Lack of proper consideration of the interaction between biological and environmental factors limits our understanding of the development of depression. Our cross-sectional study investigated whether recent stress influences the effect of affective temperaments on depressive symptoms.1015 general population participants completed the Brief Symptom Inventory to capture depressive symptoms, the List of Threatening Experiences Questionnaire to assess recent stressors, and the Temperament Evaluation of Memphis Pisa, Paris, and San Diego Autoquestionnaire to evaluate affective temperaments (TEMPS-A). Linear regression models were built to investigate the effect of temperament and stress on depression, temperament on stress, and the effect of temperament on depressive symptoms in different stress exposure groups.Recent life events and anxious, depressive, cyclothymic, and hyperthymic temperaments significantly predicted depressive symptoms, and cyclothymic, and hyperthymic temperaments significantly predicted recent life event exposure. While in case of mild stress all affective temperaments except irritable predicted depression, in case of moderate exposure only the effect of depressive, cyclothymic, and hyperthymic temperament, while in the high exposure group only the effect of anxious temperament was significant.All measures were based on self-report, and subjective impact of life events was not considered. This was a cross-sectional study with a correlational nature which does not allow for causative conclusions.The contribution of affective temperaments to depression is much higher compared to stress, and severity of exposure to life events influences the impact of affective temperaments on depressive symptoms, pointing to divergent pathways of emotional reactivity mediating the effects of stress on depression which can be exploited for prevention and treatment. Depression is a highly prevalent condition contributing to significant subjective suffering, dysfunction and is predicted to become in the following years one of the illnesses associated with the highest burden . HoweverTemperaments by definition represent the biologically determined and heritable core component of personality, and show a strong temporal stability manifesting early in development and persisting through the lifespan . While mTemperaments describe emotional reactivity and also determine reaction to environmental influences, which plays a significant etiological role in depression. As gene x environment studies have shown, the effects of genetic determinants of depression in several cases are not manifested without exposure to environmental events, as the majority of depressogenic genes do not directly contribute to depression, but increase vulnerability to stress, and similarly, the effects of environmental stressors of depression may not lead to the emergence of depression without the presence of vulnerability genes –14. TherThe aim of our present cross-sectional study was to investigate the effect of affective temperaments on depressive symptom severity in participants exposed to different levels of recent negative life events occurring in the previous year in a large general adult population.The reported study was part of the EU funded NewMood study   approvedNonrelated, European white ethnic origin participants from the general adult population aged 18 to 60 years and recruited through general practices and advertisements from Budapest, Hungary (N = 1015) completed the Hungarian version of the NewMood questionnaire pack and were included in the present study. Inclusion criteria included voluntary participation, signing of informed consent, providing genetic material  and returning the questionnaire pack. Inclusion was independent of any positive psychiatric anamnesis. Exclusion criteria included only withdrawn consent to participate. Details of the population and the recruitment process have been published in previous publications , 17. TheCurrent depressive symptoms were measured by the depression items plus the additional items of the Brief Symptom Inventory (BSI), a 53-item psychological self-report scale developed as a shorter alterative to the widely used SCL-90-R to evaluate the psychological symptom status of psychiatric and medical patients and non-patients, which latter has been validated in several languages including Hungarian , 19. BSIWe used the List of Threatening Experiences (LTE) questionnaire  to identAffective temperaments were evaluated by the Temperament Evaluation of Memphis, Pisa, Paris, and San Diego , an instWe used IBM SPSS Statistics 21 for statistical analyses. We ran linear regression models with enter method to test the effect of recent life events (RLE) as a continuous predictor on BSI depression score as the continuous outcome variable; to test the effect of the five affective temperaments as predictors on BSI depression score as the continuous outcome variable; and to test the effect of the five affective temperaments as predictors on recent life events as the continuous outcome variable. Age and sex were predictors in all these separate regression models.In the next step, the population was separated into three groups according to RLE score according to low, moderate, and severe RLE exposure. In each group we ran a single linear regression model with enter method including the effect of all five temperaments  as well as age and sex as predictors on BSI depression score as the continuous outcome variable in all models. The three models where all the five temperaments and age and sex were predictors were corrected for multiple testing by Benjamini-Hochberg's FDR correction yielding q-values.Descriptive data and statistics of our study population are presented in Cronbach alpha coefficients for TEMPS-A were 0.6832 for depressive, 0.8232 for cyclothymic, 0.7775 for hyperthymic, 0.7923 for irritable and 0.8680 for anxious temperament subscales. These figures were highly similar to those reported during the validation of the Hungarian version of TEMPS-A where, with the exception of the depressive temperament with a Cronbach alpha of 0.65, Cronbach alpha coefficients for the other four subscales were between 0.75 and 0.81 which reflect satisfactory internal consistency .For the depression subscale of BSI (BSI-DEP) Cronbach alpha coefficient was 0.9104, whereas for the currently used measure also containing the four additional items the Cronbach alpha coefficient was 0.9278 reflecting excellent internal consistency.p < 0.001, q = 0.000) .In the total sample unseparated by recent life even exposure, recent life events significantly predicted BSI depression scores , depressive , cyclothymic  and hyperthymic  affective temperaments significantly predicted BSI depression, and these effects remained significant after correction for multiple testing. The effect of irritable temperament on BSI depression scores was not significant  .In the total sample unseparated by life event exposure, anxious  and hyperthymic  temperaments significantly predicted recent life events, with effects remaining significant after correction for multiple comparisons. However, anxious , depressive  and irritable  temperaments had no significant effect .In the unseparated sample only cyclothymic , moderate  and severe  recent life exposure. In the group with low recent stress exposure after correction for multiple testing anxious , depressive , cyclothymic  and hyperthymic  temperaments all had a significant effect on BSI depression score while irritable temperament did not  , cyclothymic  and hyperthymic  affective temperaments on BSI depression was significant, the effect of anxious temperament was nominally significant but did not survive correction for multiple testing , and irritable temperament had no significant effect  , while depressive , cyclothymic  irritable  and hyperthymic  temperaments had no significant effect  of current depression scores compared to recent life events (7.8%). While in all three recent life event exposure groups the predictive value of affective temperaments was comparably high , the effect of individual temperaments on current depression depended on severity of exposure to recent stress. Therefore innate emotional reactivity appears to contribute to current severity of depression with a higher magnitude than recent stress, however, the type of emotional reactivity playing the most prominent role in depression severity depends on severity to recent stress exposure  temperaments except for irritable temperament were significantly associated with current depression scores indicating that in the absence of recent stress, the effects of all types of emotional reactivity contribute to severity of depressive symptoms either increasing risk or protecting against it. While cyclothymic, depressive, and anxious temperaments appeared to increase risk, hyperthymic temperament was protective against current depression. However, in case of moderate recent stress exposure, only the effect of depressive and cyclothymic temperaments remained significant on current depression severity while the effects of hyperthymic temperament was marginally significant, which suggests that in case of moderately severe life events, low mood, and mood lability will be the relevant contributors to depressive symptoms. In case of severe recent stress exposure only anxious temperament was significantly associated with current depression scores. Notably, with increasing stress, the protective effect of hyperthymic temperament against depression also diminished. Age did not influence depressive symptoms in case of any level of exposure to recent life stressors, and the effect of sex was significant only in case of moderate exposure.Besides explaining a high portion of current depression scores, affective temperaments also had a small contribution to predicting recent life events, indicating that affective temperaments determine the likelihood of encountering recent stress to a significant but small portion (6.66%). Notably, of the five affective temperaments, cyclothymic, and hyperthymic temperaments were both significantly and positively associated with recent life event exposure.Our results add to the long debate and ever-expanding research focusing on the relative role of nature or nurture, that is, biological or environmental contributors in the development and severity of depression . AlthougThere appears to be a continuum in case of different manifestations of depression depending on the relative contribution of environmental and genetic determinants from more “reactive” to more “endogenous” forms, however, although with differing weight, both biological/genetic and environmental contributors are necessary for the emergence of depression which develops in the interaction of these two major factors –14. Thatvia cyclothymic, irritable, and anxious temperaments , which may have implications in how temperaments contribute to the explanation of variance in the model. Fifth, we consider depression as a continuum of symptom severity rather than a categorical variable and thus used a general adult population sample in our study, which also included participants with lifetime major depression. Therefore further study is warranted to establish the effect of affective temperaments on depression scores in case of patients with formal diagnoses.In conclusion, while we found that both recent stress and affective temperaments are associated with current depressive symptoms in a general adult population, we also found that the contribution of affective temperaments was much higher, and different temperaments were associated with current depression in case of different levels of stress exposure. Our findings, beyond providing insight on the role of temperaments in depression, may also pave the way for developing prevention and intervention methods based on a combination of temperamental makeup and recent stress exposure.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The study protocol was reviewed and approved by Medical Research Council, Scientific and Research Ethical Review Board. The participants provided their written informed consent to participate in this study.XG, GB, and GJ designed and conceptualized the study and collected the data. NE, SS, and NA participated in statistical analyses. All authors participated in interpreting the data. XG, NE, and SS wrote the first draft of the manuscript. SS created figures and graphical abstract. All authors participated in developing further and final versions of manuscript. All authors contributed to the article and approved the submitted version.This study was supported by the Sixth Framework Program of the European Union ; the Hungarian Academy of Sciences (MTA-SE Neuropsychopharmacology and Neurochemistry Research Group); the Hungarian Brain Research Program ; the National Development Agency (Grant: KTIA_NAP_13-1-2013-0001); by the Hungarian Academy of Sciences, Hungarian National Development Agency, Semmelweis University and the Hungarian Brain Research Program (Grant: KTIA_NAP_13-2-2015-0001) (MTA-SE-NAP B Genetic Brain Imaging Migraine Research Group); the ITM/NKFIH Thematic Excellence Programme, Semmelweis University; and by the SE-Neurology FIKP grant of EMMI. Xenia Gonda is supported by the Janos Bolyai Research Fellowship of the Hungarian Academy of Science. Xenia Gonda was supported by ÚNKP-19-4-SE-19 and Sara Sutori by ÚNKP-19-1-1-PPKE-63 New National Excellence Program of the Ministry for Innovation and Technology. The sponsors had no further role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper 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.


To establish and maintain proper brain architecture and elaborate neural networks, neurons undergo massive migration. As a unique feature of their migration, neurons move in a saltatory manner by repeating two distinct steps: extension of the leading process and translocation of the cell body. Neurons must therefore generate forces to extend the leading process as well as to translocate the cell body. In addition, neurons need to switch these forces alternately in order to orchestrate their saltatory movement. Recent studies with mechanobiological analyses, including traction force microscopy, cell detachment analyses, live-cell imaging, and loss-of-function analyses, have begun to reveal the forces required for these steps and the molecular mechanics underlying them. Spatiotemporally organized forces produced between cells and their extracellular environment, as well as forces produced within cells, play pivotal roles to drive these neuronal migration steps. Traction force produced by the leading process growth cone extends the leading processes. On the other hand, mechanical tension of the leading process, together with reduction in the adhesion force at the rear and the forces to drive nucleokinesis, translocates the cell body. Traction forces are generated by mechanical coupling between actin filament retrograde flow and the extracellular environment through clutch and adhesion molecules. Forces generated by actomyosin and dynein contribute to the nucleokinesis. In addition to the forces generated in cell-intrinsic manners, external forces provided by neighboring migratory cells coordinate cell movement during collective migration. Here, we review our current understanding of the forces that drive neuronal migration steps and describe the molecular machineries that generate these forces for neuronal migration. Neuronal migration is a fundamental process to establish and maintain the nervous system , and defMigrating neurons exhibit bipolar morphology, with a long leading process and a short trailing process ; the tipNeurons migrate within tightly packed environments, including glial cells, other neurons and the extracellular matrix (ECM) , which sThe tip of an extending axon also bears a growth cone , and axoin vitro (As in the case of axonal growth cones, F-actins also undergo retrograde flow at the tip of leading process growth cones . A recenin vitro . The driin vitro . These dIn addition, shootin1 KO results in ectopic accumulation of mitral cells , olfactoThe cell body is the swollen part of migrating neurons; therefore, its translocation against the mechanical barriers of the surrounding environment must rely on the generation of robust forces. One of the candidate forces for mediating somal translocation is tension along the leading process . He et aIn the case of migrating cerebellar granule cells which extend F-actin-enriched leading process , Myosin As described above, cell adhesion is required for the generation of traction force for neuronal migration. On the other hand, it was also proposed that a decrease in the adhesion force at the rear of the migratory cells facilitates forward movement of cells . Indeed,Several studies have reported an involvement of endocytic trafficking of cell adhesion molecules in regulation of spatiotemporal dynamics of cell adhesion during neuronal migration . KawauchAs somal translocation occurs in a saltatory manner, this step would not be explained simply in terms of a balance between the leading process tension and somal adhesion. Since the nucleus is the largest organelle in the cell body, its movement, nucleokinesis, is critical for somal translocation . AccumulOn the other hand, in the case of cerebellar granule cells, F-actins do not accumulate at the rear of the nucleus . In addiLive-cell imaging analyses demonstrated that somal translocation is preceded by a swelling of the proximal part of the leading process and forward movement of the centrosome into this swelling . AccumulSome of neuronal progenitor cells, for example the cranial neural crest and zebrafish PLLP, migrate as cell clusters during development . In addi2+ imaging analyses demonstrated transient increases in Ca2+ concentration in the cell body of cerebellar granule cells, which positively correlated with their somal translocation (2+ increases and F-actin accumulation at the rear of the nucleus, resulting in inhibition of somal translocation (2+ increases are involved in the activation of actomyosin to trigger nucleokinesis. Similarly, shootin1b underwent dynamic accumulation at the leading process growth cone of migrating olfactory interneurons, which positively correlated with leading process extension (With the aid of emerging mechanobiological approaches, the molecular mechanics underlying neuronal migration is beginning to be elucidated. In this review, we have described a current view of the forces that drive the two neuronal migration steps, leading process extension and somal translocation. Spatiotemporally organized forces produced between neurons and the extracellular environment, as well as intracellular forces, play pivotal roles to drive these migration steps. Diverse molecules may contribute to the generation of these forces, depending on the neuronal cell type. As an important question, it remains unknown how neurons can switch between these processes. Molecular and mechanical interactions between the leading process and the cell body should coordinate the two processes to achieve saltatory movement. Calocation . In addilocation . These rxtension . In addixtension . To undeTM and NI contributed cooperatively to the conceptual development, literature research, and writing of the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


To compare the mechanical characteristics of a percutaneous superior pubic intramedullary screw, percutaneous bridging plate and percutaneous screw-rod system of the anterior ring for the treatment of unilateral vertical pubic fractures to provide a reference for clinical application.A finite element model of pelvic anterior ring injury  was produced. The fractures were fixed with a percutaneous superior pubic intramedullary screw, percutaneous bridging plate and percutaneous screw-rod system of the anterior ring and their combinations in 5 types of models. The fracture stabilities under vertical, bilateral and anterior-posterior load were quantified and compared based on the displacement of the hip joints’ midpoint as quantificational index of fracture stability.In the condition of bilateral and anterior-posterior load, the vertical, bilateral and anterior-posterior displacements of the hip joints’ midpoint of different models were significantly different respectively. In general, the displacements of the 5 pelvic anterior ring fixations were ranked from maximum to minimum as follows: bridging plate, pelvic anterior screw-rod system, combination of bridging plate and pelvic anterior screw-rod system, superior pubic intramedullary screw and combination of superior pubic intramedullary screw and pelvic anterior screw-rod system.For the fixation in unilateral pubic fractures of pelvic ring injury, the percutaneous superior pubic intramedullary screw is optimal, the percutaneous pelvic anterior screw-rod system is the second choice, and percutaneous bridging plate ranks the third. The percutaneous pelvic anterior screw-rod system can significantly increase fixation stability of the percutaneous superior pubic intramedullary screw and the percutaneous bridging plate. In order to preserve life, it is impossible to perform time-consuming final reduction and internal fixation with more surgical trauma and much blood loss, at the early stage of treatment of pelvic fracture with combined injuries of important organs, blood vessels, and nerves. Furthermore, due to the distinctive anatomical and physiological characteristics of the pelvis, the pelvic injury has become timeworn when the patient’s general conditions turn to be stable. In this case, the difficulty of reduction and fixation has increased significantly. The deformity is difficult to be corrected, and the risk of intraoperative vascular and neurologic injury significantly increases. This situation is common in Tile C pelvic fracture with poor stability caused by severe injury. Therefore, in order to minimize the initial mortality rate and late disability rate of pelvic injury, it is particularly essential to perform early, rapid and minimally invasive replacement and internal fixation after an injury and on the precondition that the body can tolerate it.The importance of reconstruction of posterior ring stability is self-evident in the treatment of pelvic fractures. However, in terms of some Tile B and all Tile C pelvic injuries, it has been proved that only posterior ring fixation cannot satisfy the requirements of maintaining bone position. Previous biomechanical researches have demonstrated that the stability of any posterior ring-internal fixator complex does not match the normal intact pelvis , 2. TherSo far, primary minimally invasive treatments of the final internal fixation for the pelvic anterior ring includes percutaneous superior pubic intramedullary screw, percutaneous bridging plate and percutaneous screw-rod system of the anterior ring . How to The ethics committee of Yantai Shan Hospital approved the study. Informed consents were obtained from the individual participant included in the study.In this study, the three-dimensional finite element model of pelvis established by our series of researches was used, and the related parameters were in line with the relevant literature , 2, 4. TAccording to the size of screw, plate and screw rod, parametric design models was established to simulate the operation modes of the percutaneous bridging plate, anterior ring screw-rod system and superior pubic intramedullary screw to fix the pubic superioris. The superior pubic intramedullary screw was a cannulated screw with a diameter of 7.3 mm and a length of 100 mm. The screw was placed retrograde and located in the center of the safe area of the superior ramus of pubis, and the screw thread passed through the fracture line.The percutaneous bridging plate was a reconstructed plate on the surface of the pelvic anterior ring. Its proximal part was located nearby right anterior superior iliac spine, and the distal portion was located at superior ramus of pubis beside the pubic symphysis. Three cortical screws with 3.5 mm diameter and 15-32 mm length were placed at the plate proximal and distal ends respectively.The screw of the anterior ring screw-rod system was 6.5 mm in diameter and 80 mm in length. It was inserted from the anterior inferior iliac spine and pointed to the posterior inferior iliac spine. Boolean operations were performed on the pelvic bone and internal fixators to form fixation models.Simulated fixation modes were as follows: right percutaneous anterior ring bridging plate (P), right percutaneous superior pubic intramedullary screw (S), percutaneous anterior ring screw-rod system (R), the combination of right percutaneous anterior ring bridging plate and percutaneous anterior ring screw-rod system (P + R), the combination of right percutaneous superior pubic intramedullary screw and percutaneous anterior ring screw-rod system (S + R). Table  Figs. 1, 4 and 5Tie constraints were applied between the bone-implant interfaces except for the cannulated screw stem regions where the frictionless sliding contact was applied. Penalty contact with a friction coefficient of 0.3 was applied between the interaction surfaces of fractures. The longitudinal downward load, anteroposterior load and transverse load were simulated to imposed to pelvis respectively, and all of them were 600 N.Under three different loads, the displacements of the virtual right hip midpoint in vertical, transverse and anteroposterior directions were taken as the evaluation index of stability. The smaller the displacement, the better the stability.In the simulated bipedal standing situation, there was no significant difference among the vertical, transverse and anteroposterior displacements of the virtual hip midpoint in the models of bridging plate, superior pubic intramedullary screw, anterior ring screw-rod system and their combined fixations. Similarly, the results of the simulation of standing on 1 foot were almost the same as those of the simulation of standing on 2 feet mentioned above.Under the simulated anteroposterior loading condition, there were obvious differences among the virtual hip midpoint’s displacements in anteroposterior, transverse and vertical directions in three models of pelvic anterior ring single fixation, in which bridging plate was the largest, anterior ring screw-rod system was the second, and the intramedullary screw was the smallest. Comparing the models of single with combined fixations, it demonstrated that the assistant of the anterior ring screw-rod system significantly reduced the displacement of three directions in single bridging plate fixation and sole superior pubic intramedullary screw fixation, and the displacement of the model of superior pubic intramedullary screw combined with anterior ring screw-rod system was the smallest.Under the simulated left-right loading condition, there were obvious differences among the virtual hip midpoint’s displacements in anteroposterior, transverse and vertical directions in three models of pelvic anterior ring single fixation, in which bridging plate was the largest, and anterior ring screw-rod system was the second, and intramedullary screw was the smallest. Comparing the models of single and combined fixations, it illustrated that the assistant of the anterior ring screw-rod system significantly reduced the displacements of three directions in single bridging plate fixation and the displacements of left-right and anteroposterior directions in single intramedullary screw fixation, however there is no effect on the displacement of vertical direction in single intramedullary screw fixation. The displacement in the model of the combination of superior pubic intramedullary screw and anterior ring screw-rod system was the smallest.Generally speaking, under simulated anteroposterior and transverse loading conditions, the multidirectional displacements in all models were ranked from small to large as follows: the combination of superior pubic intramedullary screw and anterior ring screw-rod system, superior pubic intramedullary screw, the combination of bridging plate and anterior ring screw-rod system, anterior ring screw-rod system and pelvic anterior bridging plate. Tables , 3 and 4Antegrade and retrograde percutaneous pubic intramedullary screw technique avoids extensive exposure during operation via ilioinguinal approach etc., and achieves ideal clinical results. However, because of the risk of bladder injury, iliac artery and vein injury, and hip joint involvement, the cannulated screw is a relatively safe choice –7. If thCompared with conventional plate internal fixation, anterior ring bridging plate has the advantage of minimally invasive percutaneous implantation, which effectively avoids the pain of surgical site and incision complications,  and signAs an ‘inbuilt external fixator’, the pelvic anterior screw-rod system creates the principle of fixation above the acetabulum in order to stabilize the anterior pelvic ring by minimal screw and more minimally invasive means and to help fracture reduction by lateral compression and stretching. Although a biomechanical study concluded that the anterior subcutaneous pelvic ring fixator had no biomechanical advantage over the traditional external pelvic fixation,  the fixaThus, three kinds of pelvic anterior ring minimally invasive internal fixation methods have their own pros and cons. Further studies are needed about how to choose an effective and safe fixation method according to the specific traumatic condition, available hardware and technical level, and maximize the biomechanical advantages of various anterior ring internal fixations, so as to achieve the best effect of minimally invasive internal fixation, which helps to define the respective indications of the anterior ring minimally invasive internal fixation methods, pre-plan the operation pertinently and effectively shorten the preoperative preparation and operation time.In this study, it was found that under the simulated bipedal standing state, there were no significant differences in the vertical, bilateral and anteroposterior stabilities of the fractures between the models of the percutaneous superior pubic intramedullary screw, percutaneous bridging plate and percutaneous anterior ring screw-rod system and their combined fixations. Then, the state of standing on a single foot was simulated, and the results were similar to those of the state of standing on two feet. This suggested that the anterior pelvic ring contributed little to the overall vertical stability of the pelvis. Therefore, backward loads and right-and-left loads were applied to the pelvis to simulate the mechanism of open-book and lateral injuries. By comparing the displacements of the virtual acetabular midpoint in vertical, transverse and anteroposterior directions, the translation and rotation stabilities of three kinds of anterior ring fixations and their combined fixations on coronal, sagittal and horizontal planes were determined. The results show a significant consistency. Comparing the multidirectional stabilities of three kinds of anterior ring internal fixators’ independent fixation, the percutaneous superior pubic intramedullary screw is the best, the percutaneous anterior ring screw-rod system is the second, and the percutaneous bridging plate is the worst, which shows the significant mechanical advantage of intramedullary centraxonial fixation. Although the fixation effect of anterior ring screw rod system is affected by indirect fixation across pubic symphysis, it still shows better mechanical characteristics than bridging plate with eccentric fixation. Considering the material consistency of the three internal fixators, it can not be excluded that this result may be related to the bridging plate’s ‘congenital deficiency’ of thin and flat plate and short screws.In order to maximize the effect of internal fixation, it was planned to combine three kinds of anterior ring minimally invasive internal fixation devices in pairs. However, the superior pubic intramedullary screw and bridging plate could not be fixed simultaneously because of the limitation of anterior ring anatomy, so only the anterior ring screw-rod system was combined with the intramedullary screw and bridging plate respectively. The experiment shows that, compared with the independent fixation modes, the combined anterior ring internal fixation modes show obvious mechanical advantages, among which the combination of the superior pubic intramedullary screw and anterior ring screw-rod system achieves the most stable fixation effect. Although the combination of bridging plate and anterior ring screw-rod system is superior to their independent fixation, it is still inferior to the single superior pubic intramedullary screw. This suggests that in the clinical practice of fixing unilateral pubic fracture, superior pubic intramedullary fixation should be preferred as far as possible. In order to minimize the failure risk of internal fixation, it is suggested to combine superior pubic intramedullary fixation with anterior ring screw-rod system fixation.However, it is undeniable that in some cases, smaller pubic diameter, a variation of pubic curvature or non anatomical reduction of pubic fractures result in the unavailability of 7.3 mm and 6.5 mm screws, so 4.5 mm or 3.5 mm diameter screws are also used by some orthopedic surgeons. As mentioned above, it was reported that the risk of cannulated screw breakage increased when the screw’s diameter was less than 6.5 m m. In ordeFor unilateral anterior ring injury of type pelvic fracture, in general, there are obvious consistent differences in transverse, vertical and anteroposterior stabilities of the three internal fixations and their combinations; In terms of stability, the combination of percutaneous superior pubic intramedullary screw and percutaneous anterior ring screw-rod system is the best, percutaneous superior pubic intramedullary screw ranks second, percutaneous bridging plate with percutaneous anterior ring screw-rod system is the third, percutaneous anterior ring screw-rod system is the fourth, and percutaneous bridging plate is the worst; Percutaneous anterior ring screw-rod system can significantly increase the stability of percutaneous bridging plate fixation and superior pubic intramedullary screw fixation.


The injury to the spinal cord is among the most complex fields of medical development. Spinal cord injury (SCI) leads to acute loss of motor and sensory function beneath the injury level and is linked to a dismal prognosis. Currently, while a strategy that could heal the injured spinal cord remains unforeseen, the latest advancements in polymer-mediated approaches demonstrate promising treatment forms to remyelinate or regenerate the axons and to integrate new neural cells in the SCI. Moreover, they possess the capacity to locally deliver synergistic cells, growth factors (GFs) therapies and bioactive substances, which play a critical role in neuroprotection and neuroregeneration. Here, we provide an extensive overview of the SCI characteristics, the pathophysiology of SCI, and strategies and challenges for the treatment of SCI in a review. This review highlights the recent encouraging applications of polymer-based scaffolds in developing the novel SCI therapy. Spinal cord injury (SCI) constitutes a considerable portion of the global injury burden is mainly caused by falls and road accidents . In 2016The subsidiary cascades remarkably enlarge the initial injury into neighboring tissues, as well as the spinal cord portions, followed by neuronal and glial wasting, scar and cavity formation, proliferation and activation of microglia and astrocytes, decreasing the extension of the subsidiary injury but also inhibit axon rejuvenation by developing chemical, as well as physical barriers to axon regrowth . During In the last decades, significant research advances have been made in increased comprehension of the SCI pathophysiology. The vital therapies for acute SCI aimed at preventing ongoing direct SCI and neuroprotection to reduce the secondary damage. At the same time, the treatments for chronic SCI center on neural rejuvenation, plasticity, and rehabilitation treatment while there were no effective conventional therapeutic attempts to restore mobility and sensation following SCI .Even though significant advances have been made in the pathophysiology of SCI provides, many great promises have been made in improving therapeutic strategies for restoring function in animal models. The few approaches that have advanced to clinical trials have demonstrated insignificant or no efficacy in facilitating functional recovery . PresentThe currents advancements in material science have resulted in the use of novel biomaterials to promote effective tissue regeneration following SCI. Biomaterial therapies are intended to regenerate the anatomic structure, as well as the function in combination with cells and/or active biomolecules . RecentlThe phages of SCI pathophysiology include immediate, acute 60 (seconds to minutes), sub-acute (minutes to weeks), and chronic . Because of the elevated CSPG content in the glial scar, it is not astonishing that axon rejuvenation and plasticity are impeded after SCI. A crucial role of CSPGs in the adult central nervous system (CNS) constitutes the formation of the perineuronal net (PNNs), which of their potential to restrict plasticity in the CNS. Additionally, ECM biomolecules may escalate the rigidity of the bioenvironment, produce a physical barrier, as well as offer non-specific topographical cues; all of these can influence cellular movement. Interestingly, removal of suppressive ECM constituents, e.g., CSPGs, improves neurite proliferation.With the augmentation of inflammatory cells, oligodendrocyte progenitor cells (OPCs) and astrocytes become activated and under the scar formation. Though the scarring development aids in fixing inflammation reaction continued low-grade inflammation caused by macrophages, as well as the subsequent gliosis, reshapes the extracellular matrix (ECM) by increasing laminin, fibronectin, and collagen in the epicenter . The exaThe degradation and atrophy of axons in combination with the glial scar and cyst development poses a physical impediment to axonal rejuvenation after SCI . Finallyin vitro and in vivo. Oligodendrocytes contain many potent axon growth-inhibitory molecules, which are release following the SCI, participate in the barrier to axonal repair and growth. Because there are no currently approved treatments for restoring the mobility and sensation after SCI, the present therapy approaches for acute SCI are restricted to surgical decompression, and intravenous high-dose methylprednisolone (MP) whose clinical efficacy remains unclear  receptor were applied to protect neurons. Neurotrophins, including brain-derived neurotrophic factor (BDNF), facilitate functional recovery through regulating inflammatory cytokine levels  supported axon regeneration in peripheral nervous systems, and they have particularly been reported to enhance axonal rejuvenation in the SCI . OlfactoThe glial and fibrotic scars constitute a physical and chemical barrier to axon regrowth. Additionally, CSGPs and other repressor extracellular matrix biomolecules interact with receptors that inhibit axonal proliferation . TherefoA second treatment method aiming for the fibrotic and glial scars is the immature astrocytes into the damaged spinal cord. The transplantation of immature astrocytes into the lesion epicenter is another therapeutic method for the fibrotic and glial scar. Transplanted glial-restricted precursor cells, differentiated into oligodendrocytes, as well as astrocytes, alter the environment and reduce glial limitans development concurrent with supporting axon rejuvenation and sprouting .Meanwhile, astrocyte progenitor transplantation promotes remarkable plasticity of rVRG-PhMN circuitry, reduction of macrophage response, and restoration of diaphragm function .Schwann cells are neuroprotective and promote axon regeneration and myelination, which were comprehensively studied as a strategy for SCI repair. Schwann cells improve motor recovery through attenuation of the activity for inflammasome complexes and associated inflammatory circuits .Nevertheless, SCI remains to be a harmful condition with no cure. Cellular, rehabilitative, and molecular training and integrated therapies have shown potential results in animal models.In recent years, a variety of materials, including natural and synthetic polymers, have been used in the preparation of scaffolds for SCI .Natural polymers mainly include hyaluronic acid (HA), collagen, chitosan, gelatin, silk protein, alginate, fibrin, laminin, fibronectin, agarose, cellulose, dextran, and compound. Here are some of the most commonly used natural polymers.in vivo , polylactic acid (PLA), polylactic-co-glycolic acid (PLGA), and polyethylene glycol (PEG) and so on, which can be individually designed according to needs to make its performance controllable .N-linked glycosidic bonds. PSA regulates nerve cell development, nerve guidance, and synapse formation by changing the adhesion of nerve adhesion molecules in the nervous system, thereby playing a pivotal role in nerve development . PLGA is a degradable functional polymer organic complex with improved compatibility, non-toxicity, good encapsulation, and film-forming properties and is extensively utilized in pharmaceutical, biomedical engineering biomaterials, and modern industrial fields . In the Polyethylene glycol is non-toxic, non-irritating, has excellent lubricity, moisture retention, dispersibility, water-solubility, and has better biocompatibility with many organic components . In the The research on SCI focuses on multiple aspects, including mechanism research, stem cell therapy, genes therapy, drug screening, and tissue engineering. Among them, tissue engineering has an irreplaceable advantage for the treatment of SCI . Tissue Due to the high water content and variable mechanical properties similar to spinal cord tissue, high permeability, biocompatibility and degradability, hydrogels are focused on as the implants for SCI, which can meet the material exchange, metabolism and adhesion of nerve cells and be used as a carrier for various seed cells and bioactive molecules .Hydrogels have been widely used in regenerative medicine . In recein vivo  and fibronectin (FN), mucopolysaccharide (GAG), various collagen components and GFs. In addition, it is in a sol state at low temperature and can be converted into a gel at body temperature, which is very convenient for injection use.N-isopropylacrylamide), polyacrylamide, etc.], PGA, PLA, polyphosphazene, and PEG and so on, which can be individually designed according to needs to make their performance controllable  are currently used as bio-inks in many printing systems.Inkjet biological printing is an economic and effective technology adopts the control method of ink-jet printing technology can be well dispersed biological ink it allows and non-contact deposited at the same time the micron resolution cells in some direction in the technology is not high due to the biological ink viscosity, often leads to low mechanical properties of the structure. Inkjet printers contain thermosensitive and piezoelectric types. FDM technology uses filaments made from thermoplastic polymers to construct 3D structures. With the application of temperature, the filaments are heated in the nozzle to obtain a printable form (semi-liquid) and extruded onto the platform. Stereo lithography consists of ultraviolet lasers that focus on a hydrogel or resin that is photosensitized by the addition of a photoinitiator.in vitro, and design new clinical methods for the treatment of neurological diseases, including SCI , bone marrow MSCs, bone marrow MSCs are widely used in the research of repair of SCI.in vitro has the ability to differentiate into neurons and glial cells, they are defined as NSCs, however, compared with the NSCs in the brain, most of the ependymal cells differentiate into astrocytes, not observed neurogenesis after SCI. In addition, in response to injury, these generated becomes with reactive astrocytes, the final formation of glial scar.Neural stem cells are those that exist in the nervous system and have the potential of differentiation. In summary, NSCs have the following properties: (1) Self-sustaining. The characteristics of stem cells are maintained in daughter cells. (2) Self-renewal and proliferation. It can continuously divide. (3) Multiple differentiations. It can differentiate into neurons, astrocytes, and oligodendrocytes. (4) The ability to respond to diseases and injuries. After neural tissue injury, NSCs can generate neural cells through suitable activation, differentiation, and maturation to establish new neural networks. In the spinal cord, has been found that are arranged in the central tube of ependymal cells Induced pluripotent stem cell-derived sNPCs and OPCs were precisely placed in a 3D-printed biocompatible scaffold. Bio-printed SNPC differentiated and extended axons in microscale scaffold channels, and the activity of these neural networks was confirmed by physiological spontaneous calcium flux studies . Is testBone marrow stromal sell (BMSC) can produce a variety of neurotrophic factors, such as nerve growth factor (NGF plays), vascular endothelial growth factor (VEGF) and so on, in the process of repair of SCI patients, the above factors can regulate the neurotransmitter generated, adjust the survival of neuron, mediated the axon growth, also can rebuild the blood vessels, promote local the formation of new blood vessels, making neurotrophic improve, improve the survival of the nerve cells rate, is advantageous to prevent the secondary damage of patients with spinal cord tissue, improve the neuron axon regeneration function, reconstruction of nerve conduction function and alternative for myelination: medicine is generally believed that BMSC to the nerve cell phenotypic differentiation, table of neuronal specific marker protein, to replace damaged or death of nerve cells in the spinal cord; But studies have shown that if the number of differentiated cell too little, spinal nerve functional restoration of the phenomenon of solution of interpretation is difficult to use alternative cell differentiation, (3) phagocytosis: BMSC transplantation to the patients of spinal cord is damaged, can devour necrotic tissue, (4) inhibition against nerve regeneration of scarring bridge: BMSC can bridge in patients with SCI end, can make the work synapse formation; A BMSC transplanted to the site of SCI can provide a scaffold to promote axon regeneration and guide chemotactic axon forward growth. Studies have confirmed that the co-culture of BMSC and NSCs can induce the differentiation of stem cells into neurons for self-repair and promote the recovery of spinal nerve function in patients.In vivo studies of immune-capable mice showed that PNP hydrogel enhanced the retention of hMSC at the injection site and retained hMSCs locally for more than 2 weeks  hydrogel platform, utilizing the polyvalent non-covalent interaction between modified biopolymers and biodegradable nanoparticles, has shown promise for the inclusion and delivery of human mesenchymal stem cells (hMSCs) based therapy due to its extensive differentiation ability and the production of therapeutic paracrine signaling molecules,  2 weeks . Of this to form .Induced pluripotent stem cells are derived from differentiated somatic cells after a certain genetic modification. They have many advantages of stem cells. They have the self-renewal capacity and differentiation potential like ESCs, avoiding immune rejection and ethical issues. IPSCs serve as a source cell that can be directly obtained from tissues and used in autologous transplantation, have become a hot spot in the field of stem cell research at home and abroad. Neurospheres derived from human iPSCs implanted in the damaged spinal cord can survive and migrate there and transform into neuronal astrocytes or oligodendrocytes. Neurons differentiated by hiPSC-NSs can establish functional synaptic connections with host neurons, increase the expression of NGF, promote the regeneration of blood vessels in the injured area and the formation of myelin sheaths and neural precursor cells. After implantation of iPSCs, the injured spinal cord microenvironment can be improved by promoting the expression of VEGF, thus indirectly increasing the number of its own neurons and promoting the regeneration of distal spinal axon.Embryonic stem cells are highly undifferentiated cells with totipotency and the ability to differentiate into adult animal cells due to their high degree of undifferentiation. Since ESC is a totipotent cell that can differentiate into all tissue cells, including neurons, it is also currently considered as a seed cell with great potential for neurodegenerative diseases. ESCs from blastocysts, and has a developmental totipotency and can develop into three layer derived the ability of cervical SCI model, from the brain and spinal cord tissue of the embryonic spinal cord or spinal cord neural progenitor cells as a graft, transplanted cells can survive and differentiate into neurons cells, make the movement function of SCI model obviously improve. it is worth noting that the chest and amyotrophic lateral sclerosis, SCI model in the transplantation methods effect is good; In clinical practice, NSCs from embryonic tissue were transplanted to the site of cervical and thoracic SCI.Growth factors play an important regulatory role in the development and damage repair of the central nervous system. After SCI, the deficiency of endogenous GFs secretion and generation is another important factor inducing difficulty in nerve regeneration. Therefore, supplementing exogenous GFs will greatly promote SCI repair. However, due to its short half-life in the organism, it needs to be administered for many times, and the traditional intramuscular injection is difficult to pass the blood-spinal cord barrier, nor can it improve the local drug concentration in the damaged area, so its application in the field of SCI repair is severely limited. In this context, the emergence of engineering three-dimensional stents provides good prospects. In addition to combining 3D scaffolds with transfected stem cells as described above, directly combining GFs to form functional engineering 3D scaffolds also shows good therapeutic effects.in vitro, but also promote the recovery of SCI in vivo , BDNF, fibroblast growth factor (FGF), Glial cell derived neurotrophic factor (GDNF) and insulin-like GF have been used in combination with tissue engineering scaffolds for repair of SCI. NGF is one of the most important bioactive molecules in the neurotrophic factor family, NGF is not only abundant in the nervous system, but also widely distributed in the non-nervous system. NGF plays an important role in promoting the regeneration and neuroplasticity after the growth and demyelination of axons in the survival differentiation of neurons. In this study, a PLGA porous scaffold was prepared by phase conversion method, and the scaffold surface was modified with polydopamine (PDA) as substrate, and then the NGF was adsorbed to obtain the PDA-PLGA/NGF scaffold, PDA modification can significantly improve NGF adsorption capacity and provide continuous release of NGF PDA-PLGA/NGF scaffold can not only enhance NSC proliferation and neuronal differentiation  in vivo . Electro in vivo .Glial cell derived neurotrophic factor was isolated from the rat glioma cell line containing a 134 amino acid residues with dimers proteins, the molecular weight is 33∼35 kD, it is widely expressed in the central nervous system, and the expression of after puberty and damage increased GDNF in the neurons to protect glial scar reconstruction axon regeneration and sprout and then play an important role in myelination. GDNF can save the apoptosis of neurons after SCI. GDNF gene therapy with adenovirus vector can maintain the regeneration of neuron fibers and promote the recovery of motor function of the hind limb in spinal cord contusion. GDNF is a kind of neurotrophic factor, which plays an important role in neurotrophic aspect. GDNF can protect neurons from dying and necrosis, and it has a bidirectional regulation mechanism.Brain-derived neurotrophic factor is a small molecule dimer with alkaline secretion that has been isolated and purified from the pig brain. BDNF plays an important role in promoting neuronal survival and proliferation against neuronal apoptosis. It also stimulates neurite growth and protects axonal excised neurons.Basic fibroblast growth factor (bFGF) is a kind of neural protection because of the present study more, it is mainly distributed in the pituitary adrenal retina nerve tissue and placental tissue, such as the highest content of pituitary the main biological effects including bFGF promote tissue regeneration of the wound healing and tissue repair, and can participate in nerve regeneration, repair hair and in the central nervous system damage in has the vital significance. In addition, bFGF also plays a protective role in protecting the microenvironment from SCI by inhibiting nitric oxide toxicity and reducing free basal formation of stable cell calcium and magnesium ionized water.Will be equipped with NT-3 of the chitosan carrier inserted in the ridge pulp crosscutting clearance, the results show that with the Nestin, Tuj1 and NeuN positive cells in nerve tissue bridging the transection clearance, but also to sports and somatosensory evoked potential and hind leg movement significantly improve further confirmed that the chitosan carrier implants by causing endogenous neurogenesis to promote the formation of nerve tissue, improve the recovery of function.Small molecule drugs play a vital role in the treatment of various diseases such as anti-tumor, nerve damage, tissue repair, are a popular choice for clinicians and patients. Many small molecule drugs have been developed to promote the repair of the spinal cord. Such as cortisol hormones, immunomodulators, and traditional Chinese medicine extracts such as curcumin and ginsenosides. However, recent literature has suggested that the simple application of MP in the treatment of SCI cannot achieve satisfactory results, and the serious complications brought by the systemic high-dose application of MP cannot be ignored. 3D engineering scaffolds have unparalleled advantages as drug carriers and are an effective alternative.Methylprednisolone is the only drug approved by the FDA to treat SCI. MP is one of the types of corticosteroid hormone, can inhibit lipid peroxidation and edema after injury and so on support of the inflammatory response in the SCI repair but lately have been put forward, the application of pure MP for the treatment of SCI is not satisfactory, and systemic high-dose serious complications brought by the application of MP also not allow to ignore. Therefore, the use of stent-loaded MP for local release for the treatment of SCI is widely studied. MP was encapsulated in degradable PLGA NPs and embedded into agarose hydrogel to locate contusions, When through the hydrogel nanoparticles system conveying, MP into the SCI, and spread in the injury of spinal cord within 2 days about 3 mm to 1.5 mm deep and in addition, the local MP significantly reduced inflammation early delivery in the spinal cord contusion injury .in vivo and in vitro has obvious anti-inflammatory and neuroprotective activity PSM management can significantly prevent neurons and myelin damage, reduce the formation of glial scar, the recruitment of the lesion site endogenous NSCs, promote the regeneration of the neurons and the extension of the glial scar long axons, which largely improve movement function of SCI in rats and imposed a superior therapeutic effect , preparation of PSM for collaborative treatment in SCI in both c effect .L-lactic acid) (PLLA) microfibers, and it was confirmed that taxol released from well-arranged electrospinning microfibers promoted neurite extension in growth-friendly and growth-inhibiting environments , a neuroprotective drug, and paclitaxel (PTX), a neuroregenerative drug, to enhance tissue regeneration in rat SCI halfcut models, to this end, PTX-encapsulated PLGA microspheres were combined with MH into alginate brine gel. The continuous release time of MH and PTX in alginate hydrogel was over 8 weeks, Histological evaluation showed a reduction in inflammation after 7 days of dual-drug therapy. In addition, rats on the dual-drug regimen had reduced scar tissue and increased neuronal regeneration after 28 days. Over time, the animals receiving the dual–drug regimen showed rapid and sustained improvement in function compared with other groups . Taxol wronments .Curcumin is a natural polyphenolic compound extracted from the Traditional Chinese medicine curcumin, which has shown good efficacy in the repair of SCI. Curcumin can inhibit the neuritis reaction, reduce the formation of glial scar, reduce free radical release and lipid peroxidation in local nerve tissues and it can also reduce neuronal apoptosis and improve SCI microenvironment.Spinal cord injury is one of the most damaging human pathologies, severely impacting the quality of life and the overall society. Since the pathology of SCI is robust and evolving in nature with the progressive interplay between different molecular and biochemical cascades, therapies designed to control only one aspect of these cascades cannot modulate and control the parallel axes that indirectly or directly influence the selected axis. The first challenge is to prevent the progression of cascades of subsidiary injury. The second challenge is to regenerate the injured spinal cord and to restore neuronal connectivity. Therefore, we recommend tailoring the incorporation of biological and engineering approaches derived from the identified interplay between their respective mechanisms throughout recovery from SCI. In this regard, polymer-based therapy can play an essential role as it can hence neuroprotection and promote axon regeneration. Especially, polymer-based therapies can play a dual role in neuroprotective, as well as neurogenerative therapeutics and acting as a scaffold for tissue engineering and cell-based treatments to enhance rejuvenation. Additionally, the polymer, in combination with proliferation factors and the neuroprotective agent, could prospectively promote rejuvenation and functional recovery after SCI.Current polymer-based therapies have shown therapeutic prospectives in animal models, but their potential to mediate clinical improvements after SCI remains elusive. From our perspective, we recommend that combinatorial therapy paradigms primarily targeted to the chronic stage are further pursued in the field since there are millions of people globally suffering from SCI that are well past their moment of injury.MW, YW, and WQ conceived the article. WQ wrote the article with the support from BC. WS, HT, XO, and XZ revised the article and approved the final version. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We describe the basic principles of mental health care during the COVID-19 pandemic that should be endorsed by the mental health professional associations and incorporated in the health strategies for the management of the COVID-19 pandemic. The main principle is that there should be no substantial differences in the provision of health care for COVID-19 between persons with pre-existing mental health disorders and the ones without previous disorders. Subsequently, the organization of the health care should reflect that as well. These principles should (a) prevent the possible effects of stigmatizing attitudes toward mental health issues, possibly leading to potentially deleterious situations, such as psychiatric patients being treated (even temporarily) separately from other patients, in psychiatric facilities, where the staff is not equipped and trained adequately for the management of COVID-19; (b) highlight the fact that patients with mental health disorders are at greater risk for developing serious complications of COVID-19 infection due to other factors—they often smoke and have comorbidities such as hypertension, diabetes, all associated with higher morbidity and mortality from COVID-19 infection; (c) highlight that measures should be taken to minimize the risk of the spread of infection in psychiatric wards/institutions; (d) provide a general framework for the reorganization of mental health services toward the provision of services for persons in need, including frontline medical workers and patients with COVID-19 without previous mental health problems as well as for persons with pre-existing mental health problems under new circumstances of pandemic. The World Health Organization (WHO) developed following a series of events, with the first one of them being the International Sanitary Conference (in 1851), organized as an attempt of the Western countries to stop the spreading of cholera by maritime routes from Asia.Subsequently, series of activities were introduced to limit the epidemics and set the ground for achieving the global health, including the revision of the international lists of diseases and causes of death, prevention of malaria, biological standardization, control of tuberculosis, quarantine, unification of pharmacopeias, control of sexually transmitted diseases, international pandemic control, revision of the pilgrimage clauses, international control of habit-forming drugs, alcoholism, crime prevention, housing and town-planning, influenza, insulin, medical examination of immigrants, public health service, and radiotherapy in uterine cancer ,2. LayinWith the situation of the pandemic, the rise in stigma toward the vulnerable population or the population perceived as the source of danger is significant and may have deleterious consequences . More sp1.There should be no substantial differences in the treatment of SARS-CoV-2 infection between persons with mental disorders and those without mental disorders. The same care for physical health and safety should be available and provided to persons with pre-existing mental disorders and their close ones as to all other members of society. Concordantly, mental health services and staff should receive the personal protective equipment under the same epidemiologically justified conditions as other health care services.2.Health care policy makers and planners should envisage the unintended secondary consequences of the widely applied restrictive measures on non-pandemic related health conditions and illnesses as well as on various other socioeconomic factors alongside beneficial effects on controlling the pandemic, and ensure adequate resources to tackle the issues emerging from this unprecedented interruptions of social structures and functions. Having in mind the influences of social determinants of health, this may be of particular importance in the aftermath of COVID-19 pandemic. Here, of special importance are mental health disorders as not only are they generally prevalent, but may also affect previously, in that sense, presumably healthy populations, such as health care workers and other frontline responders. The pandemic context followed by comprehensive restrictive public health measures  may cause significant distress resulting in occurrence of mental disruptions and disorders in general, and of previously unaffected populations .3.Considering that the necessary restrictions implemented as security measures for the containment of the infection during the pandemic with SARS-CoV-2 also increase the risk of low adherence and interruption of long-term pharmacological treatments and of rehabilitative interventions of patients with mental health disorders, it is critical to ensure a rearrangement of psychiatric services in order to maintain the continuation of mental health care to all persons with pre-existing mental disorders. This may include several interventions: (a) organization of available (24/7) psychiatric liaison service in health care facilities for patients infected with SARS-CoV-2, on-line or in person, respecting all safety measures; (b) organization of available (24/7) on-line psychiatric liaison service in health care facilities for patients suspected of infection with SARS-CoV-2 or close contacts requiring isolation at home; (c) organization of available (24/7) psychiatric services in psychiatric facilities for patients with pre-existing mental health problems, on-line or in person, respecting all safety measures. These services should employ a proactive strategy in ensuring adherence to previous mental health treatment by actively contacting the patients, and ensuring support thought remote  services and ensuring services that allow the maintenance of previous pharmacotherapy . This may imply establishing a closer collaboration with general practitioners and pharmacists, as well as the introduction of e-medical documentation and remote  psychiatric services if there were not any.4.Persons with pre-existing mental disorders, but also persons with no known previous mental disorders may develop safety/life threatening behavior  during the infection with SARS-CoV-2. Agitation can also develop as a symptom of delirium, as part of the COVID-19 pneumonia, but also as a symptom of the abstinence from psychoactive drugs during isolation and/or during more focused physical treatment. These conditions, even though those usually require immediate psychiatric care and interventions should not be considered as an absolute indication for the admission to psychiatric facilities, especially if these are not adequately prepared for physical care. Instead, mental health services should be widely available as a consultation service, and urgent mental health care should be delivered in a separate unit of the same facilities where somatic care is provided, only for the duration of the imminent threat.5.It is necessary to employ all preventive measures to limit the spread of pandemics in psychiatric facilities. Population of patients with chronic mental health conditions present a group of persons particularly vulnerable for development of complicated COVID-19 illness, due to the presence of firmly established mortality risk factors, including smoking, comorbidities such as metabolic syndrome, hypertension, especially if they are of older age . In comb6.Mental health care should be organized following principles of holism, availability, and accessibility to patients and medical staff, according to good clinical practice and epidemiological principles. Secondly, it should be organized following the principles of collaboration with all other providers of mental health services. In that sense, there is a great need to adjust mental health services to be widely available to the most severely affected populations: (a) persons with suspected or with developed SARS-CoV-2 infection with psychiatric symptoms; (b) front line medical staff; (c) persons with pre-existing mental health problems; (d) all others which lives, health, and safety is severely affected by the pandemic and corresponding public health measures . As poin7.The term “social distancing” which is being widely used by government officials, media, and the public evokes associations of being rejected, isolated, and distanced, particularly among vulnerable groups such as those with mental disorders. For this reason, the technically correct term of “physical distancing” should be adopted and used instead of “social distancing” by all government officials, media, and the general public . It is a8.Professionals working in the field of mental health should be actively involved in the organization of the health care by providing education, guidance, and administrative framework/supporting documents to disseminate relevant information to policy makers, health care workers, and general public. Here they should not only serve as advocators for their patients , but may contribute significantly to anticipating the needs, planning, and delivering much needed mental health protection of the whole community.Thus, it is crucial that we learn from lessons from the past and assure that there is an equal level of health care for persons with mental disorders. While the WHO clearly stated that the management of mental disorders is listed among the essential health services to be guarantee during the COVID-19 pandemic , it is eExceptional times urge for exceptional measures. However, the burden of exceptional measures, if applied unwisely, tend to fall on the shoulders of those most vulnerable, further increasing already existing inequalities and inequities. Every strategy and measure of battling the pandemic has its’ efficacy, efficiency, and safety profile. The public health ethics stance should be promotion and provision of equality for all persons and just distribution of harms and benefits within a society. In that sense, advancement of societies could be measured on how their members treat the most vulnerable among them, not only during peaceful and prosperous times, but also, or even more indicatively, during demanding times marked by widespread and omnipresent uncertainties.


Because of its importance, the metabolic interplay between the gut microbiome and host metabolism has gained special interest. While there has been great progress in the field driven by metagenomics and experimental studies, the mechanisms underpinning microbial composition and interactions in the microbiome remain poorly understood. Genome-scale metabolic models are mathematical structures capable of describing the metabolic potential of microbial cells. They are thus suitable tools for probing the metabolic properties of microbial communities. In this review, we discuss the most recent and relevant genome-scale metabolic modelling tools for inferring the composition, interactions, and ultimately, biological function of the constituent species of a microbial community with special emphasis in the gut microbiota. Particular attention is given to constraint-based metabolic modelling methods as well as hybrid agent-based methods for capturing the interactions and behavior of the community in time and space. Finally, we discuss the challenges hindering comprehensive modelling of complex microbial communities and its application for the  For instance, composition changes of the intestinal microbiota drive ecological interactions among microbial populations and the host Experimental elucidation of microbial interactions is challenging as the number of possible relations grows exponentially with the number of species in the community, thereby hindering implementation of conventional experimental designs. On the other hand, computational methods can readily simulate and propose plausible biological interactions within the gut community, which can be later verified experimentally In this review, we review the most relevant metabolic modelling tools for inferring the composition, interactions, and ultimately, the biological function of the constituent species in a microbial community with particular emphasis on the human gut microbiota. Following a brief overview of relevant CBM methods for community modelling, we present recent tools and applications for describing microbial community behavior in time and space, with emphasis but not limited to the human gut. Both time and space dependencies are critical for shaping the collective behavior of the community 22.1Genome-Scale Metabolic Models (GSMMs) are mathematical structures derived from GEnome-scale Network REconstructions GENREs; A. The laThe availability of genome sequencing data supported by (semi)automatic tools for GENREs construction has led to the emergence of various network reconstruction resources for exploring the behavior of microbial communities. The most comprehensive resource is AGORA, which is an open repository of over 800 semi-automatically reconstructed GENREs of microorganisms from the human gut 2.2From a defined GENRE, a GSMM can be constructed by mathematically encoding the metabolic reactions in the stoichiometric matrix, which represents the mass balances for each intracellular metabolite located inside the cell. Then, the imposition of the steady-state assumption for the latter enables writing a system of linear equations that represents the metabolic state of the system, here the metabolic network B. AlthouThere are four types of CBMs that have been employed for modelling microbial communities 3Genome-scale metabolic tools can be categorized according to their mathematical features or biological/ecological scope. Using the latter criterion, we review the most relevant and recent tools for modelling the composition, interaction and biological function of microbial communities A. The pr3.1Metagenome samples can be sequenced for their 16S rRNA content to determine the species and their abundance – as determined by the number of reads – in the microbial community A recent CBM for microbial composition prediction is SteadyCom The change of microbial composition over time is of great importance for understanding biological interactions. For this task, d-FBA is the most used CBM for metabolic modelling. μbialSim is a d-FBA-based simulator that describes the dynamic evolution of the biomass composition and metabolite concentrations in a microbial community growing in batch culture B [49]. NSimulation of community growth in time and space and assuming different objectives has also been achieved. For instance, d-OptCom 3.2Bacteroides and Eubacterium genera to be responsible for acetate and propionate consumption, respectively, while Shigella and Escherichia genera were responsible for their production, which is not been commonly reported in vivo. Additionally, MICOM showed that competition was a common interaction between almost all members of the gut microbiota due to the large set of metabolites that could be consumed. Notably, simulation results also suggested niche partitioning in the gut microbiota  from the environment, whereas cross-feeding (syntrophy) describe the exchange of metabolites from one organism to another . The previously mentioned MICOM method has been applied to simulate cross-feeding interactions involved in SCFA production Lactobacillus rhamnosus and Caco-2 cells. CASINO E. coli auxotrophs By using different metabolic reconstructions from various sources, the Microbiome Modelling Toolbox (MMT) Faecalibacterium prausnitzii and Bifidobacterium adolescentis in the gut microbiota. In this case, F. prausnitzii was predicted to produce four times the amount of butyrate in co-culture with B. adolescentis, which was in agreement with experimental data Pseudomonas putida and Pseudomonas veronii. More specifically, simulations predicted the growth of facultative anaerobes with the concomitant production of acetate in the center of a soil aggregate under wet conditions, whereas in the outer region, aerobic growth was sustained by the produced acetate. Another agent-based method called MiMoSa Trichodesmium erythraeum, and accurately predicted the differential activation of biochemical pathways by varying the weights of the objective function according to cell size. This function prioritized biomass production at small cell sizes and production of either glycogen or cyanophycin for larger cell sizes below the threshold of cell division. Although these tools have been deployed for simulating environmental habitats, they can be readily applied to represent other situations such as proliferation of infectious bacteria in human tissues like the lungs or aerated epithelial tissues colonized with microbes like the mouth As mentioned in the previous section, agent-based modelling methods are both useful for capturing the dynamic and spatial distribution of species and flexible for integrating results derived from FBA. For instance, Agent and Constraint-Based Modelling Framework ACBM, D [18] saenabled  when the metabolic network of another organism interacts in a simulated co-culture per se, it can be readily implemented within a CBM framework, for example, for better understanding how mutualistic interactions may be affected by media composition.Finally, the study of pairwise interactions of mutualistic nature, or between two closely interrelated cell types, might be complemented with the quantification of the metabolic support that each species brings to the other. To this task, the Metabolic Support Index (MSI) quantifies the number of reactions of a metabolic network that are 3.3The biological role or function of a community depends inevitably on environmental factors such as nutrients and oxygen availability, light intensity, shear forces, water activity, or temperature. To appropriately capture this interdependency, the time evolution and spatial distribution of the cells and molecules need to be described. These are particularly the cases of ACBM, InsiMeSH, and MiMoSa.Pseudomonas stutzeri A1501 under wet and dry conditions of soil. Under dry conditions, the entire population was in fully aerobic metabolism thanks to oxygen penetration, whereas under wet conditions, nitrate consumption was predicted  in silico tools A more detailed understanding of the composition, metabolic interactions, and ultimately, biological functions of microbial communities within a given environment will enable the design of synthetic consortia with desired functions. Synthetic communities have already been used in bioremediation Álvaro Altamirano: Conceptualization, Writing - original draft. Pedro A. Saa: Conceptualization, Writing - original draft, Writing - review & editing, Funding acquisition. Daniel Garrido: Conceptualization, Writing - review & editing, Funding acquisition.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.