The design of a computer-aided system for identifying the seizure onset zone (SOZ) from interictal and ictal electroencephalograms (EEGs) is desired by epileptologists. This study aims to introduce the statistical features of high-frequency components (HFCs) in interictal intracranial electroencephalograms (iEEGs) to identify the possible seizure onset zone (SOZ) channels. It is known that the activity of HFCs in interictal iEEGs, including ripple and fast ripple bands, is associated with epileptic seizures. This paper proposes to decompose multi-channel interictal iEEG signals into a number of subbands. For every 20 s segment, twelve features are computed from each subband. A mutual information (MI)-based method with grid search was applied to select the most prominent bands and features. A gradient-boosting decision tree-based algorithm called LightGBM was used to score each segment of the channels and these were averaged together to achieve a final score for each channel. The possible SOZ channels were localized based on the higher value channels. The experimental results with eleven epilepsy patients were tested to observe the efficiency of the proposed design compared to the state-of-the-art methods. Epilepsy is one of the most common chronic diseases of the brain ,2. AccorIn different epilepsy studies, the use of feature extraction methods to design a machine learning system was a measure of statistical dispersion from continuous EEG signals. Gotman et al.  proposedA frequency domain or frequency subband is an important factor in the analysis of epileptic EEG. To design a computer-aided solution to detect epileptic focus, the existing studies can be categorized into low-frequency components (LFCs) ,13,14,15Recent studies have reported that HFCs consisting of ripple 80–250 Hz) and fast ripple (250–600 Hz) bands bear the potential to guide the surgical treatment of drug-resistant focal epilepsy ,24,25. I0 Hz and Apart from the use of such a biomarker, our recent study  suggesteWe propose 12 feature extraction methods, consisting of nine statistical and three entropy measure features that are important to characterize epileptic signals. Several studies of epilepsy used these statistical features to characterize normal and epileptic brain activities ,8,9,10, A data-driven grid search method using MI scores is developed to optimize bands and features jointly. The joint selection of appropriate bands and features related to epileptic activities may improve the performance of the proposed computer-aided solution and this joint selection has not been reported in previous SOZ detection studies.We compared different designs with SVM and standard state-of-the-art LightGBM classifiers and selected an optimal method to provide a graphical representation for epileptologists to identify the possible SOZ channels. The SOZ detection was performed based on the scoring for each segment of channels estimated using the LightGBM algorithm.To address the above problems, we hypothesized that simple statistical features are still efficient in SOZ localization because these statistical features have already been used in other epilepsy study contexts ,9,10,17.To evaluate the method, we analyzed the iEEGs of 11 patients by way of time series prediction. The proposed method’s methodological framework will be more practical for use in clinical applications to identify possible seizure onset channels. To date, there has been no formal comparison between patient-dependent and -independent design in HFCs. To assess the possibility of building a patient-independent design (PID), we also compared the proposed framework’s performance with patient-independent design.The dataset used to evaluate this study’s performance is collected from the Epilepsy Center of Juntendo University, Tokyo, Japan. The study was jointly approved by the Ethics Committee of Juntendo University Hospital and the Ethics Committee of the Tokyo University of Agriculture and Technology. To record data, the epilepsy surgeon implanted platinum subdural grids  with 4-mm diameters and 10-mm distances for the cortical surface and platinum strip electrodes  with 3-mm diameters and 5-mm distances for the vertical direction and the bottom of the cortex. The dataset consists of long-term iEEG collected from adult and pediatric patients with focal epileptic seizures. The data were collected from eleven patients with medically intractable epilepsy caused by focal cortical dysplasia (FCD) represented as Pt1, Pt2, Pt3, Pt4, Pt5, Pt6, Pt7, Pt8, Pt9, Pt10, and Pt11. The dataset includes males and females between 5 and 39 years. In this study, one-hour multi-channel interictal iEEG was split into 20 s segments. Each segment was filtered with a third-order Butterworth bandpass filter to extract the high-frequency components from interictal iEEG.N was 10 for eight patients with sample frequency of 2 kHz and 7 for three patients with a sample frequency of 1 kHz. In other words, the cut-off frequencies were from 100–450 Hz for patients with 1 kHz sample frequency and the cut-off frequencies for patients with 2 kHz were from 100–600 Hz, which cover ripple and fast ripple bands in HFOs.Several studies have proposed subband decompositions that enhance the detection results. In those studies, multiple filters with different passbands were used ,40,41. En-th subband as L is the length of Feature extraction is an important step in designing a computer-aided system. In different bio-signal processing research ,17,42,43The coefficient of variation LD=ei for a given time series m-th subsequent values is defined as:m is the embedding dimension. An ordinal pattern associated with this vector defines permutation as The permutation entropy Sn-th subband for a channel can be defined as:D indicates the number of total features Mn method  to estimn-th subband as:n-th subbands. The set of sorted From Equation , we can d-th feature can be defined as:d feature. The set of sorted average D features can be defined as:The scores of the J and features K for a channel is defined as:n-th subbands.Finally, we applied a grid search method between the subbands and features with the higher scores , specificity (Spe), and F-score : The multi-channel interictal iEEG signals were split into 20 s segments. The N bandpass filters were implemented using a third-order Butterworth filter to decompose each segment of the high-frequency components (ripple and fast ripple) in iEEG. The different types of statistical feature extraction methods were applied to each subband to extract features. An SVM and LightGBM with the ADASYN method were used to score each electrode for identifying possible SOZ channels.FbFM with Subband and Feature Selection (FBFM/Sb/FS): In this case, subbanding and feature extraction were applied in the same way as the above (FbFM) method. A data-driven grid search method using In this study, we developed a method to detect the SOZ channel on a case-by-case basis. For each of these cases, we investigated the improvement of the system performance with statistical evidence. First, we discussed the selection of optimal features with the most significant subbands in K and subbands J by aggregating the top ranked A recent EEG-based study provided evidence that the selection of appropriate operational bands can significantly improve the system performance compared to the use of a wide range of frequency bands . The chaJ and features K were adopted based on the maximum value of the F-score in the proposed computer-aided solution.Equation  and 24)MI scoresIn this study, we proposed FbFM and FbFM/Sb/FS with SVM and state-of-the-art LightGBM classifiers to identify SOZ channels with eleven epilepsy patients. The performance of different methods in term of Sen, Spe, and The previous section confirmed that the joint contribution of bands and feature selection can significantly improve the performance of the method. The performance of the optimal method (FbFM/Sb/FS) with LightGBM was observed in terms of the AUC for identifying SOZ channels. In fact, the patient-independent design (PID) of the system is more preferable for real-world applications compared to patient-dependent design (PDD). Therefore, it is desirable to compare the proposed PDD with PID to assess the possibility of designing a patient-independent system. Thus, in this study, we compared the proposed PDD and PID with AUC for localizing SOZ channels using the optimal classifier LGBM. For the PID, the feature extraction and model were created using the pooled training data of all subjects except the given test subject. Then, the resulting model was tested using the given data of test subjects for testing the model. To balance the class features, ADASYN with its default settings ,69 was aThe mean computational time for each feature extraction method (12 methods) using 10 subbands was measured by Python on an iMac Pro (with Intel Xeon W processor and 128 GB RAM). Notably, to detect a single segment at the testing phase, the mean results were estimated with 100 runs. In this study, we used HFCs (>80 Hz) that include ripple and fast ripple bands for identifying SOZ channels. In a conventional clinical system, epileptologists visually inspect long-term data  to observe the extent of interictal epileptic discharges (IEDs). The epileptologists decide (or diagnose) SOZ channels in order to carry out epilepsy surgery via an epileptic focal resection. In this study, we explored a method of epileptic band and feature selection to design a system for identifying SOZ channels in HFCs (>80 Hz) of iEEGs. The first results highlighted the SVM and LightGBM classification performance to detect individual segments with different conditions (FbFM and proposed FBFM/Sb/FS). We obtained consistent performances with only 35 min of signals in the interictal phase. That made the proposed FbFM/Sb/FS using a LightGBM classifier particularly interesting for the identification of SOZ electrodes. Finally, we simulated the results to identify the possible electrodes related to SOZ from multi-channel iEEGs, which can help epileptologists to hypothesize the SOZ and non-SOZ channels. In our dataset, eight patients were “seizure-free” after surgery. Three patients  were “residual”, even though the SOZ labeled by epileptologists were removed after surgery. For residual patients , our computer-aided solution also suggested some channels, which were very close to the SOZ. This suggestion may assist epileptilogists to make a more confident decision about SOZ channels.Moreover, we compared the proposed design with patient-independent design (PID). First, the results showed very poor performance for PID compared to the proposed PDD. Second, the AUC of PID for the patients  was less than 0.60. The possible reasons of the poor performance may be the very different locations of electrodes and the subject-specific nature of EEG signals. Compared to the proposed prior-based design, the major suitability of PID is that it requires no training data for new patients to detect SOZ channels. For identifying the SOZ, Varatharajah et al.  proposedFor a direct comparison of other epilepsy-related studies to design an SOZ detection system, we have summarized the computer-aided solution under three different categories, including LFC- ,13,14,35In addition, the other LFC-related epilepsy studies used Bonn , FreiburIn HFO-related epilepsy studies, some research works ,25,77 haThis study developed an effective epileptic channel identification method using HFCs in interictal iEEG data. The twelve types of statistical feature extraction methods with filter bank analysis were used. The joint contribution of bands and features was selected based on MI-based approach with a grid search to improve the performance of the proposed method for identifying possible channels with epileptic events in multi-channel iEEGs. The proposed methods were evaluated by eleven medically intractable epilepsy patients with focal cortical dysplasia (FCD). The experimental results indicated that the proposed statistical feature-based computer-aided method can efficiently identify SOZ electrodes in the HFCs of iEEGs.


Lung cancer remains among the most lethal malignancies with a high mortality rate, which is in part due to the metastatic nature at the time of diagnosis. Untreated, the prognosis of metastatic non-small-cell lung cancer (NSCLC) is poor with a median overall survival of 7 months . The intThe clinical manifestations and severity of COVID-19 are broad but typically manifest as fever, cough, dyspnoea and myalgia . In thisThe immune-related adverse events (irAEs) of anti-PD-1 or anti-PD-L1 agents are typically inflammation caused by the immune system directed against organ-specific targets. While the exact pathophysiology of irAEs is not known, patients receiving anti-PD-1 or PD-L1 therapy can develop complications not limited to pneumonitis, myocarditis, nephritis, hepatitis, colitis, thyroiditis, hypophysitis, dermatitis, arthritis and encephalitis. No clear effect of microbial coinfection has been demonstrated in the type or frequency of irAEs. Specifically, there was no increased incidence of hepatitis in patients with chronic viral hepatitis nor increased risk of immune reconstitution in patients with HIV infection receiving treatment with immunotherapy ,15. HoweWhile PD-1 therapy was not in use during recent viral outbreaks, we can look at their impact on lung cancer patients to gain insight into the specific challenges that COVID-19 will bring. A total of 79 NSCLC were prospectively followed during the SARS outbreak in 2003 . While tWhile the data for the impact of COVID-19 are limited and emerging, there are early indications that suggest significant impact on the oncology patient population, in particular, lung cancer. A retrospective case study across three hospitals in Wuhan identified 28 cancer patients suffering from COVID-19 . Lung caAnother challenge for lung cancer patients receiving immunotherapy and the current COVID-19 pandemic is a diagnostic one. The current WHO definition of a confirmed case of COVID-19 is based on laboratory confirmation typically via PCR. There is an evolving role for computed tomography imaging in the diagnosis of COVID-19, with advantages including rapid results and the ability to reflect the severity of ARDS . There iModels of care associated with the delivery of immunotherapy in lung cancer will also have to be reconsidered. Currently, patients continue on immunotherapy for 2 years or longer in some instances should they continue to derive benefit. This can represent a significant period of time during which patients are attending clinic appointments, visiting pathology, radiology diagnostic centers and spending time in infusion centers. With no vaccine or disease modifying intervention currently available for COVID-19, the only strategy to reduce mortality associated with the outbreak is social distancing . For patThe duration of treatment should also be considered when reducing direct patient interaction with the healthcare system. The duration of treatment for patients who are responding to immunotherapy has been a point of contention in lung cancer immunotherapy. Depending on the drug used and the line of therapy, some clinical trials have opted for 2 years of drug treatment or until progression. The Checkmate 153 study randomized patients who had completed 1 year of nivolumab to either treatment discontinuation with the option to resume nivolumab at time of progression and continuing nivolumab until progression. Importantly, this study reported superior progression free survival in patients who continued nivolumab . 2 yearsWhile recent cancer therapy appears to be a risk factor for serious events with COVID-19 infection, it is not clear whether the treatment modality mediates this risk. In a retrospective case series of cancer patients from three hospitals in Wuhan, six patients had received anticancer therapy in the preceding 14 days from COVID-19 diagnosis; two with cytotoxic chemotherapy, two with targeted therapy, one with radiotherapy and one with combination chemoimmunotherapy. Although it is difficult to draw a conclusion from this series due to small numbers, it is reasonable to make the assumption that cytotoxic chemotherapy would be more immunosuppressive than immunotherapy, and hence more harmful in patients with COVID19 coinfection. While there is a clear benefit of single-agent pembrolizumab versus conventional chemotherapy in the PD-L1 >50% group, there has been no comparison of single-agent immunotherapy versus chemoimmunotherapy in a clinical trial. Therefore, in the current climate, clinicians may be inclined to use protocols with single-agent immunotherapy versus combination chemoimmunotherapy, especially in patients with PD-L1 >50%. This has to be balanced with the inferior response rate seen in Keynote 024 of single-agent pembrolizumab (44%) versus combination chemoimmunotherapy (61.4% for PD-L1 >50%) in Keynote 189 ,4.The current end point to the COVID-19 pandemic likely involves reaching heard immunity or the mass availability of an effective vaccine. The time frame, delivery and toxicity of any potential vaccine is beyond the scope of this commentary. However, it is important to reiterate the safety of inactivated influenza vaccination for cancer patients receiving immunotherapy . In the The impact of COVID-19 and the social distancing required to combat this pandemic has had a devastating impact on our society, healthcare and culture. We have highlighted the challenges within thoracic oncology, where significant number of patients whose life expectancy and quality of life have been vastly improved with novel anticancer therapy such as immunotherapy. Initial data from China’s experience with COVID-19 highlighting that these patients are at higher risk for serious events from COVID-19 should be taken into serious consideration when making decisions regarding patient selection for therapy, duration of therapy and the decision to combine immunotherapy with cytotoxic chemotherapy. Significant gains have been made in lung cancer morbidity and mortality since the introduction of PD-1 therapy. These benefits still exist in the ongoing COVID-19 pandemic, however, ongoing treatment may place a subset of patients at increased risk. As the COVID-19 crisis impacts upon healthcare systems across the world, we hope this commentary provides some guidance to thoracic oncologists as they deal with this emerging problem.


Health state utility values are commonly used to inform economic evaluations and determine the cost-effectiveness of an intervention. The aim of this systematic review is to summarise the utility values available to represent the health-related quality of life (HRQoL) of patients with thyroid cancer.Eight electronic databases were searched from January 1999 to April 2019 for studies which included assessment of HRQoL for patients with thyroid cancer. Utility estimates derived from multiple sources (EuroQol questionnaire 5-dimension (EQ-5D), time trade-off [TTO] and standard gamble [SG] methods) were extracted. In addition, utility estimates were generated by mapping from SF-36 and EORTC QLQ-30 to the EQ-5D-3L UK value set using published mapping algorithms.Searches identified 33 eligible studies. Twenty-six studies reported HRQoL for patients with differentiated thyroid cancer and seven studies for patients with general thyroid cancer. We identified studies which used different methods and tools to quantify the HRQoL in patients with thyroid cancer, such as the EQ-5D-3L, SF-36, EORTC QLQ-30 and SG and TTO techniques to estimate utility values. Utility estimates range from 0.205 (patients with low-risk differentiated thyroid cancer) to utility values approximate to the average UK population (following successful thyroidectomy surgery and radioiodine treatment). Utility estimates for different health states, across thyroid cancer sub-types and interventions are presented.A catalogue of utility values is provided for use when carrying out economic modelling of thyroid cancer; by including mapped values, this approach broadens the scope of health states that can be considered within cost-effectiveness modelling.The online version of this article (10.1007/s11136-020-02676-2) contains supplementary material, which is available to authorised users. Thyroid cancer is the most common type of endocrine-related cancer . There hThyroid cancers are divided into four main sub-types. Papillary (PTC) and follicular thyroid cancers (FTC) are commonly grouped as differentiated thyroid cancer (DTC) and account for approximately 94%  of thyroTreatment depends on the sub-type of thyroid cancer; however, initial therapy often involves a partial or total thyroidectomy. Radioactive iodine therapy and radiotherapy may also be offered to reduce the risks of recurrence . TargeteSeveral of the health technology assessment (HTA) organisations in Europe require an economic evaluation to be submitted as part of the evidence base used to appraise health technologies, with effectiveness expressed in quality adjusted life years (QALYs). QALYs can be used to represent both the quality and quantity of life in each health state described in an economic evaluation, where a health state represents aspects of the condition treated by the health technology e.g. disease-free, progressed disease or post-surgery.The HRQoL element of the QALY is measured in terms of utility values. HTA organisations, such as the National Institute for Health and Care Excellence (NICE) and the Scottish Medicines Consortium (SMC) stipulate that utility should be measured using the EuroQol questionnaire 5-dimension (EQ-5D) . The EQ-NICE and the SMC prefer to consider utility estimates derived from the EQ-5D as it is a generic questionnaire and the estimates generated can be compared across diseases. The EQ-5D can be used to generate preference-based weighted utility estimates from the perspective of the general public; i.e. from the people who pay for the NHS, as the NHS is funded by UK taxpayers.There are two versions of the EQ-5D questionnaire, one with three levels (EQ-5D-3L) and one with five levels (EQ-5D-5L). The EQ-5D questionnaire comprises five dimensions . The EQ-5D-3L has three response levels for each of the dimensions: no problems, some problems and extreme problems; the EQ-5D-5L has five response levels: no problems, slight problems, moderate problems, severe problems, unable to/extreme problems. NICE and the SMC prefer utility estimates derived using the EQ-5D-3L UK value set, therefore if the EQ-5D-5L is used in a study to collect HRQoL data then estimating utilities by converting the responses to the EQ-5D-3L UK value set is recommended.In the absence of directly measured EQ-5D-3L values, economists can use utility estimates that have been generated by ‘mapping’ from other generic HRQoL questionnaires to EQ-5D-3L values. This method involves using a dataset containing both EQ-5D-3L responses and the alternative HRQoL questionnaire responses to generate a mathematical relationship between the responses to the two questionnaires. The regression equation generated can be used to convert the responses to the alternative HRQoL questionnaire into EQ-5D-3L utility estimates. Mapping algorithms are designed to be used with individual patient-level data to incorporate some of the uncertainty associated with estimating HRQoL within a cohort. However, mapping using mean values can offer an alternative in the absence of patient-level data . Values To date, EQ-5D-3L utility values sourced directly from patients with thyroid cancer have been largely absent in economic evaluations of treatments for this population. Due to the increasing incidence of thyroid cancer, there has been a rise in the demand for targeted cancer therapies which has led to a growing number of drugs receiving market authorisation for a thyroid cancer indication . The IntThis systematic review follows the Centre for Reviews and Dissemination (CRD) guidance on conducting systematic reviews in healthcare .The search strategy included thyroid cancer terminology and a HRQoL search filter   the authors must have mapped the values using algorithms that converted the estimates into EQ-5D-3L utility estimates using the UK value set or (b) it must have been possible to do this ourselves from the data presented.Study selection was performed by a single reviewer (RH). An inclusive strategy was adopted at the title and abstract screening stage meaning that publications that met the inclusion criteria Table , as wellDescriptive and methodological characteristics of the studies were extracted. For example, data fields included: sample characteristic, sub-type of thyroid cancer, country of origin, interventions assessed, study design, some details of the patient groups for which HRQoL data were collected, sample size, method of HRQoL data collection , and the health states for which utility values were available or could be calculated.The results were ‘mapped’ onto the utility scale using published mapping algorithms , 17 to cA hierarchy of data extraction was developed for those studies reporting multiple HRQoL estimates. Only one set of utility values was extracted from each study. Directly reported utility values from the EQ-5D took precedence, followed by questionnaire data that could be mapped to the EQ-5D-3L using published algorithms , 17 and Data from studies that reported only HRQoL changes from a baseline value were also extracted or mapped to the EQ-5D-3L to give a more complete picture of the evidence available. Change from baseline estimates of utility can be useful in economic modelling to populate a model in the absence of health state utility estimates and to validate model outcomes; however, the baseline characteristics of the study populations must be considered to ensure the change estimate is appropriate. Utility values reported for reference purposes only, such as the HRQoL of the general population, were not extracted from the included studies.A narrative synthesis was used to summarise the information extracted from the included studies; utility values were grouped according to thyroid cancer sub-type and then by the health states that were most similar to each other. More formal methods of synthesis such as meta-analysis could not be used as multiple estimates for sufficiently similar populations were not available.The searches of the electronic databases identified 5327 citations Fig. . FollowiThe evidence was reported according to the sub-type of thyroid cancer studied . There were no publications that described patients specifically with ATC or MTC; however, the general thyroid cancer (GTC) group included patients with several sub-types of thyroid cancer or included patients for whom the sub-type of thyroid cancer was not reported. A summary of the characteristics of all of the included publications is presented in Table In 21 of the included studies (24 publications) –52, 54, Six studies (seven publications) , 51, 53 The reporting of the pain domain of the EORTC QLQ-30 was missing from some studies which meant these studies could not be included in the review; the mapping algorithm includes the pain domain and requires a complete set of domains to be used to estimate utility. Only three , 47, 51 Seven studies –44, 52 iSymptoms and comorbidities have a negative impact on HRQoL. Surgery has an initial impact on HRQoL that seems to resolve over time. A ceiling effect, where patients report full-health on the utility scale, with 51% of the population reporting full-health on the EQ-5D, was reported in one study . The utiThe purpose of the review was to collate the utility values reported in the published literature and to highlight any populations for which utility estimates were not available. This review highlights the lack of utility values available for patients with ATC, MTC and the more severe form of DTC, radioiodine-refractory disease (RR-DTC). Evidence for patients with RR-DTC is limited to the data collected during the DECISION trial . EvidencSuccessful thyroidectomy surgery and radioiodine treatment can return patients to a HRQoL that approximates the average EQ-5D of the UK general population (0.856 mean for the UK population ) althougThe lowest estimate of utility for a health state (0.205) comes from patients with low-risk DTC  for bilaAlthough ATC is the most severe sub-type of thyroid cancer, the only utility value for patients with ATC is higher than the values estimated for the other sub-types . This utThe ‘ceiling effect’ of a large proportion of people valuing their health as the highest value that can be recorded on the EQ-5D-3L using the UK value set was observed in the study by Economopoulos  and may The Botella-Carretero  study prWhen conducting economic evaluations, judgements must be made about how well the available evidence represents the health states of interest . These jIn addition to the review, we used mapping algorithms to convert the SF-36 and EORTC QLQ-30 questionnaires to the UK value set of the EQ-5D-3L. Using alternative algorithms would likely generate different results. However, we used algorithms considered to be the most appropriate for generating utility values for use in economic evaluations in the UK. The use of other mapping algorithms based on other HRQoL questionnaires would further broaden this catalogue. It should be noted that mapping algorithms have inherent flaws which make them less preferable for the estimation of utility values than direct measures of utility. In the absence of utility estimates for many of the health states experienced by patients with thyroid cancer, the mapped values presented in this study provide starting estimates.The utility estimates contained within this review were not all derived from generic preference-based tools. However, when building an economic model or conducting an economic evaluation, it is necessary to attribute a utility value to each health state that is relevant to the population being studied. In the absence of an EQ-5D derived utility value for the population of interest, the use of a proxy value may be necessary. The applicability of the estimates available for each health state included in the evaluation needs to be assessed considering the population from which the estimate was obtained, the country of origin of the utility estimate, and the method used to obtain the estimate. Testing the importance of each of the parameters specified in an economic model using the results generated is important, and it may be preferable to use health state utility values which were obtained through less than perfect methods rather than omit health states completely due to a lack of values. Expert opinion can also be elicited to provide parameter estimates for use in any economic model or economic evaluation; however, the impact of proxy values on the overall results of the model should be evaluated using sensitivity analysis .Authors of published studies with a similar aim to our review  haveThe populations described in the included studies are not all based in the UK, and therefore the appropriateness of mapping HRQoL responses to UK EQ-5D-3L value sets may be questioned. However, including only the studies estimating utility values in a British population would vastly minimise the scope of the catalogue as few health states would be available. Nevertheless, this review provides a catalogue of utility values for patients with thyroid cancer and at the same time offers details of the study methods used to elicit these values, allowing the end-user of the data to make an informed choice about which utility values to include in an economic evaluation. The information presented in the catalogue also enables health economists to quickly select individual publications of interest and choose to use alternative mapping algorithms, such as those to EQ-5D value sets other than the UK, if so desired.Formal tools to assess the robustness of utility values estimated from a variety of study designs and HRQoL tools are currently not available, largely because the most appropriate estimate is dependent on the nature of the question posed. The most robust source of utility values is likely to be from prospective studies obtaining patient-reported outcomes using generic preference-based questionnaires , 48, 50.Studies that included only data describing a change in HRQoL from baseline were included. When combined with other baseline HRQoL estimates, these data could be useful for economic evaluations if the population from the original study and the modelled health state being considered were sufficiently similar. This study has some drawbacks. Some of the studies included had small sample sizes and some of the utility values presented are derived from mapping based on mean values. Utility values derived from HRQoL tools other than the EQ-5D-3L were mapped to the EQ-5D-3L UK value set in line with NICE’s reference case. However, it is plausible that disease specific HRQoL tools may provide a better insight into the utility experience by patients . If available, the use of utilities derived from other HRQoL instruments may be more appropriate than expert opinion.This review provides published utility values for estimating the HRQoL of patients with thyroid cancer and includes in addition, utility estimates that could be estimated by mapping the SF-36 or the EORTC QLQ-30 scores to the EQ-5D-3L UK value set. There are few utility estimates for ATC and MTC sub-types specifically; however, utility values are available for DTC and for a broader mixed population of people with thyroid cancer, which include patients with different sub-types of thyroid cancer. Utility estimates are available for patients who have been treated with a wide range of thyroid interventions across different disease stages. The utility value estimates presented are, on the whole, consistent with each other and what would be expected from a clinical point of view, with the most severe sub-types having the lowest utility estimates, although based on only a few estimates, and the most invasive interventions having the biggest impact on utility. The available estimates in the catalogue provide a useful resource for health economists as they undertake economic evaluations of interventions for thyroid cancer.Supplementary file1 (DOCX 19 kb)Supplementary file2 (DOCX 19 kb)Below is the link to the electronic supplementary material.


The human population is in the midst of battling a rapidly-spreading virus— Severe Acute Respiratory Syndrome Coronavirus 2, responsible for Coronavirus disease 2019 or COVID-19. Despite the resurgences in positive cases after reopening businesses in May, the country is seeing a shift in mindset surrounding the pandemic as people have been eagerly trickling out from federally-mandated quarantine into restaurants, bars, and gyms across America. History can teach us about the past, and today’s pandemic is no exception. Without a vaccine available, three lessons from the 1918 Spanish flu pandemic may arm us in our fight against COVID-19. First, those who survived the first wave developed immunity to the second wave, highlighting the potential of passive immunity-based treatments like convalescent plasma and cell-based therapy. Second, the long-term consequences of COVID-19 are unknown. Slow-progressive cases of the Spanish flu have been linked to bacterial pneumonia and neurological disorders later in life, emphasizing the need to reduce COVID-19 transmission. Third, the Spanish flu killed approximately 17 to 50 million people, and the lack of human response, overcrowding, and poor hygiene were key in promoting the spread and high mortality. Human behavior is the most important strategy for preventing the virus spread and we must adhere to proper precautions. This review will cover our current understanding of the pathology and treatment for COVID-19 and highlight similarities between past pandemics. By revisiting history, we hope to emphasize the importance of human behavior and innovative therapies as we wait for the development of a vaccine. Global shutdowns, widespread reduction in economic activity, and stalls in the workforce and education systems are just a few of the major historic events that have amalgamated in 2020 due to the outbreak of the COVID-19 pandemic. According to the data collected by Johns Hopkins University, there are more than 8 million confirmed coronavirus cases and 437,500 deaths worldwide as of June 15, 2020 [History repeats itself and when assessing the proper responses to the current pandemic, it is important to learn from the past. In a historical review of viral pandemics, the 1918 Spanish flu stands out which infected 500 million people and led to an estimated 17 to 50 million deaths . Like thThis review will cover our current understanding of the pathology of COVID-19 and highlight similarities between the Spanish flu and past pandemics’ pathology, social behavior, and treatments. By focusing on these disease overlaps, in particular convalescent plasma and stem cells targeting the virus entry point, we may gain insights on the best treatments and human behavior to address the current pandemic. Furthermore, we will discuss the latest preclinical and clinical data of available therapies and by highlighting critical gaps in knowledge, we hope to emphasize the importance of human behavior and innovative therapies as we wait for the development of a vaccine.Coronaviridae that cause respiratory tract infections in humans. Coronaviruses classify into either alpha and beta subtypes that infect humans, or into gamma and delta subtypes, which mainly infect avians. Severe Acute Respiratory Syndrome Coronavirus (SARS-Cov) and Middle East Respiratory Syndrome-related Coronavirus (MERS-Cov), are two betacoronaviruses that precipitated the SARS and MERS epidemics in 2003 and 2012, respectively. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Cov-2) is a new genetically-related betacoronavirus species responsible for the COVID-19 pandemic.The term coronavirus refers to more than 40 species of viruses within the family SARS-Cov-2 is a single-stranded, non-segmented, positive-sense RNA virus that measures 65–125 nm in diameter and 29.9 kb in length , 8. It iACE2 is a type 1 integral membrane protein that functions as an extracellular receptor attached to the plasma membrane of cells in the lungs, heart, brain, and other vital organs , 15. It The potent interaction between ACE2 and SP mediates the efficient entry of the virus into host cells. Electrostatic interactions between the negatively charged ridges that flank the catalytic domain of ACE2 and the positively charged receptor-binding domain (RBD) of SP enable SARS-Cov-2 to localize to its receptor . ACE2 reAfter binding and proteolytic processing, the final step for infection is the viral entry into the host cell. It is not entirely clear how SARS-Cov-2 enters the cell, as there is evidence for both fusion and endocytosis. In a fusion-based entry model, SARS-Cov-2 fuses its envelope with the plasma membrane of the host cell and empties its genetic contents into the cytosol, where it hijacks the host machinery to replicate its genes and produce more virus. In the endocytosis model, SP interacts with ACE2 to cause a pH-dependent internalization of the virus-receptor complex . On the The SP gene of SARS-Cov-2 determines its affinity for ACE2, in contrast to the SPs of related coronaviruses with slightly different sequences that favor binding to other targets. Each cycle of viral replication within the host cell produces additional copies of the viral RNA genome, including the regions that encode this specific SP variant. Reverse-transcriptase polymerase chain reaction (RT-PCR) recognizes the SP of SARS-Cov-2 and measures total viral load. This technique utilizes a primer that binds to regions of the SARS-Cov-2 RNA genome, including the SP region, and amplifies the amount of virus present such that the fewer cycles it takes to reach a threshold value indicates a higher initial concentration of SARS-Cov-2. SP expression and viral load are highest at the onset of infection and lowest during recovery . ElevateSP is integral for SARS-Cov-2 to recognize and internalize into cells. Viral binding and fusion with host cells are obliterated in the absence of SP expression. After uptake, the virus uses host cell ribosomes to replicate; however, the cell will eventually undergo apoptosis or immune system-mediated destruction . TherefoThe critical interaction of SP and ACE2 as the gatekeeper of SARS-Cov-2 entry into host cells can be confirmed and exploited using human recombinant soluble ACE2 (hrsACE2). ACE2 is a transmembrane protein and is not present endogenously in a soluble form; therefore, SP always binds to cell-surface ACE2. However, the administration of hrsACE2 introduces soluble ACE2 into the circulation that can complex with free SARS-Cov-2, thus blocking its ability to bind to cell-associated ACE2 . The vir498, Thr500, and Asn501 on the RBD interact with Tyr41, Gln42, Lys353, and Arg357 on ACE2 [417 and Tyr453 on the RBD associate with Asp30 and His34 on ACE2 [474 and Phe486 on the RBD and Gln24 and Met82 on ACE2 [The specific structural features and amino acid sequences of SP and ACE2 underlie the selectiveness of their binding and explain the preferential binding of SARS-Cov-2 to ACE2 and rbsACE2. SP makes direct contact with ACE2 at three different points. In the first region of interaction, Gln on ACE2 . In the  on ACE2 . Similar on ACE2 . In addi on ACE2 .Although there are animal reservoirs of the virus, SARS-Cov-2 is most strongly associated with pathological effects in humans. Transgenic animal models expressing human ACE2 recapitulate its specificity and affinity for SP. Upon inoculation with SARS-Cov-2, mice expressing human ACE2 rapidly display signs of lethal infection in the lungs and brain, whereas mice expressing murine ACE2 do not develop infection . In the 5 and 2.7 × 105 copies per gram of tissue, respectively [The capacity of SP to utilize human ACE2 to enter cells ensures the viability of the virus in several tissues. ACE2 expression is high in the small intestines, kidneys, heart, and lungs, although it is also present in key organs such as the nerves and brain . RT-PCR ectively –32. The The highly specific interaction between SP and ACE2 is well defined and is a critical target for therapeutic strategies that attempt to prevent infection. A variety of vital organs express the ACE2 receptor and are thus susceptible to SP-binding and the lethal damage induced by viral infection. Therefore, it is crucial to evaluate the effects of SARS-Cov-2 in the most commonly affected organ, the lungs, but also in other ACE2- and SP-expressing organs such as the brain, heart, intestines, and liver.The lungs are the primary site of infection and nearly all patients with COVID-19 present with some form of respiratory impairment. The most common complaints upon hospitalization are cough and shortness of breath, with 69% and 66% of patients reporting these symptoms, respectively. SARS-Cov-2 spreads through person-to-person contact or via small droplets, measuring less than 10 µm in diameter, that enter the respiratory tract after inhalation , 34. As The lungs are the primary organ of the respiratory system and oversee numerous critical functions for survival and homeostasis, including acid-base balance and thermoregulation. They perform their primary role of gas exchange by drawing air into alveoli lined with pneumocytes. Oxygen diffuses across type 1 pneumocytes, which comprise 95% of the surface area of the alveoli. Type 2 pneumocytes are the most common cells in the alveoli, although they are small and do not constitute a large proportion of the total surface area. They secrete the pulmonary surfactant that prevents the alveoli from collapsing, and they can divide into type 1 or type 2 pneumocytes. [The coexpression of ACE2 receptors and TMPRSS2 transmembrane proteases by type 2 pneumocytes explains the susceptibility of the lungs to SP-mediated SARS-Cov-2 infection . Well-di . Further . SP inte . After r .The pathogenesis of SARS-Cov-2 produces severe respiratory outcomes within a few weeks of initial infection, even in the absence of preexisting respiratory comorbidities such as chronic obstructive pulmonary disease (COPD) . In halfOne of the highest concentrations of ACE2 in the body is in the lung tissue. The potent binding of SP to ACE2 and subsequent cellular infection may explain the prevalence of respiratory symptoms in COVID-19 patients. Transgenic mice expressing hACE2 in the lungs exhibit a very similar pathology in the lungs compared to human patients, including pneumonia and macrophage infiltration; however, these respiratory symptoms are absent in wild-type mice . Thus, tSARS-Cov-2 produces more severe symptoms in elderly patients than young patients, implicating an age-based loss of protection. Approximately 90% of infected pediatric patients are asymptomatic or exhibit mild symptoms . Given tWhile the severity of respiratory symptoms is useful in predicting outcomes, several non-invasive methods also allow tracking of the extent of COVID-19-induced lung damage. Computer Tomography (CT) analysis is a diagnostic imaging procedure useful for evaluating the pathology of the lungs. CT image-calculated well-aerated lung volume predicts the risk of ICU admission and death . Thus, aThe interaction of SARS-Cov-2 with the lungs directly explains its tremendous infectivity potential. Not only is the respiratory tract is the primary point of entry of the virus into the body, but it also contains the highest concentration of ACE2 receptors for SP to complex with. Furthermore, SARS-Cov-2 survives within the respiratory tract more effectively than it can in other tissues, highlighting the imminent need for therapeutics targeting the lungs . SP mediThe lungs are a conduit through which SARS-Cov-2 accesses the systemic circulation to infect other vital organs and tissues. As the virus travels from the lungs to the rest of the body, it propagates widespread damage and dysfunction by promoting inflammation that culminates in a cytokine storm . This woThe neuroinvasive capacity of SARS-CoV-2 has been demonstrated in both humans and animals. Intensive care patients display neurological symptoms such as nausea, headaches, and vomiting . A recenCardiac involvement in SARS-CoV-2 infection is prevalent among patients . As noteGastrointestinal abnormalities were seen in 2%-10.1% of patients positive for SARS-CoV-2 . SymptomLiver injury is linked to multiple etiologies such as alcohol consumption, toxins, bile duct dysfunction, and viral infections. Epidemiologists reported that 75 out of 148 COVID-19 patients had varying degrees of liver dysfunction . The exaSARS-CoV-2, the cause of viral pneumonia spreading across the globe, can infect many vital organs via SP-ACE2 mediated cellular infection. SP is critical to extrapulmonary organ infection due to its ability to promote viral uptake in these tissues. Furthermore, certain mechanisms in the gastrointestinal tract and heart bolster SP-mediated viral uptake. In the gastrointestinal system, the high concentration of the TMPRSS2 protease enhances the ability of SARS-Cov-2 to enter intestinal epithelial cells . In the Although COVID-19 is primarily a respiratory virus, it may have acute and chronic consequences on non-lung organ systems. Delineating how quickly COVID-19 progresses, particularly in patients who develop dire respiratory, cardiovascular, and cerebrovascular complications, is key to understanding the virus’s multi-organ pathology and establishing appropriate treatment.The incubation period for COVID-19 is approximately 5.1 days. For 97.5% of symptomatic patients, the estimated number of days before symptom onset is 11.5 . Acute rThe cardiovascular repercussions of COVID-19 infection may be primarily due to the presence of the ACE2 receptor in cardiac tissue. COVID-19 internalization via the ACE2 receptor leads to a loss of the ACE2 peptidase pathway, which can generate a rise in blood pressure, fibrosis, and inflammation . InfecteThe multi-organ pathology of COVID-19 also includes the cerebrovascular system since the virus may have neurotrophic capabilities . The proThe incidence of stroke in COVID-19 patients exemplifies the need for vigilance on non-respiratory diseases that may present with devastating symptoms as that produced by the primary lung pathology. Cerebrovascular disease appeared in 5.7% of COVID-19 patients with dire symptoms during the late onset of the virus . On averAlong with ischemic stroke, other acute cerebrovascular diseases in the clinical setting of COVID-19 have been explored. In Wuhan, 36% of 214 COVID-19 patients suffered from neurological complications, and 6% of the patients developed acute cerebrovascular disease . COVID-1In addition to acute repercussions, COVID-19 infection may have chronic neurological consequences. Although a direct link between COVID-19 and demyelinating disease, such as multiple sclerosis, has not yet been established, the association between human coronaviruses and multiple sclerosis (MS) has been explored. An OC43 coronavirus detection test was conducted on human brain autopsy samples for patients with MS. The MS samples demonstrated a substantially higher level of OC43 than the control group . In addiAlthough the exact mechanism mediating the chronic manifestations of SARS-CoV-2 infection is currently unknown, the interaction of SP and ACE2 contributes significantly. SP-ACE2 binding results in host-cell dysfunction that precipitates the development of these acute and chronic symptoms, including host-cell death. Therefore, the serious long-term repercussions of COVID-19 should be closely monitored in infected patients with high SP and ACE2 expression.Like the current pandemic, the 1918 Spanish flu pandemic disrupted the daily life of the plagued countries . When thCOVID-19 has disrupted the lives of people worldwide in an eerily similar fashion. The virus originated in Wuhan, China with the first case documented in December 2019. After only a few months, the virus began spreading worldwide. By March, COVID-19 was declared a pandemic by the World Health Organization (WHO). Many schools and universities shut down beginning in the middle of March and transitioned into virtual classes taken online at home. Adults have also been quarantined at their homes with jobs and businesses shutting down around the same time as schools in March with an exception to essential workers such as healthcare workers and grocery store workers. Having individuals stay home largely limits the number of people gathering in public. These measures, more commonly known to the public as social distancing, are implemented to reduce the number of interactions between individuals. This prevents individuals who are infected with the virus but have not been diagnosed with COVID-19 or are asymptomatic to interact with healthy individuals. COVID-19 is transmitted by one individual to another when in close proximity . Social Quarantine is an old yet effective tool in controlling disease outbreaks. This practice was commonly employed in fourteenth-century Italy when ships coming from a plague-infected port arrived at a port in Italy . The shiThis quarantine method was also implemented during the SARS epidemic in 2003. This measure was thought to be successful and effective . QuarantQuantitative assessments of the effectiveness of quarantine may provide empirical evidence for the recommended guidelines. The Susceptible-Exposed-Infectious-Recovered (SEIR) model shows the speed at which individuals move from the susceptible state onto the exposed, infectious, and recovered state . PreventGood hygiene also plays a key role in preventing the spread of disease. Hand hygiene has been proven to be especially significant. Appropriate handwashing can break the transmission cycle and reduce the risk of spreading disease remarkably . Health When the Spanish flu began spreading to other countries such as the U.S., finding a vaccine became a tantamount goal for scientists and clinicians alike. During the peak of this epidemic Spanish flu “vaccines” were developed and distributed throughout the U.S. Health officials informed the public that these vaccines would protect from the influenza. However, the specific cause of influenza was yet to be discovered . These vThe Spanish flu vaccine was not developed until 2005, more than 80 years after the beginning of the outbreak. The virus causing the Spanish Flu, known as the H1N1 virus, is considered an avian influenza virus that underwent multiple mutations. Another avian influenza virus known as H5N1 began to infect humans and had a mortality rate of approximately 60% . AlthougCurrently, there is no vaccine that prevents COVID-19. While human behaviors, including social distancing and proper hygiene that plagued the Spanish flu, remain a challenge in battling COVID-19, there is much clamor for evidence-based and science-supported treatments in the current pandemic. In particular, databases for registered clinical trials have been established allowing a much better translation of safe and effective approaches for COVID-19. The genome of the SARS-CoV-2 was sequenced in mid-January triggering researchers around the world to begin developing a vaccine . The firMost of the COVID-19 vaccines that are being developed are in North America, while there is also development activity in China, other parts of Asia, Australia, and Europe. The global vaccine effort has been exceptional in terms of scale and speed. Projects indicate a vaccine may be available as soon as early 2021. This would be a massive change from traditional vaccine development which takes on average over 10 years. Even the accelerated development of the Ebola vaccine took 5 years . To asseIn response to the influenza virus, the Global Influenza Surveillance Network was established in 1947 and is responsible for the continuous monitoring of antiviral drugs for clinical treatment . Two antin vitro studies for effectiveness [There is currently no proven effective antiviral treatment for COVID-19. However, many antiviral treatments have demonstrated efficacy for the treatment of COVID-19 including lopinavir and ritonavir, chloroquine, and hydroxychloroquine that may help to alleviate symptoms in patients. With over 300 clinical trials currently testing various antiviral drugs, treatment has focused on the uses of chloroquine, hydroxychloroquine, lopinavir/ritonavir, favipiravir, remdesivir, and oseltamivir. The focus has been primarily on repurposing the available therapeutic drugs to treat patients with the SARS-CoV-2 infection. Hydroxychloroquine and chloroquine are antiviral drugs that possess similar chemical structures and have been commonly used for the treatment of rheumatoid arthritis and malaria . Their mtiveness . The U.SIn vitro studies have demonstrated the ability of lopinavir in inhibiting SARS-CoV, reducing symptoms such as diarrhea and recurrence of fever, and lowering the risk of acute respiratory distress syndrome with LPV/r and ribavirin [Another antiviral drug being explored for the treatment of COVID-19 is lopinavir/ritonavir (LPV/r). Lopinavir is a protease inhibitor and ritonavir is a booster and they are commonly used to treat HIV infection in combination. ibavirin . The useibavirin . A combiibavirin .Favipiravir (brand name Avigan) has been developed and used for the treatment of avian influenza or other types of influenza that are resistant to NA inhibitors. Favipiravir inhibits the RNA-dependent RNA polymerase of RNA viruses such as Ebola, influenza, and norovirus and induces lethal RNA transversion mutations to produce a nonviable virus phenotype . FavipirIn vitro testing has developed to demonstrate remdesivir activity against SARS-Cov-2 and demonstrates clinical improvement. In animal experiments, the drug has proven to reduce viral load in lung tissue of mice with MERS-CoV, improve lung function, and alleviate the lung damage. Additionally, Remdesivir yields promising results for COVID-19 patients in recovering from pneumonia. In a study of patients using the drug in the United States, 70% of patients had improvement in regards to oxygen requirements and were extubated from mechanical ventilation [Remdesivir is another novel antiviral drug that was originally developed for the treatment of the disease Ebola. Remdesivir can inhibit viral RNA polymerases and has widespread activity usage against filoviruses and coronaviruses. tilation . Currenttilation . RemdesiAdditionally, oseltamivir (Tamiflu), which is approved for the treatment of influenza A and B, is used to target the neuraminidase distributed on the surface of the influenza virus to inhibit the spread throughout the body. Several clinical trials are studying the effectiveness of oseltamivir against COVD-19 and also in combinations with chloroquine and favipiravir. However, a study in Wuhan reported no positive outcomes after administering oseltamivir and it does not serve as a recommended treatment for COVID-19 .A potential target for drug development for COVID-19 also involves inhibition of ACE2, the host cell receptor for the S protein of SARS-CoV-2 that is primed by TMPRSS2 protease and may prevent the entry of the virus. The antimalarial drugs, chloroquine, and hydroxychloroquine have been shown to inhibit terminal phosphorylation of ACE2 and serve as candidate drugs against the COVID-19 disease . ChloroqWith over 300 clinical trials targeting various antiviral medications for the treatment of COVID-19, there are still no final verified antivirals specific to COVID-19. Further testing is still needed to explore the efficacy and safety of these antiviral drugs. Research regarding SARS-CoV-2 has demonstrated the potential of repurposing drugs with appropriate pharmacological effects and therapeutic efficiencies in the treatment of COVID-19 patients . The antIn vivo studies during this outbreak highlighted the protective abilities of plasma therapy. Specifically, transfusing blood from immune species into healthy species decreased the severity of the symptoms. These discoveries opened the possibility of utilizing plasma therapy to battle against viral outbreaks. Tremendous advancements were made in the molecular techniques and production of human immunoglobin during the years after each subsequent pandemic or epidemic, including measles, HIV/AIDS, and 2003 SARS-CoV. After several past experiences with viral outbreaks worldwide, there was one constant observation: plasma therapy must be applied as soon as possible after the first onset of disease. Clinical trials have reported that healthy and infected patients who received plasma therapy early displayed a decrease in symptom severity and mortality rate [Plasma therapy is the process of extracting therapeutic molecules, such as antibodies and plasma, from the immunized or recovering individual and transferring the extracted molecule to ill individuals . This tyity rate . Based oPlasma therapy may be used to harvest antibodies from individuals who have been exposed to the SARS-Cov-2 to treat COVID-19 patients with pulmonary, neural, or cardiovascular dysfunctions. The transplanted antibodies may bind to SP or ACE2 sites, preventing the coronavirus from fusing with the cell membrane and injecting its viral genome. By blocking this crucial entry point, inflammatory symptoms and infections significantly decreased compared to patients without antibodies . This ocBased on previously mentioned research advancements in plasma therapy, its utility for COVID-19 patients has reached clinical testing. In addition to 152 publications of review and commentary articles on convalescent plasma therapy for COVID-19, there are 173 ongoing clinical trials that are investigating the use of convalescent plasma for COVID-19. Small clinical studies conducted in the US and East Asian countries have displayed an increase in antibody titers and a decrease in the viral activity of plasma-treated patients –105. TheIn one clinical trial, 10 Chinese patients with severe cases of COVID-19 received convalescent plasma treatment after approximately 16 days of contraction . 200-mL Both clinical studies presented findings that parallel previous discoveries from earlier pandemics and studies regarding convalescent plasma treatment. Earlier treatment after exposure to SARS-CoV-2 was more effective compared to later treatments . As seenAs noted above, plasma therapy involves the use of convalescent plasma to transfer antibodies and boost the patient’s anti-inflammatory response against COVID-19 , 107. WiStem cell therapy stands as the prominent regenerative approach in a wide range of diseases, which interestingly include COVID-19 primary symptoms  and co-morbid diseases such as but not limited to diabetes, cardiovascular and cerebrovascular disorders . BesidesProminent sources of stem cells for regenerative therapy are embryonic stem cells (ESCs), fetal stem cells, induced pluripotent stem cells (iPSC), and adult stem cells. Pluripotent ESCs generated from the blastocyst can differentiate into all three germ layers . Their gBecause MSCs possess the ability to regulate the immune and inflammatory activity, MSC therapy can potentially be used to treat COVID-19. As previously described, the intermolecular interaction between the viral SP and human ACE2 initiates the infection of host cells . Once thIn addition to its anti-immune and anti-inflammatory mechanisms, MSCs may possess the ability to interfere with viral docking via ACE2-SP interaction. As previously discussed, MSCs regulate immune and inflammatory activity by inhibiting inflammatory factors and cytokine storms. MSCs are able to bind to various surface receptors to activate these mechanisms, such as IL-1R, TNFI, and IIR . Due to Preclinical studies have investigated the use of MSCs in treating lung diseases with similar dysregulation of regular immune and inflammatory responses as COVID-19. In one notable study, the endotoxin model of acute lung injury was used to observe the therapeutic effects of MSC . Mice weAlthough the efficacy of the treatment of lung diseases with MSCs is not yet conclusive, its safety and promising preclinical data warrant further exploration to COVID-19—especially in face of the high morbidity and mortality of the current pandemic. Because of the overlapping pathology of neurological diseases stemming from a harmful inflammatory response and COVID-19-induced pulmonary, cardiovascular, and cerebrovascular disorders, MSCs may provide therapeutic benefits to COVID-19 patients where multiple organ systems are affected.The envisioned MSC therapy for COVID-19 entails a minimally invasive approach. MSCs injected intravenously (IV) display the propensity to migrate to the lungs making IV administration favorable to treat pulmonary diseases , 131. AnThe potent immunomodulatory capacity of MSCs renders it a promising option as a novel treatment method for COVID-19. Although there are currently 43 proposed or ongoing clinical trials employing stem cell therapy against Sars-Cov-2 infection, there are no approved MSC-based treatments or therapies. Preliminary results from the US and China demonstrate improved immune function without adverse events in COVID-19 patients treated with MSCs , 135. InStem cells are at the forefront of innovative regenerative medicine-based strategies targeting tissue repair and immunomodulation of COVID-19 –142. TheSince the report of dozens of cases of pneumonia of unknown causes in Wuhan, Hubei Province in December of 2019, COVID-19 has infiltrated across the globe and shaken the lives of the vast majority of the human population. Despite the US leading the world at 2.1 million confirmed cases and 116,130 deaths, many states have begun reopening in response to an economic crisis [Although COVID-19 primary triggers a respiratory disease, pervasive myocarditis and fatal arrhythmia cases in infected patients suggest COVID-19’s deleterious effects on the cardiovascular system. Moreover, a subset of patients also manifests neurologic symptoms likely due to the virus’ ability to retrogradely travel from the lung to the brainstem cardiorespiratory center via neuronal synapses. This multi-organ, heart-brain infection may exacerbate respiratory failure. The critical entry receptor for SARS-CoV-2, the virus responsible for COVID-19, is the ubiquitous ACE2 receptor to which viral SP docks. The ACE2 may reveal acute and chronic multi-organ effects of COVID-19 which warrants further investigation and continued action to lessen the spread of the virus.As the race for a vaccine continues, anti-viral drugs, convalescent plasma treatment, and stem cell therapies should be explored in tandem to reduce the current mortality rate which ranges from 0.1% to as high as 10% with the elderly (> 65 years of age) and those with pre-existing conditions like hypertension, diabetes, and heart disease , 152. Wi


Despite extensive research efforts on diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains a devastating disease and the third leading cause of cancer-related death in the United States. Resistance to current therapeutic approaches is a major reason for the poor survival of pancreatic patients. In order to overcome this major challenge and improve patient outcomes, we are in desperate need of novel therapeutic approaches. PDAC chemoresistance mechanisms are complex and multifaceted. Novel therapeutics must be equipped to deal with this challenge. microRNAs (miRNAs) have emerged as strong candidates to fill this role due to their multitargeted function. miRNAs have been shown to have important roles in pancreatic cancer resistance. In this review, we summarize the recent advancement in miRNA research related to PDAC therapeutic resistance mechanisms and the potential of miRNAs as therapeutic agents for future clinical management of PDAC. Over this time, the efficacy of different therapeutic regiments based around gemcitabine, have been tested including combination of gemcitabine with several other agents such as 5-fluorouracil (5-FU), oxaliplatin, cisplatin, and capecitabine.–9 Despite these efforts, the impact on patient survival has remained limited, due in part to the various resistance mechanism involved in PDAC cells. Some PDAC patients will have intrinsic resistance and never respond to therapy, while others will have acquired resistance that will develop during the course of treatment leading to recurrence. Since resistance is such a major issue for treating PDAC patients, extensive research efforts have been aimed at understanding the mechanisms involved in PDAC chemoresistance. These efforts have demonstrated that PDAC chemoresistance is multifaceted. PDAC cells have altered expression of several important genes such as KRAS, p53, and BCL-2 among others. These cells also have changes in important signaling pathways such as Notch and Hedgehog.–13 Factors in the tumor microenvironment, secreted by tumor-associated fibroblasts, also contribute to resistance.–17 The presence of PDAC stem cells also contributes to resistance, as these cells have several characteristics that make them highly resistant to chemotherapy. These cells are slowly dividing, making them more resistant than rapidly dividing cells. These cells also have a very plastic nature, and altered metabolism that allows them to cope with the challenge of therapy. The need for novel therapeutics is clear based on the poor survival for PDAC patients, only 3% for patients with metastatic disease. The fact that various mechanism contribute to resistance makes microRNA (miRNA) an ideal candidate to combat this challenge as their multitargeted function may be more challenging for cancer cells to develop resistance.In the past several decades we have made some great progress in treating several cancers; however, there is still much more that needs to be done to have a dramatic impact on patient survival. Pancreatic ductal adenocarcinoma (PDAC) in particular remains a considerable challenge. Several factors including typically late presentation, early metastasis, and resistance to chemotherapy, all contribute to PDAC being the third deadliest cancer in the United States.miRNAs are short (18–22 nucleotides) noncoding RNAs that regulate gene expression by base pairing primarily to the 3′-untranslated region of target messenger RNA (mRNA) to inhibit translation or induce mRNA degradation. Each miRNA is able to target several different target genes, allowing them to inhibit the expression of a network of targets. Depending on the target genes they inhibit, miRNAs may promote cancer progression and resistance (onco-miRNAs) or inhibit progression and resistance (tumor suppressor miRNAs). In the past decade, it has become clear that miRNAs have important roles in all cancers including PDAC. We have also come to appreciate the potential for manipulating miRNAs for therapeutic intervention. There are plenty of examples of the important functions miRNAs have in PDAC resistance. Some miRNAs promote chemoresistance in PDAC. miR-21 is one of the best characterized onco-miRs in many cancers. In PDAC high expression of miR-21 has been shown to inhibit the effectiveness of gemcitabine. High expression is also associated with shorter patient survival. These effects of miR-21 are a result of its targeting phosphatase and tensin homolog, and suppression of miR-21 results in cell cycle arrest, apoptosis, and enhanced sensitivity to chemotherapy.–22 In addition to miR-21, several other miRNAs have been shown to promote resistance in PDAC. miR-320a, promotes resistance to 5-FU in PDAC by targeting programmed cell death domain 4. miR-221–3p also increases PDAC resistance to 5-FU by targeting Retinoblastoma 1 (RB1). In addition to promoting chemoresistance, by targeting RB1 miR-221–3p promotes cell proliferation, migration invasion, and epithelial-to-mesenchymal transition (EMT). miR-106a is another miRNA that promotes chemoresistance. In the case of miR-106a, it is expressed in exosomes from cancer-associated fibroblasts. miR-155 also has chemoresistance-associated functions in PDAC involving exosomes. Gemcitabine treatment promotes miR-155 expression which induces increased production of exosomes and inhibition of apoptosis to promote resistance. miR-155 is also packaged in exosomes promoting resistance in nearby cells. In PDAC stem cells, the miR-30 family promotes invasion and migration.It is now understood that miRNAs have important functions in PDAC and dysregulation of their expression may play a role in cancer development as well as resistance. miRNAs regulate tumorigenesis, cell cycle control, apoptosis, proliferation, chemoresistance, invasion, and metastasis.,29 Similar to miR-34, miR-205 has also been shown to inhibit PDAC stem cells and promote sensitivity to gemcitabine. Various studies have also shown that the miR-200 as well as the let-7 family are reduced in gemcitabine resistant cells and expression of these miRNAs promote chemosensitivity. Several groups have also demonstrated the importance of miR-506 in combating chemoresistance in PDAC. Through the regulation of several different targets, miR-506 promotes apoptosis, induces cell cycle arrest and enhances chemosensitivity.,33 miR-15a is another miRNA with important roles in PDAC resistance. miR-15a suppresses the growth of chemoresistant PDAC cells and inhibits EMT by targeting WNT3A, FGF7 as well as BMI-1.,35 These are just some examples of the important functions of miRNAs in PDAC resistance  that needs to be overcome. A number of strategies have been developed to overcome such hurdles. Various nano-vehicles and nanoparticles have been developed and tested.–41 However, many of these delivery vehicles cause host toxicity. Various improvements have also been developed to enhance stability of anti-miR by modification of the backbone with 2′-O-methyl group, phosphothioate, or with the locked nucleic acid.There are several strategies to develop miRNA-based therapeutics in PDAC. One is to suppress onco-miRNAs via antisense or antagomir-based approaches, the other is to restore and replace tumor suppressor miRNAs.,44 By incorporating 5-FU into miR-129 and miR-15a, we created a potent new miRNA-based drug with the power of tumor suppressive function of miRNA together with 5-FU  with 5-FU in the guide strand. We initially developed this approach using miR-129 and miR-15a in colon cancer.ith 5-FU . We demoin vitro by inhibiting cell proliferation and impacts cell cycle control. We have demonstrated that 5-FU-modified miR-15a is a potent inhibitor for PDAC both in vitro and in vivo and improves survival, either alone or in combination with gemcitabine. The effects of miR-15a are mediated through the regulation of several important target genes . All of these targets are elevated in PDAC and many are good target candidates for therapeutic development in PDAC. B lymphoma Mo-MLV insertion region 1 is an oncogene associated with poor prognosis.,47 Yes-associated protein 1 is crucial in promoting pancreatic tumorigenesis as well as invasion, migration, and chemosensitivity.–50 Wee1 and Chk1 are 2 key G2/M checkpoint regulators, which can affect Cdc2 activity.,52 These targets have been recognized as candidates for therapeutic development by the pharmaceutical industry.,53,54 The regulation of all of these important targets combined with the effectiveness of the 5-FU incorporation makes 5-FU-modified miR-15a an intriguing candidate for PDAC therapy.Our recent studies demonstrated miR-15a functions as a tumor suppressor in PDAC In addition to reintroducing tumor suppressor miRNAs, suppression of onco-miRNAs also has potential. By inhibiting these miRNAs expression of their target genes can be restored which may have therapeutic effects. A recent study has demonstrated the potential of anti-miR-21. Delivery of antimiR-21 was shown to be effective in patient derived PDAC organoids and patient derived xenograft models using tandem peptide pTP-iRGD.There are many mechanism that contribute to both the intrinsic and acquired resistance seen in PDAC. The adaptive nature of these cells makes overcoming resistance a moving target. This is highlighted by the fact that efforts focusing on single protein coding targets have yielded little progress on PDAC drug development in the past decades. In the face of this challenge, miRNA therapeutics may be excellent therapeutic candidates. Their ability to quickly modulate the expression of multiple targets gives them the unique ability to regulate several pathways at once. This should make it more difficult for cells to adapt and overcome miRNA therapy. As a result, a number of miRNAs have shown great potential as novel therapeutics in PDAC. With advancement in miRNA research and therapeutic development, we expect that tumor suppressive miRNAs, including 5-FUmodified miRNAs will allow us to better manage clinical treatment and enhance survival and minimize toxicity for PDAC patients.


Self-stabilizing biodegradable microcarriers were produced via an oil/water solvent evaporation technique using amphiphilic chitosan-g-polyester copolymers as a core material in oil phase without the addition of any emulsifier in aqueous phase. The total yield of the copolymer-based microparticles reached up to 79 wt. %, which is comparable to a yield achievable using traditional emulsifiers. The kinetics of microparticle self-stabilization, monitored during their process, were correlated to the migration of hydrophilic copolymer’s moieties to the oil/water interface. With a favorable surface/volume ratio and the presence of bioadhesive natural fragments anchored to their surface, the performance of these novel microcarriers has been highlighted by evaluating cell morphology and proliferation within a week of cell cultivation in vitro. Cell microcarriers were first introduced in a mid-1960s for a large scale culture of anchorage-dependent cells in vitro for the production of several biopharmaceutical drugs . For theThis study aimed to evaluate the fabrication’s features of self-stabilized microparticles via the oil/water technique using novel amphiphilic chitosan-g-polyester copolymers, and to assess them in vitro controlling animal cell adhesion and growth on their surface. To provide, along with better mechanical properties, a required flexibility to the macromolecules for their successful migration to the oil/water interface, amorphous poly(lactide-co-glycolide) moieties were grafted onto chitosan to produce an amphiphilic chitosan-g-PLGA copolymer (marked as CPLG). As a second option, an effect of the additional presence of hydrolyzed protein, i.e., gelatin, within the chitosan-g-poly(L-lactide) copolymer  was studied in terms of the self-stabilization ability of formed microparticles and the further effect on their biocompatibility.w/w) dissolved in methylene chloride. This screening study has highlighted that the two amphiphilic chitosan-g-polyester copolymers efficiently stabilize the oil/water interface in the absence of any additional emulsifier in the water phase. As disclosed in Amphiphilic chitosan-g-polyester copolymers, i.e., CPLG copolymer consisting of a chitosan backbone and grafted amorphous poly(lactide-co-glycolide) (PLGA) chains, and CPG copolymer comprising a chitosan backbone with grafted semi-crystalline poly(L-lactide) fragments and gelatin, were used as a core material for producing self-stabilizing biodegradable cell microcarriers. The detailed compositions and conditions of the synthesis of these copolymers are given in Although this microsphere processing is well-known to be complex with the different physico-chemical events associated during the emulsification, evaporation, and hardening phases, the recovery yield and size distribution of microparticles are mostly governed by the stability and hardening kinetics of the oil/water interface. The kinetics of microsphere formation using traditional surfactants in aqueous phase is well-known to be controlled by several formulation parameters, such as processing temperature, agitation speed, nature of the oil and aqueous phases, and the macromolecular features of polymers used to generate the microparticles . AdoptinA kinetic study of microparticle interface stabilization was carried out by monitoring the evolution of the emulsions under optical transmission microscopy every 5 min. Interestingly enough, in the presence of a limited amount of the chitosan copolymers, i.e., 10 wt. % to PDLA dissolved in oil phase, the kinetics of microparticle formation were significantly slowed down. As highlighted from micrographies given in Indeed, up to 15 min, very few microparticles were detected. Instead, heterogeneous emulsion droplets with irregular shape were mostly visible under transmission microscopy. Further, after 25 min of emulsification, more distinct solid microparticles were identified, as disclosed on With an extended duration needed to stabilize and solidify the oil droplets, other physico-chemical events could occur, such as the coalescence or aggregation of oil droplets, but also foam production. Accordingly, these other interfaces could attract in a competitive way our copolymers. From the histogram given on The content of the copolymer in the oil phase, expressed in terms of wt. % to the total amount of polymers dissolved in the oil phase of the emulsion, has been also investigated to test their amphiphilic effectiveness and to verify the possibility to produce microparticles made only of these copolymers, thus free of any homopolyesters. Accordingly, the influence of the copolymer content, 10, 30, 50, and 100 wt. %, has been assessed for both copolymers measuring the total yield and size distribution of the resulting microspheres. As highlighted in This correlation between microparticle size and recovery yield is however more ambiguous with the terpolymer CPG, which highlighted a more complex behavior in terms of recovery yield and size distribution. Indeed, the mean microsphere size became lower up to 50% replacement of PDLA by CPG, while when microparticles were made from 100% CPG the proportion of particles above 500 µm is close to 50% see b.Expecting an influence of the amphiphilic copolymers on the surface of the microspheres, their morphology has been visualized under SEM microscopy. Compare to PDLA microspheres stabilized with PVA, which disclosed a smooth and regular surface, the copolymer microsphere roughness was gradually increased when increasing the copolymer content in the oil phase .When made only of the copolymer, the surface roughness is not only affected, but the overall shape also became quite heterogeneous. According to these morphology observations, a 30 wt. % copolymer content could be considered as an “optimal” loading in order to achieve a maximum recovery yield without significantly affecting the surface roughness and cohesiveness of the microparticles. SEM observation showed a significant difference in morphology between the core and the surface of the particles (The migration of the graft-copolymer to the microsphere surface and the accessibility of the amino groups of chitosan or/and gelatin has been verified after fluorescein isothiocyanate (FITC) labelling and fluorescent microscopy. Although qualitative, this test should allow us to control the presence and accessibility of pending groups, well-known to affect adhesion of anchorage-dependent cells. As clearly highlighted in The feasibility to produce microparticles in the absence of any common synthetic emulsifier in the aqueous phase make these amphiphilic copolymers particularly attractive for valorization. Indeed, the removal of stabilizer use allows to save several unit operations during the microparticle manufacturing, such as emulsifier dissolution, removal/washing out, and its regeneration/utilization. Moreover, in spite of the rather complex and slow kinetic of interface stabilization, these systems are very reproducible. The copolymers are especially promising to adopt them for the fabrication of microcarriers for tissue engineering. Indeed, in addition to their role in efficiently stabilizing the interfaces during processing, these biodegradable and natural made macromolecules provide binding moieties favorable to enhance cell adhesion.The next step of the study was to evaluate animal cell interaction with these original microcarriers. In this study, L929 mouse fibroblasts were used as a model, taking into account that this cell line represents the reference for the evaluation of the cytotoxicity of medical devices according to ISO10093. This in vitro assay has been performed comparing PDLA-microparticles stabilized with PVA as a reference with the microparticles functionalized with our graft-copolymers. In order to assess the possible impact of the microparticles topography and chemistry on cell behavior, L929 fibroblasts were seeded and cultivated on the microbeads .L929 fibroblasts were seeded on the microbeads and cultivated for seven days. In order to monitor cell behavior during in vitro cultivation, cell growth was observed under light microscopy. As noticed in Already at day 5, but especially on day 7, cross-linking of microcarriers occurred as a result of the multiplication of cells to the surface of two neighboring microcarriers, giving rise potentially to macroscopic cell/microcarrier aggregates. In all cases, thus independently of the microcarrier type or the duration of cell cultivation, free fibroblasts or fibroblasts adhering to polystyrene wells were noticed during our microscopic observations. This observation is not surprising taking into account the spontaneous sedimentation of these cells in the culture medium and the difficulty to maintain their homogeneous dispersion in the wells of this culture device. Although not quantitative, these observations do not highlight any significant difference in cell behavior, whatever the batch of microcarriers and the period of cell culture.In order to assess the viability of L929 fibroblasts cultivated on the microparticles, cells were stained with vital fluorescent dye Calcein AM and DAPI after three days of cultivation. The fluorescence micrographies reported in w/w) marked as CPLG and chitosan/poly-L-lactide/gelatin blend (35/52/13 w/w) (marked as CPG). Details of all copolymer synthesis batches and relative sample codes are given in Amphiphilic chitosan-g-polyester copolymers were synthesized at ISPM RAS via the solid-state reactive co-extrusion of chitosan/poly(lactide-co-glycolide) blend (60/40 2Cl2/acetone (9/1 v/v)—was rapidly injected within an aqueous phase preliminary thermostatized at 15 °C under stirring using a 4-bladed propeller stirrer. The preparation of microspheres containing the copolymers in oil phase was carried out in mQ water, thus without any emulsifiers in the aqueous phase of this o/w emulsion. Control microspheres were made from PDLA as core polymer and a PVA solution (2.5% w/w) as aqueous phase to stabilize the oil/water emulsion. After the evaporation of organic solvents from the oil phase, the solid microspheres were carefully washed with mQ water, sieved with apertures ranging from 125 to 500 μm, and freeze-dried. The total yield of the microparticle production was calculated as wt. % of recovered microparticles to the total amount of polymer dissolved in oil phase. The microsphere size distribution was determined by sieving each microparticle batch using sieves of meshes ranging from 500 μm down to 125 μm in a wet mode. After fraction collection and drying, the weight of each particle fraction was determined by gravimetry. The mean yield of each microsphere batch was calculated as a weight percentage of recovered microspheres with given size to the total amount of polymer dissolved in oil phase. The data on total and fraction yields are given as a mean value calculated based on at least three separate processing runs; standard deviation ranged ± 3%.Microspheres were prepared by oil/water emulsion solvent evaporation technique as described previously . The oilThe kinetics of microsphere formation was monitored under optical microscopic observation starting from 5 min after emulsification sampling the dispersions every 10 min. The microparticles were observed with an Olympus PROVIS AX70 in transmission mode equipped with a VisiCam 5.0 camera (VWR).For classical scanning electron microscope (SEM) visualization of the microsphere surface and internal structure, microspheres were embedded within a concentrated PVA solution, dried, and cross-sectioned with a surgical blade. Both entire and sectioned microspheres were glued on a glass slide with double-sided carbon tape before being Pt-coated in a Balzers SCD 030 sputtering unit. Observations were carried out in a JEOL-840A (Japan) scanning electron microscope working at 20 kV accelerating voltage.For environmental scanning electron microscopy (ESEM) and elemental X-ray microanalysis (EDX), the freeze-dried microspheres (without any coating) were viewed in ESEM-FEG XL-30  with the gaseous secondary electron detector (GSE) in low vacuum condition (0.4 Torr) at 15 kV accelerating voltage. Images and position beam X-ray spectra were acquired with a silicon drift detector  for light elements and analyzed through the Quantax Esprit 2.1. Semi-quantitative data in weight and atomic % were extracted from the spectra by use of the standard-less ZAF correction matrix after automatic back-ground subtraction.The presence and accessibility of amino groups onto microparticle surface has been also verified using staining with FITC reagent as reported earlier using a Leica DFC-450 C  fluorescent microscope .2) in a CO2 incubator in 5% CO2 humidified atmosphere at 37 °C. The cells were re-seeded into a fresh medium every 2–4 days.The mouse fibroblasts (L929) were cultivated in DMEM medium supplemented with 10% FBS in flasks  without cover of the plate for 2 h under agitation (speed 200 rpm). Microparticles after sterilization were washed three times with PBS and once with DMEM supplemented with 10% FBS. Cell cultivation with microcarriers was performed in non-adherent cell 96-well plates . Each well contained 100 μL of cell suspension in culture medium (105 cells/mL) and 20 mg of microparticles.Cell growth on the microcarriers was monitored using an inverted light microscope  on days 1, 2, 5, and 7 of cultivation.Cell morphology was evaluated on day 3 of cultivation using a confocal laser scanning microscope (CLSM) Nikon TE-2000 inverted microscope equipped with an EZ-C1 confocal laser . After 3 days of cell cultivation, the cells were stained with Calcein AM and DNA fluorescent dyes (DAPI). For this purpose, the mixture of Calcein AM and DAPI in the medium (5 µg/mL of each dye) was added to the microcarrier samples, and the samples were incubated at 37 °C for 30 min. Then, the supernatant was replaced with fresh culture medium, and the samples were observed using a confocal laser microscope .Amphiphilic chitosan-g-poly(lactide-co-glycolide) and chitosan-g-polylactide-g-gelatin copolymers were successfully used as core polymers for the fabrication of biodegradable cell microcarriers. The ability of these copolymers to stabilize the oil/water interface was highlighted and monitored during the microparticle formation via the oil/water solvent evaporation technique in the absence of any emulsifier in the aqueous phase. A complex copolymers’ chemical structure and kinetics of interface stabilization led to the formation of self-stabilized microspheres with a bigger mean size and a wider size distribution than ones produced with the aim of classical emulsifier  in aqueous phase, while allowing to eliminate several manufacturing steps, such as emulsifier preparation, elimination, and regeneration/utilization. The microcarrier total yield, size distribution, and other characteristics, such as the porosity and roughness of volume/surface, have been shown to be easily modified by the modification of oil phase composition. Although no significant difference in fibroblast behavior was noticed between microcarrier batches and their surface properties, all of them were demonstrated to support efficient animal cell adhesion, spreading, and proliferation over a seven-day period. Moreover, the viability of these cells was demonstrated using green fluorescent dye Calcein staining.