The interaction between surficial shallow aquifers of poorer quality and semi-confined water-supply aquifers poses a potential risk for degradation of the water supply. Groundwater engineers and hydrogeologists use groundwater models to synthesize field data, conceptualize hydrological processes, and improve understanding of the groundwater system to support informed decision-making. Models for decision-making, called management models, aid in the efficient planning and sustainable management of groundwater systems. Management models search for the best or least-cost management strategy satisfying hydrologic and environmental regulations. In management models, a simulation model is linked or coupled with an optimization formulation. Widely used optimization formulations are linear, non-linear, quadratic, dynamic, and global search models. Management models are applied but are not limited to maximizing withdrawals, minimizing drawdown, pumping costs, and saltwater intrusion, and determining the best locations for production wells.•Several management strategies are formulated addressing well depth, seasonal pumping operation, and mapping no-drilling or red zones for new well installation.•Modeling methodologies are laid down that apply thousands of numerical simulations for each strategy to simulate and evaluate recurring patterns of contaminant movement.•The simulation model integrates MODFLOW and MODPATH to simulate 3D groundwater flow and advective contaminant movement, respectively and is transferred via FloPy to couple with the optimization/decision model using a custom Python script.This paper theoretically presents the development of groundwater wellfield management strategies and the corresponding modeling framework for each strategy's evaluation. Depending on the strategy, the modeling effort applies deterministic (simulation) and stochastic (simulation-optimization) techniques. The goals of the optimization strategies are to protect wells from potential contaminant sources, identify optimal future well installation sites, mitigate risks, and extend the life of wells that may face water contamination issues.  Specifications tableSurficial shallow aquifers are vulnerable to anthropogenic contamination due to urbanization, industrialization, and agriculture. Under favorable conditions, the shallow aquifer's contaminated water can migrate into an underlying semi-confined aquifer Groundwater models serve as simplified representations of complex natural systems that provide a quantitative framework to synthesize field data, conceptualize hydrological processes and hydrological insights, and provide insight into groundwater response to external stressors. The purposes of groundwater modeling are many, but an intent common to all is an improved understanding of the groundwater system that can serve to support informed decision-making A deterministic simulation based management model may suffice to make decision analysis for simpler problems. However, a more complex problem may require simulation-optimization based management models A variety of optimization formulations and corresponding solution methods are available. Widely used optimization formulations are linear, quadratic, dynamic, stochastic, non-linear models, and global search algorithms Khalaf and Gad The primary assumption of the presented well optimization problem is that the potentially contaminated modern water is migrating from the surficial shallow aquifer to an underlying semi-confined aquifer used for water supply through breaches in the intervening aquitard. The goals of the well optimization are to protect production wells from contamination, identify suitable locations for future wells, and extend the life of wells. To achieve the goals, four management strategies are formulated. The formulated strategies are (1) Strategy-I: well depth optimization; (2) Strategy-II: seasonal pumping operation; (3) Strategy-III: mapping no-drilling or red zone for new well installation; and (4) Strategy-IV: combined application of Strategy-I, II, and III or synchronized optimization. Detailed discussions on the formulated strategies are presented in the following sections. A projected simulation period is required to choose to ensure protection for the production wells over the design life. A typical public water supply well's lifespan is about 40 to 50 years, and at the end of this period, abandonment or reinstalment is performed Well depth optimization strategy is applicable when the water supply aquifer is thick enough to compartmentalize into two or more sections. In the strategy, production wells screened in the upper section of the semi-confined aquifer are moved to lower sections of the aquifer. The relocation may reduce the movement of modern water to the upper semi-confined aquifer or determine if increasing overall withdrawal from deeper aquifer sections result in modern water at these lower depths. Hence, the employment of the simulation-optimization technique  is used A finer vertical discretization of the water supply aquifer is needed in the flow model for the depth optimization strategy because the objective of Strategy-I mandates placing well screens at various depths. When a model layer is divided into finer vertical discretization, well screens may span over multiple numerical layers. Instead of distributing a well's withdrawal according to the portion of screen length within a layer, total withdrawal is lumped into the uppermost cell of the spanned layers except when 70% (arbitrary) of the extraction occurred in the lower layer to which the total withdrawal is lumped. Placing total withdrawal within a single layer helps simplify the optimization  process and by prioritizing the upper layer to remain conservative in the test for potential modern water contamination at the well.In the optimization process, well screen depths are optimized within a wellfield where the number of particles from a nearby breach (or breaches) is minimal or absent. The objective function is defined as the summed particle count at the well screens of the wellfield under investigation. Genes represent the model layer  and act as the decision variables in the genetic algorithm process. The genetic algorithm generates multiple well screen realizations, and FloPy enacts MODFLOW and MODPATH runs for each realization. Within each iteration, the optimization algorithm examines model results to identify a set of improved solutions and passes the better solutions to the subsequent generation until optimization criteria are met.The genetic algorithm optimization process for the well depth optimization strategy is defined as:Two stopping criteria are used: (i) a maximum number of allowable iterations, or (ii) the objective function = 0. When a solution (well-depth stratification regime) returns zero particles, the process stops, and the regime is taken as the optimized solution. Otherwise, the simulation continues up to the maximum allowable generation, and the solution returning the lowest summed particle count is taken as the optimized solution. The number of maximum iterations depends on the complexity of the problem and can be approximated by experience. The Python multiprocessing package for the parallel simulation is used to distribute parallel optimization runs on a computer cluster to reduce computation time.As expected for municipal consumption, water demand fluctuates by season, where more water resources are extracted in warmer periods. This seasonal pattern can be used to potentially reduce the movement of modern water during seasons of low water demand  by turning off wells screened in the upper section of the semi-confined aquifer and withdrawing groundwater from deeper section wells in the aquifer. The strategy assumes that the deeper wells can run at full capacity to meet the water supply demand of the wellfield. In this strategy, upper semi-confined aquifer wells are wells that pump 30% or more (arbitrary) from upper one-third of the aquifer's total depth. In contrast, the wells pumping 70% or more (arbitrary) from lower two-thirds of the aquifer are lower semi-confined aquifer wells. The low-demand period can be determined by comparing each monthly stress period's pumping rate with the 25th percentile pumping rate. The 25th percentile pumping rate is calculated from the stress period's pumping rate data of the studied wellfield.Withdrawals from the deactivated upper semi-confined aquifer wells are redistributed among the active semi-confined aquifer wells screened within the deeper section of the aquifer. Like before, particles are placed within cells representing breaches in the confining aquitard, and well-screen bearing cells (sink/source cells) in the semi-confined aquifer are defined as the particle termination locations. The ‘stop_at’ option for weak sinks/sources is defined for the particle tracking simulation. The strategy estimates the number of particles received by the wells and generates particle path lines for evaluation after the projected simulation period of 50 years. The major steps in Strategy-II are shown in The goal of the location optimization strategy is to identify locations of minimal modern water contamination for future groundwater production wells installation. The risk of modern water contamination via the separating confining layer is minimized or non-existent at these identified locations. The safe new well locations are delineated through examination within a predefined zone. The predefined zone is delineated by encompassing the studied wellfield, its nearby breaches, and the distance that particle may travel over the projected simulation period . In this strategy, a multilayer well regime can be used. In multilayer well regimes, well screens are spanned over multiple numerical layers.Using FloPy, the scripted deterministic MODFLOW-MODPATH simulation code traverses a new well in the predefined zone, systematically placing the well in each unoccupied cell . A constant pumping rate is applied to the new well where the assigned rate can be taken from the highest extraction rate of the stress period data for the wellfield under consideration. Like the depth optimization strategy, particles are generated at the center of the separating confining layer breach cells. The cell hosting the moving well is defined as the particle termination location in this strategy. After the simulation, the number of particles that terminates at the moving well cell is determined. The analysis includes screening the new well within each layer (from the top to the bottom layer of the semi-confined aquifer) before moving the well to the next unoccupied cell. The predefined zone is defined to reduce the total number of traversing cells to limit the overall simulation time for the strategy. Yet, the iteration of the well in the zone for the optimization process may need thousands of model runs per layer depending on the number of model grids covered by the zone. Only the installation of a single well is tested in the strategy, not the insertion of two or more wells at a time. Exported model results are gridded using a scripted Geographical Information System postprocessing tool within ESRI® ArcGIS Pro, and contour maps are generated. These maps delineate the extent of leakage migration within each layer simulated as the semi-confined water supply aquifer for the studied wellfield outside of which construction of future wells can be assumed safe over the projected future.The synchronized optimization analysis simultaneously applies location, seasonal, and depth optimization strategies to provide an improved solution for the wellfield management problem. The workflow for Strategy-IV is shown in Based on the well capacity, additional production wells may be required to maintain water production of the studied wellfield, followed by turning off the endangered wells during the low demand months. The well location optimization (Strategy-III) modeling framework is implemented at this stage to map safe locations for the new wells to place. For simplicity, the additional wells are screened within a single model layer.During the high-demand period of the year, the new wells also remain active along with the pre-existing wells. The total wellfield withdrawal is equally distributed over all the active wells (new and pre-existing). The distribution of pumping among the new wells decreases the pumping load from the pre-existing wells during the high demand period. The strategy uses the deterministic MODFLOW-MODPATH based management modeling framework to evaluate the effect of seasonal well operation on modern water contamination, followed by the stochastic depth optimization simulations based on MODFLOW, MODPATH, and genetic algorithm modeling framework.A conceptual problem is solved to validate the simulation-optimization computer code developed for the well depth optimization strategy, a process common in new code development The pumping regime concept is adopted from McKinney and Lin 3/d, and cells containing wells cannot go dry. The genetic algorithm optimization process comprises a population of 100 members (chromosomes) where each member contains ten genes representing pumping rates at the ten wells. Elitism method is applied to select parents, a one-point crossover method at a random location is implemented to generate offspring, and a mutation rate of 0.01 , cell drying occurs. The head distribution for the pumping rates obtained from different optimization processes are clustered along with a narrow band; therefore, it is concluded that the developed simulation-optimization code can produce a near-global solution for the groundwater pumping maximization problem. It may also be inferred that the algorithm originally developed to solve the well depth optimization problem would also produce the best solution for the problem.A finer discretization of the decision variables with a larger population size suggests that the presented optimization model offers an improvement over the simulation-optimization model of McKinney and Lin The four management strategies and associated modeling frameworks can provide practical solutions to the well contamination problem due to modern water inflowing from a surficial shallow aquifer to a semi-confined aquifer. The utility of the developed four strategies for wellfield management are summarized below:The well depth optimization strategy relocates well screens vertically downward to exploit the safe lower section of a semi-confined aquifer of sizable thickness. The strategy also considers minimizing the implementation cost by reducing affected wells. The objective of the strategy is to protect pre-existing wells from contamination for a projected period in the future, typically the design life of the groundwater wells. The strategy is useful for wellfields as the current lands can be used for relocating the pre-existing wells to a deeper section of the water supply aquifer. Therefore, costs associated with land acquisition and threats from surrounding unexplored contamination sources  are minimized.The seasonal well operation strategy schedules turning off upper semi-confined aquifer wells as modern water from the contaminated shallow aquifer remains within the upper production zone of the semi-confined aquifer. The strategy exploits the seasonal variation of water demand since the winter and spring months consume less water than the summer months. The strategy intends to relax modern water encroachment and extend the life of potentially at-risk  pre-existing wells. The strategy does not warrant an additional cost because no drilling and land acquisition is needed for its implementation.A water supply utility may need to install a new well or multiple wells due to several reasons- maintaining increased demand, contamination, and end of life of the pre-existing wells. The strategy focuses on protecting against contamination of the new wells. The no-drilling or red zones for each wellfield surrounding its contamination sources (breaches) theoretically delineate the minimal contamination impacted areas in the horizontal plane for each numerical layer  simulated as the semi-confined water supply aquifer. The red zone maps would help the concerned utility to select appropriate locations and depths for new well installation, evaluating other facts such as land use, city planning, contamination sources, and hydraulic properties.Strategy-I and II depend on wellfield-specific characteristics such as a wells' configuration  and their distances (distribution densities) around known or potential breaches. In contrast, Strategy-III does not consider the effect of altered flow dynamics (due to adding new wells in a wellfield) on the contamination potential to the pre-existing wells. Strategy-IV is more conservative as it assumes a lower pump capacity and considers wells located in proximity to a breach as vulnerable. Although Strategy-IV offers a better solution as it addresses and eliminates the shortcomings of the individual approaches, it could be more expensive to implement as drilling, land acquisition, and other infrastructure developments  are required.The selection of a flow model depends on its spatial and vertical resolution, hydrogeologic and hydraulic features, and ability to generate desired output in the context of the management models. A finer horizontal and vertical resolution of the flow model is desired to evaluate Strategy-I and to improve the accuracy of transport code simulations. In contrast, the selection of transport modeling code depends on the contaminant transport processes in the studied aquifer system. Advective transport dominates modern water migration to a semi-confined aquifer than dispersion, reaction, and retardation processes. Therefore, particle tracking simulations are adopted to evaluate useful information for decision analysis in this paper.The integration of optimization models with the flow and transport models depends on cases when a spectrum of solutions is required to satisfy certain physical and technical measures from which the best solution needs to be identified. The general task of an optimization model is to identify the best solution by minimizing/maximizing a mathematical expression called the objective function formed by decision variables. Besides an objective function(s), it is critical that some constraints be defined based on which the optimization model would optimize the objective function. Strategy-II does not require meeting any constraints based on physical or technical regulations because only pumping rates are being shifted from shallow wells to deeper wells. Regarding Strategy-III, it only requires land access which is not constrained. Therefore, a flow model linked to a transport simulator can evaluate Strategy-II and III. In contrast, Strategy-I and IV require a simulation-optimization model because lowering a well screen can result in contaminating other wells, whether shallow or deep; hence, optimization is needed to choose the best configuration from the several possible well configurations.The modeling framework is developed utilizing the powerful programming platform Python and FloPy. FloPy is a Python library that allows simulating MODFLOW and its related codes in the Python environment. Besides building flow and transport models using FloPy, groundwater modelers can use Graphical User Interface (GUI) based modeling software to build flow models and load into FloPy to run the models programmatically. The application of Python and FloPy in model development is particularly useful because decision tools  can be conveniently developed using Python codes and integrated with the FloPy-based simulator models. The platform also offers great efficiency since multiple processes can be performed parallelly using the Python multiprocessing library, reducing simulation time significantly. The platform also presents great flexibility to the modeling framework since it can be modified easily to solve any groundwater management problem.Some or all data, models, and results that support this study are available from the corresponding authors and the Center for Applied Earth Science and Engineering Research (CAESER) upon reasonable request.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Amyotrophic lateral sclerosis (ALS) is known as a progressive paralysis disorder characterized by degeneration of upper and lower motor neurons, and has an average survival time of three to five years. Growing evidence has suggested a bidirectional link between gut microbiota and neurodegeneration. Here we aimed to report one female case with ALS, who benefited from washed microbiota transplantation (WMT), an improved fecal microbiota transplantation (FMT), through a transendoscopic enteral tube during a 12-month follow-up. Notedly, the accidental scalp trauma the patient suffered later was treated with prescribed antibiotics that caused ALS deterioration. The subsequent rescue WMTs successfully stopped the progression of the disease with a quick improvement. The plateaus and reversals occurred during the whole course of WMT. The stool and blood samples from the first WMT to the last were collected for dynamic microbial and metabolomic analysis. We observed the microbial and metabolomic changing trend consistent with the disease status. This case report for the first time shows the direct clinical evidence on using WMT for treating ALS, indicating that WMT may be the novel treatment strategy for controlling this so-called incurable disease. In 25% of the affected cases, the bulbar-onset ALS occurs with oropharyngeal muscle involvement, therefore affecting the function of swallowing and speech. Besides motor impairment, some patients may develop cognitive or behavioral impairments due to the degeneration in the frontal and temporal lobes.Amyotrophic lateral sclerosis (ALS) is a systemic disorder that involves dysfunction of multiple organs. There is a large spectrum of clinical presentations in patients with ALS. The most common ones are muscle weakness and impairment in mobility of the limbs and edaravone have shown some efficacy to some extent, though extensive efforts are being made to develop ALS-specific drugs. In recent clinical trials, several pharmacological treatments, such as the calcium sensitizer levosimendan and the combination of sodium phenylbutyrate and taurursodiol (known as PB-TURSO), have been investigated. However, the results were not satisfactory, and there is still a long way for these treatments to be approved for legitimate use in humans.Presently only riluzole–8. These studies indicated the potential to use microbial biomarkers for ALS diagnosis and to manipulate microbiome for the treatment. It has also been reported that gastrointestinal motor dysfunction can occur in ALS, manifested as delayed gastric emptying and colonic transit times. Here we aimed to report the first human case with ALS accompanied by refractory constipation, who benefited from the washed microbiota transplantation (WMT) during a 12-month follow-up, and discussed this topic with a narrative review.Recent studies demonstrated that gut dysbiosis may be a potential factor contributing to the development of ALS in both mice and humansThe study was approved by the Research Ethics Committee of the Second Affiliated Hospital of Nanjing Medical University ([2012] KY No. 026), China. Informed consent was obtained for the publication of the clinical photographs from this patient.Fig. 1). Investigations including routine biochemistry, hematology, vasculitic screen, metabolic screen, infective screen, respiratory testing and imaging studies of the brain and spine showed nothing abnormal. The patient reported no remarkable history of past illness, and there was no family history of any malignant tumors. Neurologic examination showed muscle atrophy in both legs and increased muscle tone in all extremities with generalized pathological hyperreflexia. Electromyographic and nerve conduction examination revealed denervation in the myotomes innervated by cervical, thoracic, and lumbosacral nerves, supporting the final diagnosis of ALS.A 48-year-old woman presented with muscle stiffness and weakness in November 2019. She also complained of moderate to severe constipation for the same duration of time. Early in the fall of 2019, she noted stiffening and weakening of her left leg muscles, and later developed muscle fasciculation, followed by amyotrophy, initially involving the left leg, but spreading gradually to the right leg and two arms without obvious sensory symptoms , 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40), clinical classification of muscle tone and Modified Ashworth Spasticity Scale was observed since the first WMT , the long-term treatment using WMT through mid-gut or colonic transendoscopic enteral tube was strongly required by the patient and was approved by the expert group. Initiation of WMT brought about a plateau of her symptoms. The impaired balance and gait were gradually improved as well, when muscle tone decreased.She developed aggressive symptoms though she had taken riluzole, baclofen, coenzyme Q10, and vitamin E. In November 2020, she was referred to the Second Affiliated Hospital of Nanjing Medical University for treating complicated refractory constipation with WMT. WMT is an improved methodology of fecal microbiota transplantation (FMT) based on the automatic purification system and washing process13 bacteria) for each WMT. This patient was given a repeated WMT course each two to three months according to Nanjing consensus on the WMT methodology–10. The patient did not change or add more drugs for targeting ALS during the follow-up.Several months after the initiation of WMT, she suffered an accidental fall that caused scalp trauma, followed by an obvious turning point of ALSFRS-R. The kinds of antibiotics (amoxicillin sodium and clavulanate potassium by injection) were given for 11 days in another hospital to control potential bacterial infections caused by scalp trauma. Her movement limitation reached a peak, and she had to rely on a wheelchair. Her muscle tone returned to her worst status. She was then referred to our department for WMT immediately after her discharge from the previous hospital. This course of the rescue WMT successfully stopped the progression of the disease again with a quick improvement. She could get out of her wheelchair and walk with the help of others, and her muscle tone was also alleviated. The improvement was maintained by the repeated courses of WMT till the submission of this report. All WMTs used freshly washed microbiota, and the dose ranged from 4 to 5 units . Some bacteria from the donors colonized successfully after WMTs, such as the Firmicutes and Verrucomicrobia phylum, Prevotella spp. and Ruminococcus spp., may contribute to the treatment results of ALS . The changing trend of the potentially harmful bacteria, such as the Proteobacteria phylum, changed as the ALSFRS-R after WMTs. Microbiome and metabolome disturbed by antibiotics were reconstructed by WMTs . No adverse events were observed within both short-term and long-term follow-up after WMTs.Microbial analysis indicated that the diversity and composition of the gut microbiota from the patient after WMT treatment were closer to those of healthy donors  database. However, van et al suggested that the source of above-mentioned data should be cautiously considered, because the time period of 20 years was too long to match the advancing accuracy of diagnosing ALS. The more important confidence in this case is coming from her experience after her condition was worsened by antibiotics treatment for her scalp trauma. Notably, this patient didn't change the usage of any drugs for ALS during the whole 12-month follow-up, nor did she add any other interventions except WMT. The clear finding is that WMT stopped the deterioration of ALS again. The use of antibiotics was observed on worsening disease progression in the SOD1G93A model of ALS,22. In general, the microbiota may influence the CNS neuronal health in different ways by directly producing neuroactive metabolites or toxins, or by indirectly modulating the immune system. Another hypothesis is that microbiota can affect circulating levels of inflammatory cytokines that may damage the CNS. Blacher et al noted that administering some probiotics such as Akkermansia muciniphila can attenuate the symptoms of ALS exacerbated by antibiotics in mice by increasing nicotinamide levels in the CNS. Cox et al found the microbiota restrains neurodegenerative microglia to slow down the progress of ALS by the production of metabolites or modulating peripheral immune cells that traffic to the CNS.In this case, her clinical symptoms and scores were improved by WMTs in the early stage. However, the evidence based on this period is not enough to confirm the role of WMT on ALS. Bedlack .There are limitations in the present case report. One case might not be enough to provide a solid evidence for supporting clinical practice, even though this case experienced periods without and with antibiotics treatment. The results from this patient is preliminary and observational, and the protocol of using WMT for other ALS patients at least should put the stage of treating the disease and the delivering way as well as the frequency of WMT into careful consideration. For constituting a treatment recommendation, randomized controlled trials are needed to meet more sustained ALS reversals and clarify the value of WMTIn conclusion, we for the first time reported the positive clinical outcomes of using WMT for treating ALS. Although the disease condition of the present case was exacerbated by the use of antibiotics, the administered WMTs successfully reversed the worse status of the disease through a long-term follow-up. The current clinical findings would open a new window on the microbiota-based treatment for the life-threatening ALS.


In this study, an artificial intelligence tool called gene expression programming (GEP) has been successfully applied to develop an empirical model that can predict the shear strength of steel fiber reinforced concrete beams. The proposed genetic model incorporates all the influencing parameters such as the geometric properties of the beam, the concrete compressive strength, the shear span-to-depth ratio, and the mechanical and material properties of steel fiber. Existing empirical models ignore the tensile strength of steel fibers, which exercise a strong influence on the crack propagation of concrete matrix, thereby affecting the beam shear strength. To overcome this limitation, an improved and robust empirical model is proposed herein that incorporates the fiber tensile strength along with the other influencing factors. For this purpose, an extensive experimental database subjected to four-point loading is constructed comprising results of 488 tests drawn from the literature. The data are divided based on different shapes (hooked or straight fiber) and the tensile strength of steel fiber. The empirical model is developed using this experimental database and statistically compared with previously established empirical equations. This comparison indicates that the proposed model shows significant improvement in predicting the shear strength of steel fiber reinforced concrete beams, thus substantiating the important role of fiber tensile strength. The concept of fiber-reinforced building materials is by no means new, ancient West Asia, Africa, and South America were the earliest civilizations that were familiar with reinforcing adobe bricks with straw fibers . Much deShear failure is one of the most dangerous types of failure, due to its inherent uncertainty and catastrophic nature. In order to avoid this sudden and explosive failure, typical vertical web reinforcement is provided that is spaced at varying intervals. However, the provision of web reinforcement can be challenging if the available space is narrow, irregular, and congested. In such cases, as pointed out earlier, steel fiber reinforcement can be used to effectively increase the shear strength. Although the use of steel fibers, such as metal chips and screws, started as early as 1910 . ConsequCongestion of reinforcing bars at beam-column intersection and placement of concrete in such a region has been a challenging problem for a long time. Steel fiber reinforced concrete (SFRC) has been suggested as one of the potential alternatives. Wang and Lee  have shoBuilding design codes such as ACI has encouraged the use of steel fiber as a replacement for minimum stirrups . It may,Recently, a new technique of machine learning models has been able to predict the mechanical properties of concrete with higher accuracy. Several evolutionary algorithms for the shear capacity predictions of steel fiber reinforced (SFRC) concrete beams are proposed by different researchers. For instance, two models using multi-expression programming are proposed by Sarveghadi et al. . GreenouThe study is motivated by a similar investigation by Sabetifar et al. , where aThe shear failure of a structural element built from concrete is very dangerous because of the greater uncertainty and the catastrophic nature of failure . This haIdentifying key influencing parameters is the most important step toward generating an accurate model. The influencing factors chosen for modeling the shear behavior of steel fiber reinforced concrete (SFRC) beams herein are the concrete compressive strength, the tensile reinforcement ratio, the span to depth ratio, the fiber aspect ratio, the number of fibers in concrete, the fiber tensile strength, and the span of a beam. Of special interest in these parameters is the fiber tensile strength, which has been overlooked by all the previous studies ,27,28,29Khuntia et al.  have shoFinally, the effect of steel fiber tensile strength has a significant influence on the steel fiber reinforced concrete (SFRC) beams. Studies have shown that the toughness and the shear strength of the RC beam can be increased by improving the tensile strength of the steel fiber . MoreoveBy increasing the reinforcement ratio l action ,32,33.By increasing the effective depth By decreasing the shear span to depth ratio , the normalized shear capacity is increased, as indicated in By increasing the fiber volume fraction This section is concerned with a parametric study performed to enhance the understanding of important factors influencing the shear strength of steel fiber reinforced concrete (SFRC) beams. The aim is to create a set of circumstances across which only one parameter, affecting the outcome of interest, varies. To achieve this objective in the current parametric study, it is essential to make concrete compressive strength uniform, so that its confounding effect is minimized. Therefore, the shear strength values are normalized with respect to the concrete compressive strength to create a circumstance in which the effect of the compressive strength on the outcome is small in comparison with other varying key factors under study. There exists some discrepancy in the literature on whether to normalize with respect to square root or cube root of concrete compressive strength . TherefoBy increasing the fiber’s mechanical and geometric properties, such as increasing the length of fiber or the tensile strength The increase in the diameter of the fiber results in decreasing the shear strength of a steel fiber reinforced concrete (SFRC) beam as shown in The increase in the tensile strength of the steel fiber tends to increase the shear strength of a steel fiber reinforced (SFRC) concrete beam shown in The effect of aggregate size in the steel fiber reinforced concrete (SFRC) beam is observed in Although the shear strength benefits of steel fiber reinforced concrete (SFRC) have been known for a very long time, a systematic study in this context started in the mid-1980s. Much development has taken place since, and various types of steel fiber reinforced concrete (SFRC) have been proposed based on the properties of concrete and steel fibers.Many analytical and experimental investigations have highlighted the effectiveness of steel fibers in enhancing the shear strength of steel fiber reinforced concrete (SFRC) beams, provided care is taken in the selection of these fibers. The details of the experimental results of the shear strength of steel fiber reinforced concrete (SFRC) beams are summarized in Based on the experimental investigation, numerous researchers have proposed prediction equations for the shear strength of steel fiber reinforced concrete (SFRC) beams. These equations are given in An extensive experimental database of 488 experiments of steel fiber reinforced concrete (SFRC) beams without the shear reinforcement is considered for proposing a GEP model. Moreover, only those experiments are reported in this study that have failed in shear. The experimental studies have been undertaken by several other researchers ,101,102 Gene expression programming (GEP)  is a genGEP  selects Over the past decade, structural engineering has seen a significant increase in the use of GEP. Many authors have used GEP to create models for estimating structural component capacities ,20,21. RIn this section, the proposed GEP models for steel fiber reinforced (SFRC) concrete beams are discussed. The GEP  models gThe accuracy of any empirical model is strongly dependent on training and validation sets. It has been shown by several researchers ,108 thatAnother measure is the average absolute error (AAE), expressing the arithmetic average between the model and the experimental observations. The AAE isA commonly used measure to test model reliability is the coefficient of determination  and (8), the approach proposed by Gandomi et al.  is emploxi) are the max and min of the estimated output over the The 2 = 0.97, which shows better prediction when compared to the other available models. In addition, higher performance factor and lower average absolute error suggest the merit of the current model. The model of Imam et al. [The graphical plots of experimental and predicted values are demonstrated herein. It can be seen from m et al.  demonstrThe Chaabene and Nehdi model  has one The remaining models reflect a greater difference in the predictive performance, see Sensitivity analysis is carried out to assess the contribution of each input variable to the predicted value. The frequency values of these variables are presented in It is observed that an increase in the concrete compressive strength, reinforcement ratio, fiber volume, and fiber tensile strength, each increases the shear strength of steel fiber reinforced concrete (SFRC) beams. Contrarily, an increase in the span to depth ratio, the beam effective depth, and the aggregate diameter, each result in a decrease in the shear strength of the beam.The proposed empirical equation can accurately determine the shear strength of steel fiber reinforced concrete (SFRC) beams by incorporating all the aforementioned influencing factors. Moreover, the behavior of different influencing parameters in the proposed model shows consistency with the experimental data.Statistical investigation demonstrates the accuracy and validity of the proposed model, as the values obtained from the statistical analysis are very close to the benchmark values. More specifically, 0.97 of coefficient of determination (R2) is close to the benchmark value of 1.00, which indicates the higher reliability of the proposed model. Similarly, the performance factor of the proposed model is 1.00, which is also the benchmark value. The average absolute error (AAE) of the model is 16%, which firmly confirms the accuracy of the proposed model.A particular virtue of the proposed model is that it can approximate the shear capacity of the steel fiber reinforced concrete beam more closely than other available models. A comparison is made with fourteen different models to evidence the predictive ability of the developed model.In conclusion, it is believed that the proposed regression model offers a robust predictive apparatus for determining the shear capacity of steel fiber reinforced concrete (SFRC) beams. Hence, the model can be confidently prescribed for the shear design of these beams.In future work, it is planned to conduct experimental and numerical studies investigating the effect of steel fiber strength on the shear capacity of steel fiber reinforced concrete (SFRC) beams. This can also be an effective way to further validate the current GEP model.The present study is aimed at developing an efficient genetic shear capacity model of steel fiber reinforced concrete (SFRC) beams in the absence of stirrups. In contrast to the available shear capacity models, the important influencing parameter of fiber tensile strength is implemented in the current model resulting in higher accuracy. A total number of 488 experiments are employed to estimate the shear strength of steel fiber reinforced concrete (SFRC) beams, out of which 190 experiments are used to validate the proposed model. The proposed genetic model is benchmarked against 14 previous empirical or semi-analytical models. The following conclusions are drawn:


Venoms are mixtures of toxins—bioactive molecules that serve predatory, digestive and defensive functions vital for the survival of venomous animals. This Research Topic contains two review articles and four original research papers, highlighting recent advancements in venomics and its applications in the functional characterization and medical importance of venoms and toxins.Mesobuthus tamulus), a potentially deadly but rather understudied species from the Indian sub-continent, was described. The authors summarized the research progress made toward understanding the M. tamulus venom proteome over the years, and correlated the venom proteome with the pathophysiology of envenoming resulting from its sting. The poor immunorecognition and neutralization by scorpion antivenoms of the low molecular mass toxins in the venom were highlighted. In addition, the proteomic analysis unveiled the richness of pharmacologically active molecules in the species’ venom, suggesting its potential for drug discovery. The second in-depth review article, by In the review article by Naja samarensis from the southern Philippines . Similar problems were reported for N. sagittifera venom, which contains more long neurotoxins but the venom is poorly cross-neutralized by existing Indian antivenoms, which are raised against the subcontinent’s “Big Four”. The phylogenetic study showed that N. sagittifera is more closely related to the monocled Cobra (Naja kaouthia) than it is to N. naja (its closest relative amongst the Big Four); however, the Thai Monocled Cobra Antivenom was also found to be poor in neutralizing its venom. These two studies of poorly known species of cobra thus come to similar conclusions. Both unravel the toxin compositions of the venoms and highlight the need for species-specific antivenom products to improve the treatment of snakebite envenoming in the Philippines and India.The Research Topic also includes research papers on the venom proteomes of two lesser-known cobra species: lippines , and Najd, India . Short-c2 (PLA2), from Australian brown snakes (genus Pseudonaja), which are responsible for a majority of life-threatening bites in that country. The authors demonstrated that PLA2 toxins are implicated in Pseudonaja aspidorhyncha, Pseudonaja nuchalis and Pseudonaja textilis venom-induced vasorelaxation and the sympatholytic effects of Pseudonaja affinis and Pseudonaja textilis venoms. There were little to no direct venom-induced cardiac effects observed, hence it was proposed that cardiovascular collapse following brown snake envenoming is likely because of a fall in mean arterial pressure instead of a specific mechanism for inducing cardiac toxicity. In demonstrating the abrogation of the PLA2-mediated toxic effects of Pseudonaja venoms by the small molecule phospholipase A2 inhibitor Varespladib, their finding also supports the potential use of this drug as an initial  and/or adjunct (in combination with antivenom) therapeutic agent for brown snake envenoming. Further pre-clinical , and ultimately clinical, research will be required to validate this possibility.The article by Protobothrops flavoviridis) causes severe tissue damage due to the presence of myonecrotic toxins in the venom. 2 myotoxins in the venom. The catalytically inactive TLSP2 (TLf2) was demonstrated to be a target protein of antiserum that prevents habu venom-induced necrosis caused by the Lys49-PLA2. The finding highlights the fact that venoms are complex systems in which individual components often work together to potentiate toxic effects, and suggests that such synergistic properties of different toxins in a venom should be considered in the design and development of treatment for snakebite envenoming. For example, a synergistic co-factor may be more immunogenic or possess more stable epitopes than the toxin it chaperones or potentiates, making it a rational target for the design of targeted therapeutics.In southern Japan, envenoming by the habu snake , and the potential use of toxins in drug discovery.


A case of monkeypox was diagnosed in a returning traveler from Nigeria to Maryland, USA. Prompt infection control measures led to no secondary cases in 40 exposed healthcare workers. Given the global health implications, public health systems should be aware of effective strategies to mitigate the potential spread of monkeypox. Since the eradication of smallpox, monkeypox has assumed the role of the most prominent orthopoxvirus affecting human communities  and the CDC Laboratory Response Network protocol. CDC used viral culture and RT-PCR to confirm the diagnosis of monkeypox, further identifying the specimen as part of the West African clade, which has driven the outbreak in Nigeria since 2017.Upon confirmation of the monkeypox diagnosis, we identified all healthcare workers (HCWs) involved in the case and classified 40 as contacts by CDC guidelines , although the benefit is unclear (In summary, we report a case of monkeypox in a traveler returning to the United States from Nigeria and review infection control measures to prevent secondary cases. Multiple appearances beyond disease-endemic countries indicate that monkeypox has become a relevant travel-related disease, and physicians should remain vigilant in combatting transmission of this virus.


We are a product of the foods we chronically consume, and life expectancy correlates with the quality of our diet. What we eat influences the immune and cardiovascular systems, gut permeability and microbial dysbiosis, mental activity and health, and has long-term effects on fat storage. With rapid transformative advances to contemporary tools, how we study microbial ecosystems alters our perspective in both food and the gut. Sequencing technologies originally evolved from single gene profiles to complete genomic panoramas of microbial communities, where data acquisition is no longer the limiting factor for knowledge generation. Coupled with physical and biochemical techniques, this progress provides nano-resolution of food structure and microbial activity in the gut. A new frontier in current research that integrates information across fields alters and expands what is considered wholesome. Food, and the broader aspects of diet, are the primary modulator of the gut microbiota essential for homeostasis and prevention of chronic and infectious diseases. Understanding how food composition and structure alter the microbiota-host interaction is vital to engineering the next generation of foods that meet our nutritional needs while addressing safety and long-term well-being. This widening of scope bridges gaps between disciplines to improve the cross-feeding of ideas among experts interested in designing foods to be part of a diet that pushes the boundaries of current life expectancy. This Special Issue has collected studies from authors from five countries, providing insights into current research relating food ingredients with gut microbiota, whether healthy or not.“Probiotics are live microorganisms that, when consumed in adequate amounts, confer a health benefit on the host” . In ordeLactiplantibacillus plantarum over a two-week period stimulated the production of butyrate and led to higher levels of riboflavin than the control treatment consisting of a non-riboflavin producing strain of the same species. The strain-specific activity underscores the importance of probiotic validation studies for ensuring the selection of strains with a higher probability of conferring a measurable health benefit. In vitro gastrointestinal models have an important role in screening dietary components’ effects on gut microbiota.In the study by Fan et al. , the entp-cresol) in the fecal slurries from chronic kidney disease (CKD) patients, while few differences were present in fecal slurries from healthy subjects. These in vitro results highlight the challenges confronting the formulation of effective synbiotic food products, providing a measure of confidence moving forward into in vivo studies. As another case in point for the vital contribution of in vitro models to screening processes, fecal slurries were employed by Vacca et al.  as a finTorres-Maravilla et al.  reviews Overall, this Special Issue has brought together quite distinctive viewpoints that we can expect to cross-feed ideas between researchers working with in vitro models, formulation of food components, live animals, and humans towards the common goal of improving our diets. We hope you enjoy reading this selection of papers.


For more than 150 years, war surgery has been at the heart of the humanitarian assistance offered by the International Committee of the Red Cross (ICRC) in conflict zones around the world. Mental health and psychosocial support (MHPSS) is increasingly recognized as an integral part of the medical care offered to this highly vulnerable group of patients. This study seeks to identify patient characteristics associated with high distress prior to MHPSS and predictors of improvement following it.Between October 2018 and April 2020, 2,008 weapon-wounded patients received MHPSS in ICRC-supported hospitals in the Democratic Republic of Congo (DRC), Mali and Nigeria. The 21-item Depression and Anxiety Scale (DASS21), the Impact of Events Scale Revised (IES-R) and the ICRC functionality scale for Africa were administered before and after the MHPSS response. Logistic regression models were used to measure associations between outcome and exposure variables. Data was initially collected for monitoring purposes and analyzed retrospectively for the sake of this study.p = 0.014), and stress . Violence committed by military/armed group was associated with increased likelihood of reporting high levels of anxiety . On the IES-R, high scores at baseline were more likely to be found among illiterate patients  and having been wounded by firearms considerably increased the likelihood of reporting high levels of PTSD . Following MHPSS, 92.28% of the patients showed a reduction in symptoms on the DASS21, 93.00% showed a reduction in symptoms on the IES-R and 83.04% showed an improvement on the ICRC Africa functioning scale. On the DASS21, factors negatively associated with improved anxiety included lack of social support  and suffering from a chronic medical/physical condition . Patients with reduced IES-R scores were more likely to have a high level of education  and to have received MHPSS that lasted between 22 and 30 days . Predictors of improved functioning included being 35–44 years of age  and suffering from a severe or chronic medical condition .The main reasons for surgery were firearms (65%), other weapons (13%) and mines (5%). Linear trends were found between increasing number of days between violence and first consultation and decreased likelihood of presenting high levels of anxiety (aOR 0.75, Clinical implications of this study include the increased involvement of family and other caregivers in the MHPSS and longer-term follow-up of patients with severe and/or chronic medical conditions. Further research is needed with regard to joint psychological and physical outcomes, the role of the patient’s education level and the personal styles and techniques used by the counsellors. For more than 150 years, war surgery has been at the heart of the humanitarian assistance offered by the International Committee of the Red Cross (ICRC) in conflict zones around the world . Often lA limited number of studies exist on this topic. An analysis of 953 surgical patients in a hospital in Afghanistan described injury patterns but did not consider psychological factors related to recovery . A studyTo further address the gap in research and informed clinical practice with regard to mental health and psychosocial support (MHPSS) for war-wounded patients, this study seeks to identify patient characteristics associated with high distress prior to MHPSS and predictors of improvement following it.This is a retrospective cohort study of 2,008 war-wounded patients who received MHPSS in ICRC-supported hospitals in the DRC, Mali and Nigeria between October 2018 and April 2020. Data was initially collected for monitoring purposes and analyzed retrospectively for the sake of this study.Between October 2018 and April 2020, the ICRC supported surgical care to war-wounded patients in 44 hospitals in conflict settings across Africa. In ten of these hospitals, MHPSS was an integrated component. However, systematic monitoring was only carried out in nine of these hospitals–four in the DRC, four in Mali and one in Nigeria. In these nine facilities, 3,386 patients received surgical care following war wounds and an additional 5,968 patients underwent surgery for other reasons. All war-wounded patients were approached by a counsellor at some point during the hospitalization and offered MHPSS. As many as 2,008 war-wounded patients wished to receive MHPSS during this period and were all included in the study.et al., 2020 [All data used in this study derives from an ICRC MHPSS Excel database containing routinely collected information regarding the counsellor (one variable), patient demographics (ten variables), trauma history (nine variables), type of support received (five variables) as well as pre- and post-assessment scores of psychological distress and daily functioning. To assess psychological distress, the Depression, Anxiety and Stress Scale with 21 items (DASS21) was used in the DRC and Mali, while the Impact of Events Scale Revised (IES-R) was used in Nigeria. To assess daily functioning, the ICRC functionality scale for Africa was used in the DRC, Mali and Nigeria. For a detailed description of the scales used in ICRC MHPSS programmes, see Andersen l., 2020 .Data was initially recorded on paper files by the counsellors within the hospital and subsequently entered into the ICRC MHPSS Excel database by ICRC MHPSS data clerks in the nearest ICRC sub-delegation.ICRC MHPSS programmes for weapon-wounded patients in Africa are carried out in collaboration with the Ministry of Health and/or the National Red Cross Society in the given country. An ICRC MHPSS team consisting of international and national psychologists trains and supervises counsellors working inside the surgical wards. The counsellors offer awareness-raising sessions for health staff, patients and accompanying caregivers on various topics related to MHPSS needs and services available within the hospital. The main activity of the counsellors is to provide individual counselling that is carried out in three phases–pre-assessment, follow-up sessions and post-assessment.During the first phase, a counsellor approaches the newly arrived war-wounded patient to establish first contact, answer any immediate questions and offer reassurance and emotional support, as needed. A few days later, when the physical injury is stabilized and the patient is more calm, the counsellor approaches the patient again for an in-depth psychological assessment. Information about the patient and the trauma history is collected along with psychometric tools measuring levels of distress and functioning. For patients who report psychological symptoms or reactions during the assessment and express interest in receiving further support, a psychological treatment plan is developed focusing on the main clusters of symptoms.The second phase of the service delivery is the follow-up sessions during which the treatment plan is carried out. Together with the patient, the counsellor addresses the most pressing difficulties that most often fall within four main domains:First, reactions associated with the physical injury and violent circumstances surrounding it may include trauma-related symptoms such as shock, anxiety and anger. At this acute stage, the counsellor can help the patient and accompanying caregivers by answering immediate questions about the unfamiliar hospital environment and providing psychoeducation to normalize reactions to violent events, as well as calming techniques such as breathing exercises.Second, reactions to medical procedures are common as patients may experience intense fear of pain or death to the point of refusing surgery or other medical procedures. In these situations, the counsellor may be present while the medical team explains in detail the necessity of the medical treatment and the different stages of recovery. The counsellor may then stay with the patient and caregivers afterwards to repeat some of the information given by the medical staff and offer reassurance.Third, reactions to changes in one’s physical condition are common given the life-changing impact that the injury and potential amputation has on the patient. Despair and hopelessness may arise as the patient struggles to project him or herself into a meaningful future. The counsellor may invite the patient to explore coping mechanisms used in the past and adopt a problem-solving approach to overcome obstacles for utilizing these coping mechanisms, i.e. socializing in the present.In some instances, catastrophizing thoughts and fear of re-experiencing intense pain may lead the patient to restrict movement despite medical advice to perform certain rehabilitative exercises. The counsellor may then collaborate with the medical team to understand and help the patient manage his or her thoughts, feelings and behaviour on the path to recovery.Abuse of pain-relieving drugs is also a concern that the counsellor helps the medical team address through information about these risks. Additionally, the counsellor supports the patient in managing pain through self-distraction, relaxation techniques, praying or other ways of coping.Fourth, reactions and readjustments to one’s social and family environment are likely to appear as the patient anticipates the challenges of a prolonged recovery and/or long-lasting disability. The counsellor may help to focus on what the patient has some control over and channel concerns into optimizing adherence to treatment, from following dietary and hygiene plans to medication intake and wound-cleaning.Change in social status and family role, including fear of abandonment, are themes that the counsellor can discuss with the patient individually or through family sessions. Some counsellors collaborate with former patients who participate in awareness-raising activities or individual sessions with current patients to talk about how they managed to overcome their physical and psychological wounds.Phase three is the post-assessment and closure, which most often take place when the patient is about to be discharged. During this session, the counsellor makes a summary of the topics discussed in all the sessions and administers the psychometric tools used during the pre-assessment phase, pointing out the main areas in which the patient has reduced his or her distress and/or improved his or her daily functioning. The counsellor then addresses any last questions or concerns, informs the patient about MHPSS and other services available outside of the hospital and proceeds to close the patient file. When pertinent, the medical team refers the patient to physical rehabilitation services in ICRC-supported physical rehabilitation centres.All categorical data were numerically coded. Quantitative/continuous variables (i.e. pre- and post- scores) were either kept as such or categorized depending on the type of analysis. Categorization of continuous variables was done either by identifying the median to divide the study participants into two even-sized groups or by using established clinical cut-offs.The dataset was created in Microsoft Excel with two independent data clerks to check against potential typing mistakes. The electronic dataset was protected by a password, which was changed every three months. The dataset was transferred to STATA™, version MP 16.0, for analysis.2 test to retrieve the corresponding p-value; 95% CIs were calculated around these percentages.All quantitative variables were explored by defining their means (and standard deviation), medians and quartiles. Comparisons of means were tested through the t-test, and the corresponding p-value was reported; 95% confidence intervals (95% CI) were calculated around means and means differences. Categorical variables were explored through percentages and tested using the ChiTo measure associations between variables (crude and multivariable), logistic regression models were fitted to calculate odds ratios (OR) with corresponding 95% CIs and p-values from the Wald test. All variables were initially explored in a crude analysis before being inserted in a multivariable model. Results from logistic regression were only presented if they were found statistically or clinically significant.The 2,008 war-wounded patients included in the study  resided On the DASS21 used in the DRC and Mali , anxietyOverall, 92.28% of the patients showed a reduction in symptoms on the DASS21, 93.00% showed a reduction in symptoms on the IES-R and 83.04% showed an improvement on the ICRC Africa functioning scale .Various factors were associated with high distress and low functioning prior to receiving MHPSS . On the High levels of anxiety correlated with high levels of depression  and stress . A linear trend was found between increasing number of days between violence and first consultation and decreased likelihood of presenting high levels of anxiety . Violence committed by military/armed group was associated with increased likelihood of reporting high levels of anxiety .With regard to symptoms of stress, a similar comorbidity was found with symptoms of depression  and anxiety . The timing of the response also played a role as a linear trend was found between increasing number of days between violence and first consultation and decreased likelihood of presenting high levels of stress . Also, the natural death of a loved one more than two years ago increased the likelihood of reporting high levels of stress .On the IES-R, high scores at baseline were more likely to be found among illiterate patients compared to patients with medium education level . The likelihood of reporting high levels of PTSD was considerably increased among patients having been wounded by firearms  and self-harm .Finally, with regard to functioning, low scores at baseline were more likely to be found among patients with a high education level  than illiterate patients. Compared to civilians, weapon bearers were much less likely to report low levels of functioning at baseline .Several variables correlated with reduced psychological distress and increased functioning following MHPSS . On the Reduced levels of anxiety correlated with high anxiety at baseline  as well as reduced depression  and stress  following MHPSS. An association was also observed between reduced anxiety and counsellors characterized by a high educational level, male gender and/or 40 years or older. Factors negatively associated with improved anxiety included lack of social support  and suffering from a severe or chronic medical condition .Reduced stress levels following MHPSS were associated with having reported high levels of stress at baseline  and reduced anxiety  and depression  following MHPSS. Minors were much more likely than all adult age groups to show reduced stress after the MHPSS. Also, a linear trend was found between the length of the response and the likelihood of reduced stress. Certain counsellors correlated with a decreased likelihood of reduced stress levels. These counsellors were characterized by being female and below 40 years of age.On the IES-R, the strongest predictor of improvement was having high PTSD scores at baseline , i.e. having greater room for improvement. Also, patients with reduced IES-R scores were more likely to have a higher education level  and to have received MHPSS that lasted between 22 and 30 days .Finally, when it came to improved daily functioning, predictors included having reported low levels of functioning at baseline  as well as suffering from a severe or chronic medical/physical condition . The age group most likely to improve its functioning was 35–44 years .The findings of this study were particularly rich and diverse. Levels of psychological distress and functioning prior to and following MHPSS were associated with numerous characteristics of the patient and of the response itself.Having experienced the natural death of a loved one stood out as a distinct vulnerability factor that increased the likelihood of reporting high levels of stress prior to MHPSS.Patients with a higher educational level were much more likely to report reduced PTSD symptoms following MHPSS. The link between high education level and well-being as mediated by psychosocial resources has been documented in other settings  but woulInjury from gunshots correlated with increased PTSD symptoms prior to MHPSS. This points to the pertinence of a systematic referral of this sub-group of patients to psychological support. The fact that injury from gunshots did not correlate negatively with treatment outcome indicates that the MHPSS in its current form adequately addresses the needs of patient having suffered this type of injury.Prior to MHPSS, war-wounded patients aged 0–17 were less likely to report high levels of depression. Following MHPSS, minors were more likely to show reduced stress and more likely to show increased functioning. As the monitoring tools used were designed for adults, it is uncertain whether they were as appropriate for minors as, for example, the Paediatric Emotional Distress Scale (PEDS)  would haViolence committed by the military or armed groups was a predictor of increased anxiety prior to MHPSS. This is consistent with the findings of a study among victims of violence in health facilities in similar settings  and poinPatients suffering from a severe or chronic medical condition were less likely to show reduced anxiety and increased functioning following MHPSS. While the severity of the medical condition would explain the fact that functioning does not significantly improve during the stay in the hospital, there could nonetheless be a need to more thoroughly address during counselling the anxiety experienced by this sub-group, whether health-related  or otherHigh levels of depression and PTSD prior to MHPSS was associated with wounds caused by self-harm. This finding is likely to be a case of reversed causality whereby depression and PTSD may lead to self-harm. Similarly, in Northern Ireland, more than 50% of individuals with PTSD reported deliberate self-harm . Among vPatients lacking social support were less likely to show reduced anxiety following MHPSS. This is consistent with other studies pointing to social support as a protective factor with regard to mental health in general  and anxiCertain counsellors unexpectedly stood out as correlating with increased or decreased likelihood of improvement among their patients. Counsellors associated with patients who showed considerable improvement following MHPSS where characterized by being male, having a high educational level (university studies) and being 40 years or older. Likewise, counsellors whose patients were less likely than average to improve tended to be young and female, although not necessarily less educated. Determining to what extent these findings can be explained by the fact that most of the patients were male and/or prefer a certain type of counsellor would require further investigation, possibly through a qualitative study of the styles and techniques of each category of counsellors.The earlier the support is offered, the greater the likelihood of the patient reporting acute distress. Given that psychological needs are at their highest in the days following war injury, efforts should be made to initiate MHPSS to patients at the time when they are most vulnerable.From a duration of three weeks onwards, the likelihood of positive MHPSS outcomes increased considerably. This indicates that meaningful response could be offered during a relatively short period of time.When measuring the psychological distress of war-wounded patients in Africa, the use of the DASS21 appears preferable to the IES-R. With more than two-thirds of the patients obtaining normal pre-scores on the IES-R and all patients obtaining normal post-scores, the DASS21 stands out as the most sensitive tool in terms of measuring variation and differentiating between patients with regard to their level of psychological distress.As the first-of-its kind looking at ICRC MHPSS for more than 2,000 war-wounded patients in conflict settings in Africa, the real-life settings, the uniqueness of the data and the large number of patients involved constitute major strengths of this study. Furthermore, the quality of the data derived from standardized psychometric tools and following each individual patient before and after MHPSS may be considered as important attributes.causation, i.e. whether it was the MHPSS that improved the patients’ well-being or it was simply the passage of time or other factors that led to the observed outcomes. Another limitation is the fact that all the data used in the study stems from information obtained from the patient him or herself. A bias may have been present due to the absence of objective medical information regarding, for example, the gravity of the patients’ wounds.The main limitation of this study is the absence of a control group. As in any observational study, it cannot be stated with certainty whether the observed correlations involve an element of The results of this study highlight the pertinence of addressing MHPSS needs alongside the medical needs arising from severe injury in the context of armed conflict. Just as psychological distress may hamper post-surgical recovery, so a healthy mental health status promotes physical healing. Certain characteristics of the patient and the MHPSS itself call for further discussion to informed clinical practice.Offer extended follow-up to patients with a severe or chronic medical condition and/or wounds caused by self-harmInvolve caregivers (even) more in the MHPSS to increase social supportTo improve monitoring and inform decision-making:Use the DASS21 rather than the IES-R to monitor distress, as it appears to differentiate better between patientsUse age-appropriate tools to monitor distress, such as the PEDSMonitor the therapeutic techniques used during counsellingMonitor characteristics of the counsellorCompare MHPSS outcomes with medical outcomesConduct a qualitative study of the individual styles and techniques used by the counsellorsConduct a qualitative study to explore the role of the patient’s education level in benefiting from MHPSSS1 Appendix(DOCX)Click here for additional data file.


Adaptation is the process by which bone responds to changes in loading environment and modulates its properties and spatial organization to meet the mechanical demands. Adaptation in trabecular bone is achieved through increase in bone mass and alignment of trabecular-bone morphology along the loading direction. This transformation of internal microstructure is governed by mechanical stimuli sensed by mechanosensory cells in the bone matrix. Realisation of adaptation in the form of local bone-resorption and -formation activities as a function of mechanical stimuli is still debated. In silico modelling is a useful tool for simulation of various scenarios that cannot be investigated in vivo and particularly well suited for prediction of trabecular bone adaptation. This progress report presents the recent advances in in silico modelling of mechanoregulated adaptation at the scale of trabecular bone tissue. Four well-established bone-adaptation models are reviewed in terms of their recent improvements and validation. They consider various mechanical factors: (i) strain energy density, (ii) strain and damage, (iii) stress nonuniformity and (iv) daily stress. Contradictions of these models are discussed and their ability to describe adequately a real-life mechanoregulation process in bone is compared. Adaptation in trabecular bone (TB) – the spongy component of many long bones – is characterised by changes in mechanical properties of this bone tissue and alignment of trabecular load-bearing architecture along the loading direction. The ability to predict TB adaptation to mechanical loads in terms of local changes in bone mineral density (BMD) and microarchitecture can provide an opportunity to simulate the effects of load-induced structural alterations caused by various conditions, such as altering strain magnitudes/directions in femur after total hip replacement, the effect of exercise in osteoporosis prevention and disuse-induced bone mass loss in micro-gravity conditions of spaceflights Bone is a living material, which demonstrates continuously changing structural configurations and mechanical properties. Although many engineering materials are mechanically superior, bone is unique in its ability to respond to changes in its external loading environment through the process of in silico approach, offers many important benefits for investigation of patient-specific changes in structure and mechanical properties of TB in otherwise inaccessible clinical conditions in silico approaches were proposed recently to predict the load-induced BA at different scales of bone hierarchy. At the cellular level, models primarily aim at describing activities of bone-forming and -resorbing cells and the underlying pathways of biochemical and mechanical signalling . As more bone matrix is formed by the osteoblasts, they become encapsulated in their secretions and develop into osteocytes. Osteocytes are contained within the pores in the bone matrix, called lacunae, and connect with each other and with the bone surface via tiny canaliculi, forming a 3D lacunar-canalicular network (LCN). Osteocytes are hypothesised to sense local mechanical signals and, based on these, coordinate the action of osteoclasts and osteoblasts on the nearest bone surface. Driven by the load-induced stimuli, respective bone cells resorb and deposit bone tissue in a coordinated manner aiming for adaptation of structural-functional properties of trabeculae to meet the mechanical demands of bone [Made up mostly of cells, collagenous mineralized extracellular matrix and water, bone is a living organ that adapts to mechanical stresses through resorption of old or damaged tissue and formation of new bone material via the activities of osteoclast and osteoblast cells, respectively, – the process known as  of bone ,17.Loading, that the skeleton is subjected to in daily activities, modulates mechanical properties and spatial organisation of TB. Intensified mechanical use results in thicker and mechanically stronger bones. For example, impact-based physical activities such as volleyball and combat sports resulted in higher BMD in young adults as compared to no exercise 1.2Strain energy density (SED) was among the early factors considered to drive BA. The pioneering work of Fyhrie et al. Microcracks due to excessive bone straining are hypothesised to be another trigger of BR. There is experimental evidence of fatigue microdamage leading to ruptures of the osteocytes processes and apoptosis of osteocytes near damaged regions stress nonuniformity mechanical stimulus as a driving force of BA. To support this hypothesis, the authors compared local levels of stimuli (SED and von Mises stress) and those distributed over the neighbouring bone cells (SED integration and stress nonuniformity) by measuring the distribution patterns of these stimuli on the trabecular compartment of rat vertebrae under three simulated loading cases Based on a theory of a local equi-stress state as the optimal condition at the remodelling equilibrium daily stress stimulus to regulate BA. The importance of considering the cyclic loading in regulation of BA was supported by the observation that only dynamic strain [Another approach to determine the BA stimulus was based on bone's loading history rather than on instantaneous values of mechanical stimuli. By combining a cyclic stress magnitude and a number of stress cycles during the day, Carter et al. c strain ,40, not Although there is no consensus in the literature regarding the mechanical stimulus that initiates BA, several mathematical models were proposed for prediction of mechanoregulated BR. Analysis of the literature demonstrated that there are four main groups of BA models that directly regulate TB density and microarchitecture by using one of the following mechanical stimuli: (i) SED; (ii) strain (and related damage), (iii) stress nonuniformity; and (iv) daily stress (see details in the discussion above). From each group one original well-established model was selected for in-depth analysis. The rest of the algorithms in each group have only some minor variations and modifications compared to the selected models. The following section presents numerical implementations of the four selected BA models together with the review of their recent improvements and validation.2Model A; strain and damage – Model B; stress nonuniformity – Model C; daily stress – Model D. These models are described with differential equations relating specific mechanical stimuli to the changes in BMD and the trabeculae shape. However, the underlying concept of the reviewed models can be generalized using the well-known “mechanostat” theory of Frost F . When mechanical stimulus exceeds the bone formation threshold fK, bone deposition prevails over resorption, producing a rising slope in the remodelling curve. Recent experimental evidence of increased resorption near regions of microdamage F > oK and F > dK, respectively), when the rate of bone formation cannot compensate intensified resorption.This report reviews four BA models named according to the stimuli used: strain energy density – Obviously, the authors of the following models used different notations for parameters of their models. Here we present them in the unified form .Table 1N2.1sensor cells (osteocytes) located throughout the bone material that sense mechanical stimuli and transmit them to the (ii) actor cells (osteoblasts and osteoclasts) concentrated on the bone surface. Mechanical stimulus triggering BA is based on SED calculated as given by Eq. (1)  . The valin vivo CT scans. In addition, Model A was applied to loaded healthy and osteoporotic FE models of mice vertebrae, demonstrating 98% and 94% correspondence in BV/TV and trabecular thickness, respectively, against in vivo micro-CT scans [Model A was used in many studies to predict BA. For example, when applied to 2D FE models of osteopetrotic  and reduced mineralization TB subjected to loading, this algorithm demonstrated 63% and 23% increases in bone volume fraction (BV/TV), respectively, that is in general agreement with the literature data (18–80)% CT scans ,57.ovlr) into Eq. (4), producing the remodelling curve shown in Model A was extended by introduction of an overload-induced resorption term (2.2The model proposed by McNamara et al. The described model was continuously updated by Prendergast and colleagues ,48, with2.3The adaptation model of Adachi et al. ,36 uses This model assumed that remodelling only happened at the bone surface. The local bone remodelling rate was defined using a step function (Model C was implemented for prediction of TB adaptation in proximal femur caused by such loading conditions as one-legged stance, abduction and adduction ex vivo in human biopsies in vivo in mice This adaptation model was further modified to analyse the effect of cyclic loading on BA ,70. LoadThe recent efforts of Adachi and colleagues were focused on incorporation of mechano-dependent intercellular signalling into the described model 2.4The model of Carter et al. ,50 prediin vivo human scans for the corresponding lengths of the implants. In addition, this model was employed in FE models of human femora, which had the same geometry and boundary conditions but differed in the values of initial density refF ± w (Model D was extended to introduce overload-induced bone resorption for prediction of BA around dental implants , 75. TheModel D was further improved by introduction of dependence of the daily stress stimulus on loading frequency 3The BA models reviewed in this report were demonstrated to predict structural and density changes in TB caused by various loading conditions. Although the exact nature of the mechanical stimulus that drives BA is not clear, these models considered previous experimental and simulation findings to explain the choice of the stimuli used. The stimuli employed in the Models A, B and D are the products of both stress and strain tensors and are likely to efficiently represent the response of bone material to loading. In Model C, the authors did not explicitly mention what stress component they use, making its comparison with other mechanical quantities difficult. Another factor to consider is that, in daily activities, long bones are mostly loaded in bending Introduction of parameters of loading history such as number of cycles, loading frequency and microdamage accumulation into the BA models allows the simulation of such scenarios as under-/overload and cyclic loading. All the reviewed models incorporate a similar effect of inactive bone by initiation of resorption when mechanical stimuli are below the respective threshold value. The overload is represented differently in the reviewed models. Model A accounts for the overload-induced resorption but does not consider the number of loading cycles. Model C considers neither the number of loading cycles nor microdamage accumulation. Model D accounts for the number of loading cycles but neglects the formation of microcracks. The suitability of these models for the cases of a complicated real-life loading is, therefore, questionable. Model B considers both the number of cycles and microdamage accumulation, which makes it suitable for prediction of BA in overload. Cyclic loading is better represented by Model D that accounts for the number of cycles and the loading frequency, where repeated loading condition is the subject of the study.The theory of mechanical-stimulus transmission from the in-depth osteocytes to the bone surface is believed to occur via the release of several signalling molecules All the described adaptation models include time dependency in the calculations. Yet, definition of time in these models is not uniform and sometimes could be contradictory. In many studies it is not directly related to specific time intervals of days or weeks. Most studies that used Models A Although the lazy zone hypothesis, where a physiological range of the stimulus magnitudes produces no significant adaptation response, was incorporated into all described models, it is not supported by all researchers. For example, a continuous linear relationship between the applied load and the sites of BR was found in animal tibiae and vertebrae ,89 as weA summary of the factors considered in the reviewed BA models is given in 4in silico modelling of mechanoregulated TB adaptation. Reviewed BA models incorporate different aspects of the real-life BA process, which make each of them more suitable for simulation of specific loading scenarios. Some factors influencing mechanoregulated BR are widely accepted by researchers and incorporated into the reviewed adaptation models: loading configurations (number of cycles, loading frequency and, additionally, the amplitude of the dynamic loading cycle This report discusses the recent progress in in silico approaches that limit validation of their results against in vivo longitudinal CT studies. First, some of the described studies modelled TB using 2D geometry only, whereas TB is a complex 3D structure which cannot be accurately represented in 2D. Second, many works presented TB as isotropic homogeneous material, with the trabecular microstructure neglected. Third, artificially generated trabecular architecture used in many studies may not always represent the real-life TB microstructure. One of the solutions is to use the reviewed adaptation algorithms in conjunction with FE models of TB reconstructed from high-resolution CT scans. This can allow tracking of local changes in BMD and trabecular microarchitecture and their comparison with clinical radiological studies, which is especially important for prediction of the individual-trabecula remodelling. Furthermore, neural networks can be used for generation of representative volume elements that retain morphological characteristics of TB. In addition, introduction of more complex loading regimes into FE simulations, corresponding to the real-life bone loading conditions, can also contribute to prediction of more realistic TB morphologies.There are several major disadvantages of the described in silico approaches are a useful tool for investigation and characterisation of the mechanisms underlying mechanoregulated BR. Over the last decade, BA models became more mathematically sophisticated, with their predictive accuracy improved thanks to incorporation of the recent discoveries in bone biology. From recent developments it is clear that some research directions converge, such as related to the understanding of damage/microcracks and the distance-dependent decay of mechanical stimuli. On the other hand, some areas diverge, such as description of the lazy zone and definition of mechanical stimuli. Still, these latest improvements will contribute towards further development of in silico models for better estimation of patient-specific BA in different loading conditions and evaluation of the risks for patients affected by bone pathologies.Despite the described limitations, The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.


Bursaphelenchus xylophilus  is the causal agent of Pine wilt disease (PWD) being responsible for the tremendous decline of conifers species in Eurasian conifer forests  in biological material. Based in previous studies  extensively found in the pupal chambers and the tracheae of the Monochamus alternatus. The authors found that microbial communities changed with the duration of PWN invasion, and that Serratia were more expressive in sites with the longest PWN presence. In the same line of thought, Vicente et al. showed that fungal communities also changed along sites with different PWD history, emphasizing the effect of a prolong exposure to PWN has a tremendous effect on these co-occurring multi-species interactions.The complexity of this disease is also a result of the biological interactions co-occurring between plant-nematode-microbe. Ning et al. presented a study on comparison of C-type lectin (CTL) family genes in insect-vectored and self-dispersing nematodes, and demonstrated that this gene family contributed to this evolutionary transition. In the phoretic nematode B. xylophilus, the similarity in the CTL gene family sizes, that clustered into separate phylogenetic sister clades, is due to parallel evolution, when similar phenotypes occur in closely related taxa, that are produced by orthologous genes. In a functional study, Wang et al. showed that PWN UGTs (uridine diphosphate-glycosyltransferases), specifically the UGT440A1, may be involved in the pathogenic process of the PWN in the disease. Knocking down UGT440A1 suppressed PWN core metabolism  which in planta slowed down their infectiveness. In a different approach, Cardoso et al. presented a comparative proteomic study in two PWN isolates with different virulence and geographical location. Thirteen proteins were found significantly increased in the proteome of the virulent isolate as compared with the less virulent one and were selected as potential virulence biomarkers. One of the main research challenges to study tree pathogens is the lack of genetic tools to functionally analyze nematode parasitism candidate genes. Kirino et al. described a new powerful tool for transient overexpression of nematode genes using an exogenous gene expression system applied in pine seed embryos with ALSV vector (virus vector). These authors showed that the use of natural host pine embryos is more reliable for functional analysis than using Nicotiana benthamiana-based methods.Understanding the molecular mechanisms underpinning the parasitism of the PWN are pivotal for the development of novel control strategies. Since the release of genomic and transcriptomic data there has been an effort to study potential parasitism-related genes and understand their evolutionary and functional role in plant-parasitic nematodes. Hirao et al. focused on the genetic mapping of resistance to PWD with the goal of improving resistance in Japanese Black Pine (Pinus thunbergii). The authors provided a high-density linkage map and quantitative trait loci (QTL) mapping of PWD resistance for P. thunbergii. This study also validates the GBS technology and UNEAK pipeline as tools for use in QTL mapping in the species without a reference genome sequence. The results demonstrated that the locus linked to PWD resistance was identified on LG-3. This locus will be a good candidate to develop molecular markers associated with the phenotype. In Europe, maritime pine (Pinus pinaster) is the one of most susceptible hosts to PWN and genetic variability has been found in natural populations associated to heritable PWD resistance. Rodrigues et al. presented a physiologic and primary metabolite responses of susceptible and resistance P. pinaster seedlings to PWN. The authors showed that specific traits are associated with pine resistance to PWD, such as GABA shunt-related metabolites, and the plant defense response was regulated and able to reduce the ability of the nematode migration. Jeon et al. tested previously known 12 SAR (systemic acquired resistance) elicitors to manage PWD by SAR in pine trees. Methyl salicylate (MeSA) was found to induce resistance against PWD in Pinus densiflora seedlings. Moreover, qRT-PCR analysis confirmed that MeSA induced the expression of defense-related genes, and can inhibit and delay the migration and reproduction of PWN in pine seedlings by modulating gene expression.The basis of the pine host genetic traits for resistance to PWD will be relevant to the future pine breeding programmes. Estorinho et al. analyzed the symptom development of the PWD in three pine species inoculated with PWN under controlled temperature and water availability. The authors showed that the impact of PWN is species-dependent, being infected P. pinaster and P. radiata more prone to physiological and morphological damage than P. pinea. Moreover, they suggested a synergistic impact of PWN infection and drought triggering disease symptoms and mortality of these species. The spread of PWD in pine forests of the Mediterranean regions may be possibly facilitated by predicted drought conditions . Xia et al. demonstrated a theoretical method based on the individual dispersal of the insect vector—pine sawyer beetle (Monochamus spp.)—to elucidate the dispersal of PWD and evaluated the control strategies applied for the eradication of the disease in Korea.Forest mortality due to PWN infection, and the fast spread of PWD might be exacerbated by climate (more drought events and higher temperatures), topography, and human activities . The study conducted by In summary, this Research Topic with thirteen scientific contributions consolidates and expands our knowledge regarding recent advances in pine wilt disease.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.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.