N = 40). Extending this study, we performed longitudinal rsFC analyses of resting-state fMRI data using a ROI-to-ROI approach assessing within-network and between-network rsFC in the frontoparietal (FPN), dorsal attention (DAN), default mode (DMN), and salience (SAL) networks, which all have been associated with cognitive impairment after TBI. We also performed a seed-based connectivity analysis between the right IFG and whole-brain rsFC. The results showed that neurological music therapy increased the coupling between the FPN and DAN as well as between these networks and primary sensory networks. By contrast, the DMN was less connected with sensory networks after the intervention. Similarly, there was a shift towards a less connected state within the FPN and SAL networks, which are typically hyperconnected following TBI. Improvements in EF were correlated with rsFC within the FPN and between the DMN and sensorimotor networks. Finally, in the seed-based connectivity analysis, the right IFG showed increased rsFC with the right inferior parietal and left frontoparietal (Rolandic operculum) regions. Together, these results indicate that the rehabilitative effects of neurological music therapy after TBI are underpinned by a pattern of within- and between-network connectivity changes in cognitive networks as well as increased connectivity between frontal and parietal regions associated with music processing.Traumatic brain injury (TBI) is characterized by a complex pattern of abnormalities in resting-state functional connectivity (rsFC) and network dysfunction, which can potentially be ameliorated by rehabilitation. In our previous randomized controlled trial, we found that a 3-month neurological music therapy intervention enhanced executive function (EF) and increased grey matter volume in the right inferior frontal gyrus (IFG) in patients with moderate-to-severe TBI ( Each year, there are over 50 million cases of traumatic brain injury (TBI), and it has been estimated that approximately half of the world's population will sustain at least minor TBIs during their lifetime . The conMusic is a very promising tool in TBI rehabilitation, because both music listening and participating in musical activities evoke widespread brain activation . MusicalWe have conducted the first-ever randomized controlled trial (RCT) of neurological music therapy in a cohort of 40 moderate-to-severe TBI patients, where different domains of EF, attention, and memory were systematically analyzed. We used a single-blind cross-over design with 3 timepoints (baseline/3 months/6 months) for neuropsychological assessment and s/fMRI acquisition. The neurological music therapy consisted of 20 individual therapy sessions held by a trained music therapist over a 3-month period  and was targeted primarily to the rehabilitation of EF, attention, and working memory. In a previous publication, we reported that the music-based intervention induced cognitive improvement in general EF performance as well as in set-shifting .In addition to demonstrating this improvement in neuropsychological performance, in , we condResting-state functional connectivity (rsFC) is characterized by task-free spontaneous fluctuations in brain activity that occur synchronously across spatially distant regions . These frsFC studies of TBI patients have revealed both increases and decreases in network connectivity, including the default mode (DMN) and salience (SAL) networks as well as multiple sensory and cognitive networks across the spectrum of injury severity –49. For Despite the complex abnormalities of interactions within and between RSNs following TBI, it is possible to identify some distinctive patterns. Within networks, reduced rsFC within the nodes of the DMN predicts attentional impairment . Such asThe paradoxical yet well-documented finding that functional connectivity may increase secondary to TBI , 52–56 hIn the present study, we extend our previous findings by analyzing rsFC from a subset of moderate-to-severe TBI patients  in this music therapy RCT . We usedNCT01956136) with a 6-month follow-up phase. Upon recruitment, patients were randomly assigned to one of the two groups: AB and BA. During the first 3-month period, the AB group received neurological music therapy (NMT) in addition to standard care, whereas the BA group received only standard care. During the second 3-month period, the BA group received the music therapy intervention and standard care and the AB group received only standard care. Baseline measurements were administered at timepoint 1 (TP1), and follow-up measurements were conducted at the 3-month cross-over point (TP2) and at the 6-month completion point (TP3).We conducted a single-blinded cross-over RCT  ≥ 24 h]; (2) time since injury ≤ 24 months at the time of recruitment; (3) cognitive symptoms caused by TBI ; (4) no previous neurological or severe psychiatric illnesses or substance abuse; (5) age 16–60 years; (6) native Finnish speaking or bilingual with sufficient communication skills in Finnish; (7) living in the Helsinki-Uusimaa area; and (8) understanding the purpose of the study and being able to give an informed consent.The subjects analyzed herein are a subset of our previous study . In the https://www.random.org/) by a person not involved in patient recruitment or assessments. The randomization was stratified for lesion laterality . Within each of these three strata, the randomization was done in batches of two consecutive patients. The trial was conducted according to the Declaration of Helsinki and was consistent with good clinical practice and the applicable regulatory requirements. The trial protocol was approved by the Coordinating Ethics Committee of the Hospital District of Helsinki and Uusimaa (reference number 338/13/03/00/2012), and all subjects signed an informed consent.To ensure steady allocation to both groups across the trial, randomization was performed using an online random number generator  for the present study. This is a subset of the 25 patients sample with structural MRI scans from our previous study  and (2) a fluid-attenuated inversion recovery (FLAIR) sequence .∗-weighted image sequence . During the rs-fMRI acquisition, the patients were instructed to remain still, eyes open to a fixation cross to ensure vigilance.In rs-fMRI, images were acquired with a T2https://www.nitrc.org/projects/mricron). Accuracy of the CFM was validated by an expert neuroradiologist (author J.P.) who assessed multiple modalities of neuroimaging data acquired at TP1 . For a lesion overlap map of the patients with visible lesions, see Supplementary Figure Data were preprocessed using a standard pipeline in Statistical Parametric Mapping software  running under Matlab Release 2018b . The preprocessing methods applied included slice timing correction, realignment, segmentation, normalization to the MNI template , and smoothing with a Gaussian kernel of 8 mm full width at half maximum (FWHM). Focal brain lesions were detected in 11 patients. As the presence of lesions may influence the normalization algorithm, cost function masks (CFM) were defined for these 11 lesioned patients, to achieve optimal normalization with no postregistration lesion shrinkage or out-of-brain distortion . Binary Next, within-subject T1 images from all timepoints  were coregistered using the T1 images from TP1 as the reference to ensure that they remained in spatial alignment with the T1 images and CFM from this acquisition. All images and CFM were oriented to the anterior commissure before this coregistration step. Unified segmentation with medium regularization was applied to the T1 images (masked with CFM for those patients with visible lesions on the T1); grey matter (GM), white matter (WM), and cerebrospinal fluid (CSF) probability maps were obtained for each individual . This prhttps://www.nitrc.org/projects/artifactdetect). We identified outliers as scans that exceeded 3 standard deviations in Z-scores from the global BOLD signal or with linear motion > 2 mm. Regressor files containing the list of outliers for each patient and session  were saved for the removal of outlier effects.After preprocessing, outlier identification was performed using the Artifact Detection Tools (ART) toolbox (https://www.nitrc.org/projects/conn), including the following subject- and session-specific files: T1 and rs-fMRI scans; segmented GM, WM, and CSF images; 6 realignment parameters after rigid body motion correction; and the regressor files containing the outliers. We used the default denoising pipeline in the CONN toolbox which comprises two steps in consecutive order: (1) linear regression of potential confounding effects in the BOLD signal and (2) temporal band-pass filtering. Step (1) implements an anatomical component-based noise correction procedure (aCompCor), including the following: noise components from cerebral white matter and cerebrospinal areas  as seeds and all network ROIs included in the CONN toolbox as targets. This analysis showed that music therapy strengthened network connectivity between FPN and DAN and between these networks and the sensorimotor (SM) and visual (VIS) networks, respectively. In contrast, the music therapy intervention reduced the connectivity between the nodes of DMN and SM network. The within-network connectivity revealed specific nodes of the FPN and SAL wherein coupling decreased in the pre- versus post-intervention comparison. Importantly, the decrease in the FPN and DMN-SM connectivity was paralleled by cognitive improvement in executive function (EF). Finally, using a seed-based connectivity analysis, we demonstrated that the right inferior frontal gyrus (IFG), in which we previously observed increased grey matter volume (GMV) induced by the music therapy intervention , showed Our hypothesis (1) was that NMT enhances the rsFC between primary sensory networks and higher-order networks as a consequence of the iterated interaction between the sensory-cognitive systems recruited by music production and perception . This efThe hypothesis (1) was conceptually inspired by the “global workspace”  notion empirically supported by the convergence of unimodal sensory networks into cortical hubs that contribute to perceptual integration in the human brain . Our resIn hypothesis (2), we proposed that the DMN, SAL, and FPN connectivity would be downregulated by the NMT. Our reasoning was that the repetitive engagement of cognitive control and EF during the intervention , 20 woulOne prominent line of evidence in favor of the latter hypothesis comes from the observation that hyperconnectivity secondary to neurological damage, including TBI , 56, 93,Here, we found that the neurological music therapy decreased the functional connectivity within the FPN, involving a reduction in the bilateral communication between the lateral prefrontal cortex and between the lateral prefrontal cortex and the posterior parietal cortex in the left hemisphere. Considering the hyperconnectivity hypothesis, this finding accords with recent evidence indicating that the bilateral prefrontal cortices are the subcomponents of the FPN with the highest average degree at 3 and 6 months after moderate-to-severe TBI . SeveralOne clinically relevant implication from these findings is that the music therapy effectively targeted network hubs from the FPN and SAL networks and hence may have contributed to the shift from a compensatory hyperconnected state to one that does not rely on enhanced connectivity for efficient network communication. Within the hyperconnectivity hypothesis framework, it has been argued that while this hyperconnectivity may be adaptive in the short term, chronic hyperconnectivity may render network hubs vulnerable to late pathological complications due to the chronically increased metabolic stress. Although the exact mechanisms and cognitive consequences of hyperconnectivity remain to be elucidated, this proposal has found some support from longitudinal studies examining the temporal evolution of TBI recovery , 92. ForIndirect support for this idea comes from our correlational results indicating improved performance in EF as a function of rsFC decrease within the FPN. The NMT was primarily designed to target a number of EFs , which are reflected by the three outcome measures  showing a correlation with the therapy-induced change in rsFC. In this context, it might be that the repetitive practice during the music intervention reduces the cognitive challenge and transfers to better executive functioning, thus reducing the need for a hyperconnected state to efficiently accomplish the task. This would fit well with the observation that the increased activity in the right prefrontal cortex and anterior insula cortex in a sample of TBI patients normalizes following practice of a working memory task .The simultaneous combination of both structural and rsFC measures in the context of rehabilitative strategies for TBI has only recently started to be explored . HoweverN = 23) and may preclude the detection of small effect sizes due to lack of statistical power. Given the difficulty in finding patients fulfilling all the inclusion criteria, we were more liberal in the selection of time since injury. For this reason, even if over half of our patients sustained TBI within 6 months or less at the time of recruitment, there is heterogeneity in our sample. While the interpretation of our findings is consistent with previous longitudinal studies examining rsFC in TBI, a direct comparison is not warranted and future RCT should consider a stratification of patients by time since injury. Another consideration is the cross-over design: this has the advantage that patients act as they own controls, but the potential risk of a carry-over effect for the group who first participated in the intervention. Regarding rsFC, we used the resting-state networks available in the CONN toolbox that were obtained using an ICA (N = 498) from the Human Connectome Project. This selection, however, limited the analysis of sensory-integrative network interactions since the auditory network was not included. As we have established that the music therapy effectively enhances these interactions, future analyses will benefit from including nodes from the auditory network based on brain parcellations [This study has some limitations, which need to be considered when evaluating its findings. Although this is the largest RCT using neurological music therapy in moderate-to-severe TBI to date, the final sample size is relatively modest . The shift towards a less connected state within the FPN and SAL networks is also in line with the notion that chronic hyperconnectivity in network hubs after TBI can be maladaptive in the long-term. Importantly, we found a correlation between improved performance in EF and lesser connectivity in the FPN and the DMN-SM networks, which might be linked to reduced interference. Finally, the co-occurrence of changes in brain morphometry and rsFC connectivity, in the circuits supporting music processing, suggests a complex picture with interrelated plasticity across MRI modalities. Our findings suggest that rsFC changes in brain networks can serve as sensitive biomarkers for the efficacy of music-based rehabilitation after TBI. These findings are crucial from a clinical standpoint, as effective rehabilitative tools for reducing brain network dysfunction after TBI are still under development.


Tunnels, pores, channels, pockets and cavities contribute to proteins architecture and performance. However, analysis and characteristics of transportation pathways and internal binding cavities are performed separately. We aimed to provide universal tool for analysis of proteins integral interior with access to detailed information on the ligands transportation phenomena and binding preferences.AQUA-DUCT version 1.0 is a comprehensive method for macromolecules analysis from the intramolecular voids perspective using small ligands as molecular probes. This version gives insight into several properties of macromolecules and facilitates protein engineering and drug design by the combination of the tracking and local mapping approach to small ligands.http://www.aquaduct.pl.Bioinformatics online. MD simulations have increased our knowledge of the conformational changes of proteins’ regulatory elements such as gates (de novo designed enzymes (One of the most extensively used methods for the AQUA-DUCT 1.0 is an extension of the approach focused on molecules tracking . It revevia a particular pathway (aquaduct tunnel (W) in cytochrome P450 3A4 . The time-window mode allows the analysis of long trajectories in pre-defined time windows and thus facilitates the identification of equivalent or alternative states (consolidator mode (The AQUA-DUCT 1.0 provides four distinct modes of analysis . The stae states . Differetor mode . Pre-seltor mode  or the rvia particular pathways. The application of ‘ligands-tracking’ and ‘local-distribution’ approaches together with the introduction of a ‘chemical probe’ overcomes most of the limitations of currently available tools. The user receives direct access to information about the active site, potential hot-spots, functional residues, the network of internal transportation pathways and functional voids and cavities and benefits from modules that can facilitate the understanding of macromolecules, protein engineering and drug design. Our method is able to analyze dynamic changes in the spatial distribution of the physicochemical properties with user-defined time-scales and resolution, and also with easy and fast insight into the geometry of macromolecules’ interiors and the approximation of transport energy barriers btz946_Supplementary_DataClick here for additional data file.


There have been no studies comparing patient-reported outcome measures including end-of-stem tip pain and patient satisfaction based on the use of cementing techniques in revision total knee arthroplasty (TKA). The purpose of this study was to compare end-of-stem tip pain and PROMs with hybrid and modified hybrid cementing techniques in revision TKAs.Sixty-two cases of revision TKA performed by a single surgeon were divided into two groups based on the cementing technique with a minimum follow-up of 2 years. Two types of cementing technique for femoral and tibial stems were used as follows: (1) a hybrid cementing technique (33 cases), in which cement was applied immediately distal to the modular junction of the stem and the component while the distal stem was press-fitted into the diaphysis without using cement; and (2) a modified hybrid cementing technique (29 cases), in which cement was applied to the tip of femoral and tibial stems. The thigh and shin were assessed for the end-of-stem tip pain. Patient satisfaction was evaluated based on the satisfaction items of New Knee Society Score.p = 0.029). Patients treated with the modified hybrid cementing technique showed a higher satisfaction rate (p = 0.003). Multivariate logistic regression analysis showed an increase in the odds of satisfaction 32.686-fold (p = 0.004) in patients without pain at the end-of-stem tip in the shin and 9.261-fold (p = 0.027) in patients treated with the modified hybrid cementing technique.Modified hybrid cementing significantly lowered the percentage of patients manifesting shin pain (3.4% vs. 24.2%, The modified hybrid cementing technique for fixation of long-stem in revision TKAs reduced the end-of-stem tip pain in the shin, leading to significantly higher satisfaction compared with the hybrid cementing technique after revision TKA.Level III Revision total knee arthroplasty (TKA) is more difficult than primary TKA due to severe bone defects and insufficient soft tissue , 2. StemTo the best of our knowledge, there have been no studies comparing PROMs (patient-reported outcome measures) including end-of-stem tip pain and patient satisfaction based on the use of cementing techniques in revision TKAs. The purpose of this study was to compare end-of-stem tip pain and PROMs with hybrid and modified hybrid cementing techniques in revision TKAs. Our hypothesis was that patients treated with the modified hybrid cementing exhibited a lower incidence of end-of-stem tip pain and higher satisfaction after revision TKA compared with patients treated with the hybrid cementing technique.Clinical and radiological data including patients’ charts and radiographs obtained between March 2012 and December 2016 were retrospectively reviewed. All patients who underwent revision TKA were included in this review. A total of 81 consecutive revision TKAs using the same Vanguard 360 revision knee system  with diaphyseal stem fixation were performed by the senior surgeon at a single institution. We used two types of cementing techniques for femoral and tibial stems. Between March 2012 and March 2015, 41 revision TKAs were performed using the hybrid cementing technique, in which cement was applied around the implant immediately distal to the modular junction of the stem and the component while the distal stem was pressed to fit into the diaphysis without cement , were exThe following valuables were compared between the two groups: age, gender, body mass index (BMI), the American Society of Anesthesiologists (ASA) grade, and comorbidities including hypertension, diabetes, cardiac disease , cerebrovascular event, thyroid, kidney, liver disease, and pulmonary disease (asthma and chronic obstructive pulmonary disease). The factors inducing revision TKAs were categorized except for septic cause: aseptic loosening, component malposition, stiffness, and instability. Polyethylene wear was included in aseptic loosening . ProsthePROMs were evaluated by an independent investigator based on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score  and patip value < 0.1). Odds ratios were reported for significant variables. All statistical analyses were performed using SPSS ver. 21.0 program . A p value < 0.05 was considered statistically significant.Data were compared between patient groups exposed to the hybrid and the modified hybrid cementing techniques. Linear variables were analyzed using Kolmogorov-Wilcoxon test for nonparametric date while dichotomous variables were analyzed using chi-square test or Fisher’s exact test where appropriate for two independent samples. Descriptive analyses were based on frequencies and percentages for dichotomous variables, and the mean and standard deviation for linear variables. Multivariable logistic regression analysis was used to assess the independent effects of predictors by adding backward substitution factors identified as significant in univariate analysis  than the group of patients exposed to hybrid cementing technique. The modified hybrid group also carried a lower proportion of patients with thigh pain without any statistical significance . The modified hybrid group showed significantly better subscores for pain and function and total WOMAC scores at 2 years postoperatively compared with the group treated with the hybrid cementing technique   of patients were satisfied with revision TKAs while 24.2% (n = 15) claimed that they were dissatisfied. No significant association was found between femur and tibia augmentation based on augments, and the thigh or shin pain . Patients treated with modified hybrid cementing showed higher rates of satisfaction compared with patients treated with hybrid cementing strategies . The modified hybrid approach resulted in significantly superior scores of total satisfaction   in patients without end-of-stem tip pain in the shin, and 9.261-fold (p = 0.027) in patients treated with the modified hybrid cementing technique (Table Multivariate logistic regression analysis showed that the odds of satisfaction after revision TKAs increased 32.686-fold p = 0.00 in patieThree cases of wound dehiscence were observed along with one case of superficial wound infection involving the surgical site. None of the cases showed deep periprosthetic infection during postoperative follow-up.The most important finding of this study was that the modified hybrid cementing technique significantly reduced the end-of-stem tip pain in the shin and enhanced patient satisfaction compared with the hybrid cementing technique.The use of intramedullary stem for fixation stability and proper alignment in revision TKA is widely accepted among orthopedic surgeons, although the stem fixation approach is still disputed , 7. AugmIn this study, the end-of-stem tip pain in the shin was a factor significantly related to patient dissatisfaction after revision TKAs. Although the cause of end-of-stem tip pain after revision TKA is not proven, the following factors have been implicated: micromotion at the bone-prosthesis interface, excessive stress transfer to the surrounding bone because of large differences in Young’s modulus of elasticity between the stem tip and the bone at the point of contact, and stress shielding leading to bone resorption of the tibial tray resulting in movement to the stem tip –24. BarrMihalko et al. [End-of-stem pain is commonly reported with press-fit stem revision TKAs. However, its incidence rate varies among clinical studies , 25. In o et al.  have repAlthough the overall satisfaction rate of our revision TKA patients was 75.8%, the satisfaction rate of hybrid cementing technique group was only 60.6%. Baker et al.  reportedOur study had several limitations. First, the demographic characteristics of the present study population such as the preponderance of female patients undergoing revision TKA should be considered when comparing with other populations comprising only Korean patients . NeverthOur novel technique of stem fixation in revision TKAs using a modified hybrid cementing technique reduced the end-of-stem tip pain in the shin and increased patients’ satisfaction postoperatively. Therefore, the modified hybrid cementing technique could be more effective option to reduce end-of-stem tip pain and enhance patient satisfaction following revision TKAs. Further research is needed to support our findings.


To evaluate the cost-effectiveness of ribociclib plus letrozole versus palbociclib plus letrozole in post-menopausal women with hormone receptor positive (HR+) and human epidermal growth receptor 2 negative (HER2−) advanced breast cancer from a UK payer perspective.A cohort-based partitioned survival model was developed to evaluate the cost-effectiveness of ribociclib plus letrozole versus palbociclib plus letrozole in post-menopausal women with HR+/HER2− advanced breast cancer over a lifetime horizon. The analysis was carried out from a National Health Services and Personal Social Services perspective, and results are presented in incremental costs per quality adjusted life years. Clinical data from three randomized controlled trials  were used, and supplemented with available real world evidence. Costs categories comprised of drug acquisition, medical management, and treatment of adverse events. Healthcare resource utilization data were identified from literature and unit costs sourced from secondary sources. Utility values were derived from MONALEESA-2 study and were supported with values identified from literature. Both deterministic and probabilistic analyses were carried out to assess uncertainty.In the base case, treatment with ribociclib plus letrozole increased mean progression free survival (PFS) by 4.1 months and overall survival by 5.0 months compared to palbociclib plus letrozole. Further, treatment with ribociclib plus letrozole resulted in cost-savings of £8464 and incremental QALYs of 0.261, demonstrating that treatment with ribociclib plus letrozole is dominant to treatment with palbociclib plus letrozole. The probabilistic analysis also yielded mean cost-savings of £7914 and mean QALY gain of 0.273. At willingness-to-pay threshold of £30 000 per QALY, treatment with ribociclib plus letrozole had a 92% probability of being cost-effective compared to palbociclib and letrozole.The results of the analysis demonstrate that ribociclib plus letrozole treatment is both cost-saving and a cost-effective option amongst the available cyclin dependent kinase 4/6 inhibitors for the treatment of post-menopausal women with advanced breast cancer. The biggest driver of the cost savings were the lower acquisition costs of ribociclib. Globally, breast cancer is the most common cancer in females.4The mainstay first-line treatment for the estimated 7500 post-menopausal women with advanced breast cancer in the UK are endocrine therapy with steroidal or non-steroidal aromatase inhibitors.Both ribociclib and palbociclib are administered orally  in a 3-weeks on/1-week off schedule in combination with letrozole (2.5 mg once daily). These CDK inhibitors possess similar mechanism of action and have demonstrated clinical efficacy in separate randomized trials.8−6).Clinical efficacy of ribociclib plus letrozole was assessed in the MONALEESA-2 study.Efficacy data for palbociclib plus letrozole was derived from two PALOMA studies [PALOMA-1 NCT 00721509) & PALOMA-2 (NCT01740427)]. Both were multi-center randomized studies and compared palbociclib plus letrozole and placebo plus letrozole; whilst PALOMA-1 was a Phase II open label study, PALOMA-2 was double-blinded Phase III study. Across both studies, post-menopausal women with estrogen receptor positive HER2− advanced breast cancer who have not received prior systematic treatment were randomized to either palbociclib  plus letrozole (2.5 mg once daily) or placebo  plus letrozole (2.5 mg once daily). Results in both studies confirmed statistical significant improvement in primary endpoint . Further details of these analyses are presented elsewhere.21509 & P8Earlier evaluations have estimated cost-effectiveness of different endocrine therapies and conventional aromatase inhibitors in first-line treatment of post-menopausal women.A de-novo cohort based partitioned survival model was developed in Microsoft Excel® to estimate the cost-effectiveness of ribociclib plus letrozole versus palbociclib plus letrozole. This analysis evaluated the expected costs, life-years and quality-adjusted life years (QALYs) using a 4-week cycle for a life time horizon of 40 years. The cohort characteristics modelled in the analysis were based on the patients enrolled in the MONALEESA-2 study which was similar to those enrolled in the two PALOMA trials.The analysis was carried out from a UK National Health Services (NHS) and Personal Social Services (PSS) perspective and included all direct medical costs pertinent to the NHS, which included costs pertaining to drug acquisition and monitoring, health state specific disease monitoring, subsequent therapy and management of adverse events costs. The effectiveness (benefits) of the treatment was evaluated using a generic measure for disease burden via QALYs. The cost-effectiveness results were expressed in incremental cost-effectiveness ratios .A three-health state structure including progression-free, progressed-disease and death was used to track patients along the disease pathway . Time-deSurvival for ribociclib plus letrozole and palbociclib plus letrozole were derived by applying a hazard ratio (versus placebo plus letrozole) to the reference arm modelled by fitting parametric functions to PFS and OS data for placebo plus letrozole in the MONALEESA-2. The hazard ratio for ribociclib plus letrozole (vs. placebo plus letrozole) was derived using a matched-adjusted indirect comparison (MAIC).13 The MAIC adjusted for the small differences in patient characteristics across the studies (i.e. PFS: MONALEESA-2 and PALOMA-2 and OS: MONALEESA-2 and PALOMA-1). Further details of the MAIC are presented elsewhere. For palbociclib and letrozole (vs. placebo plus letrozole) hazard ratios were derived using a conventional indirect treatment comparison.13The selection of best fitting parametric function was based on statistical goodness of fit indicators as well as clinical plausibility as recommended in NICE DSU document on survival analysis modelling.The proportion of patients in the PF sub-states was modelled with treatment specific overall response rate. Treatment specific response rates for ribociclib plus letrozole and palbociclib plus letrozole were derived by applying odds ratio to the rates observed in the placebo plus letrozole arm of MONALEESA-2 study. The response rates were assumed to follow a linear trend for the first 12 months in line with clinical data. Beyond month 12, proportion of responders was held stable but the number of responders was assumed to decline with the PFS.The drug acquisition cost of each therapy were based on pack prices sourced from British National Formulary.The total drug acquisition costs in the model were based on time to treatment discontinuation. Consistent with PFS and OS, duration of treatment for ribociclib plus letrozole was modelled by fitting a parametric function  model to time to treatment discontinuation data for ribociclib and letrozole from MONALEESA-2 study. For palbociclib plus letrozole, this was modelled by applying hazard ratio for PFS  obtained from the meta-analysis to the parametric model fitted to ribociclib plus letrozole data .The model adjusted for the dose reduction  for ribociclib based on clinical data (for the first 16 months) from MONALEESA-2 study. Dose-wise distribution of patients beyond 16 months was assumed same as that observed at 16 months. For palbociclib , any dose reduction for palbociclib was likely to result in drug wastage. This was based on data from a real world study that evaluated the utilization pattern of palbociclib by analyzing prescription claims database in the United States.17Disease monitoring healthcare resource use data was informed by literature. The health-state specific resource use included costs for healthcare professional visits, hospitalization, monitoring and imaging. Total monthly costs for each of the healthcare resource use were estimated as a product of proportion of patients accruing these costs with the resource use and its specific unit costs.Healthcare professional visits included costs associated with visits to the general practitioner, oncology consultant, community nurse, clinical nurse specialist, social worker or radiographer. Hospitalization costs accounted for general and oncology specific and were applied to a proportion of patients. Routine monitoring costs included costs related to blood tests. Imaging costs comprised of bone-scintigraphy costs, x-rays, ultrasound, magnetic resonance imaging and positron emission tomography. Further details of these cost elements are presented in A monthly subsequent therapy cost was also applied to account for the costs of further therapies (either endocrine or chemotherapy) in the second and third line following disease progression using the same methodology as used by Das and colleagues.et al.The MONALEESA-2 study collected health-related quality of life data using EuroQoL 5-dimension (EQ-5D-5L) questionnaire during the screening phase, with follow-up every eight weeks during the first 18 months and then every 12 weeks thereafter until disease progression or at the end of treatment. Health-state utility values were estimated using EQ-5D-5L UK social tariff reported by Devlin Both one-way deterministic and probabilistic analyses were performed to adjust for the uncertainty associated with the key parameters. In the one-way sensitivity analysis, the values of parameters were varied by its 95% CI . The results of one-way sensitivity analyses were presented in Tornado plot depicting the impact on the net monetary benefit for the parameters that had the biggest impact.A probabilistic analysis using a Monte Carlo simulation of 1000 iterations was performed.An additional scenario analysis was also carried out that used an alternative distribution (Weibull) for modelling the placebo plus letrozole PFS to which the HR’s were applied. This distribution was selected in the scenario analysis as it has been used to model PFS in women with HR+/HER2− advanced breast cancer in an earlier economic evaluation.Compared to palbociclib plus letrozole, ribociclib plus letrozole treatment increased mean PFS by 4.1 months and mean OS by 5.0 months over a 40-year time horizon. Treatment with ribociclib plus letrozole was cheaper and resulted in a greater QALYs compared to palbociclib plus letrozole. The total treatment costs with ribociclib plus letrozole and palbociclib plus letrozole were £104 230 and £112 694. The total QALYs were 3.296 and 3.034. This resulted in the dominance of ribociclib plus letrozole over palbociclib and letrozole. A breakdown of the costs and health benefits is presented in The probabilistic analyses also confirmed the results of the deterministic analyses. Based on a mean costs savings of £7914  and mean incremental QALYs of 0.273  treatment with ribociclib was cost-effective compared to palbociclib in 92% of the probabilistic simulations , and was dominated in 1.3% of the iterations. The results of the probabilistic analyses are presented in Results of the one-way deterministic sensitivity analysis are presented in the Tornado plot . Key modThe scenario analysis using the Weibull distribution also demonstrated cost savings with ribociclib plus letrozole treatment. The savings were £7884 compared to the base-case analysis.Breast cancer is a life-threatening form of cancer; having severe impact on survival in patients with this condition. This necessitates urgent need for therapies that have better impact on reducing the risk of progression or death in patients with HR+/HER2− advanced breast cancer.EMA granted marketing authorization for use of ribociclib for the treatment of locally advanced or metastatic breast cancer.27This is the first study that evaluated the cost-effectiveness of ribociclib plus letrozole versus palbociclib and letrozole in post-menopausal women with HR+/HER2− advanced breast cancer from a UK payer perspective. Clinical data were derived from MONALEESA-2, PALOMA-1 and PALOMA-2 studies. The study results demonstrated slight clinical benefit (increased PFS and OS) with ribociclib treatment compared to palbociclib treatment. Consequently, ribociclib plus letrozole treatment was associated with an incremental QALY gain of 0.261 over lifetime. The results also indicate cost savings with ribociclib treatment. Unlike ribociclib, dose reduction for palbociclib results in potential drug wastage that has the cost implications and was one of the drivers of the cost savings. These cost savings were due to the linear pack pricing (cost per mg) for ribociclib compared to flat pack pricing for palbociclib; with patients moving to the lower (therefore less costly) ribociclib doses over time.There are some limitations of the analysis. Firstly, there is uncertainty regarding the parametric survival modelling and extrapolation of the OS endpoint. As both ribociclib and palbociclib are recently launched CDK inhibitors, there are no studies which have presented longer term survival for patients who received these. Therefore in order to validate, we compared the OS projections for placebo and letrozole which was used for modelling survival of ribociclib plus letrozole and palbociclib plus letrozole. The predicted survival projections for placebo and letrozole  of 95%, 82% and 26% at 1-, 2- and 5- year landmark closely aligned the OS projections elicited through expert consultation and literature.The second limitation is that the key inputs in the analysis such as utilities and time on treatment were assumed to be equal between the two treatments. This was due in part to lack of publicly available data from the PALOMA-2 study. Given the dosing structure of the two drugs, it is highly likely that time on treatment might be different and therefore might have an impact on the results.Furthermore, the analysis evaluated cost-effectiveness of ribociclib plus letrozole vs. palbociclib and letrozole using effect estimates derived from a MAIC in the absence of direct comparative evidence. There may be some uncertainty in this indirect analysis compared with head to head evidence from a direct comparative study .Recently, preliminary results for abemaciclib in combination with fulvestrant for the treatment of postmenopausal women with HR+/HER2− advanced breast cancer based on phase III study MONARCH-3 are published.The results of this study demonstrate that combination therapy of ribociclib and letrozole for the treatment of post-menopausal women with HR+/HER2− advanced breast cancer would be a cost-effective option compared to palbociclib and letrozole from a NHS and PSS perspective in the UK. The biggest driver for the cost-effectiveness results were the lower drug acquisition costs for ribociclib. Additional data from both the MONALEESA-2 and PALOMA-2 studies will increase the robustness of the cost-effectiveness estimates.


A fast and robust Jacobian-free time-integration method—called Minimum-error Adaptation of a Chemical-Kinetic ODE Solver (MACKS)—for solving stiff ODEs pertaining to chemical-kinetics is proposed herein. The MACKS formulation is based on optimization of the one-parameter family of integration formulae coupled with a dual time-stepping method to facilitate error minimization. The proposed method demonstrates higher accuracy compared to the method—Extended Robustness-enhanced numerical algorithm (ERENA)—previously proposed by the authors. Additionally, when this method is employed in homogeneous-ignition simulations, it facilitates realization of faster performance compared to CVODE. Use of a detailed chemical-reaction model, capable of accurately simulating ignition and extinction phenomena, therefore, becomes necessary.Computational fluid dynamic (CFD) analysis constitutes an integral part of and plays a significant role in practical engine development for automotive applications. However, from the viewpoint of enhancing engine efficiency and meeting ever-so-stringent emission regulations imposed in recent years, conventional combustion models such as flamelet and G-equation models2, Cantera3, and Zero-RK4. These simulations, however, only provide limited information with regard to the development of actual engine combustors. Performing CFD analysis using detailed chemical-kinetic models, therefore, becomes necessary. The difficulty encountered while performing CFD analysis using detailed chemical-kinetics models stems from the associated increase in the number of advection equations and diffusion-coefficient calculations and stiffness of chemical-reaction ordinary differential equations (ODEs). However, extant studies have reported that the primary limiting factor in this regard corresponds to solving stiff chemical-kinetic ODEs, and that use of efficient integration methods can help in reducing the computational cost involved therein6.Currently, zero- and one-dimensional simulations are primarily performed using detailed chemical-kinetics models using Chemkin-Pro, FlameMaster10. However, as the number of chemical species increases, the computational cost associated with the treatment of Jacobian matrices increases from being proportional to the square of the number of chemical species to the cube of the same number. Additionally, the said Jacobian matrix becomes sparse at the same time14. The possibility of efficient reduction in computational cost via application of the sparse-matrix method has previously been reported in several studies19. Of the various methods prescribed in this regard, the SpeedCHEM20 approach is famous and has been widely employed. The above approaches exponentially reduce the computational cost, thereby facilitating efficient treatment of the Jacobian matrix.Two main approaches have previously been considered to develop highly efficient integration methods for solving chemical-kinetic ODEs. The first involves efficient use of implicit methods conventionally employed for solving stiff ODEs22. Owing to use of the Courant–Friedrich–Lewy (CFL) number in compressible CFD analysis, the time-step size can be limited to very small values—of the order of 23, multi-time-scale method (MTS)13, and ERENA14 are examples of recently developed explicit methods widely employed in CFD analysis.The second approach for solving chemical-kinetic ODEs involves application of robust explicit methods4 and the performance was investigated via comparing results obtained upon its use during ignition simulation against those obtained using the ERENA (proposed previously by the authors)14, conventional CVODE10, and the efficiency method developed by the LLNL group (hereafter referred to as LLNL)16.The proposed study focuses on development of a Jacobian-free implicit method to leverage the advantage associated with reduction in computational time involved in Jacobian generation. This is all-the-more true with regard to cases involving sparse Jacobians. The primary objective of this research concerned the development of a fast and accurate integration method for solving stiff chemical-kinetic ODEs. Formulation of the proposed method has first been explained in this paper. The said formulation was based on optimization of the one-parameter family of integration equations (to facilitate error minimization) coupled with a dual time-stepping method. Lastly, the proposed integration method was incorporated into Zero-RK softwarey denotes the mass fraction; subscript i denotes the ith chemical species; c denotes the creation rate; and 14 was applied to Eq.  can be expressed ash influences time accuracy of the integration method. Therefore, different values of F(u) asF(u).Application of the DTS method facilitates easy attainment of the converged solution entclass1pt{minimaEquation  discretiq and Using eigenvalues mentclasspt{minimamentclass2pt{minimWhen Eq.  is applientclass1pt{minimah was divided by 4 for cases wherein the evaluated error increased within the inner loop.The proposed method based on the optimized value of n-14. Detailed reaction mechanisms considered in this study were generated in accordance with the Knowledge-basing Utilities for Complex Reaction Systems (KUCRS)25, and details concerning the number of chemical species and reactions considered have been summarized in Table This study compares the proposed MACKS approach against previously proposed ERENA, CVODE, and LLNL methods in terms of their prediction accuracy and computational cost with regard to solving several zero-dimensional, homogeneous ignition problems involving stoichiometric mixtures of mentclass2pt{minim14 in accordance with the equationIn this study, the accuracy with regard to the ignition-delay time estimated when employing the MACKS approach was first compared against that estimated using the combined CVODE, LLNL, and ERENA approaches with Next, the computational cost associated with the MACKS approach was compared against that incurred when employing the CVODE, LLNL, and ERENA methods with Reference to the above equation demonstrates that when “Efficient ratio” equals less than 1, the corresponding computational cost exceeds that incurred when using the CVODE method; likewise, when “Efficient ratio” exceeds unity, the associated computational cost is lower compared to that incurred using the CVODE approach. Corresponding results are depicted in Fig. To facilitate better understanding of characteristics of the MACKS approach, the following subsection discusses the case involving a h values of Time histories of temperature variations concerning the 27.Figure Lastly, time histories concerning the computational cost incurred per iteration when employing the MACKS, ERENA, CVODE, and LLNL approaches are depicted in Fig. This study proposes a fast and robust Jacobian-free time-integration method called MACKS to facilitate treatment of stiff chemical-kinetic ODEs. The proposed approach was derived using the optimized one-parameter family of integration formulae to facilitate minimization of aggregate error. Results obtained in this study demonstrate that use of the MACKS approach leads to lower computational cost associated with solving zero-dimensional ignition problems whilst achieving higher prediction accuracy compared to the CVODE approach. In addition, the MACKS has been demonstrated to possess higher accuracy compared to the ERENA method previously proposed by the authors.


Chimeric antigen receptor (CAR)-T cells (CART) remain one of the most advanced and promising forms of adoptive T-cell immunotherapy. CART represent autologous, genetically engineered T lymphocytes expressing CAR, i.e. fusion proteins that combine components and features of T cells as well as antibodies providing their more effective and direct anti-tumour effect. The technology of CART construction is highly advanced in vitro and every element of their structure influence their mechanism of action in vivo. Patients with haematological malignancies are faced with the possibility of disease relapse after the implementation of conventional chemo-immunotherapy. Since the most preferable result of therapy is a partial or complete remission, cancer treatment regimens are constantly being improved and customized to individual patients. This individualization could be ensured by CART therapy. This paper characterized CART strategy in details in terms of their structure, generations, mechanism of action and published the results of clinical trials in haematological malignancies including acute lymphoblastic leukaemia, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia and multiple myeloma. Adoptive T-cell immunotherapy represents a novel approach to treat malignancies by modifying T lymphocytes of the patient to recognize and eliminate cancer cells more effectively. This kind of strategy involves methods with the use of genetic engineering to introduce antigen-specific receptors on the surface of grafted T cells, which are then infused into the bloodstream. Consequently, it enables to specifically target malignant cells, which results in better therapy outcomes and potentially less severe adverse effects than in other treatments.Currently, there are three approaches to adoptive T-cell therapies developed to treat cancer, including T-cell receptor (TCR) modified T cells, tumour-infiltrating lymphocytes and chimeric antigen receptor (CAR) T cells (CART). Amongst these methods, CART remain one of the most advanced and promising form of adoptive T-cell immunotherapy. CART represents autologous, genetically engineered T lymphocytes expressing CAR aside from their natural TCRs. CARs are fusion proteins that combine components and features of T cells as well as antibodies thereby their anti-tumour activity is more effective. Since CART are equipped in costimulatory molecules they can be activated independently on antigen-presenting cells . In an ordinary microenvironment, NFAT is responsible for the expression of products essential for the proper cell function, such as cytokines. Activation of TRUCKs leads to the NFAT-mediated induction of cytokine expression. TRUCKs deliver transgenic material directly to the targeted tumour site, thereby avoiding the systemic toxicity. These constructs can also induce a secondary immune response against cells that have not been yet affected. Fourth-generation CART may cause an increased bystander T-cell activity towards cancer cells that do not express antigens recognized by modified T cells. This type of activity enables to eliminate cancer cells that would otherwise remain undetected by antigen-targeting agents. The bystander elimination process is caused by an increased expression of cytokines such as IL-12, IL-15, and IL-18  co-administration, which is a generation of two or more T-cell populations to include in the therapy; (2) bicistronic vector injection, which enables the vectored T-cell to express two different CARs; (3) co-transduction, which remains the most akin to traditional CAR engineering method, because it incorporates simultaneous manipulation of T cells with two different CAR constructs. (4) The last method is to encode two different CARs on the same protein by implementing a single vector. However, despite the fact that multi-targeted CART are a promising link in adoptive T-cell therapy, there are still some questions regarding their safety or efficacy. While the use of multiple targets aims to overcome the target antigen loss phenomenon, this construct is not able to avoid other resistance mechanisms to CART therapy. The other concern stems from the risk of developing severe adverse effects among the patients . One of the ways to increase the effectiveness of CART is to enable them to recognize multiple antigens. This can be achieved by engineering the T cells to target more than one type of cluster of differentiation (CD) molecules present on malignant cells. The major limitation causing therapy failure is an event called antigen loss. Multiple molecular mechanisms are responsible for antigen loss, such as acquired mutations or alternatively spliced The type of CART used in therapy also plays a crucial role in proper tumour management. First-generation of CART demonstrated incomplete T-cell activation, resulting in the insufficient secretion of IL-2, which is crucial for the proliferation of T cells  cells represent another subset of immune cells that can also be engineered to express chimeric antigen receptors, and thus be applied as a form of adoptive cell therapy for haematologic malignancies. NK cells are able to induce a different spectrum of cytokines, mainly IFN-γ, IL-3 and the granulocyte–macrophage colony-stimulating factor (GM-CSF). NK cells may not fully replace CART therapies, but they might become a form of complementary therapy. CART are being extensively used in clinical trials, with gaining the FDA approvals in recent years, while the CAR-NK construct has just entered the clinical trials market, with the first results published in 2020 . Another toxicity immediately following the CRS is neurotoxicity. It is correlated with neurological abnormalities, which untreated may become life-threatening. Hence, an enormous portion of CART research focuses on minimizing the toxicity of therapy . It usually occurs within the first week from the treatment implementation due to its life-threatening aftereffects , diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM) Table . The firALL is a haematological malignancy characterized by a transformation and proliferation of lymphoid progenitor cells. Malignant cells are present in bone marrow, blood, and extramedullary sites. ALL affects both children and adults, but its incidence is most prevalent between ages 2 and 5, making children 80% of all patients diagnosed with this condition  assessing the safety and feasibility of anti-C19 CART in therapy of children with chemotherapy resistant or refractory CD19Treatment of older children and young adults with relapsed or refractory ALL was investigated in a phase I dose-escalation clinical trial (NCT01593696). Patients under the age of 30 with relapsed or refractory ALL received infusions of CD19-targeting T cells with a CD28 domain. 60% of them achieved a minimal residual disease (MRD)-negative after the CART treatment. Since the usual follow-up step for MRD-negative remission in young patients with ALL is haematopoietic stem cell transplantation (HSCT), the majority of them underwent the transplant after achieving the remission and they remained leukaemia-free at the time of the median 10 month follow-up analysis. This study concluded that the CD19-CART therapy is not only a viable form of treatment, but also an effective approach to prepare patients with chemorefractory ALL to undergo HSCT  53 adult patients received the treatment with modified T cells, the median age of this group being 44 years. These patients previously received other extensive ALL-targeting therapies, as for 36 (68%) of these patients, the CART therapy was a third or later line of treatment. Some patients also previously received anti-CD19 treatment with blinatumomab, a bispecific T-cell engager targeting CD3 and CD19. The administered anti-CD19-CART treatment resulted in CR in 44 out of the 53 (83%) patients and the remission rate did not differ between groups of different therapeutic backgrounds. The results of this trial suggest that CART treatment may be an efficient option for patients who previously received other extensive regimens, including therapies focusing on the same antigens as ones recognized by CAR constructs  phase II clinical trial was conducted to assess the effectiveness and safety of anti-CD19 CART therapy, using a developed therapeutic agent called tisagenlecleucel. This CAR construct is manufactured using a lentiviral vector and it contains a 4-1BB costimulatory domain. In this study, 75 pediatric and young adult patients with CD19CLL is a haematological malignancy occurring in adults, characterized by a clonal proliferation of mature lymphocytes. The risk of developing CLL increases with age, with the median age of diagnosis being 70 years  patients, with two (25%) patients achieving clinical CR and one (13%) achieving partial remission of disease in the bone marrow .DLBCL is the most common type of non-Hodgkin’s lymphoma in adults and it makes up approximately 30–40% of all lymphoma cases worldwide , follicular lymphoma (FL), primary mediastinal B-cell lymphoma (PMBCL), with DLBCL being one of the trial cohorts  aimed to assess the efficacy and safety of CART therapy in patients with B-cell lymphomas, including MCL, FL and DLBCL. Over a half of treated DLBCBL patients had a chemotherapy-refractory form of lymphoma and other patients had DLBCL that relapsed after a maximum of ten months after receiving autologous stem cell transplantations as the most recent treatment. The overall remission among DLBCL patients was 68%, out of which 47% achieved CR and 21% achieved partial remission. The study also measured the levels of IL-15, as it is known to induce the proliferation of T lymphocytes. Biochemical analysis showed that the expression of IL-15 is associated with the effectiveness of therapy and its levels are higher in patients that had a stronger response to the CART treatment, as blood IL-15 levels were higher in patients that achieved disease remission  patients received a novel CD19-CART agent called lisocabtagene maraleucel, which uses 4-1BB as a costimulatory domain. The study included patients with relapsed and refractory aggressive non-Hodgkin lymphomas, including DLBCL, PMBCL, FL and MCL. In the cohort of 131 patients with not otherwise specified DLBCL, 89 out of 131 (73%) patients responded to the therapy, with 64 (49%) of them achieving complete remission  a total of 93 patients received CART infusions and were included in the study evaluation. The trial enrolled adult patients with relapsed or refractory DLBCL that had a poor prognosis. The complete response to the therapy was achieved in 40% of patients and the remaining 12% demonstrated partial response. The updated results of JULIET revealed that CART therapy can contribute to durable remissions among patients with relapsed or refractory DLBCL. One of the secondary endpoints was OS and it was met due to persistence and efficacy of infused CART  patients had an objective response, with 59 (58%) patients achieving complete response and 25 (25%) achieving partial response. Although the study included different sub-types of refractory B-cell lymphomas, the treatment outcomes were similar across all groups with different malignancies. The study also showed durable responses achieved even with a single infusion of axicabtagene ciloleucel. The remission lasted for more than 2 years and did not require consolidation therapy  was designed to assess the safety and feasibility of anti-CD138-CART treatment, along with the duration of in vivo survival of modified T cells. In response to the therapy, in four out of five (80%) patients the myeloma regression was noted, three patients had stable disease for over 3 months and one patient later advanced to plasma cell leukaemia  that focused on the safety, tolerability and engraftment potential of modified CD19-targeting CART in patients with MM after the melphalan treatment and autologous stem cell transplantation. The patients progressed within a year post-transplantation. Ten patients received the cell infusions and were included in the study analysis. At 100 days after the T-cell therapy, eight out of ten (80%) patients had at least a partial response (Garfall et al. While there is a search for different therapeutic targets for CART in MM treatment, BMCA remains the most often used antigen for this form of therapy. However, exploring other possible targets is important for further development of CART use in myeloma treatment (Goldschmidt et al. CART therapy is a promising approach to treat malignancies, but there are some limitations and questions for this type of treatment. The first factor that limits the use of CART therapy is its cost and availability. The process of generating modified T cells is highly personalized, as the constructs have to be produced specifically from the patient’s immune cells. In contrast to other existing immunotherapy-based approaches, such as immune checkpoint inhibitors, CART are not universal and cannot be mass produced. This reflects in high therapy costs and a limited number of facilities that can prepare and supervise the therapy. Genetic engineering of T cells requires advanced technologies using either viral vectors or other tools of gene editing, which may not be accessible in smaller laboratories. Patients receiving CART therapy also have to be monitored in facilities fully equipped to provide a highly controlled and sterile environment to lower the risk of infections (Hettle et al. There is also a risk of developing resistance to CART therapy in response to prolonged exposure to the modified cells especially in patients with relapse of ALL with negative expression of CD19 or with splice variant of CD19 without exon 2 that is recognized by scFv of CAR-T cells (Jacoby et al. The clinical trial enrollment process requires potential patients to fill multiple eligibility criteria. During enrollment, some patients cannot qualify as subjects for the CART therapy. One of the main reasons lies in the immunity issue. Apart from the presence of targeted malignancy, patients are required to be in a relatively good health condition to undergo therapy. Since most protocols of modified T-cell infusions include preparative lymphodepletion chemotherapy, patients with immunodeficiencies are at risk of highly endangering their lives with the pre-treatment alone. Moreover, being in a state of immune deficiency right before the T-cell administration exposes vulnerable patients to infections. Most patients undergoing CART therapy present poor immune function, related both with the prior cytotoxic treatment and the CART therapy itself. Reports state, however, that the immunodeficiency-related complication is similar to that of different cancer therapies, including chemoimmunotherapies (Hill et al. Every step of CART construction performed in vitro is significant for maintaining proper architectural properties of the construct and thus, it affects CART mechanism of action in vivo. The results of clinical trials performed in haematooncology provided promising effectiveness of CART in ALL, DLBCL, CLL, and MM. However, in some patients, there is also a risk of developing resistance to CART therapy in response to prolonged exposure to the modified cells. Thereby there are still a lot of questions that are not resolved and require more observations to improve the effectiveness of this therapy and limit toxicities.


The Funding statement is incorrect. The publisher apologizes for the error. The correct Funding statement is as follows: The publication of this study was funded by Agence nationale de la recherche (ANR) "Coping with Heterogeneous Opinions–CHOp" [ANR-17-CE26-0003]. The funder of this study had no additional role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study


Background: Stroke is one of the leading causes of disability with ~80% of post-stroke survivors suffering from gait-related deficits. Conventional gait rehabilitation settings are labor-intensive and need rigorous involvement of clinicians (who use their expertise to decide the dosage of exercise intensity based on patient’s capability). This demands a technology-assisted individualized exercise platform that can offer varying dosage of exercise intensity based on one’s capability. Here, we have used an individualized physiology-sensitive treadmill-assisted gait exercise platform. We wanted to investigate the implications of this platform on one’s lower limb muscle strength and muscle fatigue by analyzing surface Electromyogram (sEMG)-related indices and standard gait-related clinical measures. Methods: We designed a feasibility study involving post-stroke patients years; post-stroke period=3.1(±3)years) and gave them multiple exposures to this exercise platform. We investigated the Gastrocnemius Lateralis and Tibialis Anterior muscle activation prior to and post multiple exposures to our exercise platform while they walked overground. The feasibility study ended with collecting feedback on the patients’ perception on the implications of having gait exercise using such a platform on their ambulation capability. Results: The results showed that repeated exposures to this gait exercise platform can contribute towards gait rehabilitation of post-stroke patients with rehabilitation outcomes measured in terms of group average improvement of (i)~14% in muscle strength and (ii)marginal (~6%) in functional mobility (as in our case). Conclusion: Such a physiology-sensitive treadmill-assisted gait exercise platform can hold promise towards contributing to post-stroke gait rehabilitation in low-resource settings with the rehabilitation outcomes being measured in terms of sEMG-based observations. Physiology-sensitive gait exercise platform can offer individualised exercise and it can contribute towards improvement in the muscle strength and functional mobility of post-stroke patients and such a platform can hold promise towards contributing to post-stroke gait rehabilitation in low-resource settings. I.rd of the post-stroke survivors exhibiting pathologic gait Stroke is one of the leading causes of death and disability To address the deficits related to ambulation, these patients are prescribed gait rehabilitation exercises. The conventional gait rehabilitation therapy often encompasses overground gait exercise along with treadmill-assisted gait exercise. In conventional therapy, while the patient is performing exercise, it is necessary to have continuous involvement of a physiotherapist. This is because the therapist uses his/her expertise to decide the exercise dosage suiting the patient’s capability to do exercise. Though powerful, this can be susceptible to suffer from subjectivity in decision-making and also poses challenges in low-resource settings. This is particularly true in countries like India having limited healthcare resources and high patient-to-doctor ratio et al.Literature shows that monitoring one’s physiological activity can offer estimates of one’s capability to do exercise in terms of energy expenditure during exercise. One’s energy expenditure can be quantified in terms of oxygen consumption during the exercise. However, measurement of oxygen consumption requires a cumbersome and expensive setup that lacks portability and can be unsuitable for use in limited-resource settings. Another alternative to quantify one’s energy expenditure during exercise is measuring heart rate One’s muscle activation pattern can be quantified by analyzing the relevant electromyogram (EMG) signals. This is because the EMG signals can be easily accessed non-invasively using portable devices in terms of surface electromyogram (sEMG) and interpreted by technology-assisted platforms. Again, the sEMG signals corresponding to different phases of gait Given the importance of studying one’s lower limb muscle  activation and use of heart rate sensitive treadmill-assisted gait exercise platform for post-stroke patients, in our present research we have investigated the feasibility of use of such physiology-sensitive  treadmill-assisted gait exercise to contribute towards post-stroke gait quantified in terms of activation of GL and TA muscles during different gait phases. Again, we hypothesize that exposure to such a physiology-sensitive treadmill-assisted platform will contribute to the improvement in the lower limb muscle strength along with reduction in muscle fatigue thereby leading to reduction in the energy expenditure during gait. The objectives of our research were two-fold, namely to investigate (i) the implication of such a physiology-sensitive treadmill-assisted gait exercise platform on the lower limb muscle strength and muscle fatigue of post-stroke patients through analysis of (a) sEMG-related indices, e.g., mean absolute and root mean square values and (b) standard gait-related clinical measures corroborating the sEMG-based observations and (ii) patients’ perception on the implications of undergoing gait exercise using this platform on their ambulation capability.This paper is organized as follows: the methodology and apparatus used for the study are described in ‘Methods and Procedures’. The ‘Result and Discussion’ presents the outcomes of the study. Finally, ‘Conclusion’ summarizes the findings, discusses the limitations and future scope.II.A.Our system comprised of i) Instrumented Shoes, ii) Heart Rate Monitor, iii) Adaptive Treadmill Speed Switching Algorithm and iv) surface Electromyogram Data Acquisition.1)Sole was stored in a workstation for subsequent offline analysis. This data was used to identify the heel-strike and toe-off events to demarcate the swing and stance phases of a gait cycle In our research, we were interested to study the sEMG-based signatures of one’s gait while an individual underwent gait exercise using our Physiology-sensitive treadmill-assisted gait exercise platform. For this, we needed to measure the sEMG signal corresponding to stance and swing phases of one’s gait. These gait phases were identified using Instrumented Shoes (Shoe2)WALK) was computed from the R-R interval WALK was (i) fed as an input to the Adaptive Treadmill Speed Switching Algorithm and (ii) used to evaluate Physiological Cost Index (PCI)  using BIOPAC MP150 (Biopac Inc.) Data Acquisition (DAQ). For this, a three-electrode configuration was used in which Ag/AgCl disposable electrodes were pasted on either side of the neck  and fourth intercostal space  ex (PCI)  quantify3)WALK) and used a switching criterion. The switching criterion considered one’s age-related maximum HR (HRMAX) . The Algorithm was empowered to decide whether to maintain or offer higher challenge by increasing the treadmill speed   to compu4)In our study, we wanted to investigate the lower limb muscle activation pattern while one performed overground and treadmill-assisted walk. For this, we recorded the sEMG signals from two lower extremity muscles e.g., Gastrocnemius Lateralis (GL) and Tibialis Anterior (TA) 5)th order butterworth band-pass filter to remove motion artifacts and high-frequency noise nd order notch filter followed by smoothening of sEMG signal using a delay adjusted moving average filter (time constant = 50 ms) The sEMG data was collected wirelessly from the GL and TA muscles at 1000 samples/second via the DAQ and communicated to the workstation. The sEMG signals were filtered using a 2–200 Hz, 56)We extracted time-domain sEMG-related indices e.g., Mean Absolute Value (MAV) and Root-Mean Square (RMS) Here, s is the sampling frequency, fmed is the median frequency and P(f) is the Power Spectral Density (PSD) of the signal computed using a Kaiser window.Here, fB.In our present work, we have designed a study with post-stroke hemiplegic participants =48.33(±13.46)years). The recruitment of S_Group participants (who volunteered for the study) was based on a purely convenience sampling. While enrolling, care was taken that all the participants were capable of taking part in a 10 m overground walk test without any external support, could understand the experimenter’s instructions and have not undergone any major surgery in the recent past. Additionally, patients in the acute stage of stroke were not recruited. Out of the 15 post-stroke volunteers, 6 patients discontinued from the study due to personal reasons and their data was not included in the subsequent data analysis. The patients belonged to different ambulation categories 1)Sole).The experimental set-up  included2)FIRST), intermediate eight sessions and last session (SessionLASThenceforth) of gait exercise spanning over ~1 month while using our Physiology-sensitive Treadmill-assisted gait exercise platform. Each session comprised of a resting state baseline measurement, a 10m overground walk, a brief warm-up period with the treadmill and treadmill-assisted gait exercise for 10 minutes . The study began after obtaining the signed consent. A physiotherapist in our team examined the medical records  and conducted clinical evaluation of Motricity (indicative of muscle strength in the lower limbs) FIRST and SessionLAST. The experimenter helped the participant to wear the ShoeSole and applied electrodes post skin preparation. A harness was used to ensure safety during treadmill-assisted walk. No body-weight support was offered to the post-stroke patients.In our present research, we designed a feasibility study that exposed post-stroke participants to the Physiology-sensitive Treadmill-assisted gait exercise platform. A commitment of ~30 minutes per session was required from each volunteer. After collecting the participant’s demographic details, the experimenter showed the data collection setup and explained the purpose of the study to the participant. Each participant was informed that he could discontinue from the study at any time in case of inconvenience. The experimenter told the participants that they will be offered 10 sessions . While there are maximal and sub-maximal approaches to normalization FIRST and SessionLAST. Subsequently, we investigated whether the standard gait-related clinical measures corroborated with the sEMG-based observations. Given a limited sample size, we opted for non-parametric statistical test, such as Wilcoxon Signed-rank Test Additionally, as a step towards understanding the clinical significance of the changes in sEMG-related indices, we carried out a comparative analysis of the standard gait-related clinical measures, such as Motricity Index quantifying muscle strength and Rivermead Mobility Index quantifying the functional mobility during overground walk prior to SessionIII.OGhenceforth) and physiology-sensitive treadmill-assisted walk  exercises, we computed their sEMG-related indices corresponding to stance and swing phases as identified by the ShoeSole. Our aim was to investigate the implication of the physiology-sensitive treadmill-assisted gait exercise platform on one’s lower limb muscle strength and muscle fatigue in terms of time-domain and frequency-domain sEMG-related indices. For this, we carried out analysis of the standard gait-related clinical measures to understand whether these can corroborate the sEMG-based observations. Finally, we wanted to understand one’s perception on the implications of undergoing gait exercise using such a platform on their ambulation capability.While the participants volunteered in the overground  and SessionLAST.While the participants took part in the feasibility study, we wanted to investigate the implication of the physiology-sensitive treadmill-assisted gait exercise platform on the muscle strength and muscle fatigue of post-stroke survivors in terms of the time-domain and frequency-domain sEMG-related Indices. We examined the sEMG pattern and analyzed the sEMG-related indices for WalkComparative Analysis of Time Domain sEMG-related Indices during PreWalkOG and PostWalkOGPre WalkOG and Post WalkOG. It can be seen from Pre WalkOG to Post WalkOG on the Affected side of the patients thereby reflecting increased muscle strength of the lower limb muscles of the Affected leg during the overground walk. In contrast, for the Unaffected leg, we see a reduction in the MAV and RMS values for both the GL and TA muscles from Pre WalkOG to Post WalkOG. Such an observation can be attributed to a reduction in compensatory gait strategies We wanted to investigate the sEMG-related time-domain indices, such as MAV and RMS values Pre WalkOG and Post WalkOG. For the statistical analysis, we had 16 degrees of freedom and we also analyzed the effect size (r) for the Wilcoxon signed-rank test. For the Affected side, results indicate statistical significance  for MAV of GL, marginal significance for RMS value of both GL and TA muscles. Again, for the Unaffected side, the MAV and RMS of GL were found to be statistically significant . In short, we can say that exposures to the physiology-sensitive treadmill-assisted gait exercise platform have contributed to statistical improvement in one’s lower limb muscle strength.We carried out a dependent sample non-parametric statistical test (Wilcoxon signed-rank test) on the MAV and RMS values corresponding to OG and PostWalkOGComparative Analysis of Frequency Domain sEMG-related Indices during PreWalkPre WalkOG and Post WalkOG. It can be seen from the Pre WalkOG to Post WalkOG. However, for the TA muscle, we observed a decrease in the MF and MDF values for the Affected leg that was not the case for the Unaffected leg. An increase in the MF and MDF values for the Unaffected side might imply a reduction in the muscle fatigue. Such an inference can be bolstered by quantifying the energy expenditure in terms of Physiological Cost Index (PCI)  . In factPre WalkOG and Post WalkOG. The MF and MDF values for GL and TA muscles were found to be statistically different  for the Unaffected side and  for the Affected side between the Pre WalkOG and Post WalkOG, except that for MDF for GL in the Unaffected side. To summarize, we can say that exposures to the physiology-sensitive treadmill-assisted gait exercise platform have contributed to statistical reduction in the muscle fatigue.We carried out a dependent sample non-parametric statistical test (Wilcoxon signed-rank test) on the MF and MDF values corresponding to OG and PostWalkOG: Morphology of the sEMG Pattern during PreWalkPre WalkOG and Post WalkOG through visual inspection. The Figs. 5(a)-5(h) display the envelope of the average rectified sEMG signal of one of the participants -5(h)) for both GL and TA muscles in their respective gait phases  inferring improvement in muscle strength. While considering Figs. 5(a), 5(e), 5(c) and 5(g), we could observe a reduction in the activation of GL and TA muscles during Post WalkOG inferring reduction in compensatory gait mechanisms during one’s walk after multiple exposures to our platform. In other words, it might infer that the post-stroke patients increased the usage of their Affected leg during their walk. Again, from Figs 5(b), 5(d), 5(f) and 5(h), we can see that there was an increment in the GL and TA activity in the Affected leg during Post WalkOG as compared to that during Pre WalkOG inferring improved muscle activity and muscle strength during one’s walk. Also, improved TA muscle activity in the Affected leg from Pre WalkOG to Post WalkOG, but not for the Rivermead Mobility Index. To summarize, we can say that exposures to the physiology-sensitive treadmill-assisted gait exercise platform have contributed to variations in the standard gait-related clinical measures (through varying degrees) that corroborated with our sEMG-based observations. In other words, the sEMG-related indices can hold promise towards offering complementary measures for monitoring gait rehabilitation outcomes while patients are exposed to such a physiology-sensitive treadmill-assisted gait exercise platform.C.We wanted to understand the users’ perception on their ambulation capability based on their experiences after undergoing repeated gait exercise using our physiology-sensitive treadmill-assisted gait exercise platform. For this, we recorded post-study feedback from the patients to understand the implications on their ability to walk with improved toe clearance, heel lift and their endurance while walking for longer distances during their daily activities after undergoing gait exercise using our platform. Different participants narrated varying experiences. For example, P1, P2, P4 and P7 mentioned that they felt that they were able to raise their toes sufficiently helping them to easily avoid any small obstacle on their path post exercise. This might infer improved muscle activation and strength related to TA muscle during walking. Also, they reported that they felt using staircase less difficult than before. This might be due to their improved muscle strength related to GL and TA muscles. Additionally, P4 and P7 said that he could walk longer distances with reduced discomfort in his lower limbs. When asked to specify the nature of the discomfort, he said that earlier he used to feel that his legs were becoming heavy after a short walk. However, now he can walk longer distances at a stretch (without taking breaks in between) since he does not feel that his legs are becoming heavy. It can be seen from literature that this feeling of heaviness in the legs might be associated with muscle fatigue IV.Neurological disorders, such as stroke can severely affect one’s muscle activity, thereby deteriorating one’s ambulation capability and functional independence. A deconditioned stroke survivor needs to be offered with gait exercise based on his capabilities. In our present research, we have investigated the use of a physiology-sensitive treadmill-assisted gait exercise platform for offering gait exercise to post-stroke patients in an individualized manner. Specifically, the platform was adaptive to one’s individualized energy expenditure estimated from his / her heart rate and in turn offered treadmill-based varying exercise intensities. Our post-stroke patients were offered multiple exposures to this platform while they took part in a feasibility study. Additionally, we acquired the surface Electromyogram (sEMG) data from one’s lower limb muscles that can offer implicit gait-related measures. The idea was to investigate the implication of such a physiology-sensitive treadmill-assisted gait exercise platform on the lower limb muscle strength and muscle fatigue of post-stroke patients through analysis of the sEMG-related indices. Further, we measured standard gait-related clinical measures to corroborate our sEMG-based observations. The feasibility study ended with collecting feedback to understand the patients’ perception on the implications of having gait exercise using such a platform on their ambulation capability. Results of our study showed that repeated exposures to our physiology-sensitive treadmill-assisted gait exercise platform can contribute towards gait rehabilitation of post-stroke patients with rehabilitation outcomes measured in terms of (i) sEMG-based observations and (ii) standard gait-related clinical measures corroborating the sEMG-based findings.Though the results are promising, yet our study had some limitations. For example, we had a limited sample size and the post-stroke volunteers had heterogeneous characteristics. Also, the number of exposures given to each patient was limited. While our study was designed as a proof-of-concept and not as a full-fledged rehabilitation work, in future, we plan to extend our work by carrying out longitudinal study involving larger participant pool while segregating the post-stroke patients based on their extent of disability. This might help us to understand whether there exists any relation between the dosage of exercise (that is the number of exposures to our gait exercise platform) and the extent of gait-related disorder. Another limitation is that here we offered varying exercise intensities by changing the treadmill speed. It might so happen that one’s neurological or biomechanical factors can prevent one to cope up with the increased treadmill speed. Presently, to account for such a limitation, we have enrolled patients who could walk on level ground without any external support. Another alternative to offering varying exercise intensity can be to increase the elevation of the treadmill belts while maintaining the treadmill speed. Additionally, a limitation of our presently used physiology-sensitive treadmill-assisted gait exercise platform was that it used BIOPAC MP150 module to measure one’s Heart Rate and sEMG wirelessly. This is an expensive device and comes with wearable transmitters along with tabletop mounted receiver adding to the complexity and cumbersomeness of the platform. With an aim to reduce the cumbersome and complex nature of the connectivities on account of the measurement of heart rate and sEMG, we are now working towards interfacing our system to commercially-available, light-weight, wearable watches (offering heart rate information) and light-weight sEMG modules.Nonetheless, the findings of our feasibility study show that gait exercise with such a physiology-sensitive treadmill-assisted exercise platform can contribute to improvement in one’s muscle strength and reduce muscle fatigue along with ensuring efficient energy expenditure. Again, such a physiology-sensitive treadmill-assisted exercise platform can offer a complementary tool in the hands of a clinician so that one therapist can cater to multiple patients at the same time, thereby alleviating problems of limited healthcare resources. Thus, such a physiology-sensitive treadmill-assisted gait exercise platform can hold promise towards bringing a paradigm shift in the area of post-stroke gait rehabilitation in low-resource settings.