Convolutional neural networks (CNNs) trained on natural images are extremely successful in image classification and localization due to superior automated feature extraction capability. In extending their use to biomedical recognition tasks, it is important to note that visual features of medical images tend to be uniquely different than natural images. There are advantages offered through training these networks on large scale medical common modality image collections pertaining to the recognition task. Further, improved generalization in transferring knowledge across similar tasks is possible when the models are trained to learn modality-specific features and then suitably repurposed for the target task. In this study, we propose modality-specific ensemble learning toward improving abnormality detection in chest X-rays (CXRs). CNN models are trained on a large-scale CXR collection to learn modality-specific features and then repurposed for detecting and localizing abnormalities. Model predictions are combined using different ensemble strategies toward reducing prediction variance and sensitivity to the training data while improving overall performance and generalization. Class-selective relevance mapping (CRM) is used to visualize the learned behavior of the individual models and their ensembles. It localizes discriminative regions of interest (ROIs) showing abnormal regions and offers an improved explanation of model predictions. It was observed that the model ensembles demonstrate superior localization performance in terms of Intersection of Union (IoU) and mean Average Precision (mAP) metrics than any individual constituent model. Computer-aided diagnosis (CADx) tools have gained immense prominence in medicine by augmenting clinical expertise and reducing observer variability . Data-drmodality-specific transfer learning. This strategy induces knowledge in the form of modality-specific feature representations toward improving generalization and performance for similar tasks. Transfer Learning (TF) strategies are commonly adopted when limited data is available, e.g., medical images. Here, CNNs are trained on a large-scale selection of natural images and the learned knowledge is transferred and repurposed for the new task . HoweverCNNs are found to be sensitive to the noise present in the training data since they learn through stochastic optimization and error backpropagation. This leads to variance error and may result in overfitting since the learning algorithms may also model the random noise in the training set resulting in poor generalization to real-world data. A machine learning paradigm called ensemble learning reduces the prediction variance by combining constituent model predictions. This results in a model with superior performance compared to any individual constituent model . SeveralCNN models are commonly perceived as black boxes with an increasing ask for an explanation of their decision-making process. A lack of explanation of learned interpretations has been viewed as a serious bottleneck in acceptance of the technology for medical screening or diagnostic applications . ExploraResearchers have attempted to explain CNN model predictions and interpret the learned representations toward disease detection using CXRs. This work aims to simplify the analysis in a binary triage classification problem that classifies CXRs into normal and abnormal categories. In this study, we propose modality-specific ensemble learning toward improving abnormality detection in CXRs. CNN models are trained on a large-scale CXR collection to learn modality-specific features. The learned knowledge is transferred and repurposed for detecting and localizing abnormalities using a different CXR collection. A custom, sequential CNN and a selection of pretrained models including VGG-16 , VGG-19 The publicly available CheXpert  and RSNACheXpert CXR collection: Radiological Society of North America (RSNA) CXR collection: The dataset has been released as a part of the RSNA Kaggle pneumonia detection challenge, jointly organized by the radiologists from RSNA, Society of Thoracic Radiology (STR), and the NIH . The datThe datasets have been split at the patient-level into 80% for training and 20% for testing for the different stages of learning performed in this study. We have randomly allocated 10% of the training data for validation.The CXRs contain regions that do not contribute to diagnosing lung abnormalities. Hence, CNN models may learn irrelevant features that impact decision making. Under these circumstances, semantic segmentation is performed using algorithms like U-Net  to perfoThe cropped lung boundaries are preprocessed as follows: The images are (a) passed through a median filter with a 3 × 3 kernel to preserve edges and remove noise; (b) rescaled to the pixel range [0 1]; and (c) mean-normalized and standardized for identical distribution of the extracted features.We evaluated the performance of the following CNN models at different stages of learning performed in this study: (a) Custom CNN; (b) VGG-16; (c) VGG-19; (d) Inception-V3; (e) Xception; (f) DenseNet-121; (g) MobileNet; and (h) NASNet-mobile. The custom CNN is constructed as a linear stack of depth-wise separable convolution, nonlinear activation, pooling, and dense layers. Depth-wise separable convolution applies the convolution operation to individual channels, followed by a point-wise convolution with 1 × 1 kernels. These operations are shown to result in fewer model parameters and reduced overfitting as compared to conventional convolutions . The arcThe convolutional block consists of a separable convolution layer, followed by batch normalization and ReLU non-linearity layers. We added padding to the separable convolutional layers to ensure the feature map dimensions of the intermediate layers match the original input size. We used 5 × 5 kernels for all separable convolutional layers. Each convolutional block is followed by a max-pooling layer; the number of kernels is increased by a factor of two in the succeeding convolutional blocks to ensure the computation roughly remains the same across the separable convolutional layers. The model is added with a global average pooling (GAP) layer, followed by dropout (ratio = 0.5), and a final dense layer with Softmax activation to output prediction probabilities.We performed Bayesian learning  to optimThe pretrained CNN models are instantiated with the ImageNet weights and truncated at their fully-connected layers. The truncated models are appended with the following layers: (a) zero-padding; (b) convolutional layer with 3 × 3 kernels and 1024 feature maps; (c) GAP; (d) dropout (dropout ratio = 0.5); and (e) dense layer with Softmax activation. The customized architecture of the pretrained CNNs used in this study is as shown in The hyperparameters of the pretrained CNNs including momentum, learning rate, and L2-weight decay, in modality-specific transfer learning and coarse-to-fine-learning, are optimized through a randomized grid search . The sea® is used for custom CNN optimization. The models are trained and evaluated on an Ubuntu Linux system with 64GB RAM and NVIDIA 1080Ti GPU.The models in modality-specific transfer learning, coarse-to-fine-learning, and ensemble learning are evaluated in terms of the following performance metrics: (a) accuracy; (b) AUC; (c) sensitivity; (d) specificity; (e) F measure; and (f) Matthews correlation coefficient (MCC). We used Keras API with Tensorflow backend and CUDA/CUDNN libraries for GPU acceleration. Matlab R2018bcoarse models.We propose modality-specific transfer learning where the pretrained CNNs with ImageNet weights and the custom CNN with random weight initializations are trained end to end and evaluated on the large-scale CheXpert data set to classify abnormal and normal CXRs, thereby making all the weight layers specific to the CXR modality. The idea behind this approach is to induce knowledge pertaining to a large-scale selection of CXR lung abnormalities and provide possible hints to how the abnormal and normal lungs look like. The CheXpert dataset includes normal CXRs and abnormal images containing the following abnormalities: (a) enlarged cardio-mediastinum; (b) cardiomegaly; (c) lung opacity; (d) lung lesion; (e) edema; (f) consolidation; (g) pneumonia; (h) atelectasis; (i) pneumothorax; (j) pleural effusion; (k) pleural other; and (l) fracture. CXRs with disease manifestations are grouped to form the abnormal class and used to solve the binary classification task. The learned knowledge is then transferred and repurposed to perform CXR abnormality detection using the RSNA CXR dataset, with an aim to improve models’ adaptation, performance, and generalization. During model training, we augmented the CXR images with horizontal, vertical translations and rotations with an aim to improve generalization and reduce overfitting to the training data. The modality-specific trained CNNs are henceforth called as fine models and the process, coarse-to-fine learning. The workflow is shown in For coarse-to-fine learning, we instantiated the convolutional part of the coarse models and extracted the features from different intermediate layers with an aim to identify the optimal layer for feature extraction toward the current task. Pretrained models differ in their depth and learn different feature representations pertaining to their depth. Deeper models are not always optimal for all the tasks, especially in the medical domain, where the data distribution is different compared to stock photographic images. In this regard, it is indispensable to identify the layer in the individual models to extract features that deliver the best performance toward classifying the classes under study. We used class weights to penalize the majority class with an aim to prevent model bias. The retrained models are henceforth called as We constructed ensembles of the top-7 fine models with an aim to reduce (i) prediction variance, (ii) sensitivity to the specifics of the training data, (iii) model overfitting, and (iv) improve performance and generalization. We performed majority voting, simple averaging, weighted averaging, and stacking with an aim to build a predictive model with reduced prediction variance and improved performance as compared to any individual constituent model . In majoModel stacking performs learning at distinct stages: (a) Stage-0: The base-learners are trained, validated, and tested using the RSNA CXR test set to output predictions; (b) Stage-1: A neural-network-based meta-learner learns to combine the predictions of individual base-learners. The meta-learner consists of a hidden layer with 14 neurons that interprets the input from the base-learners and a dense layer with Softmax activation to output the prediction probabilities. We freeze the trainable weights in the individual base-learners and train the meta-learner with an aim to output improved predictions as compared to any individual base-learner.We performed statistical testing to investigate the existence of a statistically significant difference in performance between the models in different stages of learning discussed in this study. Confidence intervals (CI) are used in applied DL to present the skill of predictive models by measuring the precision of an estimate through the margin of error. A relatively precise estimate is inferred by a short CI and therefore a smaller error margin. A larger error margin is inferred by a long CI and therefore low precision . In thisx, y). A prediction score Sc is calculated at each node c in the output layer. Another prediction score Sc iscalculated after removing a spatial element  in the feature maps from the deepest convolutional layer. The CRM Sc and Sc calculated from all nodes in the output layer of the CNN model. The learned behavior of the individual models and their ensembles is visualized based on the CRM visualization tool  to localAccordingly, a spatial element having a large CRM score can be considered as playing an important role in the classification process since removing that node results in a significant increase in the mean squared error (MSE) at the output layer. An ensemble CRM is created by combining and averaging multiple CRMs generated from different CNN models; the workflow for a selection of three CNN models is shown in area of the overlap”/“area of the union” between the GT bounding box and the predicted bounding box for a given input image  Ensemble-3; (b) Ensemble-5; and (c) Ensemble-7. These ensemble CRMs are generated by averaging the CRMs from the top-3, top-5, and top-7 performing CNN models that are selected based on the IoU and mAP scores as shown in We observed that each individual CRM highlights different areas as their ROIs for the given image and the bounding boxes surrounding these ROIs have low IoU scores even though all ROIs detected are actually located within the GT bounding boxes. On the other hand, the proposed ensemble CRM highlights ROIs resulting from averaging the ROIs from individual CRMs. The ensemble CRM visually and quantitatively demonstrates superior performance in objection detection and localization than any individual constituent model; the resulting ROIs are found to have their bounding boxes more closely overlapped with the GT boxes and significantly improved IoU scores, compared to those from individual CRMs. Therefore, we demonstrate that our ensemble approach improves not only the classification performance but also the object detection performance overall.Since the coarse models have already learned the ability to classify the normal and abnormal CXRs with a large-scale dataset with a range of data distributions, the learned weights served as a promising initialization for a related abnormality classification task in a dataset with a different distribution, as compared to ImageNet weights learned from stock photographic images that are visually distinct from medical images. The size of the CheXpert data set is much larger than the RSNA CXR data set, thus transferring knowledge to the CXR-modality on the first hand allowed for improved initialization and adaptation of the CNNs that are subsequently trained and evaluated for a related classification task. The VGG-16 model demonstrated superior performance, followed by VGG-19 as compared to the other models. As well, tests for statistical significance showed that the VGG-16 model demonstrated a tighter CI and a smaller margin of error for the AUC values as compared to the other models. This may be because the architectural depth of VGG models is optimal for the current task as compared to the other DL models used in this study.We observed that the weighted averaging ensemble outperformed the other ensemble methods. We believe this may be due to the fact that deeper models are not always optimal for all the tasks, especially in the medical domain, where the data distribution is different compared to stock photographic images. We empirically observed that the VGG-16 model demonstrated superior performance in all performance metrics, followed by VGG-19, as compared to the other models. By awarding higher weights to the predictions of the best performing VGG models, we were able to improve the performance as compared to the other ensemble methods.We chose CRM as our visualization method for localizing abnormal CXR regions based on the recent study  where CRTo summarize, modality-specific transfer learning helped to improve performance and generalization in a related target task. The performance of the ensemble improved with using the models that inherited modality-specific knowledge from a large-scale CXR data collection. The performance of ensemble visualization improved with the use of models that benefited from modality-specific knowledge transfer and provided a combined prediction that is superior compared to any individual constituent model.The combination of modality-specific model training and ensemble learning helped to: (a) transfer modality-specific knowledge that is repurposed to improve classification performance in a similar task; (b) reduce prediction variance, sensitivity to the training data, and model overfitting; and, (c) improve overall performance, and generalization. However, ensemble methods are computationally expensive, adding training time and memory constraints to the problem. It may not be practicable to implement model ensembles at the present; however, with the advent of low-cost GPU technology and availability of high-performance computing solutions, model ensembles could become practically feasible for real-time applications. Ensemble visualization helped to interpret the models’ behavior, compensated for the error of missing ROIs using individual CNN models and demonstrated superior ROI detection and localization performance as compared to any individual constituent model. Further, CRM offers improved interpretation and understanding of the model’s learned-behavior. We believe that the results proposed are valuable toward developing robust models for medical image classification and ROI localization. Future studies could explore the application of ensemble CRMs to other diagnostic/screening applications, for example, detecting cancers in various image modalities, separating pneumonia from TB in pediatric CXRs, skeletal malocclusion detection from 3D-Cone Beam CT images, etc. In addition, it is desirable to compare the performance of ensemble CRMs to other state-of-the-art visualization strategies.


Successful development of agents that improve cognition and behavior in Alzheimer’s disease (AD) is critical to improving the lives of patients manifesting the symptoms of this progressive disorder.There have been no recent approvals of cognitive enhancing agents for AD. There are currently 6 cognitive enhancers in Phase 2 trials and 4 in phase 3. They represent a variety of novel mechanisms. There has been progress in developing new treatments for neuropsychiatric symptoms in AD with advances in treatment of insomnia, psychosis, apathy, and agitation in AD. There are currently 4 AD-related psychotropic agents in Phase 2 trials and 7 in Phase 3 trials. Many novel mechanisms are being explored for the treatment of cognitive and behavioral targets. Progress in trial designs, outcomes measures, and population definitions are improving trial conduct for symptomatic treatment of AD.Advances in developing new agents for cognitive and behavioral symptoms of AD combined with enhanced trial methods promise to address the unmet needs of patients with AD for improved cognition and amelioration of neuropsychiatric symptoms. Alzheimer’s disease (AD) is a progressive neurodegenerative disorder manifested by cognitive and functional decline and the emergence of neuropsychiatric symptoms. The underlying biology of AD includes aggregation of soluble amyloid species into insoluble amyloid plaques, hyperphosphorylation of tau with formation of intracellular neurofibrillary tangles, and neuronal death along with a variety of related processes including neuroinflammation, synaptic and circuit dysfunction, mitochondrial and bioenergetic disorders, epigenetic changes, and vascular abnormalities , 2. NeurAll currently approved treatments for AD are “symptomatic” agents that aim to improve cognitive and behavioral symptoms without altering the underlying course of the disease . Most cuFour cholinesterase inhibitors (ChE-Is) and one N-methyl-D-aspartate (NMDA) receptor antagonist have been approved by the FDA for the treatment of AD. One ChE-I --- tacrine --- is no longer available on the market; the three available ChE-Is are donepezil (Aricept™), rivastigmine (Exelon™), and galantamine (Razadyne™). The NMDA receptor antagonist is memantine (Namenda™). Clinical trials show that these agents produce improvement on the AD Assessment Scale – cognitive subscale (ADAS-cog) in the range of 1.5 to 3 points of 70) with corresponding changes on the Mini Mental State Examination (MMSE) 0 with co. Meta-anChE-Is capitalize on the unique biological circumstance in AD of loss of presynaptic cholinergic cells in the nucleus basalis of Meynert with preserved post-synaptic cortical cholinergic neurons, creating the opportunity for functional post-synaptic stimulation producing cholinergic augmentation with corresponding cognitive improvement , 14. TheCognition is dependent on intact circuit function that includes cholinergic innervation as well as involvement of other transmitters. Imaging investigations such as those with functional magnetic resonance imaging (fMRI) and fluorodeoxyglucose (FDG) positron emission tomography (PET) typically show enhanced cortical circuit activity following treatment with ChE-Is , 17. EnhThe clinical methodology and instrumentation for AD trials was defined by trials of tacrine, the first agent approved for the treatment of AD by the FDA , 20. PatFigure GV-971 (Oligomannate™) is an oligosaccharide that has putative effects on the gut microbiome to reduce systemic inflammation and neuroinflammation . In a 9 6 antagonists have been the subject of several recent clinical trials. Intepirdine, idalopirdine, and masuperdine are drugs in this class assessed in Phase 3 development programs [6 receptors are exclusively found in the central nervous system where they modulate primarily gamma-aminobutyric acid (GABA) and glutamate levels, facilitating the secondary release of other neurotransmitters including noradrenaline and acetylcholine which are compromised in AD [5-HTprograms . All tried in AD .Cholinergic stimulation can be achieved with nicotinic cholinergic agonists or muscarinic cholinergic agonists in addition to the currently approved ChE-Is. Although promising results have been observed in early stage trials with these agents, none have succeeded in late stage trials or been approved by the FDA . A nicotNew versions of ChE-Is are in development programs including octohydroaminoacridine and AD-35 [ChE-Is in combination with peripheral cholinergic receptor blockers have been tested in an attempt to achieve greater central cholinergic stimulation while limiting peripheral cholinergic side effects. CPC-201 is an example of this strategy . These aA trial of MK-7622, an M1 positive muscarinic allosteric modulator, was stopped for futility and showed no drug-placebo differences on cognitive or functional outcomes . Other mThe adrenergic system is a target of putative cognitive enhancing agents. Guanfacine is an alpha-2 adrenergic agonist currently in trials. The locus coeruleus and associated adrenergic projections to cerebral cortical regions mediating key aspects of cognition and behavior are atrophic in AD making adrenergic function a candidate for AD therapy .The dopaminergic system may play a role in cognitive function, especially executive measures mediated by frontal-subcortical systems. The dopaminergic midbrain is altered in AD and substantial evidence links this structure to the cognitive and behavioral changes of AD . RotigotPhosphodiesterase inhibitors (PDE-Is) are another class of agents which have been assessed in multiple AD clinical trials, so far without successfully demonstrating a drug-placebo difference in cognition Table . In manyXanamem®(UE2343) is a an 11-ß-hydroxysteroid dehydrogenase (HSD) antagonist intended to produce cognitive enhancement through blocking the adverse effects of endogenous glucocorticoids on memory and cognition . A recenBeyond the mechanisms noted above and addressed in late stage trials, a number of other mechanisms are being considered to achieve cognitive enhancement in AD. Among the targets currently addressed by agents under study are drug-induced effects on metabotropic glutamate receptor 5, cyclic adenosine monophosphate, norepinephrine, glucagon-like peptide 1, polyphenols, flavonoids, D1 and D2 dopamine receptors, and calcium channel modulation –55. SomeThere are substantial challenges in the development of both DMTs and cognitive enhancing agents. Table The contrast of symptomatic cognitive enhancing therapies and DMTs artificially simplifies these categories. There is evidence that combination therapy with cholinesterase inhibitors and memantine slows the progression of AD and may have a disease modifying effect . Some chThere are currently no approved treatments for any neuropsychiatric symptom in AD; there is progress in clinical trials and trial methodology, several drugs are in late stage trials for behavioral disorders in AD or dementia, and one agent has been submitted to the FDA for approval as treatment for dementia-related psychosis (discussed below). Most of the agents in trials are re-positioned from successful development programs for behavioral changes in patients with major mental disorders . Figure The neurobiological bases of behavioral changes in AD are not precisely known. Behavior is an emergent property of integrated circuits with distributed anatomies and reliance on multiple transmitters. Distinct circuits comprising unique anatomies and neurotransmitters underly different behavioral phenotypes . In AD, Development of new therapies for agitation is currently the most active area of drug development for neuropsychiatric symptoms in AD. There are 8 agents in clinicals trials for agitation. Brexpiprazole (Rexulti™) is approved for treatment of schizophrenia and as adjunctive therapy for major depressive disorder. Preliminary trials in AD demonstrated a drug-placebo difference in agitation reduction with the 2 mg daily dose, not the 1 mg dose . A confiThere are no approved treatments for psychosis in any form of dementia. Pimavanserin (Nuplazid™) is approved for psychosis in Parkinson’ disease (PD) without dementia . PimavanPsychosis is associated with more rapid cognitive and functional decline in AD , 79. FutApathy is among the most common manifestations of AD and other dementias . No treaPET and fMRI studies of apathy in neurodegenerative disorders show abnormalities in frontal regions associated with impairments in planning and decision making and in the anterior cingulate cortices related to emotional blunting and loss of motivation .Sleep disorders are common in AD and affect the lives of the patient and the caregiver , 87. PooSuvorexant, a dual orexin antagonist (DORA), was recently shown in a double blind, placebo-controlled phase 3 trial to reduce insomnia in AD. Total sleep time was significantly increased and wakefulness after sleep onset (WASO) was significantly decreased . SuvorexLemborexant, a DORA, is being investigated for irregular sleep wake rhythm disorder (ISWRD) in AD . ISWRD iAdditional agents currently under study for sleep disorders in AD include zopiclone and zolpidem .A major challenge for clinical trials of treatments for neuropsychiatric syndromes is the occurrence of robust placebo-group improvement. This reduction in symptoms in the no-active-treatment group may be a true placebo response in the participant, a placebo response in the caregiver who reports the response in most clinical trials, regression to the mean of elevated scale scores at the time of screening for the trial, natural history of agitation, and behavioral improvement in response to the clinical trial circumstances including increased family involvement, greater staff attention in residential settings, and interaction with research staff .The substantial placebo response in behavioral trials is the greatest challenge to being able to demonstrate a treatment effect of the active agent. A variety of strategies have been implemented in an attempt to understand and manage the placebo-group effects in trials of neuropsychiatric agents Table . Placebo1A agonists, 5-HT2C antagonists and agonists, 5-HT3 antagonists, 5-HT6 antagonists, and 5-HT7 antagonists), gamma-aminobutyric acid (GABA) allosteric modulators, neuropeptide agents , cannabinoids, anti-inflammatory agents (producing cytokine reduction), and targeting of trace amine-associated receptor 1 (TAAR1) and 5-HT1A are being assessed in nonclinical models of schizophrenia or in early human trials and, if successful, will likely be evaluated for their ability to ameliorate psychosis or agitation in AD [Most drugs directed at behavioral symptoms in AD are assessed first in primary psychiatric disorders such as schizophrenia, bipolar illness, depression, or sleep disorders. The absence of a known symptom-specific biology for the neuropsychiatric syndromes of AD makes it difficult to target these behaviors with agents unique to AD. There are few neuropsychiatric agents in Phase 1 AD development programs because the early evaluation of the agents is conducted in psychiatric programs. The diversification of targets for schizophrenia suggests that agents with more varied mechanisms of action will eventually be directed to behavioral symptoms of AD. Glutamatergic agents , serotonin agents , oxidative and nitrosative stress, PPAR γ, glucagon-like peptide 1, mitochondrial modulation and bioenergetics, glutamatergic pathways, S-adenosyl-methionine, neurotrophin signaling, PDE 10A, receptors of psychedelic agents, and the opioid system [There are no drugs currently in clinical trials for treatment of depression in AD despite a high prevalence of depressive mood changes in the disorder . Conventd system –111.There is a high rate of negative outcomes in clinical trials for drugs being developed to improve cognitive and behavioral symptoms of AD . Most trPrecision drug development depends on demonstrating a pharmacodynamic effect of the agent that predicts the expected cognitive or behavioral impact . A varieSensitive clinical outcomes are needed to demonstrate drug-placebo differences, and new tools that promise to perform well in trials are being introduced. The Neuropsychological Test Battery (NTB) may be more sensitive than the ADAS-cog in mild AD and more likely to show a drug-placebo difference in this population where progression is modest in the course of a short trial . ComputeThis review is limited by its dependence on clinicaltrials.gov as the source of information on agents currently in trials. While this registry is comprehensive, it under-represents agents in Phase 1 and some cognitive enhancers or psychotropic agents in early development may have escaped detection. There is no similar registry for agents for behavioral and cognitive symptoms of AD in the nonclinical phases of development, and the catalogue of agents in this stage is no doubt flawed. The principles of drug development applicable across development programs are emphasized.There has been progress in developing new therapies for behavioral aspects of AD. Suvorexant has been shown to improve insomnia in AD, and pimavanserin has been submitted to the FDA for dementia-related psychosis including psychosis in AD. Trials of agitation and apathy have promising preliminary results. New criteria for specific behavioral syndromes  in AD assist in reducing heterogeneity of trial populations, presenting agents to the FDA, and educating prescribers on how best to use emerging treatments. Trial designs and means of managing the placebo response in trials of behavioral disorders have advanced. Less progress is currently evident in the development of cognitive enhancing agents but better trial participant characterization, use of pharmacodynamic biomarkers, and implementation of more sensitive outcomes may assist in improving the success of development programs. Continued improvements will result in progress toward developing cognitive enhancing and psychotropic agents to address the unmet needs of patients with AD.


Low-grade waste heat harvesting and conversion into electric energy is an important way of renewable energy development and thermo-electrochemical cells are promising devices to solve this problem. In this paper, we report original data on the current density and maximum output power dependents on voltage of the thermos-cells with nickel hollow microspheres electrodes and different electrolyte concentration (from 0.1 to 3.0 mol/l)which exhibit excellent hypothetical Seebeck coefficient and accordingly high open-circuit voltage values at low source temperature. The composition, microstructure and morphology of the hollow nickel microspheres based electrodes are included here. Because of the low cost of nickel based thermo-cells could be commercially feasible for harvesting low-quality thermal energy, in this connection, the raw data of measurements of their properties are given here.The data is related to “High Seebeck coefficient thermo-electrochemical cell using nickel hollow microspheres electrodes”, Burmistrov et al., Renewable Energy, 2020  Specifications Table•The data set directed to use by researchers interested in developing new renewable energy sources and understanding the mechanism of metal nickel electrodes working in thermo-electrochemical cell, supercapacitors, batteries, etc.•The open-circuit potential of the electrolyte concentration for the hollow Ni-microspheres based thermos-cells could give an insight into the chemistry of the electrode process and could help to explain extremely high Seebeck coefficient.•Comparison with data acquired for other electrochemical couples may be done as well as further experimental studies in the field of increasing the range of electrolyte concentrations.1The data set in this article describes the electrode materials based on nickel hollow microspheres produced by ultrasonic spray pyrolysis. The hollow structure and particle size of microspheres after synthesis are presented in 2The measuring cell is classic for electrochemistry and consists of two flasks with electrodes connected by an ion-conducting bridge . The hotElectrodes weighing 0.3 g are pressed in a mold with a diameter of 12 mm at 0.5 tons. Low pressing force allows to form the electrode without harming the structure of the microspheres. The electrode is placed in a flask on a thin stainless steel wire, which acts as a current lead.The load curves were obtained with the ELINS Pi-50-Pro potentiostat-galvanostat in the potentiodynamic mode. The parameters of the potentiodynamic mode were established as follows: the counter potential increased from 0 mV to the open circuit voltage at a rate of 5 mV/s.SEM analysis of nickel microsphere powder  made it The presented current-voltage characteristics (The authors declare that they have no known competing financial interests or personal rela- tionships that could have appeared to influence the work reported in this paper.


Z value of the diameter of the tricuspid valve. The essential associated cardiac finding of PA-IVS is ventricular-coronary arterial communications (VCAC). The hypertensive RV forces blood through the intramyocardial sinusoids with continuous fistulous contact with the epicardial branches of RCA. It is called the VCAC. A color Doppler can detect VCAC due to its location in the pericardium along the coronary artery. If patients have VCAC and tricuspid Z score below -4, all of these conditions are infallible signs of high mortality rates in their fetal or postnatal lives. Our aim in presenting this case is to remind perinatologists if they detect an abnormal four-chamber view of the fetus's heart, they should also carefully examine whether VCAC exists. Herein, we report a case of PA-IVS and VCAC at 21 weeks' gestation with fetal echocardiographic images.Pulmonary atresia with the intact ventricular septum (PA-IVS) is a rare anomaly that has an absent communication between the right ventricle and pulmonary arterial circulation. PA-IVS has a hypoplastic and hypokinetic and thickened right ventricle with the intact ventricular septum. It can be diagnosed with PA-IVS in routine obstetric ultrasound examination because the four-chamber view of PA-IVS is generally abnormal. The size of the right ventricular cavity is proportional to the  Pulmonary atresia with the intact ventricular septum (PA-IVS) is a congenital cardiac anomaly which occurs due to the disjoint communication between the right ventricle (RV) and the pulmonary arterial circulation. The circulation is associated with an intact ventricular septum, which does not allow any connections between the RV and the left ventricle (LV). PA-IVS has a prevalence rate of 0.042-0.053 per 1000 live births [Z score -4.75), and the pulmonary valve annulus was 2.8 mm (Z score -3.77). The pulmonary artery had an extremely thick pulmonary valve. Antegrade pulmonary blood flow to the lungs was not detected (thick membranous pulmonary atresia), and the pulmonary arteries were perfused by retrograde ductus arteriosus flow. Another intriguing finding of the color Doppler examination was that it detected the turbulent flow from the apex along the pericardium via the right coronary artery to the aorta. This condition is known as VCAC (video 1). Pulse waved Doppler interrogation was performed to demonstrate and further prove the findings of VCAC bidirectional flow (systolic flow towards the aorta and diastolic flow towards the right ventricle cavity)  . Our pedThroughout the fetal life, the prognosis of PA-IVS is subject to change, and the prognosis will depend upon the size of RV's cavity and its functions. There is a strong positive association between having a good prognosis in fetal life and having an excellent biventricular hole. If the RV inlet and outlet septum are well-preserved, pulmonary valve perforation will be performed in the fetal or neonatal life , 4. PatiZ score below -4, all of these conditions are infallible signs of high mortality rates in their fetal or postnatal lives. Death in utero may occur, with overall mortality in live-borne children of greater than 50% [The retrograde filling of the coronary circulation, which flows from the hypertensive RV, is known as the RV-dependent coronary circulation (RVDCC). Patients with RVDCC can also have atresia or stenosis in their proximal major coronary arteries. This deteriorated condition can be visualized by an angiographic study in postnatal life . Even ththan 50% . It is nZ score below -4, which was indicative of a bad prognosis. This case was consulted with the Department of Maternal-Fetal Medicine, and our team decided to terminate the patient's pregnancy.Single-ventricle palliation is often the best treatment option for RVDCC. RVDCC accounts for almost all of the mortality in patients with PA-IVS  in the p


During the last decade, diverse in vitro 3D cell systems have been proposed as a bridging link between two-dimensional (2D) cell cultures and in vivo animal models, both considered gold standards in pre-clinical settings. The latest awareness about the power of tailored therapies and cell-based therapies in eradicating tumor cells raises the need for versatile 3D cell culture systems through which we might rapidly understand the specificity of promising anti-cancer approaches. Yet, a faithful reproduction of the complex tumor microenvironment is demanding as it implies a suitable organization of several cell types and extracellular matrix components. The proposed 3D tumor models discussed here are expected to offer the required structural complexity while also assuring cost-effectiveness during pre-selection of the most promising therapies. As neuroblastoma is an extremely heterogenous extracranial solid tumor, translation from 2D cultures into innovative 3D in vitro systems is particularly challenging. In recent years, the number of 3D in vitro models mimicking native neuroblastoma tumors has been rapidly increasing. However, in vitro platforms that efficiently sustain patient-derived tumor cell growth, thus allowing comprehensive drug discovery studies on tailored therapies, are still lacking. In this review, the latest neuroblastoma 3D in vitro models are presented and their applicability for a more accurate prediction of therapy outcomes is discussed.The potential of tumor three-dimensional (3D)  Over time, the complexity of in vitro systems has increased according to the needs of various branches of life science. The enhancement of in vitro techniques applicable in these two-dimensional (2D) systems greatly changed the perception of cell-related processes and allowed more accurate deciphering of the fundamental biomolecular and biophysical mechanisms active in both, physiological conditions and disease  multicellular entities, while approaching as much as possible in vivo situations  components  followed by  animals . The higmponents . The tumal cells , 7. The  success . Many efin vivo animal models are still considered the gold standards in pre-clinical settings in oncology. However, the traditional means of drug efficacy evaluation faces serious limitations, since many compounds that show good anti-cancer effects in murine models fail to provide meaningful clinical benefits for humans  or induced pluripotent stem cells (iPSC) (Organoids are s (iPSC) . To dates (iPSC) ).PDTOs cultures show strong phenotypical and genetic similarities to the original tumor, enabling their use across a wide spectrum of applications. PDTOs allow long-term culture and cryopreservation for the generation of patient-derived tumor organoid biobanks . Howeverin vitro.In general, we are currently faced with an extremely low efficacy of pre-clinical studies. In oncology, less than 10% of drugs successfully conclude clinical trials , resultiEach tumor can be considered as a heterogeneous structure deriving from the interaction between cancer cells and the surrounding microenvironment, which provides important physical and biochemical signals for its growth. The information coming from the native 3D human cancer structure can affect, for example, the expression of specific genes as well as the diffusion of nutrients and oxygen within the tumor mass. Moreover, this complex network of interactions determines the ability of tumor cells to resist and escape from pharmacological treatments. This diversity could be at the root of treatment failures, which remain a peril in the neuroblastoma field today.in vitro 3D models as a valid system for initial testing of new anti-cancer agents  when grown on different chemical modifications of collagen, one with glycosaminoglycan (Collagen-GAG) and the other with nanohydroxyapatite (Collagen-nHA)  . When trnditions . Physicanditions . Micro- nditions . The usenditions . Althougnditions . This apnditions . On the nditions . Moreovenditions .Neuroblastoma cells with different molecular backgrounds show distinct patterns of growth inside biomimetic 3D structures. Moreover, neuroblastoma cells can also be cultured in a mixture of collagen and agarose that is often proposed in order to modify the mechanical properties of pure collagen . The encVarious 3D printing techniques have been employed to develop more accurate constructs for cell-growth supports . PrintinA mix of GelMA and methacrylated alginate (AlgMA) have allowed the optimal mechanical properties and porosity for the growth of neuroblastoma cells . SimilarDifferent neuroblastoma cell lines have been explored using the freeform reversible embedding of suspended hydrogel (FRESH) bioprinting method for conductive scaffolds . Althougin vitro the complexity of the pathological environment in order to gain a better understanding of disease etiology and progression  with human umbilical vein endothelial cells (HUVEC) on temperature-responsive poly(N-isopropylacrylamide) (PIPAAm)-grafted culture plates. A collagen-gel base with microchannels is used as a support for the vascular bed  used to test neurotoxic chemical agents. This system is developed starting from the OrganoPlate  in which neuroblastoma cells (N2a), astrocytes (C8-D1A) and microglia (BV-2) are cultured in a collagen type I solution to recreate the brain parenchyma. The neurovascular environment is assured by also including endothelial cells (bEnd.3). The entire system requires culturing in perfusion conditions to permit appropriate 3D cell organization. This plate-based microfluidic platform may be applied for automated, high-throughput and high-content imaging with relatively fast readouts . Neverthin vitro models for testing the efficacy of these therapies at a personalized level is still an issue  and their ligand on tumor cells (e.g. PDL1), allowing the immune system to become able once again to kill cancer . The CARin vitro 3D models that will allow a close relationship between target and effectors as occurs in vivo are needed for pre-clinical efficacy evaluation of immunotherapeutics. As shown in Currently, several types of immunotherapy are being studied for use against neuroblastoma , 87 and in vitro model has been developed by Pavesi and colleagues  has been recently proposed. VITVO is a small, portable bioreactor integrating a synthetic and biocompatible fiber-based matrix, and can host several types of cells, also in combination. Using this platform, primary cells harvested from human lung cancer specimens have been evaluated to predict the patient specific anti-tumor immunity of TILs triggered by checkpoint inhibitor Nivolumab printing and fabrication of microfluidic platforms in the field of neuroblastoma can therefore amplify the possibilities for HTS in 3D conditions. It is particularly intriguing if the described, versatile 3D cell culture systems could advance the pre-clinical evaluation of newly proposed tailored therapies and cell-based therapies that are currently under investigation for defeating neuroblastoma tumor cells.The more effective targeting of malignant cells remains a highly challenging task since the existing therapeutics approaches do not adequately achieve the same efficacy of rotocols Figure 5DC, SA, OC, and SF wrote the manuscript. DC, SF, SA, and OC reviewed the literature and collected available data. CD, SA, OC, EG, and SF designed the figures. HF and MD revised the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the Fondazione Italiana per la Lotta al Neuroblastoma (project number 19_20FNBL).MD is founder and member of the Board of Directors of Rigenerand srl, a University start-up company. MD interests are managed by the University of Modena and Reggio Emilia in accordance with their conflict of interest policies. SF, OC, and EG are currently employed by Rigenerand srl.The remaining 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.


So, based on this, the role of the NLRP3-inflammasome during ageing and the inflamm-ageing is very evident. However, the complexity of the inflammasomes shows an independent role of these with respect to the canonical inflammatory pathways. Nlrp3 -/- mice have shown similar levels of other cytokines compared to their littermates controls. Youm et al., showed increased levels of IL-6 in serum from aged Nlrp3 -/- and WT mice [Inflammasomes are multiprotein complexes that are formed and activated after exposure to danger signals with the activation of caspase-1 causing the maturation and release of IL-1β and IL-18. In the formation of inflammasome complexes, several cytosolic pattern recognition receptors (PRRs) act as sensors of pathogen-associated molecular patterns (PAMPS) and damage-associated molecular patterns (DAMPS) . Many of WT mice . These fFurther investigation focused on the specific role of NLRP3-inflammasome in cardiac ageing will be required to address these issues and would open a new pharmacological target for the use of the specific NLRP3 inhibitor with respect to anti-inflammatory treatments. We invite to the scientific community to discuss this possible new topic.


Staphylococcus aureus, one of the most important human pathogens, is the causative agent of several infectious diseases including sepsis, pneumonia, osteomyelitis, endocarditis and soft tissue infections. This pathogenicity is due to a multitude of virulence factors including several cell wall-anchored proteins (CWA). CWA proteins have modular structures with distinct domains binding different ligands. The majority of S. aureus strains express two CWA fibronectin (Fn)-binding adhesins FnBPA and FnBPB (Fn-binding proteins A and B), which are encoded by closely related genes. The N-terminus of FnBPA and FnBPB comprises an A domain which binds ligands such as fibrinogen, elastin and plasminogen. The A domain of FnBPB also interacts with histones and this binding results in the neutralization of the antimicrobial activity of these molecules. The C-terminal moiety of these adhesins comprises a long, intrinsically disordered domain composed of 11/10 fibronectin-binding repeats. These repetitive motifs of FnBPs promote invasion of cells that are not usually phagocytic via a mechanism by which they interact with integrin α5β1 through a Fn mediated-bridge. The FnBPA and FnBPB A domains engage in homophilic cell-cell interactions and promote biofilm formation and enhance platelet aggregation. In this review we update the current understanding of the structure and functional properties of FnBPs and emphasize the role they may have in the staphylococcal infections. Staphylococcus aureus, a formidable pathogen that colonizes 30% of the population asymptomatically . The most studied group of this family of proteins is represented by the microbial surface components recognizing adhesive matrix molecules (MSCRAMMs). All MSCRAMMs share a similar structural organization and are involved in binding specific host ligands  and Sar  global regulators  strain 252)  . Both thThe Fn-binding repeats bind individually to the N-terminal domain (NTD) of Fn and have considerable sequence variations, which in turn explains the differences in affinity of each repeat for the ligand .FnBPA and FnBPB are good examples of promiscuous proteins that exhibit a great capability to interact with several structurally different host extracellular matrix/plasma proteins such as Fbg, Fn and elastin. Recently, these proteins have been shown to bind Plg/plasmin, a blood component that degrades many blood plasma proteins including fibrin clots, and histones.Fn is a large glycoprotein composed of two almost identical subunits. It occurs in a soluble form in plasma and other biological fluids and in a fibrillar or reticular multimeric form in the extracellular matrix (ECM), an organized network of secreted macromolecules immobilized in the extracellular space. Functionally, Fn is involved in attachment of cells to surfaces, assembly of ECM, angiogenesis and would repair. The transcript of Fn gene generates by alternative splicing several mRNAs, each encoding similar but not identical monomeric subunits .The subunits of the dimer of both plasma and cellular Fn are disulfide-bonded at the extreme C-terminal ends. The monomers are composed of three different types of modules named type I, II and III repeated units. Sets of adjacent modules in both the chains form specific domains, each involved in binding to various partners (proteins and carbohydrates).The N-terminal domain (NTD) interacts with ligands such as fibrin, thrombospondin-1, and heparin and many bacterial adhesins, including FnBPA and FnBPB, and is the major site for Fn self-association in the matrix. The NTD contains five type I modules, each of which consists of a double- and a triple-stranded antiparallel β-sheets stacked on top of each other. Each module has four cys residues, which form disulfide bridges that stabilize a double loop structure .Downstream to this region is the gelatin/collagen-binding domain composed of four type I and two type II modules that also binds to tissue transglutaminase. The type II modules (approximately 45 residues each) consist of two double-stranded anti-parallel β-sheets connected by a loop and are stabilized by two intrachain dsulfide bridges . All mod10) that directly binds to the integrin α5β1 and a synergy site (FnIII9) that re-enforces binding of Fn to cell surface. Binding of FnIII10 motif to the integrin connects the ECM to the cytoskeleton and generates signaling pathways. The region following the CBD includes a second high affinity heparin-binding domain and the C-terminal fibrin-binding domain  from the Aα chain and a 14 residue fibrinopetide B (FPB) from the Bβ chain. The uncovered N-terminal ends in the α- and β-chains of Fbg promote interactions with complementary sites in the C-terminal domains of neighbouring Fbg molecules, thus triggering the protofibril formation and soft clot. The soft clot is converted to hard clot by activated transglutaminase (FXIIIa), which promotes covalent crosslinks between the α and β chains . The fibormation . Fbg is ormation .561–Val562 peptide bond in the catalytic domain by the tissue Plg activator (t-PA) and urokinase Plg activator. The cleavage results in the formation of plasmin, the active enzyme that contains the catalytic triad made up of the amino acid residues His603, Asp646 and Ser741 , each containing a typical pattern of four cysteine, and a proteinase catalytic domain. The kringle modules interact with fibrin clots and surface receptors from both eukaryotic and bacterial cells. Proteolytic activation of Plg to plasmin occurs through cleavage of the Argd Ser741 . Staphyl plasmin .vβ3 integrin via a GRKRK motif , proline (10–13%) and other hydrophobic residues (over 40%). Individual polypeptide chains of soluble elastin, named tropoelastin, assemble into large fibers stabilized by multiple lysine-derived cross links (desmosines) formed by the copper-requiring extracellular enzyme lysil oxidase . TropoelRK motif . The cenRK motif .Histones are basic proteins classified either as lysine-rich  or arginine-rich (H3 and H4). In eukaryotes, histones H2A, H2B, H3 and H4 have a structural role in the formation of the nucleosome units, concurring to the assembly and compactation of chromatin. Together with DNA, histones are also the most abundant proteins in neutrophil extracellular traps (NETs), which are networks of extracellular fibers released by neutrophils to catch and kill infecting bacteria . HistoneDock, Lock and Latch) mechanism (Sequence homology between FnBPA and clumping factor A (ClfA), a CWA Fbg-binding protein, the observation that the binding site in Fbg is the same  and the finding that both ClfA and FnBPA bind to Fbg with similar affinity, all suggest a very similar mechanism of Fbg binding. Both the proteins interact with Fbg by the DLL  and steered molecular dynamics simulations, . aureus . It remaThe A domain of FnBPA and FnBPB also binds Plg by a mechanism that does not involve DLL . DiffereS. aureus from the bactericidal effect of the total histones released by neutrophils in the form of NETs  with similar affinity . The weak force needed to separate neighbouring cells might help cell detachment during the dispersal phase that follows the biofilm formation  and a repeat region (R region). The N-terminal A domain of SpsD binds Fbg, Fn, elastin and cytokeratin 10. The binding site of the SpsD A region was mapped to residues 395–411 in the fibrinogen γ-chain. SpsD also bound to Gly- and Ser-rich omega loops within the C-terminal tail region of cytokeratin 10  has been described. SdsY shares 68% identity with SpsD from S. pseudintermedius, 36–39% identity with FnBPs and possesses the typical structure of Fn-binding proteins, including an N-terminal signal sequence, an A domain, a typical repeated region and a cell wall anchor motif. SdsY is involved in Fn-dependent internalization of bacteria into host osteoblast cell lines  on which the outcome of the infective process depends.The role of FnBPs in virulence has been the object of several studies over the years. Since FnBPs are multifunctional, it is reasonable that these proteins play different roles in specific pathogenetic contexts. Importantly, the interpretation of these S. aureus strain lacking all of its cell-wall anchored proteins was less virulent that its wild type strain. Strains specifically lacking FnBPA and FnBPB or other surface CWA protein such as protein A and ClfA also showed a significantly reduced virulence. Conversely, when a model of skin necrosis was studied, the S. aureus surface proteins could not be shown to be involved  (eczema) more efficiently than the biopsies taken from normal or psoriatic skins. In human atopic skin enhanced bacterial binding was primarily due to the increased level and availability of fibronectin present in the stratum corneum and in these conditions FnBPA and FnBPB expressed on the surface of S. aureus promoted better adhesion to AD sections compared to healthy ones    and the in (PVL) . Using aneumonia .S. aureus is one of the most important causes of implant-associated infections , the definition of the X-ray crystal structure of FnBPs in complex with the new ligands such as Plg and histones and the binding mechanisms remain to be revealed. Moreover, a more detailed structural analysis of homophilic interactions will be beneficial for understanding the biochemical basis of biofilm formation promoted by FnBPs. These studies would help in designing inhibitors of the various processes mediated by these MSCRAMMs and in controlling infection. Furthermore, it will be of biological importance to test the role of Plg binding to FnBPA and FnBPB in infection models with mice.However, one should be cautious when studies with murine infection models are performed. In fact, differently from human Plg, the mouse Plg reacts poorly with staphylokinase . MoreoveS. aureus cells express two FnBPs with apparently similar properties. It is possible that expression of each adhesin is differentially regulated and dependent on external factors such as growth conditions. Indeed, a closer examination of these proteins reveals subtle differences both in the structure and function. For example, both proteins bind to Plg via different subdomains of region A, but, more intriguingly, only FnBPB protein interact with histones and prevents them from damaging the bacterial membrane. The discovery of new ligands and functions for FnBPs also deserves attention. Such discoveries must be followed by a detailed biochemical and physical investigation and rigorous analysis in vivo to prove the biological significance of bacterial interactions with new ligands. Another issue regards the immunological properties of FnBPs. The repetitive region of FnBPs does not appear to be promising for vaccine development, while it remains to be determined whether A region of FnBPs can be used as vaccine. In fact, if some observations indicate that FnBPA antibodies are protective in animal models of infection (FnBPA and FnBPB share several structural and functional similarities. Hence, an important question is why nfection , on the nfection . Severalnfection  or by munfection  and possnfection . TherefoPS conceptualized and coordinated the work. PS and GP contributed to this article in terms of data collection and writing and performed critical revision for the work. Both 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.


Furthermore, the next-generation experiments would also improve 2-3 times on neutrino millicharge δν than the current experimental bounds.The millicharged particle has become an attractive topic to probe physics beyond the Standard Model. In direct detection experiments, the parameter space of millicharged particles can be constrained from the atomic ionization process. In this work, we develop the relativistic impulse approximation (RIA) approach, which can duel with atomic many-body effects effectively, in the atomic ionization process induced by millicharged particles. The formulation of RIA in the atomic ionization induced by millicharged particles is derived, and the numerical calculations are obtained and compared with those from free electron approximation and equivalent photon approximation. Concretely, the atomic ionizations induced by mllicharged dark matter particles and millicharged neutrinos in high-purity germanium (HPGe) and liquid xenon (LXe) detectors are carefully studied in this work. The differential cross sections, reaction event rates in HPGe and LXe detectors, and detecting sensitivities on dark matter particle and neutrino millicharge in next-generation HPGe and LXe based experiments are estimated and calculated to give a comprehensive study. Our results suggested that the next-generation experiments would improve 2-3 orders of magnitude on dark matter particle millicharge


A 25-year-old male presented after a motor vehicle accident with tricuspid valve (TV) regurgitation, due to a flail TV secondary to papillary muscle rupture. We highlight the importance of three-dimensional echocardiographic imaging of the tricuspid valve and its utility in aiding a successful surgical repair. The majority of injuries to the tricuspid valve (TV) apparatus are related to blunt chest trauma . Motor vA 25-year-old healthy male presented to a peripheral hospital in Johannesburg, South Africa, after an MVA. He was an unrestrained passenger who hit the car dashboard after sudden deceleration from high speed. He sustained multiple injuries including bilateral hemopneumothoraxes. An admission transthoracic echocardiogram (TTE) revealed severe TR of unclear mechanism.He was referred 2 weeks after the index admission to a tertiary hospital. On arrival, he was asymptomatic and haemodynamically stable. He had abrasion marks on the chest . CardiovThe patient underwent a successful surgical repair of the TV . A flailOur case brings attention to the following pertinent aspects related to traumatic tricuspid valve insufficiency: (1) underreporting of TV injury in Africa and the importance of meticulous screening for TV injury in patients with history of blunt chest trauma; (2) the value of three-dimensional imaging of the TV prior to surgical referral; and (3) early referral for surgery of patients with severe TR due to TV injury.14. However, TEE is not widely available and needs specialized expertise.Motor vehicle accidents are an important cause of TV injury , 10. SouRecently, more attention has been focused on 3-dimensional imaging of the TV . It alloA surgeon with sufficient skill and experience in repairing tricuspid valves is crucial, and all imaging is complementary to direct anatomical inspection. Early referral of patients with severe TR is advised to prevent right ventricular dysfunction from chronic volume overload . It has In conclusion, we have presented a case of successful TV repair with the aid of 3D echocardiographic imaging from Africa. We hope that this case will stimulate readers to actively search for and report on TV-related injury in a patient with a history of chest trauma.


We hypothesized that spatial heterogeneity exists between recurrent and non-recurrent regions within a tumor. The aim of this study was to determine if there is a difference between radiomics features derived from recurrent versus non recurrent regions within the tumor based on pre-treatment MRI.A total of 14 T4NxM0 NPC patients with histologically proven “in field” recurrence in the post nasal space following curative intent IMRT were included in this study. Pretreatment MRI were co-registered with MRI at the time of recurrence for the delineation of gross tumor volume at diagnosis(GTV) and at recurrence(GTVr). A total of 7 histogram features and 40 texture features were computed from the recurrent(GTVr) and non-recurrent region(GTV-GTVr). Paired t-tests and Wilcoxon signed-rank tests were carried out on the 47 quantified radiomics features.A total of 7 features were significantly different between recurrent and non-recurrent regions. Other than the variance from intensity-based histogram, the remaining six significant features were either from the gray-level size zone matrix (GLSZM) or the neighbourhood gray-tone difference matrix (NGTDM).The radiomic features extracted from pre-treatment MRI can potentially reflect the difference between recurrent and non-recurrent regions within a tumor and has a potential role in pre-treatment identification of intra-tumoral radio-resistance for selective dose escalation. Out of the 87 patients treated within this period, a total of 14 patients who developed histologically proven recurrence in the nasopharynx were included in this study. This study was approved by Singhealth institutional review board and the requirement for informed consent was waived.Follow up After treatment, patients were followed up every 2 months in the first year, every 4 months in the second year and every 6 months from the third to fifth year, then yearly afterwards. Locoregional imaging with contrast-enhanced CT, or MRI or PET-CT scans were requested routinely on a yearly basis and/or earlier if clinically indicated.3. Out of the various MRI sequences, we have selected the contrast-enhanced fat-suppressed T1-weighted spin echo sequences in axial planes  for analysis. [Pre-treatment and recurrent MRI scan of the skull base and neck were performed with a 1.5 Tesla scanner . Gadopentetate dimeglumine  at 0.1 mmol/kg of body weight was administered and images of the patients in their customized radiotherapy immobilization shell were acquired. The reconstructed voxel size was 0.7 x 0.7 x 5 mmnalysis. ,39 CE FSIntensity Based HistogramIntensity-based histograms were computed for both recurrent and non-recurrent regions. The histograms of both regions were then normalized on the same intensity scale for a fair comparison between their distributions. On the basis of the first-order statistic, 7 histogram features were computed for both recurrent and non-recurrent tumor volumes: mean, variance, skewness, kurtosis, mean absolute deviation (MAD), hyperskewness and hyperflatness.Texture Analysishttps://github.com/mvallieres/radiomics/tree/master/TextureToolbox) was used to compute different texture features for both recurrent and non-recurrent regions, such as gray-level co-occurrence matrix (GLCM), gray-level run length matrix (GLRLM), gray-level size zone matrix (GLSZM) and neighborhood gray-tone difference matrix (NGTDM) texture matrices. [An open source radiomics library  values with p-values were computed for the paired differences of the recurrent and non-recurrent regions for the significant features. Principal component analysis (PCA) was performed on significant features to reduce dimensionality. All statistical analyses were performed using R software (version 3.6.0).Out of the 87 T4NxM0 NPC patients treated in National Cancer Centre Singapore between January 2010 and December 2012, 14 patients had developed histologically proven recurrence and had both the pre-treatment and recurrent MRI scans available. The 14 recurrent MRI scans were fused with the corresponding pre-treatment MRI scan to segregate the initial tumor into two regions of interest, the recurrent and non-recurrent regions. A total of 7 histogram features and 40 texture features were computed for the regions of interest. Paired t-tests and Wilcoxon signed-rank tests were carried out on the 47 quantified radiomics features, and 7 features were statistically significant at p-values < 0.001 as shown in To reduce dimensionality, the principal component analysis was applied on the 7 significant features. Among the 7 computed principal components (PC), PC1 explained 71% of the variance and PC2 explained 12% of the variance. The 14 recurrent regions and 14 non-recurrent regions were then plotted as dots in the 2-dimensional PCA plot, where PC1 and PC2 yield x and y axes, respectively, as shown in To our knowledge, this is the first study of its kind to assess intra-tumoral radio-resistance using MRI radiomics features in patients with in-field recurrence after IMRT. The novelty of our study is that we performed intra-tumoral partitioning on the MRI at the time of diagnosis using information from MRI at the time of recurrence to characterize spatial heterogeneity. In this proof of concept study, we found a difference in the radiomics pattern between recurrent and non-recurrent regions within the NPC tumor. Notably, the results from the PCA showed that the recurrent regions contained more textural variations and were more heterogeneous than the non-recurrent regions. These results are hypothesis-generating and have potential clinical implications as we are currently unable to reliably predict the region of in-field recurrence from pre-treatment MRI. At present, a homogenous dose of radiotherapy is generally prescribed with the assumption that the whole tumor is homogenous. Recent technological advances in the field of radiation oncology have made it possible to escalate the dose safely. High risk tumor sub-regions associated with radio-resistance can then be targeted with a radiation boost or “dose painting” to potentially improve local control and patient survival.There has been tremendous interest in radiomics research in NPC in the last few years. Previously, the majority of the radiomics studies in NPC have been focused on the analysis of the entire primary tumor as a whole to prognosticate disease outcomes or predict response to treatment. While the results from this approach supported the potential of radiomics in improving patient stratification for therapy, it assumes that the tumor is heterogenous but well mixed and ignores the regional variations within a tumor. ,35,36 StHowever, the enthusiasm for the implementation of radiomics in routine practice should be tempered by a realization of its unique challenges. One of the main challenges includes the lack of standardization of image acquisition protocols. –45 SeverSegmentation is a crucial step in the radiomics workflow as the radiomics features are extracted from the segmented volumes. In our study, the MRI images at the time of recurrence (without immobilization mask) were not perfectly matched to the MRI images at the time of diagnosis (with immobilization mask) given the difference in patient positioning. To minimize the geometrical uncertainties related to image fusion, we focused the region of image registration to a small volume of interest (VOI) centering at the recurrence area in the nasopharynx by using the pterygoid process and skull base as bony landmarks for matching in rigid registration and further fine-tuning. Accurate and robust tumor delineation is essential to ensure the reliability and reproducibility of the radiomics data. This is challenging since many NPC tumors have indistinct boundaries and are primarily treated with radiotherapy, thus neither the histological ground truth nor the robustness of the segmentation can be confirmed. Nonetheless, most authors would consider manual segmentation by experts the ground truth despite the lack of a standard for delineation and  being prOur study has several other limitations. Most notably, the sample size was small, and hence the results of this exploratory study are hypothesis-generating, not confirming. Nonetheless, we hope that these preliminary results could encourage multi-institutional collaborative efforts for further verification with larger datasets. Secondly, the retrospective nature of data collection and retrieval of MRI at the time of local recurrence is an intrinsic limitation. Furthermore, the follow up MRI scans of four patients were performed after significant progression of the local recurrence as the recurrent regions occupied a big volume within the original tumor. Nonetheless, the treatment and follow up care schedule of NPC is protocolized given the high prevalence of NPC in our tertiary center and patients were followed up in a standardized manner. Although a prospective cohort study design is preferred, the protracted follow up periods required for recurrence to occur can require large resources. Third, we have only considered the MRI images from a single sequence  in this study. Our results would likely improve when additional information from other sequences is integrated.In conclusion, our study showed that the radiomics features extracted from pre-treatment MRI could potentially reflect the difference between recurrent and non-recurrent regions within a tumor. The results from this study showed encouraging potential of MRI based radiomics for pre-treatment identification of intra-tumoral radio-resistance for selective dose escalation.S1 AppendixAxial slice pre-treatment MRI showing GTVr (gross tumor volume at recurrence) largely within the 95% isodose line.(JPG)Click here for additional data file.S2 AppendixLeft showing side by side overlay of MRI pre-treatment and MRI at recurrence showing GTV (light green): gross tumor volume at diagnosis (contoured on MRI pre-treatment); GTVr (red): gross tumor volume at recurrence (contoured on MRI at recurrence). Right showing all three GTV on MRI pre-treatment, GTVnr (yellow): non recurrent regions within GTV, obtained by subtracting the overlapping GTVr from the GTV (GTV-GTVr).(JPG)Click here for additional data file.


There is limited best- practice evidence to address behavioral and psychiatric symptoms for those with dementia in Australian rural nursing homes. This study aims to evaluate the outcomes of a person-centered, non-pharmacological dementia care model, ‘Harmony in the Bush’, based on the Progressively Lowered Stress Threshold principles and person-centered music in rural Australia.A quasi-experimental  intervention study was conducted in five rural nursing homes in Queensland and South Australia. Seventy-four residents with dementia participated in this intervention study, which yielded a sample power of 80%. Eighty-seven staff completed the Caregiver Stress Inventory at pre-post four-weeks of intervention. Staff training workshops focused on the theory of the Progressively Lowered Stress Threshold principles and delivery of person-centered care plan with integrated music intervention. We used reported changes in agitation of the residents, measured using Cohen- Mansfield Agitation Inventory, and staff’s caregiving stress, using Caregivers Stress Inventory. This study adheres to the CONSORT guidelines.Mean age of residents with dementia was 82.4 (7.7) years and 69% were females. The mean age of admission was 80.1(8.4) years. Baseline measures indicated that 32.7% had mild- severe pain and 30.5% reported mild-severe sadness. The results showed statistically significant decline in aggressive behaviors, physically non-aggressive behaviors, verbally agitated behavior and hiding and hoarding. There was similar reduction in staff stress in the domains of aggressive behaviors, inappropriate behaviors, resident safety, and resource deficiency.The Harmony in the Bush model is effective in reducing agitation among dementia residents with significant reduction in staff stress levels in nursing homes in rural Australia.https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374458Australian and New Zealand Clinical Trials Registry (ANZCTR) on 20/2/2018 (Registration No: ACTRN12618000263291p).  In Australia, 60–70% of the people residing in nursing homes have dementia , 2 and aEvidence of non-pharmacological interventions is growing and have been recommended to be pursued at first instance, rather than pharmacological treatments, in the management of behavioral and psychiatric symptoms of residents with dementia. Non-pharmacological interventions are recommended to be person-centered to truly mitigate behavioral symptoms in residents with dementia . Person-The Progressively Lowered Stress Threshold (PLST) is an established model that provides a framework for person-centered dementia care . The modMusic intervention is one of the non-pharmacological methods used to reduce behavioural and psychiatric symptoms in dementia. Person-centered music interventions are a promising non-pharmacological approach of dementia care in nursing homes . IndividThis intervention did not adopt PLST as a theoretical framework for staff education and employed music intervention as stand-alone intervention without a comprehensive person-centered care plan , 23. PLSHarmony in the Bush is a co-designed dementia care model that integrates PLST based person- centered care plan and music (during rest time using MP3 players), for the development of a low stress, person-centered organizational culture. Person-centred music was adopted as a main component of the Harmony in the Bush study as it requires minimal training for staff and can be integrated into the PLST based care plan. This paper reports the 4-week outcome of the intervention on residents’ behavioral outcomes and staff stress in the nursing homes. It is hypothesized that this person-centered, non-pharmacological intervention will reduce agitative behaviours of residents with dementia with parallel reduction in caregiver stress in staff.n = 2) and Queensland (n = 3)]. The nursing homes were purposely selected, and their managers were approached by the investigators and the former expressed interest to participate. To reflect on the diversity of the participating nursing homes, two were privately owned; one was a public funded (state-run center); and one was a not-for-profit facility. The fifth facility was a not-for- profit, partly funded by the government, Aboriginal Residential and Community Aged Care home.Harmony in the Bush is a quasi-experimental study conducted in five rural nursing homes of Australia [South Australia  of 0.61 calculated from 12 studies , and by Participants included eligible residents with dementia and staff from the participating nursing homes. Resident participants were recruited following receipt of informed consents to participate in the study by their legal guardians/power of attorney appointees. In each of the four nursing homes, 15–20 residents were selected as potential participants; but in one aged care home, which has a total of 15 residents, all residents with dementia were approached to participate. As a result, a total of 77 residents with dementia were recruited as participants. Inclusion criteria for the residents were: (a) diagnosis of dementia within the Diagnostic and Statistical Manual of Mental Health Disorders 5 (DSM-5) ; (b) a SThe study intervention included:Demographic details and baseline clinical data were collected for each of the resident in the study. The demographic information included age, sex, education level and occupation. In this stage, each participant was assessed using the SMMSE or Kimberley Indigenous Cognitive Assessment (KICA-Cog); Pain Assessment in Advanced Dementia (PAINAD) scale; Cornell Scale for Depression in Dementia (CSDD) or Kimberley Indigenous Cognitive Assessment-Depression (KICA-Dep); Barthel Index of Activities of Daily Living (ADL); Apathy Evaluation Scale (AES); and Cohen-Mansfield Agitation Inventory (CMAI).Introduce consistent individualized routines to compensate for cognitive decline;Organize small group activities to eliminate overwhelming stimuli;Allow residents to set their own sleep/wake cycle to prevent fatigue;Plan activities based on past experiences and practices considering present cognitive and functional abilities; andEliminate misleading stimuli that trigger illusions.The staff training workshops were conducted by an experience nurse educator. The training focused on symptoms associated with Alzheimer’s disease and related disorders, the theory and delivery of the PLST, person-centered dementia care and the use of the measurement instruments listed in stage 1 – Baseline assessment. The Harmony in the Bush intervention entailed the introduction of person-centered care plan based on the following principles of the PLST theory:Understanding of person-centered approach to dementia care and PLST principlesOne each of the cognitive, affective and conative losses associated with Alzheimer’s disease and related disordersFive non-cognitive symptoms associated with Alzheimer’s disease and related disorders; andFour stressors that may potentiate non-cognitive symptoms.Implement person-centered activities and music appropriate to each residentThe expected learning outcome after completion of the training was that staff who attended training should be able to identify:All staff on duty were responsible for observing and recording the residents’ behavior on each shift. Two staff in each facility were appointed as change champions by senior managers and trained in the process to ensure sustainability of the research outcomes after the project completion.Individualized music forms the basis for the person-centered music intervention. Individualized music aims to identify specific music preferences including exact song/composition titles and performers. We used The Assessment of Personal Music Preference Protocol in the Evidence-Based Guideline of Individualized Music for Persons with Dementia  to assisA person-centered care plan and personalized preferred music playlists were provided to participants based on the PLST principles  Table 11; Fig. 1Standardized Mini Mental State Examination (SMMSE) , was useThe Barthel Index of Activities of Daily Living (ADL)  (10-itemPain Assessment in Advanced Dementia (PAINAD) scale was used to measure pain. PAINAD is a frequently used simple five-item observational tool with a range of 0 to 10 . The fivCornell Scale for Depression in Dementia (CSDD) , was useCohen-Mansfield Agitation Inventory (CMAI)  was used; (b) physical nonaggressive behavior ; and (c) verbally agitated behaviors . CMAI was administered consecutively for 5 days pre and post intervention. A maximum of three assessments per day consistent with staff shifts . An aggregate score that reflects the number of incidents per shift was calculatedCaregiver Stress Inventory (CSI)  was usedThe paper reports the outcomes related to resident behavior and caregiver stress, while other elements of the Harmony in the Bush study such as sleep, and psychotropic medication use will be reported separately. We recently reported on the determinants of person-centered care in rural nursing homes using follow-up qualitative data from the Harmony in the Bush study .p < 0.05. Descriptive data was checked for outliers and assumptions for parametric analyses. Paired-t test was used to analyze the difference between baseline and 4 weeks follow-up of CMAI and CSI scores. Cross tabulation and chi-square tests were used to analyze the factors associated with caregiver stress. Repeated measures ANOVA were used to understand difference in baseline and follow-up assessments to understand the changes in behavioral and psychological symptoms in residents after adjustments for age and sex. Similarly, repeated measures ANOVA were used to analyze changes in staff stress in caregiving measured using CSI adjusted for age and sex.All analysis of pre- and post-test data was analyzed using SPSS IBM Version 23. Statistical tests were considered significant at Data was available for 74 residents with dementia who took part in the intervention. Their demographic characteristics and baseline measures for the participants are described in Table p = 0.015).Table n = 87) and 4 weeks post-intervention (n = 58). About 39 completed both baseline and follow-up measures. The changing work shifts, and staff turnover reduced the response rate for follow-up assessment. The mean age of staff was 44.9 (13.5) years, 84.1% were female. Among the staff who completed the CSI, 69.3% were personal carers, 18.2% were registered nurses, and 11.4% were enrolled nurses. More than one-third of the staff had country of origin other than Australia and the majority (59.8%) had work experience of more than 6 years in nursing homes.Of the nursing home staff involved in the Harmony in the Bush intervention, 87 completed the Caregiver Stress Inventory questionnaires at baseline (p = 0.02). The other significant difference was that staff whose country of birth was not Australia reported high stress scores in the domains of aggressive behaviors  and resource deficiency .The Caregiver Stress Inventory scores are presented in four domains i.e., aggressive behavior, inappropriate behavior, resident safety, and resource deficiency. The mean score of Total CSI was 3.6 (0.92) at baseline. Table p = 0.05).Table The present study provides promising evidence that ‘Harmony in the Bush’ model results in the reduction of behavioral symptoms in residents and reduces staff stress in caregiving. We found statistically significant decline in aggressive behaviors, physically non-aggressive behaviors, verbally agitated behavior and hiding and hoarding behaviors in the study sample after 4 weeks of intervention in persons with dementia. Similarly, there was reduction in staff stress in the domains of aggressive behaviors, inappropriate behaviors, resident safety, and resource deficiency measured using Caregiver Stress Inventory tool. Thus, a person-centered, non- pharmacological intervention using PLST framework was effective in rural nursing home settings.Our study results were consistent with a previous study, which found staff education and care based on the PLST model was clinically effective in reduction of behavior problems of care recipients, decreased caregiver burden and depression of family members, and in increasing their quality of life . SimilarOur study also illustrates that implementation of individualised music as part of routine care by nursing and direct care workers provide a great avenue for person-centered care in rural nursing homes. While there is growing evidence of the positive impact of music in dementia care ; most arBest practices to improve dementia care in nursing homes are difficult to establish and comply with factors intrinsic to the resident and complexity of care relating to dementia. Rural nursing home staff are highly stressed due to factors including long hours and heavy workload in managing the complex needs of the residents . FurtherThe present study explains a best practice model for dementia care in Australian rural nursing homes with a good sample of 77 participants which yielded sample power of 80%. The quasi-experimental pre-post design was appropriate and feasible in rural nursing homes and the measurement tools were reliable and validated. However, there are some inherent limitations in the study. The lack of a control group prevented comparison with treatment as normal practice. The behaviours were recorded by the staff in each shift, which were collated by the research nurse/investigator and later analysed by the investigators. While the training; on-floor mentoring and frequent audit by the research nurse to ensure study fidelity, we also acknowledge there are potential variations in the exposure of intervention for each participant based on their interest and behaviours. Additionally, we were not able to disassociate the effect related to environmental modification, attitude change or music intervention on patient and carer outcomes. We also acknowledge the changing work shifts, and staff turnover reduced the response rate for follow-up assessment of staff stress.Harmony in the Bush model facilitates and provides a structure for staff education in person-centered practice to reduce the impact of behavioral and psychiatric symptoms of dementia among residents and improve staff wellbeing in rural Australia. Future investigations of this Harmony in the Bush model needs to employ controlled trial approach to determine the reliability and cost-effectiveness of the model.


Macroautophagy  is a cytoprotective pathway for sequestration of cellular components  into autophagosomal vesicles, followed by clearance l system . Autophal system . Most orl system . Autophal system . On the l system . Variousl system . The focSu et al., on Mitophagy in Hepatic Insulin Resistance: Therapeutic Potential and Concerns, focuses on advances in the understanding of relationship between mitophagy and hepatic insulin resistance and the potential value of mitophagy in the treatment of hepatic insulin resistance and metabolic syndrome (via clearance of damaged mitochondria and subsequent reduction of lipid accumulation). This observation is supported by an elegant study demonstrating that loss of Parkin-mediated mitophagy promoted further β-cell failure under pathological stress conditions including STZ exposure and leptin receptor defects  may be of therapeutic value in the treatment of human fatty liver disease . A specific focus is set on mechanisms by which autophagy can target the main events in the pathogenesis of NAFLD, including hepatic steatosis, inflammation, oxidative stress, and apoptosis.In another review article, Fan et al. provides novel data supporting a protective role for methylprednisolone (MP) in an experimental autoimmune hepatitis (AIH) model, possibly mediated by the Akt/mTOR signaling pathway. MP seems to ameliorate apoptosis and promote autophagy in hepatocytes in in vitro and in vivo mouse model. They suggest a potential use of MP to treat AIH. Their study provides interesting insights into the mechanisms underlying the effect of MP on hepatocytes.The research article by Guo et al. explores the effects of 6-bromo-indirubin-3′-oxime (6BIO), a potent inhibitor of glycogen synthase kinase-3 (GSK-3), on the aging rodent liver. They found that 6BIO mitigates oxidative stress, improves lipid metabolism, enhances autophagy, and significantly retards liver aging via modulating the GSK-3β and mTOR pathways. They suggest that 6BIO could be a potential agent to protect the liver in the field of anti-aging pharmacology.The interesting study by Vescovo et al. investigates the impact of mevastatin (a cholesterol-lowering agent isolated from Penicillium citinium) on HCV replication and autophagy in MMHD3 non-transformed hepatocytes harboring sub-genomic HCV replicons, specifically in relation to the extracellular lipid uptake. In contrast to the previous studies in transformed human cell lines, they observed drastic upregulation of intracellular cholesterol in MMHD3 cells upon mevastatin treatment, which is associated with enhanced lipophagy and HCV replication. However, these effects are reversed when cells are cultured in delipidated serum, which establishes the fact that suppression of extracellular lipid uptake is as important as inhibiting cholesterol biosynthesis in suppressing HCV replication. This study may have implications in the development of treatment modalities targeting cholesterol levels to limit HCV replication.Hepatitis C virus (HCV) dysregulates lipid metabolism to accomplish several steps of its life cycle . VescovoFan et al., in their original research article, report on isoorientin-mediated suppression of APAP-induced hepatotoxicity in mice via activation Nrf2 anti-oxidative pathway and the involvement of AMPK/Akt/GSK3β signaling. This hepatoprotective effect of isoorientin could be mediated by autophagy activation, as reported by others  signaling pathway, resulting in subsequent amelioration of stellate cell-mediated hepatic fibrosis. However, we cannot rule out the possible involvement of autophagy in the hepatoprotective effect of salvianolic acid B as it has been reported that autophagy may be required for stellate cell activation and hepatic fibrosis in alcohol liver disease (y others . The las disease .The field of autophagy research is growing at a rapid pace and the discoveries revealing novel roles for the autophagy pathway in diverse pathologies are making it a very attractive target for pharmacological intervention. Strategies are being envisaged for therapeutic upregulation and/or suppression of autophagy and/or specialized processes like lipophagy or mitophagy. The collection of articles in this Research Topic, including original research and reviews, are aimed at summarizing some of these ideas within the specialized field of gastrointestinal/hepatic pharmacology and beyond.All the authors contributed to this editorial work.We acknowledge support from grants SAF-2015-CIBEREHD,and by AGAUR SGR-2017-1112.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.


At the height of the second wave of the COVID-19 pandemic, two fat lipid nanoparticle-vehicled RNA vaccines for SARS-COV-2 completed phase 3 trials with excellent results in terms of safety and efficacy  doctors and health professionals; ii) residents and staff of residential care centers for the elderly; iii) elderly population ; and iv) population with at least one chronic comorbidity . Accordiwhat vaccination priority strategies in cancer patients should there be?According to AIRTUM data, about 6% of the Italian population is affected by a neoplastic disease, corresponding to over 3.5 million people  . Accordisubjects undergoing radical surgery who are candidates for adjuvant systemic treatments starting within 1-2 months after surgery aimed to improve both relapse-free survival and overall survival  whose tumor burden and biological assessment allows for a one-month postponement of the beginning of systemic treatments.which criteria could be applied for advanced patients during systemic treatments, including chemotherapy, targeted therapies, and immunotherapy? What could the management be for patients under hormonal therapies? Are cancer patients previously infected by SARS-CoV2 candidates to receive the vaccine? What kind of interactions could occur between antiviral vaccines and both antineoplastic therapies and the associated ancillary drugs including steroids? How long should immunity be expected to last in these patients?Recently, ESMO published 10 statements to address these issues and concerns . HoweverToday, national health institutions and the scientific community are urged to answer these questions. To fulfill this commitment, in the absence of published data, large-scale collaborative post-trial, and registry monitoring studies are required.Conception or design of the work: NS. Literature research: OB. Drafting and writing the article: OB, NS. Critical revision of the article: RB, SC. 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.