Inhibition of TXNRD is thus an appealing strategy in cancer chemotherapy. The inhibition of TXNRD may further cause oxidative stress to tumor cells, resulting into cell death via different pathways. The increasing use of small molecules as inhibitors of cytosolic TXNRD1 and mitochondrial TXNRD2 have been disclosed in the past decades. Targeting TXNRDs may reverse the growth of numerous tumors, making TXNRDs attractive targets for cancer chemotherapy (Selenoproteins have the selenium (Se)-containing amino acid selenocysteine (Sec) at their redox active motifs (or key activity sites). They are involved in diverse functions in human development, physiology, health, and diseases . Usuallyotherapy .via interaction with the highly reactive Sec residues of the enzymes  of Frontiers Publishers aimed at a better understanding of the mechanisms and actions of small molecules inhibiting mammalian selenoprotein TXNRDs: Interactions, mechanisms, and applications. In this Research Topic, small molecules included natural products, their interacting mechanisms for the inhibition of TXNRD, their downstream signaling pathways, their effect to human diseases and the results of their use in clinical trials.Wenxuan Jiao et al., reported therapeutic effects concerning the organic selenium compound Butaselen (BS) as an inhibitor of TXNRD on liver fibrosis by downregulation of the transforming growth factor-β1 (TGF-β1)/Smads Pathway. In the study, liver fibrosis models were established using male BALB/c mice through intraperitoneal injection of CCl4. The authors revealed that BS, an inhibitor of the TXN system, exerted significant therapeutic effect on CCl4-induced liver fibrosis in mice. Hepatic stellate cells (HSCs) were used to examine the action mechanisms of BS against the progression of liver fibrosis. BS not only inhibited the activation of HSCs but also induced HSC apoptosis by inhibiting the TXN system. Thereby, BS attenuated hepatic fibrosis through inhibition of the production of α-smooth muscle actin (α-SMA) and collagens by HSCs by downregulating the TGF-β1 expression and blocking the TGF-β1/Smads pathway. This study shows the great potential of inhibitors of TXNRDs as drugs for the clinical treatment of liver fibrosis.Liver fibrosis is a precedent in the progression of liver injury into cirrhosis or even liver cancer. The role of the TXNRD/TXN system in liver fibrosis is unknown. Junmin Zhang et al., showed that inhibition of TXNRD by Santamarine conferred anticancer effects in HeLa cells. In this study, a knockdown for TXNRD and cell lines overexpressing TXNRD were employed. The activity of TXNRD regulated the physiological effect of Santamarine in cells. In brief, the natural product Santamarine inhibited TXNRD and weakened the antioxidative function of the enzyme in cells, resulting in a high-level accumulation of ROS that finally induced an oxidative stress-mediated apoptosis to HeLa cells. The authors unveiled TXNRD is a novel target of Santamarine, proposing thus a previously unrecognized mechanism to explain its anticarcinogenic properties. Their findings provide a basis for the further development of Santamarine as a potential cancer therapeutic agent.Natural products frequently have unique physiological activities and new action mechanisms due to their structural diversity and novelty. They are considered an important source for the development of innovative drugs and lead compounds. Vanessa Pires et al., unveiled that mercury (Hg) compounds were among the most effective inhibitors of TXNRD and TXN due to their high affinity for binding thiols and selenols. Organomercurials such as Thimerosal (TmHg) could effectively cross the blood-brain barrier (BBB), to reach effective concentrations for the treatment of GBM. TmHg and its metabolite ethylmercury (EtHg) were evaluated over the mouse glioma cell line (GL261): both TmHg and EtHg inhibited the TXN system, triggered the cellular oxidative stress, and induced apoptotic cell death at low concentrations. Their study indicated that EtHg and TmHg have the potential of a therapeutic approach against GBM.Glioblastoma multiforme (GBM) is the most aggressive and common form of glioma. In these tumors, TXN and TXNRD are overexpressed to cope with high levels of ROS and resist chemotherapy and radiotherapy. Thus, tackling the activity of these enzymes is a potential strategy to reduce cell viability/proliferation and most importantly achieve tumor cell death. Mirna Jovanović et al., the role of the TXN detoxification system in cancer progression and resistance is presented. The authors discussed some studies where the highly active TXN system contributed to the poor response of drug treatment, thus making it an attractive target for the development of drugs-inhibitors to be used for chemotherapy. Excessive oxidative stress is a characteristic of highly proliferative, metabolically hyperactive cancer cells, which are forced to mobilize antioxidant enzymes to suppress the increase in free radicals and thus prevent irreversible damage and cell death. Components of the TXN system are involved in high-rate proliferation and activation of pro-survival mechanisms in cancer cells, particularly those facing increased oxidative stress. The review highlighted the importance of the TXN system in tumor progression, as well as in the detoxification and protection of cancer cells from oxidative stress and drug-induced cytotoxicity. The authors further emphasized the importance of developing novel multitarget therapies encompassing the inhibition of the TXN system to overcome limitations in the current treatment of cancers.Redox regulators such as TXN and TXNRD have proved of utmost significance for the regulation of the redox milieu in normal cell survival, proliferation, invasion, metastasis of cancers and chemotherapy. In the review of The above four contributions from diverse range of fields, have already been published by the Frontiers in Molecular Biosciences (FMB). FMB’s success is due to an effective collaboration of authors, reviewers, and a dedicated editorial team under the leadership of Editor-in-Chief. We three guest editors are confident that these articles will be of interest to wide readers of FMB and will provoke new discussions in developing novel small molecules and novel targeting anti-tumor strategies.Last but not the least, we would like to express our great gratitude to all authors of this Research Topic for their invaluable scientific contributions. Simultaneously, we thank all comments and opinions from the reviewers that have improved the article quality and scientific perspective. We hold our faith in bioscience and look forward to serving the Frontiers journals and research contributions in the future. Finally, we would be most happy if people with further questions or suggestions, contacted the executive editor of FMB. Please feel free to do so, it will be most helpful in further improving the quality of this journal.


The symposium includes four studies exploring the impact of mild cognitive impairment and/or young onset dementia on the workplace, and area of increasing interest due to the aging workforce and government interest in prolonging work life. The papers adopt a rare, multi-level approach by examining both employee and employer perspectives, and how the interaction of both individual and organizational factors impact their self-reported outcomes. Following the paper presentations, Dr. Allison Gibson will lead a paper discussion. The goal of the symposium is to foster a research conversation amongst the presenters and symposium participants interested in exploring overlaps, potential for multi-disciplinary collaboration and future research into resolution of workplace and workforce optimization with worker satisfaction that are identified with progressive cognitive impairment.


We describe an infrequent case of endoleak Type-III due to an unrecognized, inadvertent bilateral limb deployment into the same limb gate of the Ovation aortic endograft, accompanied by thrombosis and acute ischemia. The following computed tomography angiography revealed the open limb gate with the characteristic of radio-opaque polymer in the sealing rings. Intraoperative angiographies via the brachial route identified the open limb gate and facilitated the successful use of an occluding plug to manage the Type-III endoleak. The Ovation trimodular endograft is based on a pair of polymer-filled sealing rings to ensure optimal sealing on the infrarenal neck of abdominal aortic aneurysms (AAAs), accommodating even to challenging neck anatomies.A 62-year-old male presented with an infrarenal AAA of 51 mm. The treatment chosen for the patient was endovascular repair with the use of the Ovation endograft  and a main-body 29 mm with iliac limbs of 14 × 16 mm and 14 × 14 mm for the right and left side, respectively. After deployment of the endograft and during polymer filling of the inflated rings, the impression of inadvertent anteroposterior position of the limb gates was given. Under left anterior oblique view, the contralateral limb catheterization was assumed to take place uneventfully, confirmed with the classic tests to ensure proper position.A computed tomography angiography (CTA) was conducted showing placement of both iliac limbs within the same limb gate on the right accompanied by collapse and thrombosis of the left iliac limb  at the top end of both iliac limbs with restoration of distal palpable pulses on the left. Accordingly, a 16-mm nitinol-meshed occlusion plug  was ordered to treat the endoleak.After a few days, open vascular access was achieved through the left brachial approach. An angiographic catheter was advanced to the endograft's main body and placed within the right limb gate , arrow Our article presents a challenging case of identifying correctly and catheterizing the contralateral limb gate of an endograft for treatment of AAA. Moreover, it underscores the diagnostic difficulty and uncertainty that a nonexperienced radiologist or interventionist may encounter to identify the proper type of the emerging endoleak.Since both iliac limbs in our case were adequately perfused at the end of the implantation, the retrograde angiographic control via the iliac route proved inappropriate to identify the intrasac leak, due to the anteroposterior position of the endograft allowing no splay of the limb gates. Another important feature for identifying properly the endoleak type was the awareness of the radio-opacity of the filling polymer within the sealing rings of Ovation . Apart Notably, the continuous education of radiologists should keep up with the advent of new endografts, especially those involving radiopaque polymer agents associated with consequent findings that could be missed or misinterpreted.It should be mentioned that the aforementioned difficulty presented with the particular endograft has been properly addressed recently with the incorporation of a crossover lumen in the endograft, facilitating reliable contralateral gate access in the current Ovation iX design, which should be used in any case of questionable limb cannulation. Yet, such intraoperative challenges with respect to visualization and catheterization of the contralateral limb can be encountered with all other endografts. Therefore, in such cases we strongly advocate anterograde selective angiography and catheterization via the brachial access without delay, as well as multiple oblique projections of the C-arm to ensure the optimal visualization during catheterization.In cases of ambiguous catheterization of the endograft's contralateral limb gate during endovascular treatment of AAA, high level of suspicion, multiple projections, and anterograde selective angiography via the brachial route should spare intraoperative time and avoid inadvertent failures. Availability of proper embolization materials render the management of endoleaks Type-III quick and effective, while the acknowledgment of each new endograft's special, unique features precludes misdiagnosis and dictates proper management.The educational value of this report underscores the comparative advantage of the anterograde angiography via the brachial route in ambiguous diagnostic cases and marks the need for continuous education of physicians on the unique, specific features and structure of new endografts to avoid delay in detection and misdiagnosis of associated complications.


Interventions to promote health-enhancing physical activity in early childhood education and care settings are most successful when tailored to the specific needs of each childcare centre and providing ongoing support to address context-specific barriers. Our research project therefore initiated organizational development processes in 12 childcare centres in Southern Germany supported by coaching and self-assessment tools. The staff of each centre was instructed to set three centre-specific SMART goals targeting physical activity and to use Goal Attainment Scaling in order to track the success at implementation. This qualitative study aims at exploring childcare centre directors' views on the guided planning process and identifying facilitators and barriers for its implementation.We conducted guided semi-structured interviews with the directors of the centres after the 12- month organizational development process. 9 out of 12 directors were interviewed. The interviews were recorded, transcribed and analysed using qualitative content analysis with inductive category development.Childcare directors mainly considered themselves to be the person with the greatest responsibility for the success of the process. The coaching was regarded as helpful for structuring the process, involving the whole team and becoming clearer about goals. Several factors were identified as facilitators: a beneficial personnel situation, the intrinsic motivation of staff, good team cooperation, a high priority of physical activity, previous experience with similar projects, pressure for change, individual drivers, a good infrastructure, parents' support and support from the administrating organization. Reported barriers included team conflicts, lack of willingness to accept change and shortness of time.Several contextual and interpersonal factors seem to influence the extent to which a cooperative planning process can be implemented by the staff of a childcare centre. The results help understand the process of change as a complex interventional system in which the intervention cannot be considered separately from the context.


Plectranthus barbatus in South Africa. Our model revealed a massive wave of spread driven by human-mediated long-distance dispersal and originating from the cities of first introduction. The species completed its invasion of all favorable areas a few years after, in the mid-1990s. Without human-mediated long-distance dispersal, the maximum population would have been obly 30% of the current population. The delayed reproductive maturity explained the invasion lag phase. It highlights the importance of early eradication of weedy horticultural alien plants around urban areas to hamper the invasive spread.Understanding biological invasion mechanisms is crucial to design effective management strategies preventing their impacts on ecosystems. If the role of long-distance dispersal and age-dependent fecundity in plant invasion speed has been characterized in theory, empirical support is still rare given the difficulty to jointly fit demographic and spread parameters of dynamic models to available data. We proposed a statistical model to fit such parameters to heterogeneous observations collected across space and time. We can directly test hypotheses on the importance of various mechanisms in a past invasion. We demonstrated the potential of this method by determining the roles of human-mediated long-distance dispersal and age-dependent fecundity in the invasion of the shrub Plectranthus barbatus, a woody plant invader in South Africa. Our lattice-based model accounts for both short and human-mediated long-distance dispersal, as well as age-structured fecundity. We fitted our model on opportunistic occurrences, accounting for the spatio-temporal variations of the sampling effort and the variable detection rates across datasets. The Bayesian framework enables us to integrate a priori knowledge on demographic parameters and control identifiability issues. The model revealed a massive wave of spatial spread driven by human-mediated long-distance dispersal during the first decade and a subsequent drastic population growth, leading to a global equilibrium in the mid-1990s. Without long-distance dispersal, the maximum population would have been equivalent to 30% of the current equilibrium population. We further identified the reproductive maturity at three years old, which contributed to the lag phase before the final wave of population growth. Our results highlighted the importance of the early eradication of weedy horticultural alien plants around urban areas to hamper and delay the invasive spread. Plant invasions generate massive ecological and economic costs worldwide. Predicting their spatial dynamics is crucial to the design of effective management strategies and the prevention of invasions. Earlier studies highlighted the crucial role of long-distance dispersal in explaining the speed of many invasions. In addition, invasion speed depends highly on the duration of its lag phase, which may depend on the scaling of fecundity with age, especially for woody plants, even though empirical proof is still rare. Bayesian dynamic species distribution models enable the fitting of process-based models to partial and heterogeneous observations using a state-space modeling approach, thus offering a tool to test such hypotheses on past invasions over large spatial scales. We use such a model to explore the roles of long-distance dispersal and age-structured fecundity in the transient invasion dynamics of  Biological invasions are a major driver of the current biodiversity crisis and incur tremendous cost to human societies . Many stEffective management involving the early detection and prevention of the negative impacts of plant invasions demands a robust understanding of the past transient spatial dynamics on which to base predictive scenarios of future invasions. It is crucial to acknowledge the non-equilibrium reality of an introduced species with its invaded environment due to its limited residence time and dispersal constraints , which mTo design a sound dynamic model of invasion, we must ensure the coherence of the model with plant physiology and spread mechanisms while simultaneously avoiding over-parameterization for relevant and reliable interpretations. In particular, if environmentally suitable areas are prerequisites for invasion success, the ability to produce propagules at an early age and in sufficient numbers can further enhance invasion success . SeveralWe propose a Bayesian dynamic species distribution model to investigate the role of human-mediated long-distance dispersal and age-structured fecundity in the large-scale spatial dynamics of invasive perennial plants. This model is similar to other Bayesian dynamic models ,23,35,36Plectranthus barbatus in the Southern Cape region of South Africa as a case study. The species is native to tropical India and likely to northeast Africa , ]40th percentile, 70th percentile], ]70th percentile, 90th percentile], and ]90th percentile, maximum]. Based on this discretization scheme, we propose a simple way to deal with ambiguous couples  for which there is no consensus across parameter samples: Each couple where less than two-thirds of the samples agree with their population size percentile is tagged as “uncertain”. We were thus able to draw comparable maps of relative population size for selected years in https://chrisbotella.shinyapps.io/plectranthus_barbatus_sa_maps/ (accessed on 20 August 2022)Invasion syndrome spatio-temporal maps. We analyzed the growth and spread status of populations across space and time. We simplified the growth and spread status of a population by defining five discrete categories, called invasion syndromes: (i) certain population growth but uncertain dispersal (the population does not spread enough seeds for new plants to effectively grow from it in other cells); or (ii) certain population growth and dispersal ; or (iii) certain dispersal but no certainty about whether the population is growing or declining ; or (iv) certain population decline and dispersal ; or (v) certain population decline but uncertain dispersal . The growth status and spread status of any population are determined exactly and independently for each posterior sample. The growth  status of a population is considered certain if at least two-thirds of the posterior samples agree that the population is growing (resp. decreasing/generating new plants in other cells) from one year to the next. If the status of growth and dispersal does not belong to any of the five invasion syndromes, we tag the population as uncertain. We map the invasion syndrome across the cells for 6 key years in https://chrisbotella.shinyapps.io/plectranthus_barbatus_sa_maps/ (accessed on 20 August 2022). We also reconstructed the total population, seed production, shanon entropy of population across cells per year  the long-distance human-mediated dispersal , enables us to test our hypothesis on the role of the delay before reproductive maturity in determining the invasion dynamics. Plectranthus barbatus’ invasion history in the Southern Cape region of South Africa in We analyzed the model parameters’ estimability and the predictive performance in time. We produced a map-based reconstruction of the key years of A marked information gain on most parameters despite imperfect MCMC convergence. Despite the sampling heterogeneity of our presence-only data, the convergence of the MCMC chains was reasonable for most parameters from the visual inspection of their trace plots and univariate convergence criteria (PSRF < 2), but the multivariate criterion (MPSRF = 2.8) suggested that the algorithm did not fully converge to the posterior distribution  but significantly better than random and comparable to the training performances (mean AUC = 0.58) (see failed (average AUC = 0.44) in validation after 16 years of data deprivation (2016–2021), with performances worse than a random guess, while the training performance was fair (mean AUC = 0.73) in the same period. with AUC  The vali.58) see . In otheSignals of introduction hotspots and residence time. The estimated initial population sizes in 1980 varied significantly across the 24 introduction cells. Indeed, despite some uncertainty, the posterior estimates of the initial population size were significantly higher in some cells than others  of the species, most likely mediated by humans. Indeed, according to our estimates and ablation study, although Plectranthus barbatus reached an equilibrium population by 2000 or earlier, it would have been far below this equilibrium over the same period without long-distance dispersal. Hence, our results support the opinion that urban areas act as launching sites for invasive plants in natural areas of South Africa [We introduced a new Bayesian dynamic species distribution model to reconstruct the invasion dynamics of a perennial plant species from the occurrence data. This type of model merges the strengths of mechanistic dynamic models that may produce realistic and extrapolatable predictions, as shown here, with those of statistical Bayesian inference that leverages heterogeneous data and prior knowledge for parameter calibration. Although this large class of models has been used for related purposes ,35,36,48h Africa .Plectranthus barbatus in South Africa in the past, which means that the invasion dynamics of the species have not been affected (negatively or positively) by management. This makes our model a coherent simulation tool for assessing what impact an eradication plan could have had on the invasion trajectory. More specifically, our complementary simulation, redrawing the invasion trajectory of the species without human-mediated long-distance dispersal, could actually be interpreted as a scenario of what the invasion would have been if the plant had been extirpated early and systematically around urban areas. Indeed, this simulation suggested that around 1996 the population would have been suppressed by 10 compared to the historical scenario where it had already reached equilibrium at this time. This strategy could buy time for broad-scale management and regulations to be coordinated. Whereas South Africa has advanced strategies for managing invasive species, none are systematically implemented for invasions in urban areas [Plectranthus barbatus), which is only a tiny proportion of the population but several orders of magnitude more fecund, would drastically reduce the management effort for the same level of control effectiveness.The fitted ecological process model could also be useful for formulating management strategies by testing the impact of different action scenarios. We are, however, not aware of any substantial management efforts directed at an areas . Urban-oan areas . Our resA limitation of our study is that we did not account for introductions that may have happened in unreported areas or later than 1980, likely in the context of private gardens. This possibility is supported by the fact that our results suggested a first introduction prior to 1940 followed by a 50-year lag phase, which would have given more than enough time for nurseries and gardeners to propagate the species. The knowledge of early introductions in other sites would have likely decreased the estimated importance of long-distance dispersal in our model, but it would not alter our conclusion that humans have been crucial in propagating the species, ensuring its fast invasion dynamics. The intensity of gardening and the residence time have been shown to be major factors explaining the chances of cultivation escapes and the naturalization of woody plants . Our modIf this study has revealed the hidden value of massive and heterogeneous crowdsourcing records  for invasion monitoring, it also supports the broader call for better access to biodiversity data in urban areas in order to better manage the regional landscape . For insPlectranthus barbatus, which occurred in the early 1990s and led to the final equilibrium phase, was most likely preceded by at least 50 years of apparent lag phase since its introduction time, which is coherent with the lag phases of naturalized shrubs in the literature [Plectranthus barbatus. Indeed, according to our model reconstruction, the last decade of this lag phase, between 1980 and 1990, was due to the interplay between the low initial population size, the delayed reproductive maturity, and the high mortality. Empirical evidence for these types of phenomena, often documented in theory [We also showed that the last population burst of terature . In agren theory , have ben theory . Howevern theory . Still, n theory  and of dAlthough our approach targeted interpretation and not future prediction, evaluating model fit and its future predictions through validation enabled us to characterize the relevance of the modeled processes in capturing the complexity of the drivers behind the actual invasion dynamics. The AUC performance on the training data was poor to fair (using the performance taxonomy from ) likely The estimation precision of the current framework could be significantly improved by using more and/or better prior knowledge. We used informative prior distributions on the carrying capacity, which constrained the population size and the detection rates given the observed data and reduced the identifiability issues on these quantities . Even thAlthough Bayesian inference is an important aspect of our methodology, given its capacity to account for prior knowledge on parameters, it induced algorithmic difficulties and heavy computational costs due to the complexity of our model. Indeed, we faced important convergence issues with our Metropolis–Hastings MCMC sampling algorithm. Initializing the algorithm with parameters of maximal posterior likelihood was crucial for obtaining a reasonable level of convergence. However, refining these parameter starting values required heavy preliminary runs. Moreover, the high-level sample auto-correlations in the final chains, due to an extremely low acceptance rate, required drastic thinning intervals, attesting to the inefficiency of the MCMC algorithm for exploring the parameter space (or the presence of a flat and rugged likelihood surface). Efficiently sampling complex and potentially multi-modal posterior likelihood surfaces is a known fundamental problem in Bayesian statistics , even th


The Standardized Precipitation Index (SPI) is a vital component of meteorological drought. Several researchers have been using SPI in their studies to develop new methodologies for drought assessment, monitoring, and forecasting. However, it is challenging for SPI to provide quick and comprehensive information about precipitation deficits and drought probability in a homogenous environment. This study proposes a Regional Intensive Continuous Drought Probability Monitoring System (RICDPMS) for obtaining quick and comprehensive information regarding the drought probability and the temporal evolution of the droughts at the regional level. The RICDPMS is based on Monte Carlo Feature Selection (MCFS), steady-state probabilities, and copulas functions. The MCFS is used for selecting more important stations for the analysis. The main purpose of employing MCFS in certain stations is to minimize the time and resources. The use of MCSF makes RICDPMS efficient for drought monitoring in the selected region. Further, the steady-state probabilities are used to calculate regional precipitation thresholds for selected drought intensities, and bivariate copulas are used for modeling complicated dependence structures as persisting between precipitation at varying time intervals. The RICDPMS is validated on the data collected from six meteorological locations (stations) of the northern area of Pakistan. It is observed that the RICDPMS can monitor the regional drought and provide a better quantitative way to analyze deficits with varying drought intensities in the region. Further, the RICDPMS may be used for drought monitoring and mitigation policies. Drought can be described as a recurring and challenging natural calamity that arises when precipitation is substantially less than its average time . The occIn literature, various Standardized Drought Indices (SDIs) have been proposed to characterize and monitor drought occurrences . Among tOften the univariate-based frameworks and methods are utilized for the identification and description of the drought occurrences. However, several characteristics in hydrological phenomena have convoluted dependence structures which cannot be described explicitly in the univariate setting and lead to generating poor outcomes . TherefoTherefore, adaptability exists in the modeling of varying dependence structures, that underpins the use of copulas functions, which have vast appendages for assessing dependence structures of the multivariate processes. The copulas are used for evaluating joint distributions through distinctly classifying the dependence structures of random variables from their marginal distributions . The appThe natural distribution of the selected region with high altitude significantly impacts other parts of the country . The regFor the analysis of the current study, the time series data is assembled from the Pakistan Meteorological Department through the “Karachi Data Processing Center” (KDPC) from January 1971 to 2017 December. The six meteorological stations are selected for the analysis from the northern zones of Pakistan. The selected area of the country has some importance due to its significant climatological characteristics . It has Further, drought is one of the challenging environmental catastrophes that can distress the natural life of the community directly or indirectly . Therefoi.e., “Extremely dry, Severely dry, Median dry, and Normal dry”) are used for the current analysis. These intensities are used according to the requirements of the study; however, other drought intensities can be included in RICDPMS.The precipitation of the northern area see  is selecMoreover, RICDPMS is the modification of the Continuous Drought Probability Monitoring System (CDPMS) . The mengiven in . The preThe MCFS technique implemented by The proposed method comprehensively models the precipitation data for various drought intensities in a homogenous climatic region. The deficit in the precipitation triggers a significant component of the drought events. The SPI has extensively been employed for assessing, monitoring, and analyzing drought incidences since the last decade . It is aKnowing the dependency structure of two or more variables can help assess their predictive relationship. The Pearson correlation coefficient generally measures the linear relationship among the variables. However, this method of measuring relationships only reflects the degree of dependence while other structural dependence settlements remain unimportant in this way. Therefore, a rank correlation coefficient has been considered to determine non-linear dependence. Usually, Spearman rank correlation and Kendall’s Tau are preferred for associating non-linear dependence structure. So, the use of Kendall’s Tau is common because, in this way, concordant or discordant pairs’ probability can be acquired directly. Also, the well-known relationship concerning the rank correlation coefficient, the copula function, is used to assess non-linear dependencies. In this perspective, Sklar’s theorem is compulsory for the different aspects of varying studies in the literature . GeneralThe current study examines the precipitation data  and its sub-periods (monthly distribution) by the bivariate copulas-based methodology. Moreover, Archimedean copulas (Gumbel and Joe) and Meta-Elliptical copulas Gaussian were tested as candidates given in For each of the selected stations the bivariate model is established, the probability of drought occurring in the time of the rainy season is assessed by the RICDPMS. In this manner, recent precipitation records are assimilated progressively using a conditional probability for the temporal evolution of selected drought intensities. Thus, this may support anticipatory mitigation policies and be helpful to perceive early warning concerns regarding the drought incidences, raising the awareness, the civil protection authorities, and water resources management.The time-series data is compiled from six meteorological stations in the northern area of Pakistan. The climatological features of the precipitation observed in varying stations are presented in p-values, which bring substantial signals against the structure of independence. Based on values of Moreover, the bivariate copulas for modeling the complicated dependence structures existing between precipitation at varying time intervals. The most popular copulas families, are tested for the current analysis. The MPL is applied for estimating the parameters. The varying families of copulas are designated based on Akaike Information Criteria (AIC). The year 2017 is taken as an example for the region to express the skills of RICDPMS to monitor drought continuously see . In the The bivariate copulas are used with their most famous families to fulfill the study’s objective. The parameters estimation and class of the copulas are selected based on MPL and AIC accordingly. The last step refers to monitoring the progression of the drought probability at the time of the rainy season in the selected region. The RICDPMS establishes for computing drought-triggering precipitation thresholds for varying drought intensities given by the SPI . Pontes Recently, Drought is one of the complicated natural calamities in terms of disrupting the natural life of the people directly. Moreover, continuing lack of precipitation causes pernicious results on society and the economy. Therefore, meticulous measures of drought monitoring are compulsory to identify drought incidences that perform more comprehensively and credulously for early warning and mitigation policies. Moreover, accurate and comprehensive information at the regional level regarding drought characteristics will increase analysts’ and policymakers’ competencies and time efficiency to make their cost-effective plans and mitigation policies. For this purpose, we propose a method known as the Regional Intensive Continuous Drought Probability Monitoring System (RICDPMS) for monitoring drought characteristics more comprehensively and expeditiously in the selected region. The proposed method is accomplished by using MCFS, SSP, and copula-based bivariate analysis for different drought intensities. The data gathered from six meteorological stations in the northern zones of Pakistan is utilized to validate the proposed methodology. As a result, we found that the RICDPMS monitors the drought comprehensively and expeditiously in the region and provides a comprehensive approach for evaluating drought with different drought intensities in the region. In summary, the RCDPMS may use for drought monitoring and mitigation policies.10.7717/peerj.13377/supp-1Supplemental Information 1Click here for additional data file.


A 67-year-old male patient was admitted to receive surgical treatment because of lumbar spinal stenosis. Ultrasonography showed a thrombus in the middle and lower segment of the left internal jugular vein. Superior vena cava filter implantation was performed and removed on day 7 after its implantation. The patient suddenly had dyspnea, and his blood pressure decreased 9 h after filter removal. Examinations showed pericardial tamponade and hemothorax. In addition, aortic dissection occurred approximately 20 days after superior vena cava filter removal. This case aimed to provide information to clinicians about the complications of the implantation and removal of superior vena cava filter implantation. The safety and possible complications of superior vena cava filter implantation and removal should be evaluated to identify their actual clinical benefit and cost-effectiveness ratio. In recent years, with the development of clinical intervention technology, the vena cava filter (VCF) has been widely used in patients with deep venous thrombosis (DVT). Acute pulmonary embolism (PE) is the main cause of sudden death in patients with DVT. Previous studies have shown that the PE incidence in patients with DVT of the lower extremities is approximately 45% , and theAt present, inferior vena cava (IVC) filters have satisfactory clinical outcomes in preventing the development of PE and in reducing its associated mortality rates . In contAccording to statistics, in recent years, the annual incidence of IVC filter-related complications is approximately 1.5% . ReportsA 67-year-old male patient with complaints, such as repeated lumbago and radiating pain in both lower limbs for 2 years and dizziness for more than 1 month, was admitted to our hospital. Lumbar magnetic resonance imaging (MRI) showed L4/L5 intervertebral disc herniation with spinal canal stenosis. The patient was admitted to the department of spinal surgery for lumbar spinal stenosis and received elective surgical treatment.Echocardiography after admission revealed no evident abnormalities. Bilateral cervical vascular color ultrasonography showed a thrombus in the middle and lower segment of the left internal jugular vein. Considering that venous thrombus might fall off, causing severe thromboembolism events, such as PE and post-embolization syndrome, SVCF implantation was performed under digital subtraction angiography on day 3 after admission . The rigThe patient was transferred to the intensive care unit (ICU) for further treatment. During his admission, a dynamic re-examination of the bedside echocardiogram showed that pericardial effusion was not absorbed significantly, and the patient still had chest tightness and discomfort in the precordial area. On day 4 after SVCF removal, computed tomographic venography (CTV) of the upper limb vein was performed, and the results showed that the right axillary vein was not filling well. Thus, thrombosis was highly suspected . Re-examThe annual incidence of venous thromboembolism is high , and antA study showed that the degree of vena cava injury is correlated with the time of VCF implantation . When thHerein, the occurrence of complications after superior vena cava filter removal was reported, which was correlated with pericardial effusion, mediastinal pleural, and aortic membrane injury caused by filter implantation. The current study aimed to provide information to clinicians about the complications of not only SVCF implantation but also SVCF removal. Based on the current data, SVCF implantation is a safe and effective alternative method for preventing PE caused by DVT of the upper limbs if anticoagulant therapy is not feasible. However, the safety and possible complications of SVCF implantation and removal should be evaluated to identify the actual clinical benefit and cost-effectiveness ratio. Nevertheless, more clinical data are required to assess the long-term morbidity and mortality of SVCFs and to confirm the role and clinical value of VCFs.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.All clinical data in this case report were collected with the consent of the patient. Written informed consent was obtained from the patient for the publication of this report and for the publication of any potentially identifiable images or data included in this article.ZH provided intraoperative care and designed the manuscript. QZ was the physician of record. JZ collected the information of patients. XZ organized the information of patients and edited the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.This study received a grant from the Key Laboratory of Emergency and Trauma, Ministry of Education (KLET-202001).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Esophageal leiomyoma is the most common benign submucosal mesenchymal tumor. Esophageal intraepithelial neoplasia includes low-grade and high-grade intraepithelial neoplasia. The coexistence of epithelial lesions and the subepithelial lesion is rare. We recorded a case of esophageal low-grade intraepithelial neoplasia (LGIN) overlying multiple esophageal leiomyomas and followed with a review of the literature.A 49-year-old female patient came for the treatment of esophageal lesions. The submucosal eminences were observed in the right posterior wall and the left anterior wall of the esophagus by Esophagogastroduodenoscopy (EGD). Additionally, we noticed the mucosa of the right wall with brown background color and the dilated, tortuous vessels by narrow-band imaging (NBI). Then we ensured that the submucosal lesions originated from the esophageal mucosal muscle by endoscopic ultrasonography (EUS) and enhanced CT. Subsequently, the submucosal eminence of the right posterior wall and the overlying mucosal lesion were removed together by endoscopic submucosal dissection (ESD). Postoperative pathological diagnosed esophageal submucosal leiomyoma with focal LGIN. Review EGD showed white scars on the right wall of the upper esophagus three months later, while pathological biopsy showed slight squamous epithelial hyperplasia in the left wall. We decided that the left submucosal lesion can be resected at a selective-time operation, and we continue to follow up as planned.The case of intraepithelial neoplasia overlying the submucosal tumor is rare. Either missed diagnosis or overdiagnosis should be avoided through EGD and pathological biopsy. The coexistence of epithelial lesion and subepithelial tumor is rare. There were few case reports about the coexistence of esophageal leiomyoma and esophageal severe dysplasia –3 and eaA 49-year-old female patient came to our hospital for the treatment of esophageal high-grade intraepithelial neoplasia overlying subepithelial tumor, which was confirmed at another hospital 4 months ago Table 1.Physical examination findings were typically normal. Serological examination showed no obvious abnormality.Esophagogastroduodenoscopy (EGD) demonstrated submucosal eminences in the right posterior wall and the left anterior wall of the esophagus, 18–25 cm away from the incisor teeth, with the widest diameter of about 1.5 cm. Multiple redness and shallow depressions were discovered on the right posterior wall surface additionally (We definite the origin and character of the lesion by endoscopic ultrasonography (EUS). We found that esophageal epithelial lesions are clearly stratified, while subepithelial lesion displayed as multiple uniform hypoechoic, irregularly shaped, and clear-boundary masses, which originated from the esophageal mucosal muscle layer and protruded to the cavity inside and outside. The largest one had an ultrasonic diameter of about 9.9×6.9 mm  and the overlying mucosal lesion were removed together successfully by ESD without intraoperative complications such as bleeding and perforation, while the submucosal eminence of the left wall was not treated temporarily  introduced the concept of intraepithelial neoplasia to diagnose precancerous lesions and early cancers of the gastrointestinal tract; LGIN is equivalent to mild and moderate dysplasia, and high-grade intraepithelial neoplasia (HGIN) is equivalent to severe dysplasia and carcinoma for LGIN , and Ki-for LGIN .en bloc resection and is appropriate for both epithelial and subepithelial lesions  for the publication of any potentially identifiable images or data included in this article.WP, JW, CL, YH, JY conceived and designed the study, and were responsible for the final decision to submit for publication. All authors were involved in the development, review, and approval of the manuscript. All authors contributed to the article and approved the submitted version.This research is funded by Sichuan Medical Association Digestive Endoscopy Special Committee (Jiexiang) Special Research Project (No: 2021XHNJ35)The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The identification of regulatory challenges for nanotechnology-enabled health products, followed by discussions with the involved stakeholders, is the first step towards a strategic planning of how such challenges can be successfully addressed in the future. In order to better understand whether the identified regulatory needs are sector-specific for health products or might also hinder the progress in other domains, the REFINE consortium reached out to communities representing other sectors that also exploit the potential of nanotechnology, i.e. industrial chemicals, food and cosmetics. Through a series of trans-sectorial workshops, REFINE partners identified common as well as sector-specific challenges and discussed possible ways forward. Potential solutions lie in a more strengthen collaboration between regulatory and research communities resulting in a targeted production and exploitation of academic data for the regulatory decision-making. Furthermore, a coordinated use of knowledge sharing platforms and databases, trans-sectorial standardisation activities and harmonisation of regulatory activities between geographical regions are possible ways forward, in line with the upcoming European political initiatives such as the Chemical Strategy for Sustainability (CSS). Finally, we also discuss the perspectives for further development and sustainability of methods and tools developed in the REFINE project. Nanotechnology-enabled health products can offer exciting possibilities for diagnostic and therapeutic tools, but their regulation including proper quality and safety assessments might be challenging, due to their specific properties and complex structure. Understanding of such regulatory challenges and the development of adequate methodological tools and approaches was among the goals of the Horizon 2020 project REFINE Box . Identif12The opportunities provided by nanomaterials are also exploited in other sectors, and even if the risk assessment-based regulatory decisions can be very different, it became obvious that the sectors share also common challenges including the implementation of EU recommendation on the definition of nanomaterial or safety aspects related to the toxicokinetic of a material. There are certainly other commonalities but also differences which would require an in-depth analysis.one substance one assessment initiative) [For this reason, to achieve a better understanding on common and sector-specific challenges, the consortium initiated a close exchange with its highly complementary project Gov4Nanotiative) . The traBox 1 REFINE projectHorizon 2020 project (2017–2022) Grant Agreement No. 761104Aim: Development of a Regulatory Science Framework for Nano(bio)material-based Medical Products and Deviceshttp://refine-nanomed.eu/Website:https://twitter.com/REFINE_H2020Twitter account: REFINE consortium involved 13 European partner organisations from academia, governmental organisation and industry. It focused on addressing regulatory needs for nanotechnology-enabled health products, optimisation and validation of characterisation methods, development of a decision support system and engaging with stakeholders from health and other sectorsTo better understand the regulatory needs and challenges from a stakeholder point of view, a survey and series of workshops were organised in the frame of the REFINE project. An online survey (July 2020 to March 2021) aimed to obtain quantitative feedback on the REFINE White Paper [The identified regulatory challenges were also discussed at workshops and conferences with representatives of the medical field and other sectors, with the aim to identify similar challenges, knowledge gaps and regulatory questions across sectors and discuss potential common initiatives.An example of such a workshop was the Gov4Nano Regulatory Risk Analysis Summit (RRAS) , which fTwo KECs were organised in the context of the REFINE project to discuss common regulatory challenges and synergies for nanotechnology-enabled products with representatives of different sectors including medical devices, industrial chemicals, food and cosmetics. In collaboration between Gov4Nano and REFINE, trans-sectorial regulatory issues and consequent research questions were identified and presented during the 2nd KEC . The useIn addition to the already identified regulatory questions and challenges, the workshop participants raised further needs Box , such asone substance one assessment [, which aims to make safety assessment processes simpler and more transparent across regulatory domains, has outlined the future directions on how safety assessments in Europe should evolve. It will include a better coordination across regulatory frameworks and between agencies, the use of academic data, knowledge and data sharing platforms as well as coherent and possibly harmonised methodologies across different sectors. The exploitation of nanomaterials in different sectors would be an interesting case study to further explore the harmonisation of safety assessments across regulatory frameworks.The recognition of common challenges across sectors and proposed ways forward comes timely and is in line with objectives of the CSS . In partsessment , which aA better coordination across different sectors will help to reduce uncertainties, related to the assessment of innovative products based on nanotechnologies for which the selection of the regulatory path is challenging  Table . It has In the context of the upcoming regulatory initiatives and based on outcomes of the discussions with different stakeholders  and representatives of different communities, future strategies to overcome regulatory challenges for nanotechnology-enabled health products are proposed by the REFINE project Fig.  and descBox 2 Additional challenges and needs across different sectors using nanotechnologyNeed for accessibility of data, databases and data-sharing platformsComparability of test methodsAssessment of the entire lifecycle of nanotechnology productsSufficient communication with consumers and patientsDespite a significant progress in the domain of nanobioscience and the improved understanding of the interaction of nanomaterials with the living systems, there are still some remaining knowledge gaps, which might hamper the regulatory decisions in relation to nanotechnology-enabled health products. In particular, the identification of critical quality attributes that have an impact on biological effects such as the modification of therapeutic effects or changes in the safety profile can be challenging for nanotechnology-based formulations. In fact, the continuous exploitation of nanotechnology leads to more complex formulations, where a whole set of different interlinked parameters will determine the biological effects. A better understanding of the impact of physicochemical properties on biological effects is also a key for the identification of crucial parameters that determine similarity  of a follow-on product regarding an original product. Such knowledge is also of importance for emerging assessment tools in other sectors such as grouping and read across for nanotechnology-based products.For innovative products where datasets derived from high quality studies are limited, the available academic data can assist in closing knowledge gaps and support an informed decision-making. The potential of academic research to address remaining questions with targeted, thoroughly prepared scientific studies was also recommended as a strategic goal by European Medicines Agency .In any case, the use of academic data must overcome some hurdles before it can be taken up for regulatory decision-making. Currently, it is challenging and time-consuming to retrieve specific information from the scientific literature. More optimised tools to find and access the relevant scientific reports and data would enable the use of such knowledge in the regulatory environment. According to the FAIR principles,Another caveat is often the need for criteria to judge the quality of the academic study, which should rely on robust methodologies and comply with high standards for the experimental approaches and reporting. Some standards for the quality criteria and reporting have already been proposed for nanotechnology-enabled products  or chemiFinally, an increased exchange between regulatory and research communities would benefit from training and education of academic researchers in the area of regulatory science and more explicit communication of regulatory needs to the research community.A number of different fora are currently contributing to the exchange of knowledge among the international regulatory agencies aiming to increase scientific alignment in the assessment of novel and generic drugs Table . The IntIn July 2021, the US FDA and the EMA launched a pilot programme discussing the specific questions regarding complex generic drugs/hybrid products that are generally more challenging to develop with traditional bioequivalence methods. In this programme, the identified challenge on the assessment of “nanosimilars” –24 will Since multiple sectors come across with similar challenges related to the complexity introduced by utilising nanomaterials, it is expected that solutions to address these challenges will also be similar. Knowledge sharing between the various domains is key to address the challenges in the optimal and most efficient way. Although there are large differences between the different regulatory domains, it will certainly be possible and fruitful to combine efforts and find common goals where knowledge sharing will create synergy. This was acknowledged by different stakeholders across sectors during the KECs . To creaThe organisation of existing knowledge into easily accessible knowledge and data sharing platforms would facilitate the exchange between different communities of stakeholders. Some examples already exist including the European Union Observatory for Nanomaterials (EUON)Within the REFINE project, the concept of a knowledge hub (K-HUB) brings forward the need to connect, interact and exchange with the global multidisciplinary scientific, industrial and regulatory science communities. The creation of a multistakeholder functional and reliable exchange space should enable cross-fertilisation of data set, ease of access for read-across data and the creation of a multidisciplinary ecosystem, which will be more interactive than a repository archive. To achieve this goal, REFINE proposed and tested the establishment of a ResearchGate pageBesides testing ResearchGate as a tool for cross-sectorial communication, the creation of a sustainable open-access repository archive to openly share knowledge as a community hub on scientific manuscripts, standard operating procedures, protocols, assays or data generated from the project was initiated. On this matter, REFINE adopted ZenodoClearly, the success of these platforms and their contribution to global multidisciplinary scientific, industrial and regulatory science knowledge sharing is heavily dependent of a sufficient number of users representing different communities and disciplines and actively sharing their knowledge and expertise.The use of any method for product assessment will require the regulatory acceptance of such a method by the regulatory bodies. Besides method-specific evaluations, this often includes a set of target values specified in the general validation guidelines provided by the different authorities. Within given fields, such as the medical area, regulatory bodies of various countries and continents have well harmonised these target values. It eases the formal approval process for new products across different countries, because identical or at least very similar statistical data evaluations can be submitted. However, the validation of each method used for producing the regulatory data is time and effort consuming.The use of a standardised test method can ease regulatory requirements for the method validation and speed up the evaluation process. However, many currently available standardised methods were developed for small-molecule chemicals or pharmaceuticals and are not reliable when testing nanomaterials. Moreover, additional sophisticated methods are needed to evaluate nanomaterial-specific properties .The analysis of methodological gaps for nanotechnology-enabled health products performed in the REFINE project identified the most pressing needs for method standardisation and development . Some arIn addition, the applicability of standardised methods can differ depending on the regulatory framework, increasing the necessity of multiple standards across different fields. International standardisation organisations have either different subgroups, which focus their attention to a given area, or national, respectively, international standardisation organisations themselves focus largely on one field, such as consumer products Fig. . The orgThe described situation suggests that the already thin resources for the international standardisation of newly developed methods will become even more scarce. Since nanotechnology-enabled products are used across many regulatory frameworks, a closer collaboration and coordination between the different international standardisation bodies and their mutual recognition agreements would be beneficial to avoid duplication of work and focus on common priorities in this innovative and accordingly strongly growing field.Alternatively, possibilities to use non-standardised methods of sufficient quality to produce regulatory data could be investigated to reduce the necessity of the standardisation of the continuously growing number of new methods. In this case, mutually accepted quality criteria for new methods should be developed by representatives of different communities and sectors.one substance one assessment 1S1A) [The new Chemical Strategy for Sustainability highlights the need for a trans-sectorial alignment of risk assessments of substances while taking into account the specificities of each sector (nt 1S1A) . The REFIn addition, a decision support system , first steps were undertaken to initiate connections with highly innovative and industry-focused Open Innovation Test Bed (OITB) clusters such as MDOTAnother important approach was to discuss the outcomes of the REFINE work with different stakeholder groups and communities. The Knowledge Exchange Conferences and especially the exchange with highly complementary project Gov4Nano turned out to be a very fruitful connection and collaboration. Several discussions around the need for a trans-sectorial alignment of risk assessments of products resulted in the back-to-back organisation of the 2nd Regulatory Risk Assessment Summit (Gov4Nano) and the 3rd Knowledge Exchange Conference (REFINE) in January 2022. As a highlight, a joint session connecting both events was held to illustrate common and sector-specific challenges. The joint session intended to demonstrate the need for trans-sectorial strategies, to share common challenges and to provide future perspectives to facilitate harmonised regulation of products based on nanotechnology. Thus, the collaboration with Gov4Nano represents an excellent example of community bridging allowing the sustainability of the generated outcome and perspectives obtained in the project.The heritage of REFINE is certainly found in the outstanding integration and addressing of identified regulatory challenges in the experimental development of new in vitro methods for nanotechnology-enabled health products. In summary, the REFINE project can serve as a blueprint for structural and straightforward development of regulatory science frameworks in different sectors and approaches to interact and exchange information and experience within multi-sectorial community. The main REFINE outcomes and the resulting recommendations of the project are summarised in Fig.


Despite an intensive focus on worker health over the last three decades, the prevalence of work-related diseases remain largely unchanged in Denmark and internationally. In recent years, American and Australian researchers have developed new approaches to integrate health promotion, prevention of work-related disease and organization of work. The aim of this study was to examine whether an Integrated Approach to Health, Wellbeing and Productivity at Work (ITASPA) intervention would promote the mental health and wellbeing of workers.Two worksites were recruited and offered the intervention and 76 cleaners agreed to participate in the scientific evaluation. At each worksite, employees developed initiatives to improve the psychosocial work environment, building on top of existing work environment programs, practices and procedures. The developed initiatives did not hold any physical activity components. The intervention was planned to run for 12 months, and this analysis presents data from the first of four follow-ups. Data on mental health and wellbeing were obtained using the SF12 and Orebro questionnaires. Using a stepped wedge design, participants functioned as their own controls. Data were analysed using a linear mixed model with random slope and intercept. Intercorrelation of repeated measurements was included in the models as random effect.The results showed significant decrease in sleeping problems  after the intervention. Moreover, there was a non-significant increase in the amount of time participants had felt relaxed and calm  and a small non-significant decrease in the amount of time participants had felt sad . Finally, results showed a small non-significant increase in how much physical pain had challenged the daily work .The findings show that ITASPA intervention led to significantly reduced sleep problems. There was a tendency of improved self-ratings of feeling relaxed and calm as well as reduced feeling sadness. The intervention did not decrease ratings of whether physical pain challenged the daily work, however, the worksites decided to focus on the psychosocial work environment and thus changes in mental health are expected to show greatest effects.


Chinese hamster ovary (CHO) cells are by far the most commonly used mammalian expression system for recombinant expression of therapeutic proteins in the pharmaceutical industry. The development of high-yield stable cell lines requires processes of transfection, selection, screening and adaptation, among which the screening process requires tremendous time and determines the level of forming highly productive monoclonal cell lines. Therefore, how to achieve productive cell lines is a major question prior to industrial manufacturing. Cell line development (CLD) is one of the most critical steps in the production of recombinant therapeutic proteins. Generation of high-yield cell clones is mainly based on the time-consuming, laborious process of selection and screening. With the increase in recombinant therapeutic proteins expressed by CHO cells, CLD has become a major bottleneck in obtaining cell lines for manufacturing. The basic principles for CLD include preliminary screening for high-yield cell pool, single-cell isolation and improvement of productivity, clonality and stability. With the development of modern analysis and testing technologies, various screening methods have been used for CLD to enhance the selection efficiency of high-yield clonal cells. This review provides a comprehensive overview on preliminary screening methods for high-yield cell pool based on drug selective pressure. Moreover, we focus on high throughput methods for isolating high-yield cell clones and increasing the productivity and stability, as well as new screening strategies used for the biopharmaceutical industry. Chinese hamster ovary (CHO) cells are one of the most commonly used host cells for the industrial production of recombinant therapeutic protein drugs. Among the top 10 drugs in global sales in 2019, eight are biopharmaceuticals, and seven are monoclonal antibodies produced in CHO cells , mainly The expression of recombinant therapeutic proteins for clinical and commercial production requires the stable integration of gene of interest (GOI) into the CHO genome. The most common approach is to randomly integrate GOI into the host genome as part of a plasmid and then screen transgenic cells . The homIn addition to the unpredictable effects of random integration, CHO cell lines and most immortalized cell lines are subjected to highly clonal variation in genotypes and phenotypes . This trTherefore, advances in cell line development (CLD) technology are critical to support the rapid development of recombinant protein products. Improvements in development processes and the ease of producing high-yield cell lines in research conditions contribute to the rapid advancement of biosimilars and innovative products. In the production of innovative recombinant therapeutic protein drugs, shortening the time to market is also beneficial for biopharmaceutical manufacturers to maximize the profitability of the biologic product during the limited patent exclusivity period. Advances in CLD technology focus on the improvement of protein expression and screening technologies for high-yield clones. In this review, the advances in high-yield cell clone screening and evaluation techniques in cell clone sorting are summarized and assessed for the industrial production of therapeutic protein drugs.The main challenge in CLD for recombinant protein production is to generate and isolate rare high-yield clones in a short period of time from thousands of low-yield or unstable clones. The two most commonly used expression systems are based on metabolic pathway screening methods to establish stable, high-yield recombinant CHO cell lines: dihydrofolate reductase (DHFR) system and glutamine synthetase (GS) system . DHFR caThe transfected cells are cultured in the medium without GHT, and the surviving cell pool contains GOI and DHFR genes in their genomes. When the cell medium contains methotrexate (MTX) , the dihThe GS system utilizes the GS gene as a selection marker. GS synthesizes glutamine from ammonia and glutamic acid in cells, which is then hydrolyzed by adenosine triphosphate (ATP) to provide energy. L-methionine sulfoximine (MSX), a GS inhibitor, was added into a culture medium without exogenous glutamine . The resde novo synthesis of pyrimidines and purines . The survival of these bistrotrophic cells depends on the availability of purine and pyrimidine sources or the transfection and integration of the open reading frame that encodes these two enzymes. One of these double trophic deficiency forms is used to select a stable transfector carrying the target protein. The transfected clones could stably produce large quantities of recombinant proteins. This double trophic deficiency provides a rapid and effective selection method for the separate or simultaneous transfer of multiple target genes into CHO cells by using readily available commercial mediums without purine and pyrimidine  classifies cells based on the determined fluorescence level . One of The expression level of the target protein must be characterized by fluorescence signals to successfully utilize flow cytometry. The available methods are generally divided into two categories: 1) GOI co-expression with reporter gene whose expression levels in different clones can be used to determine GOI expression levels, and 2) detection of secreted GOI on or near the surface of a single producing cell by fluorescently labeled antibodies specific to GOI. Reporter-gene expression is usually maintained at a lower level than GOI expression to reduce the burden of reporter-gene expression on cells. This condition can be achieved by using a defective promoter, a weak Kozak sequence, or by placing internal IRES between the reporter gene and GOI . Common Most biological drugs are monoclonal antibodies and have heterotetramer structures composed of isomolar light and heavy chain polypeptides. Hence, the efficiency of antibody assembly is largely dependent on the expression ratio of these chains. The ratio of heavy to light chains affects the final antibody production titer. Therefore, selecting the cell lines with the optimal ratio of heavy to light chains is crucial for monoclonal antibody assembly . FACS asAnother example of a fluoresce-based automated system technology is the combination of cell growth in semi-solid medium with automated fluorescence detection and screening by automated cell pickers, such as clonal fluorescence microscopy (Clonepix). The Clonepix system detects fluorescence by adding fluorescence-bound “clone detection” reagents . Hou et The influence and heterogeneity of random integration sites of target genes on protein expression is one of the important reasons for increasing the workload of screening. Target gene integration has the potential to reduce clonal variation and thus accelerate the selection of high-yield CHO cell lines . IntegraSeveral companies have published reports of using the RMCE system to produce monoclonal antibodies. In 2013, Genentech established a CRE based monoclonal antibody expression platform for RMCE by screening transcriptional active sites in the CHO genome . InsertiScreening methods using resistance genes or report gene negatively affect the host cell metabolism. The introduced gene, other than the target gene, will occupy the cell protein synthesis resources, resulting in the decrease in target protein expression. With the progress on instrumental analysis methods, many high-yield clonal screening methods without labels have been established.By combining surface plasma resonance imaging (SPRI) and self-sorting micropore technology, In addition to establishing stable CHO cell lines that produce therapeutic recombinant proteins by antibiotic and/or metabolic selection, Traditional static batch culturing screening is not related to suspension batch culture used in production and therefore has minimal predictive utility. Small batch screening of feedstock in suspension culture is associated with the bioreactor process, but the number of clones that can be manually screened is limited. When combined with automated liquid handling, small culture systems, such as shaken deep-well plates, offer an effective way to screen many clones. Although most RNAs are spliced into transcripts that encode secretory proteins, Novel cell line screening methods mostly rely on high-throughput technology to improve the screening efficiency. Moreover, several high throughput methods for CLD are listed, and ® is a high-throughput microfluidic single-cell analysis and screening system, which uses the droplet wrapping technology to quickly separate and wrap thousands of single cells in a short time to form hundreds of skin liters of small droplets, making each droplet an independent system for cell culture and detection of single cells  was developed by Solentim and is combined with Cytena single cell printer instruments, which combine cell seeding with microscopic imaging to ensure the single cell deposition and origin of derived clones (Verified d clones . Compare™ chamber, they can be intuitively tracked through on-chip culture, measurement and clone recovery for many days. The top level clones can be recovered with more than 99% monoclonal assurance and an advanced packet containing a separate visual record of all clones.The Beacon platform from Berkeley Lights utilizes nanofluid and opto-electropositioning technology for the culturing, manipulation, and characterization of thousands of cells in parallel on a single chip via software-controlled operations . CompareIn recent years, the progress in the field of life science has continuously optimized the process of CLD. The key steps to optimize the integrated CLD process are as follows: Set the workflow and then use gene amplification methods for clonal selection to select cell lines suitable for this workflow. The synthetic vector technology is used to improve the expression level of recombinant proteins. Although the selection of high-yield clones remains a challenging task, the choice of optimal cell lines has been simplified using more advanced techniques. This selection process is important in the continuous journey of unraveling the cellular mechanisms necessary to achieve high-quality protein production. In the future, more innovative screening methods will be explored and developed.It is worth noting that there is no one particular method suitable for all cases. Each stage of the CLD workflow needs to be optimized for a specific clone. The performance of cell lines in large-scale bioreactors is another important consideration in their application for the industrial production of recombinant protein drugs. However, with the establishment of automatic cell biology platform, the corresponding process can be optimized step by step. This is also an effective way to reduce labor-intensive processes, cost and risks. Yet, combining these automatic models will help broaden our understanding and improve the various screening systems used for the biopharmaceutical industry. These powerful tools will bring valuable contribution to the advance of high-yield cell clone screening and development in biotechnology.


Symptomatology in patients with the diagnosis of autism spectrum disorder (ASD) is very heterogeneous. The symptoms they present include communication difficulties, behavior problems, upbringing problems from their parents, and comorbidities . A predictable and stable environment and the continuity of therapeutic interactions are crucial in this population. The COVID-19 pandemic has created much concern, and the need for home isolation to limit the spread of the virus has disrupted the functioning routine of children/adolescents with ASD. Are there effective diagnostic and therapeutic alternatives to limit the consequences of disturbing the daily routine of young patients during the unpredictable times of the pandemic? Modern technology and telemedicine have come to the rescue. This narrative review aims to present a change in the impact profile in the era of isolation and assess the directions of changes that specialists may choose when dealing with patients with ASD. ASD is a concept defined as a constellation of deficits that appear in early life, involving social communication and repetitive patterns of sensory-motor behavior . It is eThe diagnosis of ASD requires the involvement of a multidisciplinary team of experts . It is eThe latest versions of the DSM and ICD allow better specification of a patient’s difficulties with a diagnosis of ASD, which is inherently heterogeneous . Both clDuring the ASD diagnostic process, dedicated tools are used in addition to the knowledge and experience of clinicians. These include the Autism Diagnostic Interview-Revised (ADI-R), the Gilliam Autism Rating Scale—Third Edition (GARS-3), the Diagnostic Interview for Social and Communication Disorder (DISCO), the Developmental, Dimensional, and Diagnostic Interview (3di), the Autism Diagnostic Observation Schedule—Second Edition (ADOS-2), and the Childhood Autism Rating Scale—Second Edition (CARS-2) . ADOS anOne of the critical clinical problems concerning ASD is the lack of dedicated treatment; then, symptomatic treatment is commonly employed. The importance of both pharmacological and non-pharmacological treatment should be emphasized . PharmacThe wide range of therapeutic methods reflects the diversity of the population of children with an ASD diagnosis and highlights the need for more structured algorithm treatment .The early diagnosis of ASD in children is crucial since the brain neuroplasticity during this developmental period allows effective interventions to alleviate the symptoms . A childPrevious research indicates that children and adolescents tend to have a mild COVID-19 course with a good prognosis . HoweverEpidemiological restrictions during the pandemic led to a disruption in daily routines and a reduction in the availability of facilities attended for treatment; children with ASD are particularly affected by these changes . In addiAre adults prepared to help the younger generation with neurodevelopmental difficulties? Despite the social isolation, the intensification of parental interactions, the continuation of therapeutic interventions in the online form, as well as the crisis intervention itself available in the form of remote telemedicine—despite earlier availability—has now significantly accelerated . The useStatistics show that nearly half of the caregivers of children with ASD used telemedicine services during the COVID-19 pandemic for the first time . ServicePublic awareness is increasing, so more and more parents are seeking help from diagnostic specialists. Isolation during the pandemic has forced the health sector to look for diagnostic alternatives. ASD diagnosis has also found its place in the online space. Studies conducted in the U.S. show that the change in the diagnostic format is accepted by both parents of children with neurodevelopmental problems as well as specialists leading the diagnosis process, but it might be less accepted by younger preschool children . RegularThe usefulness of technological solutions—live video consultations, video recordings, or phone calls—can greatly facilitate, in the future, both diagnosis and therapeutic interactions. This is not only beneficial in the case of the need for home isolation of families where there are children with neurodevelopmental disabilities but also for those for whom the availability of specialists is limited, for example, due to the place of residence  ,77. NeveThe COVID-19 pandemic has brought many changes to the health sector. Although most often children and adolescents underwent coronavirus infection in a mild symptomatic form, the impact of the pandemic on the youngest population may still be discernible in long-term observations . Childre


Coronavirus disease 2019 (COVID-19) has disastrous impacts on sustainability initiatives and worsened poverty, hunger, and health issues. The financial distress by this pandemic has resulted in psychological challenges among the people. The list of vulnerable sections of the psychological impacts of the financial problems during COVID-19 is led by students, pregnant women, children, old age people, parents, and many more. The recommendations of this article are to focus on coping strategies for managing psychological issues related to financial problems during the pandemic, facilitating social support, promoting public health facilities and health insurance, financial support for pregnant women, and child care. Special care for old-age people and support for troubling parents and students. This article also recommends interventions and policies for reviving the disrupted businesses and strengthening entrepreneurs. Measures for income generation, removal of hunger, and reducing addictions and gambling should also be on the priority list. Limited collaboration among countries was observed, but robust collaboration among the research institutions and authors. Global goals of sustainable development are going ahead with seventeen sustainable development goals (SDGs). Poverty, hunger, and health are focused on the first three SDGs. Coronavirus disease 2019 (COVID-19) has directly washed away the efforts on SDG achievements, more specifically related to poverty, hunger, and health-related goals. The negative impacts of the pandemic on these goals are yet to be completely assessed. The interim report on COVID-19 and SDG achievements  shows thCoronavirus disease 2019 (COVID-19)-related travel and social life restrictions, especially the long lockdowns had stopped the income pipelines of millions. All the businesses, except the essential goods, were closed during the first wave of the COVID-19. Even the essential good businesses were allowed to operate on selected days and restrictions on the operation time. COVID-19 impacted the global economies  and therThe COVID-19 has a multidimensional impact on people, especially related to the psychological linkages with financial wellbeing. There is evidence for the financial stress and the linkages among diversified cross-sections of the population, especially the older sections . People The literature on the psychological pinning’s on the financial wellbeing of people is very limited in the literature, especially the reviews and bibliometric analysis. This article includes the thematic analysis on this topic by adopting the systematic literature review. The bibliometric patterns of the literature are also included to cover the gap in the literature related to the psychological impacts on financial wellbeing during COVID-19. The study used the PRISMA guidelines for the selection of the articles and structure of the study. This section of the introduction is followed by methodology discussion, sections of thematic and bibliometric discussions, and followed by units for discussing the research gap and conclusion.1.To study the financial wellbeing and psychological linkages during COVID-192.To summarize the literature on financial wellbeing and psychological linkages during COVID-19 from the resources of Web of Science3.To develop future agenda for research on financial wellbeing and psychological linkages during COVID-191.What are the psychological connections of financial wellbeing during the COVID-19?2.What are psychological determinants associated with financial wellbeing, during the COVID-19?3.What are the bibliometric patterns on the topic of financial wellbeing and psychological linkages during COVID-19?4.What is the future agenda for research and recommendations on the topic of psychological connections of financial wellbeing during the COVID-19?This review on psychological connections on financial wellbeing during the COVID pandemic has used the Web of Science database for developing bibliometric and thematic analysis. The resource platform of Web of Science is professionally managed to have more than 79 million records, in a multidisciplinary fashion. In contradiction to the practice of using multiple databases for systematic review, this article has adopted a single-source model, drawing motivation from the high-quality literature with the single-source model . This reThe duplicates and anonymous records were removed and obtained 115 documents. All types of documents were used for both thematic and bibliometric analyses. All 115 papers are used for the bibliometric analysis and 53 papers are used for the thematic analysis. This review followed PRISMA guidelines along with the details of the article acceptance and rejection, shown in This section of this article analyses the bibliometric patterns related to research on psychological linkages of financial wellbeing during COVID-19 by using the database of the Web of Science. Detailed analysis of journals, authors, countries, keywords, and research institutions is also included. The annual scientific publications, starting from the breakout of COVID-19 are shown in The top journals related to psychological links related to financial wellbeing during COVID-19 based on publications, H, G, and M indexes are shown in The leading authors are Watamura SE, Lechuga-Pena S, Koppels T, Doom JR, Brown SM, Wade M, Prime H, and Browne DT. The H index and G index of all these authors are one. The M index of all these authors is 0.3 and all these authors have one publication each. Wade M of the University of Toronto, Prime H of York University, and Browne DT of the University of Waterloo are the leading authors in citations. All these three authors have four hundred and nineteen citations each for a collaborated paper related to the financial insecurity and psychological challenges among families during COVID-19. The other leading authors in citations are Watamura SE, Lechuga-Pena S, Koppels T, Doom JR, and Brown SM have two hundred and fifty citations each. The leading authors based on citations are shown in The collaboration between countries in the research on psychological links with financial wellbeing during COVID-19 is shown in The most occurred keywords used are shown in The leading research institutions engaged in the research on psychological links related to financial wellbeing during COVID-19 are shown in The collaboration among research affiliations is shown in This article focuses strictly on the three major themes of psychological impacts associated with financial wellbeing during COVID-19, and the financial struggles and stress related to financial wellbeing during COVID-19 are shown in The mental health of the financially struggled people has been deeply affected during the pandemic and the mental wellbeing of such people needs to be recovered, for copying them to lead the future life successfully . The menThe psychological stress of the people who faced discrimination, poverty, and racism during their pre-COVID-19 periods is very severe during the pandemic . ParentaPeople with mental and financial stress may react differently, like with psychological distress, anxiety, poor wellbeing, alcohol consumption, and suicidal thoughts . PsycholThe financial better than average effect has impacted many people in their perspective to the near economic conditions of home, nation, and world. These people consider that their financial wellbeing is not much affected during the pandemic. Their psychological attitude toward the financial wellbeing of the home, nation, and world proves the effect of this variable and points to another dimension of the people’s psychology toward the financial wellbeing during COVID-19 .Global financial conditions were affected by the pandemic and so the case of individuals. The impacts of COVID-related financial distress have effects on mental health and the economy. Millions were added to the list of poverty and hunger. Reduced family incomes are the primary cause of the financial struggles associated with COVID-19 . The empA study on Jordan related to the gender disparities and healthcare facilities during COVID-19 has found that the limited coverage of the health insurance coverage, reduced payments, denial of payment to women during the COVID-19, and job losses affected the financial wellbeing and the pregnant women were unable to undertake the antenatal care . The finThe financial struggle among healthcare workers, especially the nursing staff has the opinion of better compensation during a pandemic due to their heavy workload . SimilarResearchers have also found that job insecurity causes addictive behavior and financial insecurity promotes personal conflicts . The COVThere cannot be a one-time solution for all psychological pressures and all these psychological stresses cannot be handled similarly to all the financial stresses experienced during COVID-19. The psychological issues related to underpaying and overwork of nursing staff can be solved by developing better packages during pandemics . The finSpiritual wellbeing and social support are other alternatives to cope with the COVID-19-induced financial distress and related psychological stress . The proMentorship can be an alternative to coping with psychological challenges due to financial distress during pandemics among low-income students. Such innovative interventions can enhance mental strength among financially vulnerable students during pandemics . UniversThe following propositions are developed by the detailed thematic analysis of the literature related to the psychological underpinning of financial wellbeing. The scope for future research is also included in this section below in the Future researchers can concentrate on the three core themes identified by this review for research on the psychological impacts of financial wellbeing during COVID-19. The major themes can be psychological impacts on the financial challenges due to COVID-19; various financial challenges due to COVID-19; and finally the initiatives to contain the psychological impacts due to financial challenges during COVID-19.Future researchers can focus on providing training, arranging awareness programs, and counseling for coping with psychological stress and financial challenges during COVID-19. These initiatives can bring many people out of poverty and hunger. Parental stress due to loss or low or unstable income should be reduced by providing social support for reducing their stress and recovering their earning potentials. Social support can also provide for the needy ones facing depression and related psychological impacts due to psychological stress related to financial problems during COVID-19. Awareness and counseling programs for people who have avoided and postponed childbirth initiatives can be facilitated along with concepts of family planning and fertility. Business revivals can be good empirical themes for future research in the post-COVID period. Training and support for improving the psychological health and strength of entrepreneurs can also be meaningful topics for future research. Empirical or reviews on each psychological stress factor and financial challenge faced during COVID-19 can be promising themes for future research. The research on individual initiatives for coping with psychological pressure due to financial problems during COVID-19, monitoring of the initiatives, and performance appraisal can also be good niches for future research.Various policy initiatives are being recommended after the detailed literature review and thematic analysis on the research related to psychological stress due to financial challenges faced during COVID-19. The policies propositions related to this topic can be for taking initiatives and policies for speeding up the health insurance coverage and speeding up the financial support for all pregnant women and children. Better packages can be tailored for the healthcare workers for their efforts to contain the pandemic. COVID-19 has disrupted the education sector. This article recommends research and policies for removing educational disparities due to financial distress during COVID-19. Institutional support and mentoring should be provided for students vulnerable to financial problems during COVID-19. Policies, interventions, and monitoring should be initiated for controlling addictions and gambling. Schemes should be developed for providing assistance for income generation and healing the financial disruptions due to COVID-19. Old-aged people have poor financial planning and are vulnerable to financial problems and psychological stress during COVID-19. Support systems and financial planning opportunities for the old-age people for their welfare during COVID-19. Strong policies should be developed for rolling out the social security schemes, and for ensuring quality public health facilities. The policies need to be human-centric rather than focused on economic recovery because COVID-19 not just shook the economies but it is a greater challenge for the entire human community.The major financial challenges for the financial wellbeing during COVID-19 are the impacts on the income of the people , impactsThe poor coverage of health insurance and financial problems forced people to postpone or avoid the institutional services related to pregnancy antenatal care , child cThe psychological pressures of parents with unstable incomes  and smalVery few research interests have been on this topic, around 115 document publications, namely, articles, reviews, and conference papers. The United States of America leads the domain in document publications and citations and followed by Canada. Very few research collaborations exist among countries. However, there are strong collaborations among authors and institutions. This article is used for identifying the financial challenges, identifying the vulnerable communities, sorting out the psychological challenges, and developing policy interventions. This article can be useful for future research scholars and academicians for future research. Similarly, it will be easy for policymakers and administrators for focusing on the problem, measure the dimensions of impact and for implementing solutions. This article can also be useful for finding out the leading researchers, most occurred keywords, and country collaborating research on this topic. Moreover, the leading sponsors and research institutes can be identified along with the research affiliations engaged in the collaborated research.The three major funding agencies on this topic are the National Institutes of Health of the United States of America, the United States Department of Health Human Services, and the Canadian Institutes of Health Research. National Institutes of Health Research and the United States Department of Health Human Services have five funded projects on this topic with 367 citations. The topics of these funded projects include psychological wellbeing ; gamblinhttps://www.scopus.com/ and https://www.webofscience.com/.Publicly available datasets were analyzed in this study. This data can be found here: SS conceptualized the idea, wrote the introduction, and methodology. DB collected the literature and wrote the conclusion. 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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