity study highlights the potential utility and challenges of virtual control groups.

The virtual control group (VCG) concept provides a potential opportunity to reduce animal use in drug development by replacing concurrent control groups (CCGs) in nonclinical toxicity studies. This work investigated the feasibility and reliability of using VCGs in place of CCGs. A historical control database (HCD), constructed from Genentech Inc. rat toxicity study data, was reviewed to under­stand trends and sources of variability in control animals over time, and to identify data curation requirements for assembling VCGs, e.g., alignment of units of measurement. Several endpoints were investigated and stratified against different study design parameters. Sex, route of administration, fasting status, and body weight at study initiation were among the parameters that were indicated as key matching criteria. With a high-level understanding of potential sources of variability, a retro­spective proof-of-concept (POC) study was designed, evaluating a historical rat pilot toxicity study for test article-related changes. A masked interpretation of the study was conducted using its CCG and two unique VCGs that were constructed from individual animal data pulled from our HCD. While the results of the microscopic pathology assessment and most endpoints were similar across the different control groups, the POC revealed the risk of using VCGs to interpret subtle test article-related changes in clinical pathology parameters. Within the context of our POC, it appears the use of a VCG is not completely equivalent to the CCG, especially with clinical pathology parameters. Additional work is needed to understand the potential utility, and thus, viability of VCGs in other contexts.

Immune checkpoint inhibitor increased mortality in lung cancer patients with Pneumocystis jirovecii pneumonia: a comparative retrospective cohort study.

Pneumocystis jirovecii pneumonia (PJP) is a life-threatening infection in immunocompromised individuals. Immune checkpoint inhibitor (ICI) has brought significant survival benefit in lung cancer patients. Although the few studies showed there was high mortality in PJP patients with ICI use, these studies had no comparative control groups. A retrospective study was conducted to compare the mortality in PJP patients with lung cancer between those treated with ICI and a concurrent control group treated without ICI. A total number of 20 non-human immunodeficiency virus (HIV) patients with confirmed PJP and co-existing lung cancer were included in the current study, and classified into ICI group (n=9) and non-ICI group (n=11).There was a clear trend to a shorter onset of PJP in ICI group than non-ICI group (118.9 ± 60.9 vs 253.0 ± 185.1 days), although without statistical significance (p=0.053). Bronchoscopic alveolar lavage fluid were collected from all patients and used to identify Pneumocystis jirovecii. In both groups, metagenomics next-generation sequencing (mNGS) were the most used diagnostic techniques. Within 28 days after the onset of PJP, mortality was significantly higher in the ICI group than non-ICI group (33.3% vs 0, p=0.042). Lung cancer patients with ICI use had a higher mortality rate after PJP infection than patients without ICI use. Prospective studies with larger sample size and a multi-center design are warranted to further verify the present results.

Carcinogenic effect of human tumor-derived cell-free filtrates in nude mice.

Cancer remains a worldwide cause of morbidity and mortality. Investigational research efforts have included the administration of tumor-derived extracts to healthy animals. Having previously demonstrated that the administration of non-transmissible, human cancer-derived homogenates induced malignant tumors in mice, here, we examined the consequences of administering 50 or 100µg of protein of crude homogenates from mammary carcinoma, pancreatic adenocarcinoma, and melanoma samples in 6 inoculations per week during 2months. The concurrent control mice received homogenates of healthy donor-skin cosmetic surgery fragments. Mammary carcinoma homogenate administration did not provoke the deterioration or mortality of the animals. Multiple foci of lung adenocarcinomas with a broad expression of malignity histomarkers coexisting with small cell-like carcinomas were found. Disseminated cells, positive to classic epithelial markers, were detected in lymphoid nodes. The administration of pancreatic tumor and melanoma homogenates progressively deteriorated animal health. Pancreatic tumor induced poorly differentiated lung adenocarcinomas and pancreatic islet hyperplasia. Melanoma affected lungs with solid pseudopapillary adenocarcinomas. Giant atypical hepatocytes were also observed. The kidney exhibited dispersed foci of neoplastic cells within a desmoplastic matrix. Nuclear overlapping with hyperchromatic nuclei, mitotic figures, and prominent nuclear atypia was identified in epidermal cells. None of these changes were ever detected in the control mice. Furthermore, the incubation of zebrafish embryos with breast tumor homogenates induced the expression of c-Myc and HER-2 as tumor markers, contrasting to embryos exposed to healthy tissue-derived material. This study confirms and extends our hypothesis that tumor homogenates contain and may act as vectors for "malignancy drivers," which ultimately implement a carcinogenesis process in otherwise healthy mice.

The senomorphic impact of astaxanthin on irradiated rat spleen: STING, TLR4 and mTOR contributed pathway.

Exposure of spleen tissues to ionizing radiation during radiotherapy can induce cellular stress and immune-dysfunction leading to cellular senescence. The process of a cancerous development is facilitated by the accumulation of senescent cells. This justifies the incorporation of anti-senescent medications during splenic irradiation (SI). In this study senescence was induced in the spleen of male albino rats by radiation exposure (5Gy-single whole body gamma-irradiation) then after 2weeks, oral astaxanthin regimen was started once daily in a dose of 25mg/kg for 7 consecutive days. Concurrent control groups were carried out. the present data reflected that irradiation provoked an increase in the oxidative stress biomarkers (nitric oxide, lipid peroxidation and total reactive oxygen species levels)and the inflammatory biomarkers (Myeloperoxidase and interleukin-6). In addition irradiation led to the over expression of stimulator of interferon genes (cGAS-STING), mammalian target of rapamycin (mTOR) and Toll-like receptor 4 (TLR4) along with the lactate dehydrogenase (LDH), cyclin-dependent kinase inhibitor 1 (p21) cyclin-dependent kinase inhibitor 2A (p16) increment with elevation of tumor suppressor protein (p53) level. However, reduced glutathione contents and catalase activity were reduced post irradiation in spleen tissues, all these changes reflecting induction of cellular senescence. Astaxanthin treatment showed an improvement in the antioxidant/oxidative stress balance, inflammatory biomarkers, histopathological examination and immunohistochemical expressions of the tested proteins in the irradiated rats. the current findings offer a new insight into the senomorphic effect of astaxanthin following radiation-induced spleen senescence via STING, mTOR, and TLR4 signalling pathways.

The road to virtual control groups and the importance of proper body-weight selection.

Virtual control groups (VCGs) created from historical control data (HCD) can reduce the number of concurrent control group animals needed in regulatory toxicity studies by up to 25%. This study investigates the performance of VCGs on statistical outcomes of body weight development between treatment and control groups in legacy studies. The objective is to reproduce the statistical outcomes of 28-day sub-chronic studies (legacy studies) after replacing the concurrent control group with virtual ones. In rodent toxicity studies initial body weight is used as surrogate for the age of animals. For the assessment of VCG-sampling methods, three different approaches were explored: (i) sam­pling VCGs from the entire HCD, ignoring initial body weight information of the legacy study, (ii) sampling from HCD by matching the legacy study’s initial body weights, and (iii) sampling from HCD with assigned statistical weights derived from legacy study initial body weight information. The ability to reproduce statistical outcomes using virtual controls was determined by the congruence between the legacy study and the HCD weight distribution: regardless of the chosen approach, the ability to reproduce statistical outcomes was high for VCGs when the legacy study’s initial body weight distribution was similar to the HCD’s. When the initial body weight range of the legacy study was at the extreme ends of the HCD’s distribution, the weighted sampling approach was superior. This article demonstrates the importance of proper HCD matching by the legacy study’s initial body weight and discusses conditions to accurately reproduce body weight development.

Control Software Design for a Multisensing Multicellular Microscale Gas Chromatography System.

Microscale gas chromatography (μGC) systems are miniaturized instruments that typically incorporate one or several microfabricated fluidic elements; such systems are generally well suited for the automated sampling and analysis of gas-phase chemicals. Advanced μGC systems may incorporate more than 15 elements and operate these elements in different coordinated sequences to execute complex operations. In particular, the control software must manage the sampling and analysis operations of the μGC system in a time-sensitive manner; while operating multiple control loops, it must also manage error conditions, data acquisition, and user interactions when necessary. To address these challenges, this work describes the investigation of multithreaded control software and its evaluation with a representative μGC system. The μGC system is based on a progressive cellular architecture that uses multiple μGC cells to efficiently broaden the range of chemical analytes, with each cell incorporating multiple detectors. Implemented in Python language version 3.7.3 and executed by an embedded single-board computer, the control software enables the concurrent control of heaters, pumps, and valves while also gathering data from thermistors, pressure sensors, capacitive detectors, and photoionization detectors. A graphical user interface (UI) that operates on a laptop provides visualization of control parameters in real time. In experimental evaluations, the control software provided successful operation and readout for all the components, including eight sets of thermistors and heaters that form temperature feedback loops, two sets of pressure sensors and tunable gas pumps that form pressure head feedback loops, six capacitive detectors, three photoionization detectors, six valves, and an additional fixed-flow gas pump. A typical run analyzing 18 chemicals is presented. Although the operating system does not guarantee real-time operation, the relative standard deviations of the control loop timings were <0.5%. The control software successfully supported >1000 μGC runs that analyzed various chemical mixtures.

Additive manufacturing of functionally graded foams: Material extrusion process design, part design, and mechanical testing

Functionally graded foams (FGFs) were in-situ fabricated via material extrusion (MEX) additive manufacturing (AM) process. Foamable filaments loaded with thermally expandable microspheres (TEMs) at 8.0 wt% was first fabricated using a single screw extruder. The correlations between the resultant foam density and process factors, namely nozzle temperature (NT) and flow rate (FR) were established using a statistical analysis and the density predictability of the model was verified by experiment. With concurrent control of NT and FR, FGFs with density ranges as high as 0.86 g cm−3 were achieved within a single print. Various FGFs were designed using linear, concave, and convex density gradient functions. The density-process correlation model was then used to obtain the NT and FR parameters needed to produce the density values as demanded by the part design. FGFs along with their single density foam (SDF) counterparts were successfully printed with good dimensional stability. Under quasi-static compression testing, all FGFs showed higher energy absorption capacity at low stress levels, as compared to their SDF counterparts. Moreover, under impact conditions, a significant loading direction dependency was found for the FGFs. Overall, this work demonstrates the AM feasibility of FGFs as a single print with tailored density profiles which can be used in generative design optimization of AM parts for enhanced mechanical performance and other functionalities.

Considerations for the design and conduct of externally controlled trials for drug and biological products

This guidance provides recommendations to sponsors and investigators considering the use of externally controlled clinical trials to provide evidence of the safety and effectiveness of a drug product. In an externally controlled trial, outcomes in participants receiving the test treatment according to a protocol are compared with outcomes in a group of people external to the trial who had not received the same treatment. The external control arm can be a group of people, treated or untreated, from an earlier time (historical control), or it can be a group of people, treated or untreated, during the same period (concurrent control) but in another setting. The guidance addresses considerations for the design and analysis of externally controlled trials to study the effectiveness and safety of drugs, including discussion of threats to the validity of trial results from potential bias. Although various sources of data can serve as the control arm in an externally controlled trial, this guidance focuses on the use of patient-level data from other clinical trials or from real-world data (RWD) sources, such as registries, electronic health records, and medical claims. The guidance also describes considerations related to communicating with the FDA and ensuring access by the FDA to data from an externally controlled trial. This guidance does not address other types of external controls, such as using summary-level estimates instead of patient-level data. This guidance does not discuss details of the design and analysis of a natural history study nor the reliability and relevance of various sources of RWD that could be used in an externally controlled trial. Finally, this guidance also does not discuss considerations for using external control data to supplement a control arm in a traditional randomized controlled clinical trial. In general, FDA guidance documents do not establish legally enforceable responsibilities. Instead, guidance describes the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidance means that something is suggested or recommended, but not required.

Longitudinal and Concurrent Effortful Control as Predictors of Risky Bicycling in Adolescence: Moderating Effects of Age and Gender.

Collisions between bicycles and motor vehicles are one of the leading risk factors for injury and death in childhood and adolescence. We examined longitudinal and concurrent effortful control (EC) as predictors of risky bicycling behavior in early- to mid-adolescence, with age and gender as moderators. We also examined whether EC was associated with parent-reported real-world bicycling behavior and all lifetime unintentional injuries. Parent-reported EC measures were collected when children (N = 85) were 4 years old and when they were either 10 years (N = 42) or 15 years (N = 43) old. We assessed risky bicycling behavior by asking the adolescents to bicycle across roads with high-density traffic in an immersive virtual environment. Parents also reported on children's real-world bicycling behavior and lifetime unintentional injuries at the time of the bicycling session. We found that both longitudinal and concurrent EC predicted adolescents' gap choices, though these effects were moderated by age and gender. Lower parent-reported early EC in younger and older girls predicted a greater willingness to take tight gaps (3.5 s). Lower parent-reported concurrent EC in older boys predicted a greater willingness to take gaps of any size. Children lower in early EC started bicycling earlier and were rated as less cautious bicyclists as adolescents. Adolescents lower in concurrent EC were also rated as less cautious bicyclists and had experienced more lifetime unintentional injuries requiring medical attention. Early measures of child temperament may help to identify at-risk populations who may benefit from parent-based interventions.

Safety and efficacy of a new high-dose regimen of panobinostat, gemcitabine, busulfan, and melphalan for 1st or 2nd salvage ASCT for refractory/relapsed or high-risk myeloma: Matched-pair comparisons with concurrent control cohorts.

Improvement of autologous stem-cell transplantation (ASCT) for myeloma is needed. Building on our prior work, we prospectively evaluated panobinostat and gemcitabine/busulfan/melphalan (GemBuMel) with ASCT in this population. Patients aged 18-65 years with relapsed/refractory or high-risk myeloma and adequate end-organ function were eligible. Treatment included panobinostat (20 mg/day, days -9 to -2) and GemBuMel (days -8 to -2). Patients were enrolled in 1st (ASCT-1) or 2nd ASCT (ASCT-2) cohorts. We compared their outcomes with all our other concurrent ASCT patients who met eligibility criteria but received melphalan or BuMel off study, matched for age, prior therapy lines, high-risk cytogenetics, and response at ASCT. We enrolled 80 patients, 48 and 32 in the ASCT-1 and ASCT-2 cohorts, respectively; in these two cohorts, high-risk cytogenetics were noted in 33 and 15 patients, respectively; unresponsive disease in 12 and 11 patients, respectively, after a median of 2 and 3 therapy lines, respectively. Transplant-related mortality (TRM) occurred in two ASCT-2 patients. One-year PFS rates were 69% (ASCT-1) and 72% (ASCT-2); 1-year OS rates were 79% (ASCT-1) and 84% (ASCT-2). Minimal residual disease negativity improved after ASCT-1 (8.5%-23%, p < .0001) and ASCT-2 (34%-55%, p = .02), which correlated with improved outcomes. Trial patients and controls (N = 371) had similar TRM and post-ASCT maintenance. Trial patients had better PFS after either a 1st (p = .02) or a 2nd ASCT (p = .04) than matched-paired control patients. In conclusion, panobinostat/GemBuMel is effective for relapsed/refractory or high-risk myeloma patients, with better PFS than concurrent matched controls receiving melphalan or BuMel.

Concurrency control in tree data structures

With the increasing amount of data, there is a higher demand for fast access to data. Therefore, tree data structures are popular because they can quickly access data. In addition, with the increase of the cores of computer microprocessors, the tree data structure that can be concurrently controlled may be one of the most effective data structures today. However, there is still a lack of a summary of the differences in the data structures of various trees. Therefore, this paper collects code structures of different types of trees and then comments on the speed of various tree data structure types concerning parallel processing situations. The study covers the structure and performance of different kinds of trees and summarizes the method of concurrent control of these data structures. This paper can help to clearly understand the relationships and differences between various tree data structures and help them quickly learn the application of concurrency control in trees.

Concurrent Learning-Based Neuroadaptive Robust Tracking Control of Wheeled Mobile Robot: An Event-Triggered Design

In this paper, an event-based neuro-adaptive robust tracking controller for a perturbed and networked differential drive mobile robot (DMR) is designed with concurrent learning. A radial basis function neural network, which approximates an unknown perturbation, is used to design an adaptive sliding mode controller (SMC). The RBFNN weights and SMC parameters are estimated online using an adaptive tuning law to ensure performance with reduced chattering. To improve the convergence of RBFNN weight estimation error, a concurrent learning-based adaptive law is derived, which uses measured online and recorded data. Further, a suitable triggering condition is designed to achieve a reduced number of control computations while minimizing network resources without sacrificing the stability of the sampled data closed-loop control system. A finite sampling frequency is guaranteed for the designed triggering condition by establishing a positive lower bound on the inter-event execution time which is equivalent to the Zeno-free behaviour of the system. Finally, the proposed event-based neuro-adaptive robust controller is implemented on a practical system (Q-bot 2e) to show the effectiveness of the proposed design.

Adaptive hybrid control design for comparative clinical trials with historical control data

Abstract We propose an adaptive hybrid control causal (AHCC) design to leverage historical control data to reduce the sample size demanded by standard randomised controlled trials (RCT). Under the causal inference framework, we define the causal estimand of the average treatment effect and derive the corresponding estimator based on the trial data and historical control data. The AHCC design takes a multistage or group sequential approach. The number of patients randomised to the concurrent control is adaptively adjusted based on the amount of information borrowed from the historical control data. At each stage, based on the interim data, the contribution of the historical control data, quantified by the effective sample size, is updated and used to determine the randomisation ratio between the treatment and control arms for the next stage, with the goal to resemble a standard RCT upon the completion of the trial. Simulation studies show that the AHCC design has desirable operating characteristics. For example, it saves on sample size when substantial information can be borrowed from the historical control, and it maintains power when little information can be borrowed from the historical control.

Indirect (herd) effects of topical antibiotic prophylaxis and oral care versus non-antimicrobial methods increase mortality among ICU patients: realigning Cochrane review data to emulate a three-tier cluster randomised trial

ObjectiveThis study aimed to estimate the direct effects to recipients and indirect (herd) effects to non-recipients of each of topical antibiotic prophylaxis (TAP) and oral care methods on patient mortality...