The transition from traditional to truly smart dynamically adaptable manufacturing demands the adoption of a high degree of autonomy within automation systems, with resultant changes in the role of the human, in both the manufacturing and logistics functions within the factory. In the context of smart manufacturing, this paper describes research towards the realization of adaptable autonomous automation systems from both the control and information perspectives. Key facets of the approach taken at WMG are described in relation to human–machine interaction, autonomous approaches to assembly and intra-logistics, integration and dynamic system-wide optimization. The progression from simple distributed behavioural components towards autonomous functional entities is described. Effective systems integration and the importance of interoperability in the realization of more distributed and autonomous automation systems are discussed, so that operational information can propagate seamlessly, eliminating the traditional boundary between operational technology and information technology systems, and as an enabler for global knowledge collection, analysis and optimization.This article is part of the theme issue ‘Towards symbiotic autonomous systems'. The general trend is towards greater flexibility, and in the context of autonomous decentralized systems, we are in the paradigm of Industry 4.0 and digitalization where (at its heart) optimization becomes core to the realization of the smart factory.A number of research groups are looking at the potential for self-organizing manufacturing systems . Such apThe transition from traditional to truly smart, dynamically adaptable, manufacturing demands the adoption of a high degree of autonomy within automation systems, with resultant changes in the role of the human, in both the manufacturing and logistics functions within the factory. Automation should be sympathetic with its operators and sustainable as well as profitable. In the context of smart manufacturing, this paper describes research towards the realization of adaptable, autonomous, automation systems from both the control and information perspectives.Adaptive automation can only be effectively realized through a coherent system-of-systems approach where many distributed subsystems need to coexist, effectively communicate, and be mutually optimized in order for the much-vaunted potential of industrial digitalization to be attained.et al. [As reported by Ng et al. –8, thereet al.  reveals Engineering tools also have a major role to play in effectively supporting the lifecycle from design through deployment to operational optimization and to change management . From a Dynamic adaptability thus sees a distributed combination of autonomous actors in a self-organizing and adaptable system-of-systems with emergent behaviours. In the manufacturing context, this needs to be augmented by the overarching optimization of the overall production system. This paper considers the overall concepts in a symbiotic context via consideration of a set of complimentary research activities at the University of Warwick.. 2Dynamically adaptable manufacturing automation (DAMA) research at WMG aims to realize a consistent model-driven approach integrating and distributing both controls and analytics to yield more optimized production systems, which can be dynamically adapted and consistently engineered and changed with maximum robustness and security. Making KPIs visible to machine operators and managers achieving a consistent ‘single source of truth’ is a key objective of the work.Having established the context for the work, the remainder of this paper will now look at four key facets of the approach taken at WMG in relation to (i) better human–machine interaction, (ii) autonomous approaches to assembly and intra-logistics within the production context, (iii) the need for the integration of these autonomous systems, and (iv) to support the dynamic optimum combination of local autonomous activities, combined with global optimization, to meet often complex performance objectives, e.g. with regard to operational efficiency, energy and sustainability goals in the context of the circular economy and the emerging drivers for industrial performance in a Net Zero world.The Automation Systems Group at WMG is building a set of full-scale demonstrators to enable the realization of DAMA and its effective showcasing to the industry in the context of real production problems. These demonstrators are modular and reconfigurable systems and hence the applications can be progressively changed as new requirements emerge. The application scenarios being trialled all relate to real-use cases with industry partners.. 3 (a)As highlighted by Sundblad, the debate within manufacturing about whether technology will completely replace people is interesting, but it is the wrong debate . The dis (b)Autonomous systems that require human collaboration (or intervention) are known as symbiotic autonomous systems. However, introducing humans in the loop presents technical challenges. The DAMPO project focuses on developing an innovative solution (combination of hardware and software) and engineering methods to enhance the design and monitoring of complex and safety critical manual assembly processes in the manufacturing industry. The DAMPO project development relies on the effective integration of optical position tracking and data capture technology, methods and solutions for mass data visualization and analytics, and engineering methods for manual operations design optimization.The vision of DAMPO is to achieve seamless interaction between the digital systems and human operators in order to effectively augment manual operations. The key objectives of the project are to (i) enable unobtrusive and effective data capture of processes carried out by human operators, (ii) provide contextualized, structured and, when needed, near real-time information feedback to the operator and (iii) support continuous data-driven process optimization in view of improving both process effectiveness  and operator well-being .The data capture systems deployed and tested include active and passive marker-based optical pose tracking systems, marker-less 2D/2.5D/Lidar camera systems and IMU cluster systems. In order to minimize process interferences and deployment constraints, markers and IMUs when used, are fitted on various components in the station/cell  rather than on the operators. These systems allow capture of both operators' related data (e.g. skeleton pose and joints position tracking) and process-related data (e.g. fixtures/tools/parts location detection and tracking). Inside-out relative location tracking using tool-mounted camera and image processing is also being investigated and developed.The DAMPO project adopts a holistic and data-driven approach to the optimization of manual operations. Data processing and analytics functions are developed to support ergonomic and cumulative fatigue-oriented optimization of operator work, station and process layouts optimization, as well as supporting quality assurance and process traceability. The functions rely on the processing and evaluation of instant data streams , as well as on the analysis of historical datasets. DAMPO focuses on developing unsupervised machine-learning optimization models using a combination of specific datasets  in order to support station layout, processes, manual operations and potentially also product designs. The project testbed is shown in The DAMPO project includes the development of information delivery and presentation methods tailored to specific users and to the interactions required with the system. Screen-based HMIs and headset-based AR application are used to deliver contextual information back to the operators . To further develop the interaction between digital system and human operator, AR is used in the DAMPO project to develop a solution allowing the operator to identify specific product features and attach contextual information. This system was primarily developed to enable in-process and in-line labelling of defects , which effectively allows quality technicians to build the dataset required to train a deep learning-based defect detection model. This highlights the potential of human/digital system symbiosis to define and develop new roles for operators on the shop floor and to reduce the overhead of workflows associated with the deployment and use of data-driven methods; offline labelling of two-dimensional images required for the training of supervised machine-learning model in this case.. 4 (a)Many emerging manufacturing processes now require the flexible integration of people working cooperatively with robots and autonomous guided vehicles, e.g. to closely combine assembly automation with materials handling. The aim is to minimize non-value adding activities within adaptable processes, so that the product variety and volumes can be dynamically changed.With the recent shift towards more and more online trading, there has been an explosion in the need for logistics, and the biggest challenge facing the logistics industry today is labour availability. The mass arrival of robotics in logistics is no longer in question. It is happening now and the widespread presence of robots in warehouses is becoming a reality, and in turn there will be widespread utilization of robots in the intra-logistics context of manufacturing automation, with the blurring of the boundaries between internal logistics systems and manufacturing automation systems in flexible and novel configurations working alongside human operators.From relatively simple pick-and-place operations, there is a progression now to more intelligent capabilities. For example, to handle a range of tasks where different tools are required, aided by the evolution of modularity in the robotic systems and the configuration of different transport systems to allow such autonomous systems to be used for a wide variety of tasks, in a variety of environments. (b)The DIALOG research project at WMG addresses the fact that much of manufacturing and indeed industry more widely operates in a far from optimal manner in the face of volatile customer preferences and often unforeseen disturbances.The vision is for practical, dynamically adaptable automation systems that are readily scalable. Further to this, the concept is to enable a new form of low-cost manually operated intra-logistics systems that can be readily and progressively automated through the addition of autonomous mobile robots (AMRs).The application focuses on integrating this system of systems within a generic infrastructure and related configuration tools, with use cases in the automotive seat assembly, riveted body assembly fastening, battery module and pack production, horticulture, and food and drink sectors. These will be oriented around the application of a generic approach based on the use of a new modular AMR system, and related integration and engineering tools for their deployment, integration and optimization. There are many innovative aspects to this work in the context of the role of machine operators and the human-centric perspectives on such systems of systems. There are opportunities to scale such systems through the flexible interplay of autonomous production movements combined sympathetically with manual operations with the operators guided by suitable tracking and traceability technologies.The DIALOG project provides a modular platform and a generic framework for the deployment and optimization of modular plug-and-play AMR-based intra-logistic system on production shop floors to realize dynamic adaptability from both physical and control perspectives. The project exploits the use of modular trolleys with standard mechanical and electrical interfaces to enable towing of a wide range of trolleys with AMRs for various applications . To communicate and integrate with automation systems, control functions are encapsulated and hence can be deployed and (re)configured as needed without the need to reprogram the entire system controls and communication functions. The combination of this hardware and software Lego-like plug-and-play capability allows for re-design and re-configuration of the logistics system as new requirements emerge.The integration framework for the DIALOG project is shown in In the digital twin space, optimized scheduling is realized through the use of what-if engine and discrete event simulation (DES) of the physical resources coupled with optimization algorithms. The decision support module is a real-time information delivery gateway and provides an interface for operators to interact with the system to predict the performance of the overall system. The decision support module is coupled with the simulation and optimizer modules and uses an inference engine to help operators in making informed decisions. Further details can be found in ,17.. 5 (a)Previous work by the automation systems group at WMG on the knowledge-driven configurable manufacturing and other related projects has pioneered a component-based approach to reconfigurable production systems . This reThe use of a component-based approach for automation system development and implementation draws inspiration from component-based development (CBD) concepts and uses a distributed control methodology to encapsulate standard control functionality into common automation elements known as components. The manufacturing automation system can then be developed around these pre-build components by configuring them according to the desired application behaviour . The CBDCommunication between distributed components can be realized in a variety of ways, e.g. using either proprietary or open networking systems and protocols. For example, the FP6 SOCRADES project involving WMG evaluated several service-oriented architecture solutions, applicable at the device level integration, including DPWS and OPC-UA, in the context of manufacturing automation. To address the integration of very large numbers of subsystems and devices, the subsequent AESOP project took its roots in previous work in several European collaborative projects , which demonstrated that embedding web services at the device level and integrating these devices with systems at upper levels of an enterprise architecture was feasible. (b)While the previously described projects notably advanced connectivity both with, and between, autonomous devices, the ability of end-users to simply, consistently and reliably integrate key information across diverse production systems is currently a major barrier to productivity gains in industry and is thus the focus of the current SIMPLE research project at WMG.A fundamental challenge in deploying effective digital capabilities is the integration of systems within and across the operational technology (OT) and information technology (IT) layers of manufacturing organizations. This integration is typically currently hindered by either a lack of identifiable frameworks, design methods and engineering tools (technology diversity and fragmentation) or by the cost, complexity and long-term strategic lock-in associated with the adoption of proprietary and monolithic commercial solutions. The SIMPLE project applies innovative software technology to address this need, proving the resultant solution in a practical and widely applicable industrial form.Data pipelines and information flows are essential to the architectural and operational integration of various systems within and between manufacturing organizations. The SIMPLE platform development, The effectiveness of data-driven monitoring and optimization systems directly depends on the quality of the datasets. The SIMPLE PPR model promotes systems and methods that focus on collecting complete sets (product process and resource data types) of high-quality data rather than large sets of heterogeneous, unstructured and uncontextualized data (‘Big Data/Data Lake’ approach). The SIMPLE platform PPR data models support the definition of data metrics and quality assessment functions that contribute to inform (and educate) production and manufacturing engineers on the quality of the data collected from the processes and systems in the shop floor.The SIMPLE platform specification guides the implementation of the PPR model across various types of databases and data management systems. Currently, relational (v-Core), NoSQL and time series databases (v-Log) configurations are being developed for various industrial use cases, and the future project phase will focus on extending the SIMPLE data model to include knowledge representation  and their implementation in graph databases.The SIMPLE platform implementation also supports the integration of industrial and IT level networks and communication protocols. Specific platform components (v-Hub connectivity toolbox and v-Com pub/sub broker) provide IT/OT and IT/Cloud connectors to support the deployment of robust and scalable data workflows.The application layer of the platform SIMPLE provides a set of pre-defined  data processing and analytics functions, as well as the corresponding production monitoring dashboards, to support common manufacturing requirements and use cases: e.g. monitoring and predictive analysis of production-related data such as process performances, quality, product traceability and maintenance-related information. Various software modules support the deployment configuration, maintenance and general administration of the platform's components.. 6Many research projects and industrial companies are working towards the realization of Industry 4.0 and the self-organizing factory. In this context, several leading academics have recently commented on the fact that the real core concept of Industry 4.0 is related to optimization, as discussed in §1. Once the necessary connectivity has been realized to enable the collection of good quality data capable of forming the basis of actionable insights derived from the multitude of devices, the challenge is dynamically optimizing production through both local and global adaptations.Decision support and optimization of manufacturing processes in real-time are demanding tasks. Simulation-based offline optimization techniques are increasingly used in industry today to perform what-if analysis based on foresight of possible disruptions/changes on shop floors. However, such an approach only partially improves system performance. There is a need for a real-time dynamic optimization approach that couples simulation models with machine-learning and optimization algorithms.To address this problem, WMG is carrying out research in collaboration with Polytechnic Institute of Braganca using a digital twin-based optimization approach coupled with AI and decision support systems. This research is using a PPR data model developed in the SIMPLE project  to feed A proof-of-concept demonstrator has been developed at WMG using the integrated manufacturing and logistic (IML) rig at WMG which is a prototype automotive battery module and pack assembly line; Optimization is carried out based on target production and real-time data collected from IML for two different aspects: (a) AMR dispatch scheduling optimization to dynamically optimize line-side supply and pallet transportation and (b) AMR energy management to optimally charge the AMR batteries with minimum impact on production schedules. Both of the optimization problems are complex in nature as the scheduling decision is based on multiple variables and multiple criteria.The developed framework for optimization is based on three main components: a simulation module, an analytics module and a decision support module. The simulation module is essentially a DES of the facility developed in Witness which is coupled with a what-if simulation engine to simulate various scenarios. The analytics module is sub-divided into optimization and machine-learning modules. The optimization module uses mixed-integer nonlinear programming using a genetic algorithm integrated with the DES model. The ML module learns from the previous decisions taken and their resultant impact on KPIs of the system. The decision support module provides an interface for users to interact with the analytics and simulation modules to perform what-if analysis to determine optimal system variables for (re)scheduling of AMRs. The interface allows users to rate decisions which can be used to determine the trust level of decisions.Beyond simulation-based and AI-based process optimization, and as highlighted by Ng, digitization methods and tools supporting the design and improvement of next-generation manufacturing systems must be developed to take into account all levels of operation and their complex interactions, in order to provide strategic and tactical support, and operational decision-making in a multi-criteria context is needed, as exemplified by their knowledge-driven optimization research programme ,22.. 7A set of inter-related research activities at WMG have been used to describe progress towards the realization of DAMA systems. There is a significant opportunity to create a unified approach to autonomous control and analytics, both locally and globally. The DAMA vision is to enable adaptable manufacturing systems to be engineered efficiently, incorporating analytics and supporting both local and global optimization. It envisages a new paradigm of integrated data models spanning the complete lifecycle to effectively support dynamic adaptability, establishing effective lifecycle digital twins, where such models are directly deployable to the shop floor and maintained throughout the production system and associated product lifecycles.Particular challenges now relate to achieving globally optimized performance while at the same time allowing dynamic adaptation to occur within distributed autonomous systems, enabling self-optimization while at the same time adapting to global system challenges. For example, in relation to energy efficiency and sustainability, and in the context of larger ecosystems, extending across supply chains and throughout complete lifecycles in a circular economy.


Breast density is considered to be one of the major risk factors in developing breast cancer. High breast density can also affect the accuracy of mammographic abnormality detection due to the breast tissue characteristics and patterns. We reviewed variants of local binary pattern descriptors to classify breast tissue which are widely used as texture descriptors for local feature extraction. In our study, we compared the classification results for the variants of local binary patterns such as classic LBP , ELBP , Uniform ELBP, LDP  and M-ELBP (Mean-ELBP). A wider comparison with alternative texture analysis techniques was studied to investigate the potential of LBP variants in density classification. In addition, we investigated the effect on classification when using descriptors for the fibroglandular disk region and the whole breast region. We also studied the effect of the Region-of-Interest (ROI) size and location, the descriptor size, and the choice of classifier. The classification results were evaluated based on the MIAS database using a ten-run ten-fold cross validation approach. The experimental results showed that the Elliptical Local Binary Pattern descriptors and Local Directional Patterns extracted most relevant features for mammographic tissue classification indicating the relevance of directional filters. Similarly, the study showed that classification of features from ROIs of the fibroglandular disk region performed better than classification based on the whole breast region. It is estimated that one in eight women have the chance of getting breast cancer in their life time . Cancer There are different breast classification schemes in the literature based on the breast tissue features used. It has been shown that there is a strong correlation between the breast parenchymal patterns/density and the risk of developing breast cancer and Wolfe et al. classified breast density into five categories . ThereafThe classification of mammographic images based on tissue type density and mammographic risk estimation was initiated by Wolfe , which wFrom the above, it is clear that texture has played a role in density segmentation/classification. Ojala et al.  introducWe have used Elliptical Local Binary Pattern (ELBP) , UniformIn addition to our initial work in , the effA further extension to the previous work . For a neighbourhood of eight, LBP can generate 256 different binary patterns. The Ojala et al.  proposede see in a. If theELBP), for each central pixel P which lie on an ellipse , we consider the mean intensity values  and the probability of correlation between features increases. To retain only prominent features and to reduce the computational cost due to high dimensionality, feature selection was performed on the extracted feature vector. A correlation based feature subset (CFS) selection method  with a bk values from Additionally, to compare the directional feature extraction capability of the M-ELBP descriptor and the importance of directional texture feature descriptors for extracting mammographic parenchymal features, we compute the classification accuracy of the Local Directional Pattern (LDP) . The LDPSubsequently, to study the effect of classification using the whole breast and different sized ROIs, varying sizes of ROIs were extracted ranging from Similarly, to study the effect of the descriptor size on tissue classification, we performed the experiment as described in The evaluation presented in this paper was performed on the Mammographic Image Analysis Society (MIAS) dataset . The datFor the comparison of classification by different Local Binary Pattern variants, we performed LBP, ELBP, uniform-ELBP and M-ELBP and LDP on ROIs of size orm ELBP . To keepTo understand the effect of intensity features in mammographic breast tissue classification, our proposed variant of ELBP , M-ELBP Similarly, to analyze the role of directional texture descriptor for mammographic density estimation, we used the LDP  operatorWhen considering In order to analyze the significance of the test for different texture descriptors , we perfMachine learning approaches have a great impact on medical image classification and can provide valuable predictive information to guide treatment decisions . In ordes see in  taking bSimilarly, the area under the ROC curve (Az)  was calcFrom the experimental studies, the M-ELBP and LDP performed better in classifying the mammographic breast tissue showing the importance of directional filters in feature extraction. In-order to avoid the classifier effect on classification accuracy, we use the Bayesian network for further experiments in the paper.N = number of runs) for a 10-fold cross validation scheme. Similarly, from To compare the effect of descriptor size on classification, the M-ELBP operator with varying size of N indicate a distinct run) while the whole breast region  from mammographic images for breast tissue classification. The study showed that selecting the size of the ROIs at i et al.  where ROi et al.  showing Further results on the selection of the ROI size showed that smaller ROIs can lead to decreased classification due to lack of texture patterns extracted and very large ROIs can include irrelevant features, again resulting in decreased classification. The ROI size indicated is comparable with the results shown by Sharma et al. .For future work, we will focus on developing a method which extracts additional multidimensional directional pattern features by focusing on the edge responses of each pixel and gradient changes. Additionally, the classification accuracy of boosting algorithms like XGBoost based on gradient boosting will be analyzed . Similar


Cardiorenal syndrome (CRS) concerns the interconnection between heart and kidneys in which the dysfunction of one organ leads to abnormalities of the other. The main clinical challenges associated with cardiorenal syndrome are the lack of tools for early diagnosis, prognosis, and evaluation of therapeutic effects. Ultrasound, computed tomography, nuclear medicine, and magnetic resonance imaging are increasingly used for clinical management of cardiovascular and renal diseases. In the last decade, rapid development of imaging techniques provides a number of promising biomarkers for functional evaluation and tissue characterization. This review summarizes the applicability as well as the future technological potential of each imaging modality in the assessment of CRS. Furthermore, opportunities for a comprehensive imaging approach for the evaluation of CRS are defined. Cardiorenal syndrome (CRS) is an umbrella term describing the interactions between concomitant cardiac and renal dysfunctions, in which acute or chronic dysfunction of one organ may induce or precipitate dysfunction of the other . CRS hasDespite the existing literature on the classification and management of CRS, the clinical diagnosis and treatment evaluation remains difficult due to the lack of clinical practice guidelines . This haCardio-renal syndrome can be classified into five subtypes , with tyThe exact pathophysiological mechanisms of each type of CRS have not been fully elucidated. Previously, decreased cardiac output and arterial underfilling induced neurohumoral activations were believed to be the sole pathogenesis of CRS . HoweverHemodynamic alterations, especially right-sided heart dysfunction, is believed to be of critical importance in the development of acute CRS (type 1 and type 3) . In typeNon-hemodynamic pathways play a more critical role in chronic CRS (type 2 and type 4). Activation of RAAS and stimulation of sympathetic nervous system are features of both heart failure and CKD. Persistent activation of RAAS leads to peripheral vasoconstriction, exacerbated fluid overload, and sympathetic nervous system overactivation ,22. SympFibrosis has been considered as a key driver in the pathophysiology of chronic CRS . FibrogeIn most circumstances, the complex interconnected pathways between heart and kidneys have already been activated by the time clinical manifestations are detectable. Both heart and kidneys have substantial functional reserve, which makes it difficult to prevent or reverse the adverse impacts of CRS at an early phase. While all types of CRSs are faced with difficulties in early diagnosis and prognosis, the dominant clinical challenges distinguish between acute CRS and chronic CRS .The main challenges in acute CRS are related to AKI . CurrentIn chronic CRS, however, the main difficulties lie in the cardiac aspect . PatientDespite the amount of effort in research studies of novel serum and urinary biomarkers, it remains unclear whether and to what extent these biomarkers can be involved in clinical management of CRS . MoreoveDifferent imaging modalities can be applied in relation to CRS that enabling comprehensive assessment of both morphology and function . AlthougTransthoracic echocardiography (TTE) is the most available non-invasive imaging technique to measure the dimensions of cardiac chambers and to estimate ventricular functions. TTE-measured left ventricular ejection fraction is the first-line tool to differentiate between heart failure with reduced ejection fraction and heart failure with reserved ejection fraction . TTE can2), considering the potential increased risk of gadolinium retention and nephrogenic systemic fibrosis in patients with renal dysfunction  PET and β-Methyl-p-[123I]-iodophenyl-pentadecanoic acid SPECT [Nuclear cardiac imaging has played an important role in evaluating myocardial perfusion in ischemic heart diseases. Single-photon emission computed tomography (SPECT) is commonly employed for the diagnosis of CAD in patients with CKD . However imaging . Myocardid SPECT  Hybrid iRenal ultrasonography is routinely used to assess renal morphology such as renal length, corticomedullary differentiation, and to identify obstruction. The usefulness of ultrasonography to identify the underlying cause of renal diseases is limited, furthermore no distinction between inflammation and fibrosis can be identified by echogenicity . Renal DInitial applications of renal MRI have been focused on the visualization of renal and urogenital anatomy. Conventional renal MRI sequences can be used to measure total kidney volume, which is an FDA-approved prognostic biomarker , with hiRenal parenchymal oxygenation is of paramount importance in the pathophysiology of AKI and CKD . Blood oArterial spin labeling (ASL) assesses tissue perfusion by labeling the water protons in the blood before they enter the tissue of interest, and subtracting the labeled image from a control image without labeling blood water. The signal intensity of the subtracted perfusion-weighted image is proportionate to perfusion. ASL has been widely used to calculate cerebral perfusion in various brain diseases . Renal pRenal DWI, diffusion tensor imaging (DTI), T1 and T2 mapping have been studied to assess interstitial fibrosis . Renal c2). Dual-energy CT might offer opportunities to assess renal parenchyma without contrast agent. Renal nuclear imaging such as renal scintigraphy, SPECT, and PET have been used for quantification of GFR and renal perfusion. However, they are not ideal for frequent assessments due to radiation, thus not suitable for longitudinal surveillance of CRS.CT and nuclear imaging are the most frequently used modalities after ultrasonography to assess renal morphology and function in clinical settings. However, the utility of renal CT in clinical management of CRS is limited due to radiation and the risk of post-contrast acute kidney injury in patients with impaired renal function , and in patients with septic shock or in critical conditions (type 5 CRS) ,94,95. SMultiparametric kidney MRI has been studied to characterize microstructural changes in AKI in recent years. Although the value of MRI biomarkers of AKI in the context of CRS remains to be investigated, there have been studies detecting the pathophysiological alterations in AKI. These techniques may facilitate early identification of AKI, which is one of the most challenging issues in clinical management of acute CRS. It has been well accepted that renal parenchymal hypoperfusion and hypoxia are closely associated with development of all forms of AKI . BOLD teEchocardiography is currently recommended by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines for all patients initiating dialysis, due to the high prevalence of underlying abnormalities among patients with CKD . CharactCMR has the unique value of detecting myocardial fibrosis, which was found in more than 90% of patients with CKD in a postmortem study . IncreasCAD and myocardial infarction with non-obstructive coronary artery can be involved in both type 2 and type 4 CRS. Coexistence of CAD and CKD and with comorbidities such as diabetes often manifests in these patients as ‘silent’ ischemic heart disease without typical anginal chest pain. Earlier CMR study with late gadolinium enhancement showed a mixed pattern of subendocardial infarction and diffuse fibrosis in patients with advanced CKD, reflecting the dual myocardial diseases . ConsideKidney imaging has scarcely been studied in the context of chronic CRS, since cardiovascular abnormalities are more related to mortality. However, imaging biomarkers of CKD in general may have potential value in clinical management of chronic CRS, especially in early diagnosis and monitoring disease progression. Conventional kidney ultrasonography and MRI can hardly identify preclinical renal injury in chronic CRS. Although previous studies suggest that kidney size is associated with glomerular filtration and kidney function reserve , the relType 5 chronic CRS secondary to diabetes are attracting increased attention these years, in which diabetic nephropathy has been of particular interest. Chronic hypoxia is one of the major contributors of parenchymal fibrosis and CKD in diabetes ,143. LowUltrasonography remains the most versatile, accessible, and cost-effective modality for the assessment of CRS. MRI, on the other hand, is the most promising one-stop modality for the structural and functional evaluation of both heart and kidneys. Future studies aiming at finding novel biomarkers for CRS may incorporate serial ultrasonography or non-contrast MRI scans for simultaneous evaluation of heart and kidneys in their study design. In the context of acute CRS, a combination of TTE and renal sonography can be used to assess the heart and kidneys synchronously. The evaluation of right-sided congestion and intra-renal blood flow by Doppler imaging might offer incremental diagnostic and prognostic value together with circulatory and urinary biomarkers. Quantification of global ventricular strain may have the potential of early identification of cardiac dysfunction in type 3 CRS. The unique role of MRI in assessment of interstitial fibrosis in both the organs might complement the use of molecular biomarkers and provide new insights in the diagnosis and treatment of CRS in the future. For institutions with well-developed infrastructures for multiparametric MRI, a combined non-contrast protocol assessing the heart and kidneys in a single scan session could be considered in future studies for patients at risk of or with CRS. Myocardial T1 mapping and T2 mapping together with renal T1 mapping and DWI can provide information on the extent of fibrosis in heart and kidneys , which iDespite endeavors to improve clinical outcome over the past decade, hospitalization rate, symptom burden, and mortality in patients with dual burden of heart and kidney diseases are still high . Meanwhi


Objective: The cerebellar functional laterality, with its right hemisphere predominantly involved in verbal performance and the left one engaged in visuospatial processes, has strong empirical support. However, the clinical observation and single research results show that the damage to the right cerebellar hemisphere may cause extralinguistic and more global cognitive decline. The aim of our research was to assess the pattern of cognitive functioning, depending on the cerebellar lesion side, with particular emphasis on the damage to the right cerebellar hemisphere.Method: The study sample consisted of 31 patients with focal cerebellar lesions and 31 controls, free of organic brain damage. The Addenbrooke’s Cognitive Examination ACE III and the Trail Making Test TMT were used to assess patients’ cognitive functioning.Results: Left-sided cerebellar lesion patients scored lower than controls in attention and visuospatial domain, but not in language, fluency, and memory functions. Participants with right-sided cerebellar lesion demonstrated a general deficit of cognitive functioning, with impairments not only in language and verbal fluency subscales but also in all ACE III domains, including memory, attention, and visuospatial functions. The TMT results proved that cerebellar damage is associated with executive function impairment, regardless of the lesion side.Conclusion: The cognitive profiles of patients with cerebellum lesions differ with regard to the lesion side. Left-sided cerebellar lesions are associated with selective visuospatial and attention impairments, whereas the right-sided ones may result in a more global cognitive decline, which is likely secondary to language deficiencies, associated with this lateral cerebellar injury. According to this, there is a hypothesis that in the same way as the cerebellum regulates the rate, rhythm, and accuracy of movements, so it may influence the speed, capacity, and appropriateness of mental processes. Hypo- and hypermetria in the motor activation, observed in the cerebellar damage, can be extended to the non-motor domain and manifests as the cerebellar cognitive affective syndrome Cerebellar cognitive affective syndrome with visuospatial impairments, linguistic deficits, executive dysfunction, and affective disturbances   and funcAlthough most of the studies support functional lateralization hypothesis, many of them are based on the very small study samples . There iAccording to the above-mentioned research, the main goal of our study was to determine the pattern of cognitive functioning of the patients with cerebellar damage in dependence on the lesion side. Based on the available studies and neuroanatomical data , we hypoThe cerebellar lesion group was composed of 31 participants  with mean age of 51.51 years .Patients were recruited prospectively from the neurosurgery ward, rehabilitation clinic, and the outpatient care. The inclusion criteria for the cerebellar lesion group were focal cerebellar damage , whereas the exclusion criteria were the presence of extracerebellar brain damage and/or psychiatric illness. The cerebellar lesion location was determined by the radiologist, based on MRI results. Participants were diagnosed with left-sided cerebellar lesions (13 participants), right-sided cerebellar lesions (15 participants), and isolated vermis damage (three participants). Out of 31 patients, 18 were diagnosed with cerebellar tumor, seven with cerebellar stroke, two with posttraumatic hematoma, and four with cerebellar arteriovenous malformation (AVM). Patients with extracerebellar pathology seen in an MRI examination were not included in the study. Among patients with cerebellar tumors, there were seven patients with metastatic tumors, five patients with astrocytoma WHO 1, two patients with meningioma WHO 2, two patients with medulloblastoma WHO 4, one patient with glioblastoma multiforme WHO 4, and one patient with ependymoma WHO 1. None of the cerebellar patients had cerebellar atrophy.The neuropsychological examination was performed after the resection of the tumor. The mean time from cerebellar tumor resection or stroke was 4.27 months. Among the cerebellar lesion, three patients had hydrocephalus and needed shunting. None of the patients had hearing difficulties. Only two patients had visual problems.The control group was composed of 31 subjects  with mean age of 57.67 years  diagnosed with a spine degenerative disease. The exclusion criteria were history of neurological and/or psychiatric illness. These participants were recruited from the Rehabilitation Center and Neurosurgery Department of University Hospital. The control subjects were matched with patients with cerebellar damage with regard to age, sex, and education level. They were also exposed to stress related to treatment, the need to visit a doctor, and hospitalization, in some ways similar to stress accompanying the experimental group of cerebellar patients. This selection procedure allows us to control the possible distorting influence of external stress on the results of cognitive tests.The same study participants were included in our publication on the usefulness of the ACE III test in assessing cognitive processes of patients with cerebellar damage .All participants signed an informed written consent to the assessment in line with the Declaration of Helsinki. The study was approved by the local Ethics Committee. No financial remuneration was offered as an incentive to participate.The detailed sociodemographic characteristics of the sample are presented in The Addenbrooke’s Cognitive Examination ACE III  is a scrThe total ACE III score is based on the maximum score of 100, with higher scores indicating better cognitive functioning. Although the ACE III is a brief screening tool originally designed to assess dementia in a population of elderly people , its appThe TMT  is a useAll participants were tested individually by a clinical neuropsychologist during a single session lasting about 40 min. Before attending, the study participants were informed about the possibility of stopping the testing or taking a break at any time during the research.post hoc Dunn’s test with the Bonferroni–Holm correction. We decided not to use the overly conservative Bonferroni method because this kind of correction may increase the probability of false negatives (not detecting the difference between lesion patients and controls where there is one) which should be avoided in a clinical setting. Therefore, we used the Bonferroni–Holm correction which seems more appropriate in this context.Empirical distribution of continuous variables was described using median and quartiles. The comparison of groups was made using the Kruskal–Wallis test and All statistical analyses were performed using SPSS version 26.post hoc comparisons between these three groups. The results are shown in To show the difference in cognitive functioning between patients with right-sided cerebellar lesions, patients with left-sided cerebellar lesions, and controls, we performed the Kruskal–Wallis test and A detailed analysis revealed the presence of significant differences between left-sided cerebellar lesion group, right-sided cerebellar lesion group, and control group in the ACE III total scores and in most of the ACE III single cognitive domains, except the memory domain.According to the TMT results, these three groups differed significantly in time of performing part A and part B of the test, and also in the number of mistakes made on the TMT part B. There was no significant difference in the number of mistakes in the TMT part A between the three groups. The pairwise comparisons between scores of patients with left-sided cerebellar lesions, patients with right-sided cerebellar lesions, and controls are shown in The pairwise comparison indicated that patients with right-sided cerebellar lesion scored significantly lower than controls on the ACE III ; they also obtained lower scores on nearly all the ACE III subscales measuring individual cognitive domains, except for the memory domain. The ACE III cognitive profile of patients with left-sided cerebellar lesion appeared to be more selective with significantly lower results in the ACE III  and the ACE III attention and visuospatial domain, compared with the results of the control group.Both the right-sided and the left-sided cerebellar lesion groups made more errors on the TMT part B and needed more time to accomplish this part of the TMT test than controls. Moreover, patients with right-sided lesion needed more time than controls to accomplish part A of the TMT. The right-sided and left-sided cerebellar lesion groups did not differ in any of the ACE III and TMT scores.The results obtained by participants in the memory  and fluency (perseverations and intrusions) domains have been analyzed in more detail to establish whether the cognitive profile of patients with cerebellar lesions can be characterized as frontal-like, as it has been demonstrated in the previous research . MoreoveRegarding the ACE III memory domain, the detailed analysis revealed a significant difference among the left-sided cerebellar lesion group, the right-sided cerebellar lesion group, and the control group only in the memory retrieval subscale. There were no between-group differences in the memory recognition subscale.According to the ACE III fluency domain, the analysis showed that the three groups differed significantly only in the number of intrusions during the fluency trials. There was no difference in the number of perseverations.As for the ACE III language subscales, significant between-group differences were observed in the scores of articulation and confrontational naming, however, not in comprehension, graphia, lexia, and repetition scores. The pairwise comparisons of scores provided by the three groups of participants are shown in The pairwise comparison indicated that patients with right-sided cerebellar lesion scored significantly lower than controls on the ACE III memory retrieval, language-articulation, and language-confrontational naming subscales. The left-sided cerebellar lesion group made significantly more intrusion mistakes during the fluency trial compared with controls. Patients with left-sided lesion did not differ from the controls regarding language and memory subscales. Both groups with cerebellar lesion differed from each other only in the ACE III confrontational naming; the right-sided cerebellar lesion group obtained significantly lower results in this subtest than the left-sided cerebellar lesion group.In this study, we examined the cognitive functioning of patients with cerebellar damage based on their performance in neuropsychological tasks. In particular, we examined whether the cerebellum lesion localization influences the pattern of cognitive impairments demonstrated by patients.The results of our study revealed that individuals with focal cerebellar lesions after tumor surgery or stroke scored significantly lower than healthy controls in all investigated cognitive domains. They revealed the CCAS, which is considered as constellation of mild deficits in cognitive domains of executive function, language, spatial cognition, and emotions , 2010.Our study proved the previously described functional lateralization of the cerebellum , but onlIn our study, the patients with lesions localized in the left cerebellar hemisphere showed difficulties in copying geometric shapes, Mobius band, and cube or in the clock task. Previous research on adults  and pediAlthough the disturbances of the visuospatial functions in the cerebellar left-sided lesion group clearly stood out against the background of other preserved cognitive functions, especially linguistic ones, our study did not reaffirm the previously observed cerebellar intergroup difference in visuospatial functioning. The visuospatial domain scores of patients with the left-sided lesion were not significantly lower than the scores of the right-sided lesion group; the latter one was also characterized by impairments in the spatial task when compared to controls.Our research confirmed the well-documented effect of the right-sided cerebellar injuries on language functions and the absence of such impact in case of left-sided damage . HoweverWith regard to executive functions, our research roughly confirmed the hypothesis of the bilateral cerebellar representation of these cognitive processes . In our Regarding the memory domain, this study revealed a pattern characterized with difficulties in recalling previously encoded information from the long-term memory storage and relatively well-preserved recognition. The recalling difficulties are also characterized by cerebellar laterality, as in our research, they concern only patients with right-sided cerebellar hemispheric lesions. In general, our research confirms the conclusions reached in previous single studies about the frontal-like nature of memory disorders accompanying patients with cerebellar damage . HoweverOur findings show that the cognitive profile of patients with right-sided cerebellar lesions is characterized by a generally lower level of cognitive performance with weaker language, visuospatial, attention and memory functions, and slowness of information processing which is quite novel, and we could not find similar effects regarding functional cerebellar lateralization in any other research on adult populations with cerebellar damage. However, when analyzing the research on children with damage to the cerebellum, a similar imbalance in intellectual functioning and lower intelligence of children with right-sided cerebellar lesion was observed in via the nucleus ventralis intermedius and nucleus ventralis anterior of the thalamus (The selective visuospatial and attention impairments related to the left cerebellar hemisphere lesions can be explained by the crossconnections of this cerebellar hemisphere with the opposite cortical associative areas of the right cerebral hemisphere, especially the parietal lobe , whereasthalamus  crucial thalamus .It is likely that impairment of verbal skills caused by the damage of the right cerebellum hemisphere may in turn affect the scores of non-verbal tasks through dysregulation of the so-called inner speech which organizes and controls a given activity. The strong involvement of the cerebellum in the inner speech mechanism was proved in the research of Although our study provided new data concerning cerebellum lateralization, it also has some limitations that warrant mentioning. First, the findings should be interpreted carefully due to by heterogeneity of the patients’ group. The cerebellar lesion group included not only patients with tumors of the cerebellum, but also patients after a stroke of this brain structure or with vascular malformations. Moreover, cerebellar tumors that patients were diagnosed with differed significantly in terms of histology and WHO grade classification; therefore, they may vary in the risk of cognitive functioning impairment. Additionally, it is well established that emotional states affect cognitive functioning not only in individuals who undergo brain surgery, but also in controls who are treated for a spine degenerative disease.A serious limitation of our research is the use of screening tests to assess cognitive functions, and although they are short, “patient-friendly” and have sufficient sensitivity, it is advisable to exercise great caution when formulating final and radical conclusions about the presence of cognitive disorders in a studied group of patients.Future studies would benefit from including assessment of participants’ emotional state and analysis of their impact on cognitive processes in the study sample. Further research should also deal with more detailed examination of linguistic functions and their relationship with the right hemisphere, and also their possible associations with the disturbance of other cognitive processes to confirm the more global and more serious cognitive impairments related to the damage of the right cerebellum hemisphere.To sum up, our study tentatively confirmed that individuals with focal cerebellar lesions after tumor surgery or stroke differ in cognitive impairments pattern depending on the cerebellum lesion side. In line with our assumption, the analysis of individual cognitive domains indicated that patients with lesions localized in the left cerebellum hemisphere revealed decrease primarily in attention and visuospatial domains, whereas those with right-sided damage showed more global impairments which are beyond language difficulties.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Biomedical Ethics Committee of Jagiellonian University Medical College. The patients/participants provided their written informed consent to participate in this study.AS-F designed the study, qualified patients for the group and conducted psychological tests, analyzed the data, and wrote the whole manuscript. KP revised the manuscript. JK analyzed statistically the data. AC revised the manuscript from the psychiatric perspective. AM helped with preparing the reference list. BB-K drafted the grant proposals that secured financing for the study. BK revised the manuscript from the neurosurgery perspective. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Worldwide, hepatobiliary cancers are frequent diseases and often accompanied by a poor prognosis. These cancers, with hepatocellular carcinoma (HCC) and cholangiocarcinoma (CHC) being the most frequent, are often associated with a considerable amount of psychological burden such as anxiety, depressiveness, and reduced health-related quality of life (HRQOL) which may lead to psychiatric comorbidities. This systematic review gives an overview on psychological burden and on the effectiveness of psycho-oncological interventions for patients with HCC and CHC.∗) AND . Studies were eligible for inclusion if investigating patients affected with tumors of the liver (HCC/CHC) and using diagnostic instruments to assess mental health symptoms and research concerning specific psycho-oncological interventions. In total, 1027 studies were screened by one author with regard to title and abstracts. Afterward, the two authors of the paper discussed inclusion of possible articles.The databases PubMed, PubPsych, and PsycINFO were used and searched using the following combination of terms: (Neoplasm OR Cancer OR Tumor OR Carcinoma) AND , identifier (CRD42021243192). In Europe and North America cancer of the liver–with hepatocellular carcinoma (HCC) accounting for 75% and cholangiocarcinoma (CHC) for approximately 23% of all liver cancers –is a ratThe risk factors for these diseases include liver cirrhosis and viral hepatitis as well as various metabolic diseases  and the intake of certain drugs (anabolic steroids) or the consumption of food contaminated with aflatoxin . Men areTumors of the liver are characterized by a wide variety of rather diffuse symptoms: tiredness, loss of appetite and nausea, pain or weight loss, palpable or even visible mass in the right upper abdomen, an accumulation of ascites or an icterus accompanied by pruritus. The diagnosis with HCC, along with the subsequent long-term invasive treatments like chemotherapy, radiotherapy and/or surgery can lead to various psychological symptoms (or diseases). The burdened person can feel sad, threatened and uncertain and develop a high unmet supportive care needs . After aDue to helplessness, fear and a sense of being completely overwhelmed, grief, anger and despair–not only on a somatic but also on a psychological level–the diagnosis of hepatobiliary cancer often represents a state of emergency. Until now, these burdens have been given little consideration in society and clinical routine, which can lead to missing psycho-oncological treatment. Further, no systematic review has yet addressed the psychological burden of patients with hepatobiliary cancer. Additionally, little is known about the effectiveness of psycho-oncological interventions among this patient group.The current systematic review assesses the extent of psychological burden of patients suffering from hepatobiliary cancers  AND . Further, we have searched with MESH terms, too. However, we have detected a smaller number of papers using MESH terms in our search strategy. All papers which were detected by MESH terms were also found with the combination of the mentioned terms. Our search strategies were based on keywords being in the heading or in the text.To address the aims described above, a systematic literature search was conducted according to the PRISMA criteria . The datStudies were eligible for inclusion if they were published in a peer-reviewed journal, written in English and fulfilled the following modified PICOs criteria: [P] Investigation of patients affected with tumors of the liver (HCC/CHC). [I] Studies using diagnostic instruments to assess mental health symptoms and research concerning specific psycho-oncological interventions. [C] Healthy persons or patients with other tumor entities served as control groups. [O] Outcomes were influence of hepatobiliary cancer on mental symptoms  and HRQOL.Exclusion criteria were: (1) research concerning other tumor entities with only secondary involvement of the liver, (2) studies using a highly heterogeneous population of patients with cancer without presenting data and information specific to tumors of the liver, (3) research concerning other liver diseases such as liver cirrhosis or hepatitis or other disease-related phenomena , and (4) individual case studies and studies looking into highly specific groups that were not representative.After the initial search duplications were eliminated. Furthermore, one author screened the papers with regard to title and abstracts. Afterward, the two authors of the paper discussed inclusion of possible articles. In a final step the studies considered relevant were read in full and, if actually relevant, were included in the study presented here. Full texts of potentially relevant studies were assessed independently regarding the PICOs criteria.The included papers showed a high heterogeneity in the psychometric assessment tools and psycho-oncological interventions. Due to this, only descriptive data analyses  and no group comparisons were performed. SigmaStat 3.1.  was used for these comparisons.In the initial literature search 1027 potentially relevant papers were identified . After tData on the prevalence of depressive symptoms were obtained from a total of four of the included studies. In two cases the psychometric tools used were the Center for Epidemiologic Studies Depression Scale (CES-D), once the Hamilton depression scale (HAMD 17) and once the Hospital Anxiety and Depression Scale (HADS). As shown in Another study examined the incidence of depression (diagnosis according to ICD-9 or DSM-IV) in patients with HCC over a period of 6 years. After analyzing 55,973 sets of data the cumulative incidence of depression was 2.5% . When exIn three of the studies identified data concerning the prevalence of anxiety among patients with hepatocellular cancer was presented . A totaln = 1075) but also in comparison to HRQOL of patients with other types of cancer   .One of the studies selected provides data on suicide rates in patients with hepatobiliary carcinoma. After examining the data of 81,684 patients diagnosed with cancer of the liver, the suicide rate of patients affected was about twice as high  compared to the normal population . Relevann = 229) showed a considerable level of distress ] to those with other types of cancer. The burdened patients can be identified by a Global Severity Index (GSI) score ≥63 or any two subscales where the T-score is ≥63 . Accordidistress .Three of the studies investigated the effects of psycho-oncological interventions in patients with gastrointestinal tumors , hepatobiliary cancers and HCC, respectively. It is to note that these studies differed concerning the tested intervention, the control conditions and the observation period. Therefore, the respective studies will be described separately .In the first study the effect of an individually tailored psychotherapeutic care of patients with hepatobiliary cancer was tested on a total of 28 patients in a randomized longitudinal study . The 14 In another randomized longitudinal study, the effect of a continuous bedside psychotherapeutic care of patients, which had already started pre-operatively, was tested in a total of 271 patients with gastrointestinal tumors  . The intIn the last randomized psycho-oncological intervention trial a total of 136 patients with HCC that underwent a hepatectomy were examined to determine the effect of psychological-educative care over a period of 1 year compared to control support . The intDifferent studies show that patients with cancer suffer from severe psychological burden. However, to date, there is no clear knowledge about the impact of hepatobiliary cancers on mental health and the effect of psycho-oncological interventions in patients with hepatobiliary cancers. This is the first systematic review summarizing the psychological burden of patients with hepatobiliary cancers and the need for psycho-oncological interventions in this patient population.From the study data presented so far two things become apparent: Firstly, patients suffering from hepatobiliary cancers often experience a considerable amount of psychological distress. About a quarter of the patients suffer from depressive symptoms ; For depSecondly, the three intervention studies tentatively suggest that there might be beneficial effects of psycho-oncological interventions. The use of psycho-oncological intervention can reduce the prevalence of depressive symptoms and anxiety, while the quality of life and also the survival rate of patients with hepatobiliary cancer can be increased. The increase in survival might be due to an improvement in coping, a reduction in perceived stress and an improvement of immune functions as hypothesized by the authors . It seemThese data give rise to an improvement of mental health among patients affected with HCC, but the data should be interpreted with caution. One study included only a small number of patients in the follow-up assessment . The othIt has to be noted that any study on cancer should take into account that cancer is a complex and multifactorially determined disease. Many variables that cannot be directly controlled influence the course of the disease and the well-being of patients; therefore, it may be difficult to prove clear correlation or even causality. In addition, the patient population under investigation is also very heterogeneous: the patients differ in age, gender, socio-economic situation, their medical history, comorbidities, tumor size, number of lesions, lymph node involvement, the degree of metastasis, the therapeutic path taken and, for example, the use of alternative/complementary medical procedures. Due to the fact that equally structured interventions and control groups do not exist, a direct comparability of the effectiveness of the different studies is limited. The latter undertaking is also made more difficult by the fact that the measuring tools (questionnaires) used in the individual studies are rarely the same and even if they are, they are used differently: for example different cut-off values are used which results in different data concerning the prevalence of some symptoms. In addition, the studies also differ greatly concerning the timing of the patient interviews, meaning that patients are often interviewed at different stages of the disease. Lastly, the studies also differ in their exclusion criteria, e.g., other psychiatric diseases and related psychiatric treatment was an exclusion criterion in one study only. These factors have to be kept in mind as possible confounding variables.Furthermore, bias cannot be ruled out for the studies included in this systematic review. We expect different risks of bias because of the different research design of the included papers. This systematic review includes studies with cross-sectional and longitudinal study designs as well as one with a retrospective study design. Only three papers reported results of a randomized controlled study design. The risk of response bias was the most frequent type of bias which occurred because all studies applied (self-reporting) questionnaires to assess psychological symptoms. Furthermore, we expect a selection bias, as it can be assumed that patients suffering from psychological symptoms are more willing to participate in this kind of studies. Lastly, recall bias might have occurred, especially in retrospective studies, because it might be that patients cannot accurately remember their symptoms during the trajectory of the disease.Taken together, future studies should assess the effects of psycho-oncological interventions in a randomized design with desirably long follow up in well-defined/stratified patient groups and should also use–in combination with traditional face to face psychotherapeutic techniques–eHealth interventions as recently emphasized .Even though the data presented here have to be interpreted with caution it became clear that psychosocial burden is high in patients with hepatobiliary cancers (including mostly HCC and CHC) as reflected in high levels of depressiveness and anxiety as well as reduced levels of quality of life. Psycho-oncological interventions were able to reduce perceived depressiveness and anxiety in patients with hepatobiliary cancers as well as increase quality of life compared to patients receiving standard support only. Although these data appear promising, one has to keep in mind that data especially on psycho-oncological interventions in these patients are limited so far. Therefore, future studies are warranted to further investigate the effects of psycho-oncological treatment in patients with hepatobiliary cancers (most studies will be performed in patients with HCC as this is the largest group within these cancers) to better characterize and understand the effects exerted by these procedures in order to corroborate the current recommendations of treatment guidelines already recommending psycho-oncological support (subsumed as best supportive care) for patients with hepatobiliary cancers .The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.JG performed the systematic search and wrote the first draft of the manuscript. AS planned the study and critical input throughout the study. Both authors finalized the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The flexor carpi radialis brevis (FCRB) muscle, considered a rare anomaly, is not well known among orthopedic surgeons. The indications for volar locking plates to treat distal radius fractures have recently expanded, and, as a result, encounters with the FCRB are becoming more common. However, few studies have described how to retract an FCRB. Here, we describe seven of 264 patients with FCRB who underwent surgery for distal radius fractures. In one case, the retracted FCRB interfered with the internal fixation. The presented cases demonstrate that the radial retraction of an FCRB with a large muscle belly enables favorable exposure of the distal radius. The flexor carpi radialis brevis (FCRB) is a relatively rare anomalous muscle of the volar distal forearm. The FCRB originates between the origin of the FPL and the insertion of the PQ; it then runs on the radial side of the FPL and inserts into the second or third metacarpal and the radial side of the carpal bones. It has been described in several anatomical studies and has an incidence of 0.9–7.5% –3. HowevBetween 2010 and 2019, 264 patients with distal radius fractures were treated using the volar flexor carpi radialis (FCR) approach and volar locking plates. In seven of those cases, we observed during surgery the FCRB on the radial side of the flexor pollicis longus (FPL) tendon and the superficial layer of the pronator quadratus (PQ) muscle. In these cases, we examined the origin of the FCRB, size of the muscle belly, hypoplasia of the PQ, and impairments of internal fixation. The study was approved by the Tachikawa General Hospital Ethics Organization , and informed consent was obtained from all patients.The 58 men and 206 women with distal radius fractures had a mean age of 65 years . The three men and four women with FCRB had a mean age of 49 years (range, 24–64 years; The indications for volar locking plates for the treatment of distal radius fractures have recently increased. As a result, clinical reports on FCRB are becoming more common. Five reports have described FCRB muscles discovered during surgery for distal radius fractures –12. ThesSeveral case reports have described how to fully expose the distal radius in the presence of FCRB. The first report, described by Kang et al. , Lee et Nagata et al. classified FCRB muscles as tendon or muscle belly types , and allThe FCRB muscle is not a rare occurrence, so orthopedic surgeons must be aware of its possible presence when performing volar plate fixation of distal radius fractures. The cases presented here demonstrate that radial retraction of an FCRB with a large muscle belly exposes the entire volar metaphysis of the distal radius.


HLA-B*5701 in abacavir initiators has a number needed to genotype of 31 to prevent one case of abacavir hypersensitivity and is cost-saving. Genotyping HLA-B*5801 in allopurinol initiators has a number needed to genotype of 1149 to prevent one case of SCAR but is still cost-effective. Genotyping before initiating antiepileptic drugs or flucloxacillin is not cost-effective. Our results confirm the need for mandatory testing of HLA-B*5701 in abacavir initiators, as indicated in the drug label, and show genotyping of HLA-B*5801 in allopurinol initiators should be considered.Human Leukocyte Antigen (HLA) variants can be a risk factor for developing potentially fatal drug hypersensitivity reactions. Our aim was to estimate the potential impact of genotyping for the HLA risk alleles incorporated in the Dutch Pharmacogenetics Working Group (DPWG) guidelines in The Netherlands. We estimated the number of hypersensitivity reactions and associated deaths that can be avoided annually by genotyping for these HLA risk alleles. Additionally, the cost-effectiveness was estimated. Nationwide implementation of genotyping HLA risk alleles before initiating drugs with an actionable drug–gene interaction can potentially save the life of seven allopurinol initiators and two flucloxacillin initiators each year in The Netherlands. Besides these deaths, 28 cases of abacavir hypersensitivity, 24 cases of allopurinol induced SCARs, 6 cases of carbamazepine induced DRESS and 22 cases of flucloxacillin induced DILI can be prevented. Genotyping  Adverse drug reactions (ADRs) are a major cause of morbidity and mortality in modern healthcare. An adverse drug reaction (ADR) is defined by the World Health Organization as ”a response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function” . Two typBouvy et al. performed a review of all epidemiological studies quantifying ADRs in a European setting and found a median percentage of ADR related hospital admissions of 3.5% of all admissions and a fatality rate of approximately 0.15% indicating that ADRs represent a significant burden on European healthcare . IncidenIn 2005, the Dutch Pharmacogenetics Working Group (DPWG) was established by the Royal Dutch Pharmacist’s Association with the objective to develop pharmacogenetics-based therapeutic (dose) recommendations ) AND (dutch [ti] OR Netherlands [ti])” and relevant articles which include allele frequencies of the HLA variants of interest were included.Three Dutch cohorts were found in the Allele Frequency Net Database and one cohort was retrieved using the PubMed search ,18. A weThe carrier frequency was subsequently calculated as follows:The PPVs for the actionable drug–gene interactions were retrieved from studies performed in Caucasian populations or from the DPWG guideline. If available, numbers for Caucasian populations were used, otherwise PPVs derived from other populations were used.The hypersensitivity reactions included in this article are abacavir hypersensitivity, allopurinol induced SCARs including DRESS and SJS/TEN, carbamazepine induced SCAR, lamotrigine and phenytoin induced SJS/TEN and oxcarbazepine induced SJS. Finally flucloxacillin induced DILI was also included. Estimates of the mortality of the included drug hypersensitivity reactions were collected from literature ,27,28,29The number of actionable drug–gene interactions is calculated by multiplying the number of first prescriptions by the allele carrier frequency of the associated HLA risk allele. Subsequently the estimated annual number of drug hypersensitivity reactions is calculated by multiplying the number of actionable drug–gene interactions by the positive predictive value of the HLA test for the outcome. Thus the annual number of drug hypersensitivity reactions is calculated by:ADR = number HLA associated hypersensitivity reactions prevented, DISP = number of first dispensations, CF = carrier frequency of HLA risk allele, PPV = positive predictive value of HLA test.NThe annual number of deaths caused by HLA associated hypersensitivity reactions is calculated by multiplying the estimated number of drug hypersensitivity reactions by the mortality of the outcome:death = number of HLA associated deaths prevented, NADR = number HLA associated hypersensitivity reactions prevented, MORT = mortality.NWe compared the cost of two treatment strategies; no genetic test and initiation of the HLA allele associated drug, and testing for the HLA risk allele and switching to an alternative drug not associated with the same HLA risk allele when a patient tests positive for the HLA risk allele.HLA-B*5701 separately. The cost of drugs for the relevant reference drugs and the alternatives was based on the most common indication for the drug. The costs of the reference and alternative drugs were collected from the national drug price registry by selecting the most suitable dose and formulation [Costs are calculated with a one-year time-horizon, and reported in Euros at price level 2021. The costs of single-variant HLA tests were based on single-gene prices for genotyping  and a fixed price per lab-order for handling and administration set in the four hospitals who test for mulation . The altIn the case of flucloxacillin, unlike the other drugs of interest, the DPWG guideline does not recommend an alternative drug but instead recommends to monitor liver function. Only with increasing liver values, an alternative drug is recommended . For theThe costs used in the cost-effectiveness model are shown in For the costs of treating drug hypersensitivity reactions the average of the prices charged by the seven academic hospitals . The European RegiSCAR study found a median stay of 17 days for DRESS patients. Because of this, the price for “6 to 28 days of treatment for inflammation of the skin” was used (6800 euros). For SJS, SJS/TEN and TEN the price for “6 to 28 days of treatment for a skin condition with blisters” was used (9100 euros). The costs used for DILI are an average of the prices for patient receiving a liver transplantation after suffering from DILI and patients not needing a liver transplantation. In the DILIN prospective study 3.8% of the patients suffering from DILI needed a liver transplant . The priThe net annual costs for the Dutch population for the genotyping strategy versus the standard care was calculated per drug–gene interaction as following:test as the costs of the HLA test, HLA+ as the number of patients carrying the risk allele, Cmon as the costs for monitoring liver values in the case of flucloxacillin, ADR as the number of patients developing drug hypersensitivity, Calt and Cref as the daily drug costs of respectively the alternative and reference drug and CADR as the estimated costs of an hypersensitivity reaction.With DISP as the number of first dispersions, CWe calculated cost-effectiveness ratios by dividing this impact on costs by the impact on the number of ADRs and deaths.HLA-B*5701 in abacavir initiators, as indicated in the drug label, since it only has a number needed to genotype of 31 and implementation of this test is calculated to be cost-saving. Genotyping all carbamazepine, oxcarbazepine, lamotrigine, phenytoin and flucloxacillin initiators is not cost-effective in the overall Dutch population. However, our study shows genotyping HLA-B*5801 for allopurinol starters is cost-effective and can reduce morbidity and mortality and therefore it should be considered in pharmacogenetic implementation programs.This study confirms the need for mandatory testing of


Modeling-based anti-cancer drug sensitivity prediction has been extensively studied in recent years. While most drug sensitivity prediction models only use gene expression data, the remarkable impacts of gene mutation, methylation, and copy number variation on drug sensitivity are neglected. Drug sensitivity prediction can both help protect patients from some adverse drug reactions and improve the efficacy of treatment. Genomics data are extremely useful for drug sensitivity prediction task. This article reviews the role of drug sensitivity prediction, describes a variety of methods for predicting drug sensitivity. Moreover, the research significance of drug sensitivity prediction, as well as existing problems are well discussed. With the significant technological advancements, a variety of modalities have been developed to predict the sensitivity of tumors to anti-cancer drugs, which can improve drug efficacy and reduce adverse effects and the financial burden of treatment on patient. The sensitivity of tumors to anti-cancer drugs can be assessed by using patient cell lines, which can facilitate the use of synergistic regimens . Unfortuvia k-means++ clustering, random walk, and other machine learning methods  The first aspect is mainly concerned with the analysis of different drug resistance mechanisms arising from pan-cancer and tumor drug resistance based on the different tumor cell lines after treatment. 2) The second is mainly focused on the construction of a prediction model for the evolution of tumor drug resistance. In this part, gene mutations in various cell lines can be added to the prediction model according to the mutation frequency of the gene as the evolutionary condition of resistance. 3) The third aspect is mainly concerned with the design of drug application strategies that interfere with the tumor drug tolerance state. This means that the treatment plan can be devised according to genes affected by existing drugs and the classification of anti-tumor action principles. 4) The fourth aspect of methods mainly focus on the verification of the predicted medication plan through gene chip and cell experiments. Finally, the relevant interference drug plan can be developed using the prediction model, and then gene chip detection can be used for comparisons with the results obtained from the prediction model to verify the accuracy of the model.In recent years, the drug resistance state of tumors, regarded as an important process in the evolution of tumor resistance, has been well studied by using a variety of machine learning methods. This type of methods analyze the drug resistance mechanism activated by tumor cell lines in different drug resistance state. They mainly consist of four steps. 1) The first step is to analyze the drug resistance mechanism produced from the tumor drug resistance state. This step requires the construction of a time-series biological network (T-BioPPI). T-BioPPI integrates multiple database biological association networks to form a relatively comprehensive biological protein interaction network of BioPPI, in which the LINCS database provides tumor cell line gene expression profile data at three time points. The data at these time points are analyzed for differentially expressed genes. Each gene is expressed as a different node between time layers in the biological network. At this point, the gene interaction networks at various time points are linked together to construct a large time-series biological network, thus identifying the important genes in the biological network through regression analysis. Because each drug has a relatively fixed target in the cells, the key lies in the action time of the drug. Using the drug dose as an independent variable and gene expression as a dependent variable, regression analysis of gene expression over time in tumor cells following drug treatment can be performed. Following this step is an initiated step to map the genes of each tumor cell line to T-BioPPI. Then, by restarting the random walk, an analysis of walking from the nodes in the 0-h network to the 24-h network can be performed. This is followed by dimensionality reduction and k-means++ clustering. The evolution prediction model is the classification result of tumor cell lines obtained after clustering. 2) Second, a deep learning model is established for predicting the evolution of the tumor drug resistance state. In general, long short-term memory networks are applied to assess the evolution of tumor drug resistance through ordered sequences of gene expression changes. During this step, the classified cell line data are used as the basis for long short-term memory model construction, and the gene expression profile data of similar tumor cell lines are used as the training set for deep learning data. 3) The third step is to design drug application strategies that interfere with tumor drug resistance to cover single-target drug identification and combination drug identification. 4) The fourth step is to verify the predicted drug resistance evolution model and medication plan through cytology and gene chip experiments. Three main sub-steps are involved. The first sub-step is the cultivation of drug-resistant cell lines, the second sub-step involves gene chip experiments, and the last sub-step is the cell proliferation inhibition test. Computational theory tools such as graph representation learning are widely used to establish standard data sets and online databases for anti-cancer drug sensitivity mutation data using. Then analysis models are established to conduct in-depth research and exploration on anti-cancer drug sensitivity mutation prediction methods. The project mainly studied the following aspects. 1) First, the construction of anti-cancer drug sensitivity mutation databases. After collecting anti-cancer drug sensitivity mutation data from multiple cancer genome projects, a document classifier for cancer-related mutations can be constructed by using machine learning text mining technology. The classifier intends to facilitate access to the literature about cancer–mutation–drug information in the PubMed database. After obtaining these related documents, professional personnel can collect and annotate the relevant anti-cancer drug sensitivity mutation information. When mutation data information is obtained for the first time, standard tools are employed to organize the information annotations of each entry into a standard format. Then, the obtained original data sets are integrated with the source of literature mining. Finally, a user-friendly anti-cancer drug sensitivity mutation database web interface based on the Browser/Server model is developed, which is open for users to view and download data. 2) The second aspect focuses on research on the prediction method of drug sensitivity markers. According to the characteristics of drug sensitivity-related mutations, known anti-cancer drug sensitivity mutation data is sorted and preprocessed. Then, existing feature quantification methods are collected and well analyzed. Meanwhile, wild-type and mutant DNA sequences are used for feature quantification to permit the information before and after the appearance of the mutation, which can further ensure the reliability of the results. The background network is obtained by calculating the mutation–mutation similarity. 3) Third, a drug–drug network is extracted from the research on the prediction method of mutation–drug interaction pairs. Then, a multi-source heterogeneous drug interaction network is established through techniques such as similar network fusion. 4) Finally, the graph representation learning method is adopted to predict the relationship of the mutation–drug interaction pair and develop corresponding prediction software and an online prediction platform. The flowchart of graph embedding-based algorithm NEDTP is shown in Deep learning has shown impressive performance in many tasks . This deThe strategy mainly aims to establish a recombinant strain drug resistance analysis platform, and verify the hypothesis related to recombinant drug resistance by targeting circulating recombinant forms (CRFs) . Data reThis chapter mainly discusses the significance and indispensability of drug sensitivity in bioinformatics research by introducing different methods. A persistent problem has arisen in the research and development of anti-cancer drugs and in the medical and health fields, namely the issue of tumor resistance. Methods reviewed in this study can assist with the prediction of drug sensitivity. They encompass oncology, pharmacy, and computer science, and strategies to predict tumor resistance, design rational drug strategies, and construct computer models were principally covered. These methods have promoted the research and development of bioinformatic fields such as computational methodology and algorithm design. Moreover, research reviewed in this study can be directly applied to anti-cancer precision medicine, new drug identification, and other systems. They have exhibited broad market application prospects and a further possibility to improve the effectiveness of AIDS treatment and lower the cost of its prevention and control.Tumor drug tolerance is an important process in the evolution of tumor drug resistance, and the drug resistance mechanism activated by the tumor in the drug resistance state remains unclear. Bioinformatic analysis and research on mutations associated with anti-cancer drug sensitivity are expanding. Hopefully, the methods reviewed in this study will contribute to overcoming existing problems. They analyzed the drug resistance mechanism of tumor cell lines in a drug-resistant state based on a variety of machine learning  and deepIn recent years, anti-cancer drugs have consistently been the focus of new drug development. Methods that can accurately predict drug sensitivity are urgently needed to facilitate drug development and disease prevention in the field of biomedical health. In this study, a comprehensive review was provided concerning the analysis of the drug resistance mechanisms of tumor cell lines in the drug-resistant state by using a variety of machine learning methods. The two-step cancer–mutation–drug triad prediction is achieved through text mining technology based on machine learning. It has laid solid foundations for the subsequent construction and update of the drug sensitivity mutation database through a combination of manual annotations. The wide distribution of HIV-1 recombinant types and the formation of drug-resistant strains will facilitate our study of recombinant characteristic drug resistance patterns and drug resistance associations. The aforementioned summary indicates the necessity of the current review.


The ECOWAS Region and the world have learnt a lot in the last year and a half concerning the pandemic. As the pandemic continues to evolve, the region needs to put together all these lessons in other to better protect its people, rebuild its economy and strengthen the regional health security for better regional prosperity. We reviewed the response mounted by the region from January 2020 to July 2021 and the existing body of knowledge. We recommend that the region quickly increase the COVID-19 immunization coverage, sustain the enhance genomic surveillance, improve testing and the strengthen point of entry surveillance. COVID-19 has caused since 2020 an unprecedented regional crisis, including thousands of lives lost, public health systems in shock and economic and social disruptions. As of July 2021, ECOWAS Region reported over 532,258 cases and over 7,004 deaths with increasing notification of new variants capable of worsening the epidemiologic trends.ECOWAS Region has focused its response to COVID-19 pandemic on the implementation of the Test-Trace-Isolate-Treat strategy supported by important measures in Infection and Prevention and Control (IPC) and logistics. This involved expanding testing capacity, digitizing contact tracing, reinforcing point of entry surveillance, rolling out equitable vaccination, enhancing treatment and care particularly for the most vulnerable to improve the national capacity to fight devastating COVID-19 waves [In this commentary, we are looking at urgent actions that ECOWAS Countries can take to mitigate the impact of COVID-19 crisis on lives and livelihoods in West Africa. COVID-19 can be a very challenging situation with the occurrence of major COVID-19 crisis in many places around the world, West Africa needs to urgently learn from COVID-19 crisis that happened in Brazil, Peru and India in order to prepare adequately for a possible high surge of new COVID-19 cases -4. ManagThis opinion piece aimed to provide some guidance to orient ECOWAS Countries. We undertook an extensive review of literature including regional strategic meeting reports, guidelines, and recommendations on ongoing and effective public health response interventions during COVID-19 crisis in ECOWAS Region. We focused our reflections around critical response pillars that is of high important during the Management of COVID-19 crisis in West African context.Vaccines are crucial to the containment of the COVID-19 pandemic; however, they work synergistically with scientifically proven effective interventions like use of face mask, proper IPC practices and active surveillance of infection and evolution of different variants of the virus. Sourcing COVID-19 vaccine has been a great challenge in Africa in general as over 99% of its vaccine need is sourced from outside the continent and there is marked disparities in COVID-19 vaccine rollout in Africa at the regional level. Several factors have been adduced for the disparity which were not limited to challenges with pre-purchase agreements with manufacturers and stockpiling of doses to the high income country (HIC) population, exports restrictions placed on vaccines, vaccine raw materials, and on delivery supplies such as syringes and glass bottles .In West Africa, Member States have sourced their vaccines through the COVAX provision, African Vaccines Acquisition Task Team (AVATT) Initiative and through bilateral arrangements. The proportions procured as at end of June 2021 is still a far cry to what is needed to vaccinate at least 70% of the population in the region. Most member states have still focused their vaccination efforts at the high-risk group, comprising those aged 45 years and older and healthcare workers. This should remain the immediate short-term goal since younger age groups have been more affected and it may probably save the most lives and keep the health service delivery ongoing without systemic failures.Member states should accelerate vaccination effort to ensure available vaccines are quickly and efficiently made available to the populace with minimal waste. Vaccination effort should remain staggered from high risk to low risk and should be coupled with massive advocacy and risk communication to minimize vaccine hesitancy. Member states need to increase a risk communication effort to engage community and all the actors to accept vaccinations. Improved vaccination coverage will have immediate benefit for the health of the populace and improve faster economic recovery. Several challenges including vaccines hesitancy, institutional mistrust, corruption, fragile rumours management systems, insufficient funding for operations and campaigns are limiting vaccines rolling out in the region , 7.There is an urgent need to operationalize the ECOWAS Vaccines Exchange Platform and the ECOWAS Vaccines Revolving fund for pooled procurement both for vaccines and other essential vaccination supplies from different sources proposed by the Authority of the ECOWAS Head of States in January 2021 and for improving vaccine uptakes. This will create opportunity for pooling financial resources both from member states, partners and cooperating organizations in West Africa. It will also provide a better bargaining strength than individual countries, in addition to help in creating regional resilience in case things get out of hands.As part of ongoing surveillance, member states aspire to improve testing capacity, strengthen point of entry surveillance and broaden containment measures . TravellCoordination: it remains a core component of incident management structure during the Management of COVID-19 pandemic. ECOWAS Countries should build on existing structures and platforms within the region and at national levels. Member States established ad hoc coordination mechanisms both at political, strategic, and technical level to efficiently combat COVID-19 pandemic including the use of Public Health Emergency Operation Centers.There is need to improve coordination at subnational and community levels especially in high transmission area towards a “Whole of Society” response . COVID-1Laboratory and testing: the region has over the last one year increased the number of laboratories with capacity to test for COVID-19 from 2 to more than 500. Moving further, ECOWAS Member States need to focus on validating and deploying rapid diagnostic tests especially in border areas and ramp up testing capacity. Improved testing has helped better understanding of the pandemic and drivers of cases spikes and assess the effectiveness of the response. There should be improved capacity to genomic studies by adopting and implementing agreed protocols to monitor the different variants of the virus in the region. As at 11th of May 2021 six different variants has been already identified in the different countries in the region : this remains the gold standard for preventing infections during COVID-19 crisis even after the availability of the vaccines. Unfortunately, human behaviour due to a low perception of risk has contributed to low uptake of preventive measures and fuelled the spread of COVID-19 in communities., one major challenge in ECOWAS Region is to convince communities that there is a problem and that they need to take personal responsibilities to limit the spread of the pandemic [pandemic . Other cpandemic .Non-pharmaceutical interventions (NPIs) include all measures or actions, outside of vaccines and medicines, that can implement to prevent, slow the spread of COVID-19 in Community. Whilst focusing and expanding the health service that will save lives during crisis, the biggest impact will come from NPIs. ECOWAS Member Community should foster the implementation of mitigation strategies, include personal, environmental and community NPIs. Nationwide or subnational lockdowns are neither sustainable nor effective in West Africa. Though temporary application of these measures can be effective in preventing and controlling hotspots by reducing human interactions.Conclusion: COVID-19 is a long-game; the best time to start implementing effective preparedness and response measures to address the COVID-19 crisis in West Africa may have been several years ago, but the next best time is now. We need sustained political commitment to implement the available effective interventions (Annex 1) at global, regional and national level [al level , 11, 12.