Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma. It is a clinically and morphologically heterogeneous entity that has continued to resist complete subtyping. Molecular subtyping efforts emerged in earnest with the advent of gene expression profiling (GEP). This molecular subtyping approach has continued to evolve simultaneously with others including immunohistochemistry and more modern genomic approaches. Recently, the veritable explosion of genomic data availability and evolving computational methodologies have provided additional avenues, by which further understanding and subclassification of DBLCLs is possible. The goal of this review is to provide a historical overview of the major classification timepoints in the molecular subtyping of DLBCL, from gene expression profiling to present day understanding. Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in the western hemisphere . DiagnosIt was not long ago that the diagnosis of liquid tumors rested on morphology, immunohistochemical analyses, and cytogenetics. The original diffuse large B-cell lymphoma (DLBCL) molecular subclassification followed the advent of DNA microarrays, a technology that allows the analysis of thousands of expressed genes simultaneously; see Although the study population was small by current standards, with imperfect subtyping, the classification was adopted and continues today as the standard of diagnostic care, recognized within the World Health Organization’s Revised Fourth Edition of the Classification of Tumors of the Hematopoietic and Lymphoid Tissues  as germiDespite the reasonable success of standard CHOP and R-CHOP, and the growing number of precision therapies, heterogeneity remained an issue, as evidenced by inconsistent treatment responses and relapses despite COO subtyping. Although gaining favor and resolving power, it was thought perhaps that the transcriptionally based GEP was an inadequate representation of underlying aberrant genetic programming . However, practically, other technical hurdles, such as the logistical necessity for fresh tissue specimens, stood in the way of immediate clinical adoption of GEP in the subcategorization of DLBCLs. Initially, this was a difficult step to overcome, however several novel testing options were eventually able to surmount this issue, including Nanostring , HTG 1010, and RMYC aberrations along with MYC IHC over-expression. Other studies using mouse modelling also supported the molecular ideas emerging from GEP, showing oncogenic driver mutations in genes such as EZH2 and MYD88 that promoted lymphoma development . It. It66]. MYC and BCL2 and/or BCL6, helps to identify double-hit or triple-hit, high grade B-cell lymphoma with even poorer outcome and the need for more intensive treatment plans [In countries with limited resources, following H & E review, an immunohistochemistry panel with the markers for CD20, CD5, CD21, and Ki67 reaches a correct diagnosis of DLBCL in 83% of the cases . Cytogennt plans . After an initial histopathological workup, the specimen could be analyzed using a targeted sequencing panel of a limited set of genes either by sending to a sequencing company or to a central hematopathology laboratory. A more centralized or standardized approach would allow collection of additional data regarding predictive biomarkers, and eventually attribution to clinical trials. The classification of DLBCL has come a long way, and molecular techniques have provided a wealth of information to the underlying pathophysiology, prognostic, diagnostic, and therapeutic implications. Even at the time of writing and publishing this review, there will be undoubtedly be updates, if that is any indication of the speed of development in molecular techniques and novel technology that are able to further enhance our understanding of this heterogenous and diverse lymphoma.


The gut microbiota (GM) is a complex and dynamic population of microorganisms living in the human gastrointestinal tract that play an important role in human health and diseases. Recent evidence suggests a strong direct or indirect correlation between GM and both male and female fertility: on the one hand, GM is involved in the regulation of sex hormone levels and in the preservation of the blood–testis barrier integrity; on the other hand, a dysbiotic GM is linked to the onset of pro-inflammatory conditions such as endometriosis or PCOS, which are often associated with infertility. Exposure to endocrine-disrupting chemicals (EDCs) is one of the main causes of GM dysbiosis, with important consequences to the host health and potential transgenerational effects. This perspective article aims to show that the negative effects of EDCs on reproduction are in part due to a dysbiotic GM. We will highlight (i) the link between GM and male and female fertility; (ii) the mechanisms of interaction between EDCs and GM; and (iii) the importance of the maternal–fetal GM axis for offspring growth and development. In this perspective, we will describe mounting evidence that suggests a damaging effect of endocrine-disrupting chemicals (EDCs) on the gut microbiota (GM), and we will bring experimental, clinical, and epidemiological evidence that shows how dysregulation of the GM eubiotic condition might be the linking ring between EDCs and male and female infertility. Whilst this dysregulation of EDCs on the GM is evident during adult life, we will suggest that it might occur also during the early post-natal phases of life and fetal development, speculating, for the latter, a possible transgenerational effect.The GM is a complex and dynamic population of microorganisms living in the human gastrointestinal tract that exerts biochemical functions otherwise absent in the host. GM is considered a hidden metabolic organ of the human body influencing human health and diseases . ParticuThe main GM phyla are Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, Fusobacteria, and Verrucomicrobia, with the former two representing 90% of the whole population .The GM is a potential controller of wellness and disease. As demonstrated by experimental, clinical, and epidemiological evidence, a dysbiotic microbiota  is implGut eubiosis is pivotal also for the maintenance of the intestinal barrier integrity, essential to prevent the so-called leaky-gut syndrome (LGS), a condition that causes intestinal permeability resulting in the permeation of antigens, endotoxins, and pathogens and the altered production of neurotransmitters and metabolites such as short-chain fatty acids, leading to chronic low-grade inflammation, a state linked to the development of several diseases .Furthermore, increasing evidence suggests that the acquisition and development of a healthy microbiota in the infant are pivotal to exerting long-lasting beneficial effects in disease prevention . The matExtensive microbial colonization takes place post-partum  through Several factors can affect GM composition and homeostasis, and EDCs are among the most critical . EDCs arBifidobacterium longum, a key microbial species for normal gut colonization and development  and their role in the regulation of spermatogenesis .This condition determines: (i) the activation of specialized receptors known as pattern recognition receptors which serve as MAMP sensors that recognize the essential microbial components and trigger an immune response; (ii) Langerhans islet inflammation; and (iii) gastrointestinal hormonal changes with insulin resistance and the alteration of LH, FSH, and free T levels .Moreover, a novel role for the GM in the regulation of testicular development and function has been outlined, demonstrating the involvement of the GM in the regulation of the endocrine function of the testis and the integrity of the blood–testis barrier (BTB) .Noteworthy, in addition to the GM, the testicular microenvironment is not completely sterile, containing low amounts of Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. Although the role of testicular bacterial species in the testis remains to be elucidated, it has been suggested that these microbes play an important role in regulating and shaping the immune response in the testis. The gut microbes and testicular microbes together can influence human reproduction, as demonstrated recently in the study of Zhang et al. , in whicIn addition, these authors suggested a link between gut microbes and testicular microbes since testicular bacterial microbiome modifications observed in iNOA men were similar to those previously reported in the gut of elderly individuals .Altered intestinal flora can contribute to increased serum trimethylamine-N-oxide levels, promote vascular inflammation leading to cavernous endothelial and smooth muscle cell damage and to the development of erectile dysfunction .Clostridium tyrobutyricum can restore the blood–testis barrier integrity [EDCs can cause dysbiosis of the GM with consequent alteration of both the function and the anatomy of the intestinal barrier, activation of the immune system, development of metabolic disorders, and IR which, in turn, affect spermatogenesis and sperm viability . La Merrntegrity .EDC exposure during adulthood has been clearly associated with negative effect for human health; however, EDC exposure in both pre- and post-natal periods may exert even worse consequences: Firstly, because in this phase the human gut is much less resilient and much more responsive to external and environmental factors than the adult gut. Indeed, fetuses are exposed to a greater risk than adults from food contaminants due to their higher absorption rate, poor detoxification and elimination capacity, faster cell proliferation, and the still immature DNA repair mechanism . SecondlPrevotella, and P. copri and causes gut dysbacteriosis in the offspring with also an increase in seminiferous atrophy and spermatogenic cell apoptosis [For instance, it has been recently highlighted that gestational EDC exposure causes serious damage to the reproductive system in male offspring along with disturbing the GM. Gestational exposure to dibutyl phthalate determines an increased abundance of Bacteroidetes, poptosis . Moreovepoptosis . Lastly,poptosis  and malepoptosis ,97 in thpoptosis .Lactobacillus and Bifidobacterium can affect DNA methylation by regulating methyl-donor availability through their production of folate [A key point now is the understanding of the underlying mechanisms regulating the observed transgenerational effects. In this regard, some authors speculated that specific GM strains can induce epigenetic changes in the host genes relevant to immunological, metabolic, and neurological development and functions . For insf folate , or, viaf folate ,101. Morf folate . For insf folate  reportedf folate .The exact mechanism by which GM chemically modulate epigenetic marks remains to be clarified. The existence of a “microbiota–nutrient metabolism–host epigenetic” axis has been postulated . AccordiIn the era of precision medicine, a better understanding of the role of GM in reproduction opens the possibility to develop novel strategies to prevent or treat infertility and the diseases associated with it, such as maternal dietary modification , probiot


Beyond the physical transmission of COVID-19, the pandemic has had far-reaching consequences in Bangladesh, including social and cultural implications. This review paper aimed at identifying and synthesizing the costs of COVID-19 on sociocultural issues in Bangladesh. For this purpose, we conducted a systematic search in MEDLINE, PubMed, ProQuest, Web of Science, Scopus and Google Scholar up to August 2021. Studies related to the costs of COVID-19 were identified, tabulated, analyzed, and synthesized by using a thematic approach. Our final synthesis of 19 studies resulted in five analytical themes: (i) disruption in education, (ii) loss of everyday social interaction, (iii) increase of “new poor” and suicide, (iv) rise of violence against women, and (v) worsening the life of refugees. Our findings showed that the costs of disruption in education, loss of everyday social interaction, and increase of “new poor” and suicide were more evident. Finally, we recommend the government and the community to adopt some integrated actions and policies to combat the problems in improving Bangladeshi sociocultural situations. In December 2019, a novel coronavirus emerged in Wuhan, China (COVID-19), and rapidly spread across the globe to several other countries, becoming a threat to public health globally . Within Bangladesh, a South Asian densely populated developing country with a total population of nearly 166 million estimated in 2021  is facinAs the pandemic evolves, the discussion on sociocultural consequences becomes more relevant. In line with the definition, the term sociocultural includes a combination of social and cultural factors .. The isThe COVID-19 pandemic has had far-reaching consequences beyond the spread of the disease itself and efforts to quarantine it, including cultural and social implications . A sociaConsidering the loss and crisis of COVID-19 pandemic discussed above from a sociocultural perspective, a systematic review would benefit to assess and evaluate the current as well as tackling future pandemic consequences from both cross-country and cross-cultural perspectives. Therefore, to move forward with a systematic review, Bangladesh would be an impactful choice as it belongs to the list of developing countries, which also has suffered subsequently from the COVID-19 pandemic. However, a few literature reviews were undertaken in terms of COVID-19 in Bangladesh, and these were limited to identify the physical transmission rate, economic loss, food shortage and mental stress. For instance, most studies revealed the infection rate of coronavirus, human-to-human transmission, the number of new cases and mortalities . Two stuThis review follows the recently updated PRISMA guidelines for reporting systematic reviews  as this This review used five electronic databases: MEDLINE, PubMed, Web of Science, Scopus, and ProQuest Sociological Abstract, along with additional searches incorporated Google Scholar and Google. The search was completed between April to August 2021 as the case of coronavirus in Bangladesh started in March 2020. Studies from additional searches were included as studies identified from databases were not enough to find the real picture. The search included medical subject headings (MeSH) and text words for social, impact, and coronavirus. The Population, Intervention, Comparison and Outcome (PICO) model was used to develop search terms from the research question. The utilizing search strategy included keywords: “COVID-19,” “COVID-19 pandemic,” “coronavirus,” “sociocultural crisis,” “sociocultural impact” and “Bangladesh.” Detailed search strategies for each database are shown in N = 1646). To study relevant studies from databases, the title of each study was first read and then the abstract. If the abstracts were found relevant to the sociocultural costs of COVID-19, we read the whole study and included them in the review. Studies were read by the four authors  for crosschecking of information.The study adopted the PRISMA flowchart , which hInclusion and exclusion criteria are listed in The quality of the selected studies was assessed by using different assessment criteria as this review included studies from different approaches. The quality of the qualitative studies was assessed by using the critical appraisal skill program (CASP) checklists , which aThe cross-sectional quantitative studies were assessed by using the Critical Appraisal Checklist , which iTo count a total score and quality of the papers  and cross-sectional. So, thematic synthesis was used to synthesize the secondary results. There are trends of using thematic synthesis for social research . ThematiThis synthesis approach has three stages of data analyses: Free line-by-line coding, organization of “free codes” to construct “descriptive” themes and the development of “analytical” themes. Two reviewers (SKC and MRK) independently coded each line of verbatim text labeled “results” or “findings” within the 18 studies. The text included participant quotations, themes, subthemes and findings of the original authors. Afterward, discrepancies of codes were minimized with the presence of all authors, and five themes were generated from codes or subthemes . Two revAs shown in Following the assessment of 19 studies, 12 were found high, five were good, and two were poor in quality –6. StudiFive key themes related to the sociocultural costs of coronavirus emerged from the analysis of studies included in this review. The themes are (i) disruption in education, (ii) loss of everyday social interaction, (iii) increase of “new poor” and suicide, (iv) rise of violence against women, and (v) worsening the life of refugees.This theme included six studies , four ofIn the mid of March 2020, the government of Bangladesh declared the termination of schools, colleges and universities until further notice comes for reopening . AlthougIn addition, students, on the one hand, could not meet with teachers and peer mates to discuss such academic matters , on the Thus, the consequences of on-spot study closure are divided into two: academic and non-academic issues. In the first case, two studies including one review and one quantitative study identified that all final examinations of students were postponed and consequently delayed from timely completion of studies and traveling abroad for higher studies . The nonTherefore, long delays in studies not only delay study completion, but also lessen the job entry probabilities, daily social interactions and the normal student life of the youth.This theme consisted of six reviewed studies , of whicA qualitative study from A narrative review from Thus, it is clear from the findings that social isolation was evident among students, mass people, people with illness, healthcare staff and religious devotees.This theme included 11 studies , which rSeveral studies  depicted… COVID-19-related negligence in getting treatment by Bangladeshi healthcare providers. … a woman committed suicide at a hospital because she was not treated, and doctors and nurses suspected she was infected with COVID-19 and did not want to get infected themselves. , p. 1A quantitative study from Hence, the findings indicate that COVID-19 has increased the number of new poor and suicide rates in Bangladesh and that most victims are young people.This theme included six studies , of whicA quantitative study conducted by Moreover, women faced gender-based discrimination during the pandemic, for example, the pressure of extra efforts required by women to manage increased household chores . The ecoApart from the violence against women, another alarming fact that has been revealed by In short, there has been an increase in violence against women and girls by men in verbal and physical forms during the pandemic.The theme of worsening the life of refugees incorporated four studies , two of The COVID-19 pandemic resulted in panic and significant health concern for people from minorities such as the refugees. The pandemic period was found to affect the high population density of refugee settlements with various profound consequences. A quantitative study has predicted that 92% of people could become infected after a single introduction of the virus . In thisA mixed methods study undertaken by This systematic review aimed to identify and synthesize costs of COVID-19 on the sociocultural issues of Bangladesh. In the current systematic review of 19 studies, we found that the COVID-19 pandemic had several sociocultural costs, such as educational discontinuity, loss of social interaction, increase of poverty and suicide, rise of violence against women and worsening the life of refugee. These sociocultural costs resulted in the precarious lives of youth due to educational disruptions and the individualistic lives of the masses due to the loss of social ties. In addition, the lives of poor people, women and refugees became vulnerable and unequal due to the increase of poverty and violence, and the deterioration of living standards. The present study is the first systematic review and thematic synthesis in which the sociocultural costs of COVID-19 in Bangladesh has been contextualized from the existing literature, which is expected to be helpful for the social policy and practice.The first key finding of this paper showed that due to COVID-19, the prolonged shutdown of educational institutions in Bangladesh and the online education system caused immense disruptions to students’ learning process, such as lack of concentration during distance learning and access to library resources. This finding appears similar to The second major finding of this study is that the COVID-19 pandemic caused a massive loss of social interactions not only for students but also for the community people. The same situation is also found in another study where it is reported that the usual ways in which individuals interact and obtain social support were severely disrupted . Also, tThe third finding of our review showed that the new poor in Bangladesh during COVID-19 is increasing due to unemployment, low income-generating activities and fewer opportunities to involve new manpower in the production process . This neThe fourth key finding of this study showed that the COVID-19 lockdown increased violence against women. Due to the prolonged lockdown, men had to stay at home for a long time, which in turn led them to engage in different abuse against women . LikewisThe final finding of this current study showed a worsening living situation of the Rohingya refugees in Bangladesh. The refugees generally have limited access to transportation, remote and poor healthcare, education, economic activities compared to the majority of the country’s population. The lockdown situation even made it worse for the refugees staying in Bangladesh such as introducing a gender difference in early marriage and food consumption . This stTo contextualize the strength of this study, the results and discussion sections would contribute to global readers. Although the results section presents information only from Bangladeshi perspective, the discussion section compares and contrasts the results of the review with existing world literature. Therefore, to our consideration, countries from both developed and developing contexts may find this study significant while documenting the evidence and articulating prospective policies and planning to fight the sociocultural costs which arose from this current and may occur from any future pandemic. To minimize bias, we employed rigorous search methods, including an extensive and comprehensive search and data extraction by two independent reviewers. However, as only studies written in English were included, we may have missed studies published in Bengali, which would improve the insights of our review. We were unable to include studies in Bengali as there was a paucity of Bengali language literature related to the sociocultural impact of COVID-19. Furthermore, since almost all studies were conducted in Bangladesh, the results and policy-making issues may not be related to developed countries. Since the studies included in the study were from different backgrounds, multiple assessment criteria were used, which could reduce the consistency of assessing.This systematic review has analyzed the literature on the sociocultural costs of the COVID-19 pandemic in Bangladesh. This review identifies that long-term disruption in education has led to students’ lack of focus on studies, academic and job uncertainty and threats to normal life. The loss of social communication has made all classes of people lonely and individualistic. Some new social problems have been raised, such as new poor, suicide and violence against women by their partners. Also, the marginal people such as Rohingya faced widespread food insecurity and the upsurge of COVID-19.We suggest greater attention from the government and community level on initiating integrated actions and policies to combat the problems identified in this review paper. Moreover, to assess the situation further, research-oriented policies and recommendations would best serve the country to tackle the long-term effect of the COVID-19 pandemic. Thus, based on the findings of the review, the following policy recommendations can be taken to improve the sociocultural costs of the long-term COVID-19 crisis in Bangladesh and other nations which are suffering from similar crises:Although educational institutions have been reopened, an integrated approach combining both the government and stakeholders, such as teachers or students should be considered to work with the recently suggested United Nations recommendations in order to avoid risks: (a) suppress transmission of the virus and plan thoroughly for school or other institutions reopening, (b) protect education financing and coordinate for impact, (c) build resilient education systems for equitable and sustainable development and (d) reimagine education and accelerate change in teaching and learning ;The general people should be persuaded to maintain social contact through appropriately distanced in-person visits and digital methods of communication;To reduce shadow pandemics- poverty, unemployment and suicide as well as violence against women- necessitating coordinated measures not just from the government and law enforcement authorities, but also a growing awareness among the public, should be taken; andThe government of Bangladesh and donors should ensure food security to scale up and increase in-kind and voucher food support in the Rohingya camps along with awareness-raising of the spread of COVID-19.


Heat stress has become a widespread concern in the world, which is one of the major environmental stressors and causes substantial economic loss in the rabbit industry. Heat stress leads to multiple damages to the health of rabbits, such as organ damage, oxidative stress, disordered endocrine regulation, suppressed immune function and reproductive disorders, ultimately, induces the decreased production performance and increased mortality. Nutritional approaches, including feeding strategies, adjusting feed formula, and supplementing vitamins, minerals, electrolytes, Chinese herbal medicines, and functional active substances to the feed, were reported to mitigate the detrimental effects of heat stress in rabbits. Therefore, elucidating the damage of heat stress to rabbits; proper management and nutritional approaches should be considered to solve the heat stress issue in rabbits. This review highlights the scientific evidence regarding the effects of heat stress on rabbit's immune function, endocrine, blood biochemical changes, antioxidant capacity and production performance, and the potential mitigation strategies of nutritional intervention to alleviate heat stress in rabbits; which could contribute to develop nutritional strategies in relieving heat stress of rabbits. During recent years, the rabbit meat production is growing in China and European countries to meet the increasing demands of diverse meat product, which has become a highly specialized industry . There aHeat stress is a condition where rabbits are unable to maintain a balance between heat production and emission. High ambient temperature in summer is easy to cause heat stress in rabbits, which brings a series of adverse effects to rabbit production . Heat stThe immune dysfunction in rabbits caused by heat stress through the regulation of brain, sympathetic nerve and adrenal cortical hormone . The symUnder high ambient temperature, the synthesis of hypothalamic thyroid stimulating hormone (TSH) is highly reduced, resulting in a decrease of TSH in the anterior lobe of the pituitary gland and a reduction of thyroid hormone in rabbits; the decreased thyroid hormone could lower the metabolic rate and heat production of rabbits . In the + in serum, besides the concentration of copper ion (Cu2+) in plasma is decreased, while Zn2+ is increased during heat stress  and hydrogen peroxide (H2O2), through the synergistic effect in the body to maintain the physiological function and prevent cell damage  are inhibited under high temperature, which significantly affects the function of testis and decreases the semen quality in male rabbits , 52. TheAs summarized in Carcass and meat quality traits of rabbits, such as tenderness and color, are crucial to consumer acceptance . To strein vivo  (1977) during summer , potassium chloride (KCl), potassium bicarbonate (KHCO3) and ammonium chloride (NH4Cl) to the diet or drinking water of rabbits plays an important role in restoring the acid-base balance of rabbits under heat stress. The NaHCO3 is a kind of electrolyte additive and acid-base regulator, which equips the function of dissolving mucus, invigorating the stomach, inhibiting acid and increasing appetite  improved the production performance and blood biochemical indexes of heat-stressed rabbits , zinc sulfate monohydrate (ZnSO4·H2O), zinc pyridine acid (ZnPic), bacitracin zinc, granular coated bacitracin zinc, amino acid zinc, and so on. They can act alone or interact with each other and are combined with vitamins for anti-heat stress. It is noted that the use of bacitracin zinc should be permitted by the local law. The release of trace elements to milk was increased when zinc was upregulated by 50% in the rabbit diet under heat stress, and the litter size and weight were significantly affected by Zn addition  requires zinc as substrates . It is aaddition . Becauseaddition .via activating insulin receptors, which in turn facilitates the entry of glucose into cells  and follicle stimulating hormone (FSH) in the serum of male rabbits , fructose content and total antioxidant capacity in seminal plasma were increased, while the MDA content was significantly decreased (−1) to the feed could increase the body weight and average daily gain of the rabbit under heat stress, improve GSH and CAT activities and reduce the serum MDA content  was reported to decrease the rabbit's mortality during heat stress  to the feed of New Zealand rabbits reduced the damage of rabbit intestinal mucosa structure during heat stress. In addition, Li et al.  is a functional additive which work as an important role in fatty acid metabolism and energy production . It playsal diet . Adding  quality . These b quality .−1 in basal diet) was also reported to enhance the growth performance, antioxidants indices and decrease the inflammatory responses and intestinal pathogens in heat-stressed rabbit  increases the conception rate, kindling rate, litter size, embryo quality and the ovulatory response (corpora lutea number and ovulation rate) in rabbit during heat stress  increases plasma testosterone concentration and GSH activity, sperm output, sperm cell counts, intact acrosome, sperm normality, while reduces sperm cells with abnormal tail and plasma MDA contents in male rabbits under heat stress. Abdelnour et al.  and milk production. The positive effects of essential oils mainly attributed to the antioxidant activity  supplementation at a level of 50 mg·kg−1 body weight could be effectively used to enhance heat tolerance, oxidative status and semen quality of rabbit bucks under heat stress. Al-Sagheer et al.  the negative impacts of heat stress by improving metabolism, redox status, and hormonal balance of rabbit does during summer, thereby increase the reproductive performance . The mode of action of plant extract is complex due to it contains a variety of active components, which still needs further in-depth researches.Plant extract has also been used to decrease the heat stress in recent year. Grape seed extract contains a lot of polyphenols, which are powerful free radical scavengers and antioxidants to decrease the oxidative stress and DNA damage . It has r et al.  suggestey et al.  indicate−1 of diet) in heat-stressed rabbit , which causes a series of unfavorable changes in immune function, endocrine, blood biochemical indexes and antioxidant capacity, thus negatively affecting the production performance  in rabbits. Therefore, researchers need to further study the physiological change caused by neuroendocrine under heat stress and figure out a holistic approach to attenuate the detrimental effect of heat stress on rabbits. The potential use of feeding strategies and nutritional regulation could be beneficial to ameliorate heat stress. Further studies should be attempted on the combination of several approaches for relieving heat stress and evaluating the efficiency and economic benefit in rabbit production.BB and W-CL: conceptualization and writing—review and editing. Z-LL, SP, and FC: selection and collection of bibliographies, and the data curation. Z-LL and FC: writing—original draft preparation. W-CL: supervision, project administration, and funding acquisition. All authors have read and agreed to the published version of the manuscript.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.


Based on this connectome and chemo-connectome databases, functional connection patterns and detailed chemo-connectome for monoaminergic nuclei were analyzed and visualized. These databases will aid in the comprehensive research of the mouse connectome and chemo-connectome in the whole brain and serve as a convenient resource for systematic analysis of the brain connection and function.The various brain functions rely on the intricate connection networks and certain molecular characteristics of neurons in the brain. However, the databases for the mouse brain connectome and chemo-connectome are still inadequate, hindering the brain circuital and functional analysis. Here, we created mice brain connectome and chemo-connectome databases based on mouse brain projection data of 295 non-overlapping brain areas and  The functions of the brain rely on its complex and delicate networks, in which certain neural connections are responsible for specific brain functions that include sensation, movement, cognition, and emotion. Mapping neural circuits’ organization and their function are fundamental and crucial for understanding our brain. Especially, delineating the connectome, referring to the connection networks in the whole brain , is chalCaenorhabditis elegans (C. elegans) and Pristionchus pacificus, as well as partial neural circuits of mice (such as the retina and portion of neocortex) and Drosophila   . Due to in situ hybridization (ISH) data from Allen Brain Institute and other reported data, the connectome and chemo-connectome for certain brain functions in mice whole brain were obtained  virus in wild-type C57BL/6J mice were downloaded from the Allen Brain Institute . The proSimilarity analysis: the connectome data were standardized by the z-score method, then the Pearson’s correlation coefficients between each pair of source areas were calculated based on their projection density toward target areas. The hierarchical clustering, a widely applied method , was appThe ISH images were registered to the standard atlas by the previously reported graphical user interface (GUI) based on the MATLAB platform . The proIn detail, the reference points were manually labeled on both common coordinate framework (CCF) images and ISH images. These points are usually located on the boundaries of brain structures, such as the cortex, ventricles, and the prominent regions with a special texture of ISH signals. To simplify the manual operation, the slice images would be trimmed and rotated. In addition, some points could be added to slice the image automatically depending on the relative position of existing atlas feature points. In some cases, the section plane of brain slice was inconsistent with the ideal coronal plane, which was generally presented in the standard atlas. However, the three-dimensional continuity of CCF made it possible to get a 2D atlas section at any angle. Moreover, with the help of angle rotation tool of GUI in MATLAB, the slant section was registered well. Once the reference point labeling was finished, a non-linear deformation field was calculated with these point pairs by the thin plate spline (TPS) method . Becausez-score method for better visualization. The data of the top 50 connection and monoaminergic nuclei connection are stored in The pheatmap, circlize, networkD3 package, and the corresponding codes  in R sofi = 1:2,000 was used to display the top 2,000 connection network. According to different purposes, the parameters can be adjusted, and the function-related mesoscale connection data can also be imported into the projectv file for display. The codes of these files are provided in A data storage file brain.mat containing three-dimensional coordinates and connectome data of the 295 nuclei were created, which can be easily processed by MATLAB. Moreover, the script file 3d-brain.m was imported into MATLAB for visualization. Line 30 of the script command for As described in the methods part, we created the connectome database for mice brain. To obtain an overview of mice brain connectome at the mesoscale level, a three-dimensional illustration of the top 2,000 connections in the whole brain of mice is displayed in Further, we performed a three-dimensional display of connection networks for certain brain functions. Auditory and olfactory functions are relatively conservative across species, basically important for survival, and also well studied . Here, tFor olfactory function, the top 20 input and output networks of five major nuclei, i.e., anterior olfactory nucleus (AON), olfactory tubercle (OT), piriform area (PIR), cortical amygdala area (COA), and entorhinal area (ENT), are presented in When the nuclei show similar projection patterns, these nuclei may belong to the same functional modality . TherefoThe input similarity of the suprachiasmatic nucleus (SCH) with periventricular hypothalamic nucleus anterior part (PVa) and retrochiasmatic area (RCH) is highly above 0.96 . We extrThe input similarity of Globus pallidus internal (GPi) segment with subthalamic nucleus (STN) and the substantia nigra reticular (SNr) part is greater than 0.8 . AlthougThe MG, AUdp, and temporal association areas (TEas) are functionally related to the transmission and processing of auditory information . From thThe connection network is the structural basis for the brain to perform various functions, and the transmitters and receptors in the neurons decide the communication information of neural circuit. We further processed and summarized the ISH data from Allen Brain Institute to obtain the chemo-connectome of mice brain networks. The expression matrix of 50 transmission-related genes, such as transmitters  and corresponding receptors in the whole brain, were analyzed.Firstly, we converted the whole-brain expression matrix into a heatmap . In the Since monoaminergic neurotransmitters  in the central nervous system are key transmitters involved in the regulation of various essential brain functions, such as arousal and mood , we mainIn neuroscience research, mice are widely employed as model organisms, and various studies on mouse brain structure and function have expanded our knowledge of the brain. In the present study, we first created the mouse brain connectome and chemical connectome databases based on the connectivity and ISH data from the Allen Brain Institute, which achieved our goal of bridging the nuclei connectivity and circuit function. These databases provide a comprehensive perspective to dissect how the brain works and can help researchers easily to realize whole-brain connectivity and certain connection with expression patterns. The degree of similarity in brain nuclei reflects their homology in development or function. Based on connectivity data, we perform similarity processing to obtain the projection similarity data, which can also be used by evolutionists to guide evolutionary analysis. Our work, taken collectively, has the potential to advance the systematic study of the brain.Due to the limited sources of connectivity and ISH data we used, our mesoscopic connectome and chemo-connectome databases will be improved along with more circuit tracing and gene expression data released, especially the neuron-level connection data, and even microscale level connection data. As for the data analysis method in this study, we firstly selected those brain nuclei with well-known functions and then focused on the local networks in which the selected nucleus served as center nodes. However, this strategy limited the possibility of finding the unreported center brain nuclei and their connection network. Some automatic algorithms could be applied in the future for assessing the characteristic quantity of a brain nucleus network, such as centrality and modularity .The study of the mammalian brain connectome and chemo-connectome is still in its early stages. However, based on the success of genomics, we expect that as technology progresses and more researchers enter this field, the study of connectome and chemo-connectome at all scales will be improved, and our understanding of the brain will gradually become evident.The original contributions presented in this study are included in the article/JD and GC conceived and designed the study. DS and LS performed the data collection. YW and ZL performed the data analysis. YW and JD prepared the figures and wrote the manuscript. 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.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.


In the last decades, personalized medicine has been increasing its presence in different fields of medicine, including ophthalmology. A new factor that can help us direct medicine towards the challenge of personalized treatments is the microbiome. The gut microbiome plays an important role in controlling immune response, and dysbiosis has been associated with immune-mediated diseases such as non-infectious uveitis (NIU). In this review, we gather the published evidence, both in the pre-clinical and clinical studies, that support the possible role of intestinal dysbiosis in the pathogenesis of NIU, as well as the modulation of the gut microbiota as a new possible therapeutic target. We describe the different mechanisms that have been proposed to involve dysbiosis in the causality of NIU, as well as the potential pharmacological tools that could be used to modify the microbiome  and, consequently, in the control of the NIU. Furthermore, there is increasing scientific evidence suggesting that the treatment with anti-TNF not only restores the composition of the gut microbiota but also that the study of the composition of the gut microbiome will help predict the response of each patient to anti-TNF treatment. Uveitis encompasses a heterogeneous group of intraocular inflammatory diseases consisting of inflammation of the uveal tract. This can affect adjacent structures such as the retina or optic nerve. They are classified according to their etiology into infectious and non-infectious, with the latter being related, in most cases, to immune-mediated diseases. The origin of this inflammation can be attributed to an endogenous mechanism, either as part of a systemic disease , Behçet Disease (BD), multiple sclerosis (MS), Vogt-Koyanagi-Harada syndrome (VKH), etc.) or in isolated ocular (such as Birdshot disease) . The exa14 microorganisms whose genomes constitute 100 times the size of the human genome [Firmicutes and Bacteroidetes, followed by Actinobacteria and Proteobacteria, while the least represented are the Fusobacteria and Verrucomicrobia [The intestinal microbiota is the most abundant in humans and is composed of approximately 10n genome . The mosmicrobia . Its commicrobia . It is pmicrobia , althougmicrobia ,10. The microbia . The altmicrobia . This mamicrobia .Clostridia and the species Bacteroides Fragilis are usually part of the commensal microbiota, promote the differentiation of Treg, and contribute to immune homeostasis [Chronic or recurrent uveitis can be caused by local reactivations of persistent microbial agents or inadequately cleared antigens, which may intermittently break the proportion of T cells. Experimental data have demonstrated the crucial role of the gut microbiome in controlling both the innate and adaptive immune response, linking dysbiosis to immune-mediated diseases . Some baeostasis . Most cueostasis . In receeostasis . This reeostasis . In addieostasis . The ideThis review gathers published evidence on the association between microbiota and uveitis, both in the pre-clinical and clinical fields. In the publications, the different mechanisms by which intestinal dysbiosis could participate in the pathogenesis of the NIU are described, as well as the potential treatments aimed at modulating the intestinal microbiota that could be used and/or interfere positively or negatively in its treatment.Growing clinical and pre-clinical evidence points to the microbiome and dysbiosis in the immune response and susceptibility to systemic diseases, including both those of gastrointestinal origin such as Inflammatory bowel disease (IBD), and those of another origin . It has NIUs target the neuroretina, considered a part of the CNS. In addition to NIUs, multiple eye conditions have recently been linked to intestinal dysbiosis, such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and glaucoma ,27,28,29Interest in the study of the role of the microbiota in the development of NIU has been increasing in recent years, with several recent publications appearing that support its causality . DysbiosChlamydia trachomatis and Campylobacter jejuni and the genera Klebsiella, Salmonella, Yersinia and Shigella [Antigenic mimicry is an important autoimmunity mechanism in which autoreactive T cells are generated by cross-reactivity of microbial peptides with autoantigens . The patShigella ,34. ExpeShigella . EliminaShigella .161–180 peptide plus killed Mycobacterium tuberculosis (MTB) antigen as an adjuvant, whereas mice immunized with MTB alone or in combination with an irrelevant IRBP peptide that did not develop ocular inflammation were used as controls. An increased intestinal permeability was observed in IRBP-immunized mice through assessment of ZO-1 expression and a FITC-dextran assay. Both IRBP and MTB mice exhibited increased permeability compared to non-immunized mice, an increase that was more evident in IRBP-immunized mice. In contrast, only IRBP-immunized mice had increased permeability in the FITC-dextran assay that paralleled the course of uveitis. In addition, the increase in intestinal permeability coincided with changes in intestinal microbiota. Linear discriminant analysis of Effect Size (LEfSe) revealed an increased abundance in Clostridium and S24-7 bacteria, but depletion in Verrucomicrobia, Akkermansia, Dorea, and other bacteria in uveitic mice compared to MTB control mice. Interestingly, these differences were more marked at the peak of uveitis, with increased Prevotella, Lactobacilli, Anaeroplasma, Parabacteroides, and Clostridium species in IRB-immunized mice, while Ruminococcus, Bacteroidia, S24-7, Proteobacteria, and Desulfovibrio were more abundant in MTB control mice. Furthermore, the degree of intestinal inflammation correlated with the severity of uveitis [Inflammation of the mucosa caused by intestinal dysbiosis destroys the intestinal barrier, causing an increase in permeability and favors the translocation of microbiota or its products to the blood, lymphatic, submucosal, and lamina propria circulations. These products, such as lipopolysaccharides (LPS) and β-glucan, would reach different tissues through the vascular system, directly causing inflammation in target organs, and reaching the uvea and synovial tissue ,36,37. E uveitis . Therefo uveitis .Firmicutes and Bacteroidetes phyla and Alphaproteobacteria class, and increasing Gammaproteobacteria class, and reducing the severity of uveitis by increasing the proportion of Treg in various lymphoid tissues and the eye [As previously described, T cells play an important role in the pathogenesis of autoimmunity. In conditions of dysbiosis there is a loss of intestinal homeostasis, which breaks the balance between Th17 and Treg, and leads to immune activation by increasing Th17 (and IL-17) and decreasing Treg (and IL-10); thus, causing inflammation ,40. This the eye . In addi the eye .It is estimated that gut microbes produce thousands of metabolites that can regulate immune responses. The most common metabolites are short-chain fatty acids (SCFAs): butyrate, propionate, and acetate. These are metabolites obtained by the colonic microbiota through the fermentation of dietary fiber. These beneficial and protective metabolites have previously been studied in other inflammatory autoimmune diseases, such as HLA-B27-associated spondyloarthropathy . This thCorynebacterium, Propionibacterium, and Staphylococcus [Recent advances have made it possible to sequence the microbiome present in the human cornea and conjunctiva . These hlococcus . The muclococcus .The inside of the eye contains multiple immune system cells and inflammatory mediators, but the immune privilege of the eyeball prevents intraocular inflammation through mechanisms of immune ignorance and immune tolerance . DespiteStaphylococcus, Streptophyta, Corynebacterium, Enhydrobacter, and a decrease of Propionibacterium; patients with trachoma presented lower bacterial diversity and increased Corynebacterium and Streptococcus, while patients with dry eye syndrome had increased Staphylococcus aureus, Corynebacterium, Propionibacterium, Rhodococcus and Klebsiella oxytoca, the two latter considered as potential pathogens [Changes in the composition of the microbiota of the ocular surface have been found in pathologies such as blepharitis, trachoma, and dry eye . In moreathogens . Furtherathogens . HoweverThe involvement of the microbiota in the development of uveitis is based, fundamentally, on the EAU model induced by active immunization with external retinal antigen “inter-photoreceptor retinoid-binding protein” (IRBP) ,54 and tThe absence of microbiota in “germ-free” mice or the decrease in bacterial load prior to disease induction by administration of oral antibiotics has been shown to significantly attenuate the susceptibility of developing EAU induced by IRBP .In germ-free mice, lower retinal infiltration of T cells, lower levels of IFN-γ- and IL-17-producing T cells, and higher levels of regulatory T cells were found in the drainage lymph nodes of the eye . This suNakamura et al. also observed a decrease in the severity of induced EAU following administration of broad-spectrum oral antibiotics, especially with vancomycin and metronidazole, but not with other antibiotics, which not only modified the composition of the microbiota but also produced an increase in the proportion of Treg in the intestinal lamina propria at the first week, and subsequently in extraintestinal lymphoid tissues and the eye .On the other hand, Horai et al. tried to explain with a spontaneous EAU model  how immuExperimental models also demonstrated that exogenous supplementation of SCFAs decreased the severity of uveitis ,44. SuppPrevotella spp. and a decrease in Rikenellaceae, compared to wild rats, as well as an increase in Bacteroides vulgatus [Finally, experimental studies with transgenic rats for the HLA B27 gene have suggested the function of this in modulating the microbiome. The expression of HLA B27 was related to differences in the composition of the intestinal microbiome, with an increase in the relative abundance of vulgatus .Clinical studies confirm some of the conclusions derived from pre-clinical studies. They have found a decrease in the abundance and diversity of bacterial  and fungParaprevotella spp. In addition, these differences decreased after immunosuppressive treatment, with an identifiable prognostic response to treatment markers [Despite finding no differences in the gut microbiome of patients with AAU compared to healthy subjects, Huang et al. found a different metabolic phenotype in AAU patients with increased expression of seven fecal metabolites  by using markers .Dialister has also been reported, which is positively correlated with inflammatory activity, suggesting that this bacterial species may serve as a marker of activity in AS [The intestine has also been related to the pathogenesis of spondylarthritis: an alteration in the composition of the microbiota of patients with AS with respect to healthy controls, correlated with the state of their disease has been described . An assoty in AS .Experimental models, as well as results in clinical studies, lead to the conclusion that the gut microbiota can modulate the responses and behavior of uveitogenic T cells at various levels, providing adaptive and innate stimuli, as well as possible regulatory effects. This connection not only allows us to advance in the knowledge of the pathogenesis of the disease, but also opens the way to possible new therapeutic targets focused on the modification of the microbiome. The pharmacological tools currently used to modify the microbiome , and thaLactobacillus spp. and Bifidobacterium bifidum produce induction of Treg in the intestinal mucosa and a decrease in inflammatory activity [Probiotics introduce functional microbial components that are beneficial to the correct functioning of the gut and could be treatment options due to provoking an attenuation of the immune response. Bifidobacterium preserves intestinal barrier functions and produces SCFAs, and there is growing evidence demonstrating the beneficial effects of their supplementation on health, from protection against infection to different positive extra and intra-intestinal effects . Their uactivity .Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus reuteri, Bifidobacterium bifidum, and Streptococcus thermophilus) following removal of the microbiota with antibiotics reduced the severity of induced EAU in mice [Escherichia coli Nissle 1917 (EcN) prior to the induction of EAU in mice also protected against the development of uveitis and produced reinforcement of the integrity of the intestinal mucosa towards an anti-inflammatory state [Supplementation with IRT-5 probiotics ; and found that its oral administration effectively prevented the development of the disease in experimental models of mice with colitis [Despite their obvious usefulness, broad-spectrum antibiotics also lead to an increase in resistant bacterial strains, which is a serious public health problem . This ma colitis .Clostridium difficile, for which it has demonstrated its effectiveness [Another way to modulate the microbiota is the use of FMT, a procedure in which fecal matter from a healthy donor is transferred to a sick recipient. Its use is being investigated in a wide variety of diseases, and it has been approved for the treatment of recurrent colitis by tiveness . FMT frotiveness  or VKH [tiveness  to EAU mtiveness .The use of immunomodulatory drugs belonging to the group of “Disease-modifying anti-rheumatic drugs” (DMARDs) suppresses the growth of different bacteria, fungi, and viruses, and it is postulated that they could improve the severity of uveitis by acting through the intestinal microbiota ,78. SulfRecently, an immunomodulatory effect of methotrexate and mycophenolate mofetil potentially linked to changes in the intestinal bacterial composition , which iBiological drugs have the ability to modify the natural course of numerous inflammatory diseases. A better understanding of the role of cytokines has led to the publication of studies supporting the use of anti-cytokine drugs (anti-TNF and anti-IL-6) in NIUs . AdalimuProteobacteria, which abundance is associated with dysbiosis and a diseased state, and an increase of Lachnospiraceae, composed mainly of anti-inflammatory butyrogenic species, in responder patients. This is in line with the idea that anti-TNF therapy restores the intestinal “eubiosis”, i.e., the balance of the intestinal microbial ecosystem. Similarly, Zhou et al. [Clostridiales increased to the levels detected in healthy individuals, but not in non-responder patients. In addition, predictive patterns of good response to IFX treatment have been identified [Bacteroidetes and Firmicutes, without finding differences between responders and non-responders [Previous studies have suggested that treatment with anti-TNF restores the composition of the gut microbiota in intestinal  and extru et al.  also obsentified . Restoraentified . In thissponders . If thisThe above-mentioned studies have provided compelling evidence for the involvement of the microbiome in the pathogenesis and progression of NIU and have demonstrated the potentially beneficial effects of several treatment approaches that have an effect, directly or indirectly, on the microbiome, such as supplementation of probiotics or prebiotics, FMT, DMARDs and biological drugs. Probiotics and prebiotics, through direct modulation of the microbiome, have demonstrated an enhancement of the anti-inflammatory response of the intestinal immune system in animal models by increasing gut antimicrobial peptide expression  and decrWe currently have growing scientific evidence supporting the causality between intestinal dysbiosis and disease induction by altering the host’s homeostatic immune status, with speculation of a possible association between an altered microbiome and the pathogenesis of intraocular inflammation. However, there are still some unknowns in the relationship between the microbiome and uveitis, as microbial mono-association studies that demonstrate causality of changes in the microbiome with the development or maintenance of uveitis are very rare. We review the most recent studies associating intestinal dysbiosis and uveitis, both in animal and human models. The ability to modulate the composition of the microbiota through dietary supplementation or the use of drugs such as antibiotics, immunomodulators, or biologics opens a new therapeutic line for this disease. In addition, although new studies are needed to confirm this, an association between the intestinal microbiota and the clinical response to anti-TNF seems likely, which would allow personalizing and monitoring of the treatment of these patients more accurately.We believe that this review will be of great use to research groups working in this field since it compiles all the information published to date.


Purpose: Surgical treatment is an important part of the management of Crohn’s disease (CD). However, the current recommended staged procedures require two operations, with long hospital stays and high costs, while traditional primary anastomosis has a high risk of complications. Therefore, the aim of this study was to compare the clinical efficacy and safety of modified primary anastomosis using intestinal internal drainage tubes for CD. Methods: In this study, emergency and nonemergency CD patients were included separately. Then, the patients were divided into three subgroups: patients with intestinal internal drainage tubes (modified primary anastomosis), staged procedures, and traditional primary anastomosis. The main outcomes were the number of hospitalizations, length and cost of the first hospital stay, length and cost of total hospital stays, and complications. Results: The outcomes of the three subgroups of emergency CD patients were not significantly different. For nonemergency CD patients, patients with intestinal internal drainage tubes had shorter total hospital stays and fewer hospitalizations compared with the staged procedures subgroup, while no significant differences in any outcomes were observed between the modified and traditional primary anastomosis subgroups. Conclusions: For emergency CD patients, no significant advantage in terms of the main outcomes was observed for modified primary anastomosis. For nonemergency CD patients, modified primary anastomosis reduced the length of total hospital stays and hospitalizations compared with staged procedures. The placement of intestinal internal drainage tubes allows some patients who cannot undergo primary anastomosis to undergo it, which is a modification of traditional primary anastomosis. Crohn’s disease (CD) is an inflammatory bowel disease (IBD) of unknown etiology. The incidence of CD differs worldwide, with a high incidence in more developed countries and an increasing incidence in developing countries, imposing a heavy economic burden worldwide . Most paCurrent guidelines and studies recommend staged procedures in the case of a non-drainable abscess or steroid therapy with a dosage of >20 mg of prednisone, with bowel resection and protective stoma performed in the first stage and bowel anastomosis performed in the second stage. The protective stoma procedure redirects the contents of the bowel, which reduces the risk of postoperative intra-abdominal septic complications and is beneficial for alleviating the diseases ,7,8,9,10In this study, after resecting the diseased bowel segment and performing primary anastomosis, an intestinal internal drainage tube was placed on the proximal side of the anastomosis through enteroscopy or direct insertion. By combining endoscopy and surgery, we hope to reduce the tension in the intestine around the anastomosis and the risk of anastomosis leakage, creating favorable conditions and improving the success rate of primary anastomosis, which avoids second-stage surgery. This study provides a reference for the surgical treatment of CD.The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Central South University .The inclusion criteria were as follows: from 2014 to 2021, patients who underwent surgery for CD or its complications at the Third Xiangya Hospital of Central South University and the Second Xiangya Hospital of Central South University.The exclusion criteria for the subjects were a diagnosis of serious diseases in other systems, malignant tumors, and a serious lack of medical records.The sex, ages at the diagnosis of CD and operation, interval between the diagnosis and operation, smoking history, previous operation history, preoperative Montreal classification, preoperative treatment, preoperative hemoglobin level, and white blood cell count of patients were collected as the preoperative baseline data.Due to the substantial difference in the preoperative preparation  between patients undergoing emergency and nonemergency surgery, we divided patients into an emergency group and a nonemergency group. Afterward, the patients in each group were divided into three subgroups according to the operative methods: (1) patients with an intestinal internal drainage tube (modified primary anastomosis), (2) staged procedures, and (3) traditional primary anastomosis. The number of hospitalizations, length and cost of the first hospital stay, length and cost of total hospital stays, and short-term postoperative complications were compared among the three subgroups in each group . The length of first hospital stay was the interval between surgery and discharge reported in days. The cost of the first hospital stay was the total expense of the current hospitalization due to the surgery. The length of the total hospital stay was the number of days of hospital stays directly related to this surgery. The cost of total hospital stays was total expense of hospitalizations directly related to this surgery. Short-term postoperative complications were defined as an incision infection, anastomotic leak, intra-abdominal septic complications (IASC), etc.Because of the substantial differences in baseline characteristics in nonemergency patients, we used propensity score matching (PSM) to separately match patients who underwent modified primary anastomosis with patients who underwent staged procedures and those who received traditional primary anastomosis and to minimize the effects of other confounders on the outcomes. Patients who underwent modified primary anastomosis were separately matched in a 1:1 ratio with patients treated with staged procedures and those who underwent traditional primary anastomosis with a 0.1 match tolerance based on the Montreal classification and preoperative treatment.IBM SPSS Statistics 26 was used for statistical analyses. Categorical variables were reported as frequencies or percentages and were compared using chi-square or Fisher’s exact tests, as required by the test method. Categorical variables are presented as frequencies or percentages, and the chi-square test or Fisher’s exact test was used to perform the comparison according to the requirements of the test methods. Quantitative variables are presented as medians and interquartile ranges (IQRs), and the nonparametric Kruskal–Wallis test and the Mann–Whitney rank sum test were used to determine statistical significance.Based on the inclusion and exclusion criteria, 112 patients were enrolled. Among these patients, 17 received emergency surgery, including 5 modified primary anastomosis procedures, 2 staged procedures, and 10 traditional primary anastomosis procedures. The baseline profiles of the emergency patients are listed in p > 0.05). The results are summarized in We compared the clinical outcomes between patients receiving modified primary anastomosis, staged procedures, and traditional primary anastomosis in emergency situations. Modified primary anastomosis did not show significant superiority in terms of the number of hospitalizations, length and cost of the first hospital stay, length and cost of total hospital stays, or short-term postoperative complications , and the number of hospitalizations was also reduced (p = 0.009). No significant differences were observed between patients undergoing modified primary anastomosis and those undergoing traditional primary anastomosis (p > 0.05). Significant differences in short-term postoperative complications were not observed among the three groups (p > 0.05).The clinical outcomes of nonemergency patients obtained after matching are presented in In this study, after resection of the segment and primary anastomosis, we placed the intestinal internal drainage tube about 20 cm from the proximal side of the anastomosis through enteroscopy or direct insertion. Pascal’s principle was used to directly transmit the pressure in the bowel at the anastomosis to the anus, normalizing the pressure from the anastomotic site to the anus. Therefore, the tension of intestinal fluid and gas around the anastomosis on the intestinal wall are relieved such that the anastomosis is in a clean and low-tension state, providing a better physiological environment for the recovery of the anastomosis and achieving better primary anastomosis.Prior to surgery, the surgery option was determined based on the preoperative condition of CD patients, which also exerted a substantial effect on the clinical outcomes. Patients with poor preoperative conditions were more likely to choose staged procedures. On the one hand, CD and its complications affect the absorption of nutrients, resulting in poor nutritional outcomes, which increase the risk of postoperative complications such as anastomotic leakage ,14,15. OMany problems are associated with the existing staged procedures and traditional primary anastomosis for CD. The first is the large burden of surgery. Approximately 5% of patients require reoperation due to disease recurrence within 1 year after surgery, imposing an immense burden on the health care infrastructure and patients ,20. For For emergency patients, no significant differences in clinical outcomes were observed between modified primary anastomosis, the staged procedures, and traditional primary anastomosis. The potential explanations for these results are described below. First, the number of emergency patients was too small to draw meaningful conclusions. Second, although little difference was observed in the preoperative baseline characteristics of the enrolled patients, the comparison did not reflect whether differences in the preoperative conditions of the patients existed. Due to the urgency of the emergency patients, the heterogeneity of the preoperative conditions of different patients was large, such as the time from admission to operation and nutritional preparation. Third, the technical proficiency and level of the surgeon exert substantial effects on the clinical outcomes of emergency surgery, which are not adequately reflected in the study. Hence, we were unable to determine the superior and inferior results of modified primary anastomosis, the staged procedures, and traditional primary anastomosis in this study.For nonemergency CD patients, modified primary anastomosis substantially reduced the length of the total hospital stay and number of hospitalizations compared with staged procedures, without increasing the cost of hospital stay and short-term postoperative complications. No significant differences in clinical outcomes were observed between the modified and traditional primary anastomosis groups.We identified advantages for the use of intestinal internal drainage tubes over staged procedures potentially because patients undergoing staged procedures had a longer disease duration and longer-term treatment with hormones and immunosuppressants, leading to poor outcomes. However, patients who received modified primary anastomosis often had a shorter disease duration and received less clinical treatment with hormones and immunosuppressants. When PSM was performed, we were unable to match patients undergoing staged procedures with more severe conditions , which may create a bias. Hence, for patients with a shorter disease duration and less treatment with hormones or immunosuppressants, modified primary anastomosis might reduce the length of total hospital stay and number of hospitalizations without increasing the cost of the hospital stay and short-term postoperative complications, while further studies are needed for patients with a longer disease duration and more long-term treatment with hormones or immunosuppressants.Due to the insufficient number of nonemergency patients, this study was unable to show a significant difference between modified and traditional primary anastomosis. However, as outlined above, we found that modified primary anastomosis may allow patients who would otherwise need to undergo staged procedures to undergo primary anastomosis, expanding indications for traditional primary anastomosis. Modified primary anastomosis also did not increase the length or cost of the hospital stay or the risk of short-term postoperative complications. Hence, modified primary anastomosis may serve as an alternative procedure for CD patients, which requires further investigation.The limitations of this study are described below. First, as a pilot study of a modified procedure, the number of patients included in this study was small, allowing us to draw only limited conclusions. Second, studies on patients with more severe conditions were lacking, and some preoperative baseline data were incomplete, such as data on Crohn’s disease activity index (CDAI), fecal calprotectin levels, preoperative nutrition, and other baseline indicators of CD. Third, the follow-up duration in this study was insufficient, and a study examining long-term complications and control of CD was lacking. Fourth, the IQR of the internal drainage tube group in emergency patients and the IQR of the staged procedures group in nonemergency patients were markedly broad, which means that there is greatly heterogeneity among enrolled patients in these group. Further studies should be conducted to increase the number of patients enrolled, randomize the surgical option, stratify the severity of the patient’s condition, and extend the follow-up duration as approaches to explore the long-term outcomes of modified primary anastomosis.For emergency CD patients, this study was unable to show a significant difference between modified primary anastomosis, the existing staged procedures, and traditional primary anastomosis. For nonemergency CD patients, compared with staged procedures, the modified primary anastomosis significantly reduced the length of the total hospital stay and number of hospitalizations without increasing the cost of hospital stays and the risk of short-term postoperative complications. This procedure may expand the indications for traditional primary anastomosis and serve as an alternative treatment for CD patients.


In addition, we suggest that AW favors the occurrence of Wernicke’s encephalopathy (WE) in patients with known or unknown thiamine depletion. We reviewed the literature on oxidative stress as a core mechanism in brain suffering linked with those conditions: AW, epileptic seizure, DT and WE. Thus, we propose perspectives to further develop research projects aiming at better identifying oxidative stress brain damage related to AW, assessing the effect of repetitive episodes of AW, and their long-term cognitive consequences. This research field should develop neuroprotective strategies during AW itself or during the periwithdrawal period. This could contribute to the prevention of severe alcohol-related brain damage and cognitive impairments.Alcohol use is a leading cause of mortality, brain morbidity, neurological complications and minor to major neurocognitive disorders. Alcohol-related neurocognitive disorders are consecutive to the direct effect of chronic and excessive alcohol use, but not only. Indeed, patients with severe alcohol use disorders (AUD) associated with pharmacological dependence suffer from repetitive events of alcohol withdrawal (AW). If those AW are not managed by adequate medical and pharmacological treatment, they may evolve into severe AW, or be complicated by epileptic seizure or  Alcohol use is a major preventable risk factor for human health. The global health burden initiative estimated that any alcohol use is associated with an increased risk , except Apart from mortality, alcohol use is also associated with a high worldwide burden in terms of morbidity: various forms of cancers, liver cirrhosis, and brain disorders . Those aFor mortality as well as for brain morbidity, the strong association with AUD does not imply that AUD is a specific risk factor. The same association could be observed in other forms of chronic exposure to large amounts of alcohol without the specific criteria of AUD as the result of a cumulative dose-effect relationship.On the one hand, for the cumulative hypothesis, alcohol-related all-causes mortality studies have established twenty years ago that this mortality was mostly observable in subjects with the highest amount of alcohol use, especially in subjects reporting several days of heavy drinking per week .But on the other hand, favoring a specific role of AUD, it has been established from population studies that among alcohol current users, subjects meeting the categorical DSM-IV definition of alcohol dependence reported higher scores to all alcohol use measures, including number of days with either excessive alcohol use, or heavy drinking or acute alcohol intoxications . In addiTherefore, our core hypothesis is that there is a specific cognitive toxicity supported by the condition of severe AUD, through the subgroup of patients with pharmacological dependence, as they experiment the repetition and/or the severity of acute episodes of alcohol withdrawal (AW). We searched the literature for the points supporting this hypothesis and putative mechanisms of this additional brain toxicity due to inadequately treated AW syndrome.delirium tremens (DT) and seizure. Several indirect complications of the adrenergic syndrome may also occur during an untreated AW syndrome as dehydration, cardiac failure [AUD is defined by the loss of control over alcohol intake and chronic, compulsive, heavy alcohol use despite adverse consequences . Among p failure  or renal failure . AW is s failure . Milder  failure ,16,17.Recommended pharmacological treatment to lower the symptoms of AW and to avoid the associated complications can be divided in three categories: First, the treatment of withdrawal symptoms. Benzodiazepines are the first choice treatment ,16,17, aAs ethanol is a small molecule that easily passes the blood–brain barrier and is ubiquitously distributed in the brain, chronic alcohol use induces neuroadaptation ,22. ThisThe two major and well-known complications of AW, occurring in case of absence or inadequate medical management of AW symptoms, are epileptic seizure and DT. Seizures are provoked by the hyperexcitability of neurons and intracellular calcium dysregulation , associaWE is caused by the brain toxicity related to an acute thiamine diphosphate deficiency  or an altered thiamine metabolism and distribution ,37,38,39spectrum [WE is frequent in AUD patients . It is espectrum , WE alsospectrum ,43,44,45spectrum ,40.The clinical Caine’s criteria for the identification of WE are the presence of two criteria among: ataxia, oculomotor dysfunction, confusion and dietary deficiency . HoweverRegarding the imaging diagnosis of WE, brain magnetic resonance imaging (MRI) has a good specificity but a low sensitivity in clinical practice. It shows bilateral FLAIR hyperintensities in specific regions, such as the mammillary bodies, thalamus, hypothalamus, periaqueductal region and floor of the fourth ventricle . In the Regarding blood assays, free thiamine (the inactive form) represents a small part of the total thiamine. It is rarely impaired and is not an indicator of thiamine status ,48. To oIn clinical addiction medicine practice, given the prevalence of WE in hospitalized AUD patients, the absence of and the low sensitivity of the MRI or thiamine blood measurements, the majority of international medical societies recommend to systematically prescribe thiamine to patients displaying signs of AW . Some reAnimal models of alcohol-related brain damage display similar brain and cognitive alterations to what is seen in AUD patients. Numerous studies have shown that thiamine deficiency , or evenHowever, only a few studies have investigated the interaction and the synergistic effects of both ethanol toxicity and thiamine deficiency ,57,58 toWhile clinical recommendations regarding the timing of preventive management and thiamine administration acknowledge a specific risk period during AW, the link between the physiological event of AW and the occurrence of WE is only suspected but not currently demonstrated ,35.In clinical practice, assessing the time course of WE as a consequence of AW or AW occurring in patients with subtle symptoms of WE is highly difficult. The difficulties include the absence of easily accessible plasma thiamine measurements ,53, the The pathophysiology of WE is complex and multi-factorial, including glutamatergic excitotoxicity, oxidative stress, lactic acidosis and blood–brain barrier disruption  and cannThiamine is an essential water-soluble vitamin required for the Krebs cycle and the production of adenosine triphosphate in the mitochondria ,38. ThiaDuring AW, by increasing catabolism, withdrawal symptoms could increase the consumption of thiamine in the Krebs cycle, deplete its reserves and induce a further increase in lactates. Thiamine is also needed for the pentose phosphate pathway and the production of nicotinamide adenine dinucleotide phosphate, which helps to eliminate ROS and to reduce lactic acidosis ,38. ThisIn addition, astrocytic dysfunction, induced by the thiamine deficiency and this increase in oxidative stress, alters its function of reuptake and metabolism of extracellular glutamate, especially with the loss of the glutamate transporters ,59,60,61Confronted with this decreased capacity of metabolism by astrocytes, the hyperglutamatergia of AW could exacerbate the excitotoxicity caused by thiamine deficiency and worsen the induced neuronal deaths. This hyperglutamatergia contributes, notably in a context of calcium channels dysregulation by chronic alcohol use , to an iAW occurs in subjects with severe AUD and pharmacological dependence. Those patients, by the combined effects of high chronic alcohol intake, poor diet, modified intestinal absorption and social disadvantages display a high rate of nutritional depletions ,63,64,65We developed the hypothesis that AW cannot only result in severe neurological complications such as seizures or DT, but also be considered as a vulnerability period for the development of WE by exacerbating and aggravating its pathophysiological mechanisms. We now go beyond this hypothesis and suggest that even in AUD patients without WE and having not experienced seizures or DT during AW, the repetition or severity of AW could contribute to the development of cognitive deficits. Each AW episode represents an oxidative stress challenge for the brain, and may lead to a certain amount of neuronal, axonal, synaptic but also astrocytic destruction. Thus, a patient with severe AUD and pharmacological dependence may suffer from a cumulative effect of several such episodes. It is already known that repeated experience of AW results in a kindling-like process leading to increased likelihood and severity of epileptic seizures during detoxification . One stuThe neuroprogression theory applies to AW leading to persistent cognitive deficits. But at the end of the evolution when a severe cognitive disorder is diagnosed in a patient with a past history of severe AUD, despite comprehensive etiological inquiry , it is iReducing the burden of AUD in terms of alcohol-related cognitive deficits should be a health priority. To be able to propose effective neuroprotective strategies for patients with AUD, especially during AW episodes, several steps forward in research are needed. The first step is reaffirming the relevance of thiamine prescription to avoid the development of WE, especially during the critical period of AW and potentially to reduce the prevalence of alcohol-related cognitive impairments. In parallel, it is crucial to work on raising public policy awareness for the reimbursement of thiamine.The second one is to detect patients at risk to develop AW complications using new biomarkers. The validation of accessible, repeatable, and of course sensitive biomarkers of oxidative stress and brain suffering during AW is essential. If we want to move forward a precision medicine, we need to develop peripheral biomarkers of neuronal, axonal, synaptic but also astrocytic destruction applied to AW .The third and final step is the development of innovative treatments to counteract the oxidative stress and prevent the neurotoxic effect of AW and its various complications.There are now several pieces of evidence showing that AW is an oxidative stress challenge for the brain, leading to epilepsy and DT, and making this timeframe a vulnerability period for the development of WE, especially for AUD patients with subclinical thiamine deficiency. Reasoning by analogy, we support the opinion that this oxidative stress challenge induces brain lesions, which may lead through the repetition of episode through a neuroprogression effect toward an additive brain and cognitive loss. Future research should now focus on identifying and assessing this neurotoxic effect to develop specific neuroprotective strategies.


Food allergy is a common, and often lifelong, disorder with considerable negative impact on the quality of life of those affected and their families. While several promising immunotherapies for food allergy have either been approved or are in late-phase clinical trials based on demonstrated effectiveness at inducing desensitization, evidence of benefit in terms of improving patient-centered outcomes is inconsistent. Historically, health-related quality of life has not been prioritized as an endpoint in food immunotherapy trials and, even when included, findings have been undermined by methodological limitations of the measurement instruments used and issues with data interpretation. This review highlights the importance of measuring health-related quality of life as an endpoint in food immunotherapy trials and discusses the strengths and limitations of available evidence in this regard, with a focus on the appropriate use of assessment instruments and interpretation of findings. There remains much to learn regarding the impact of food immunotherapies on patient wellbeing, both during treatment and over the longer term. Our aim is to assist clinicians, researchers, policy makers and consumers in their interpretation of the existing literature, and to promote greater scientific rigor in the design and selection of outcome measurement frameworks for future studies evaluating the efficacy of immunotherapy treatments for food allergy. Food allergy is a chronic disorder that affects 10% of infants and 5–8% of children , 3. DiagTo date, studies of food immunotherapy have largely focused on efficacy and safety outcomes such as desensitization (increase in reaction threshold), remission, and treatment-related adverse events –11. WhilThe importance of patient-centered outcomes for driving value-based decision making in both health research and routine clinical practice is now well-established , 14. To Food allergy-specific HRQL questionnaires have been developed and validated for different age groups  and perspectives  , 18, 19.and HRQL, which may provide a new understanding of “benefit” for the patient and the caregiver. Sim et al. proposed a core outcomes set for food allergy clinical trials that puts patient-centered outcomes front and center, highlighting how failure to harmonize outcomes measurement using validated instruments has limited our understanding of whether food allergy treatments improve the lives of allergy sufferers  and safety but also by improved HRQL. It is likely that interactions exist between clinical outcome, safety ufferers . This reper se is known to be associated with general improvements in patient outcomes  on HRQL and other important patient-centered outcomes. Several studies suggest an interaction between allergy status and HRQL , 27, 28.The level of desensitization that is achieved following immunotherapy may also impact on the degree of HRQL benefit as there may be perceived and real differences in the degree of protection achieved. For example, low dose peanut OIT (300 mg peanut protein) and peanut EPIT have been shown to desensitize patients to 1,000 mg peanut protein , which sper se, aside from the subsequent post-treatment experience , it will be important to distinguish between these in terms of HRQL impact during the treatment phase. Burden of treatment may differ between modalities with regard to protocol rigidity, clinic visit schedule, treatment-related symptoms and adverse events, and the total duration of time for which treatment must continue, all of which may impact HRQL for patients even if clinical outcomes are similar between treatments. Measurement of patient-centered outcomes both during and after treatment allows specific examination of the impact of immunotherapy treatment perience . Emerginperience , 28, 32.Long-term follow-up post-treatment is important to determine if HRQL benefits are maintained, lost or increased, as participants adjust to their altered allergy status . Neuro-pIt is plausible that different sub-groups will respond differently to food allergy treatments in terms of HRQL outcomes. Patient characteristics, for example age of child, severity of prior reactions, and type or number of food allergies have been shown to be associated with HRQL , 53–55, To date, there has been little exploration of psychological factors correlated with HRQL outcomes , and the impact of these on treatment success , 57. TheImproved understanding of the interaction between patient characteristics and predicted HRQL outcomes from therapy will assist clinicians to discuss potential benefits and harms, and help families choose whether immunotherapy is right for them. It is plausible that many patients and their families may prefer to continue avoiding an allergen when informed of the risk of ongoing reactions, burden of treatment adherence and relative likelihood of long-term improvements in HRQL. Identification and standardization of predictors could optimize treatment by enabling tailored treatment approaches that are matched to a particular patient profile , 37.Patient-centered outcomes such as HRQL have been identified and promoted as a priority endpoint when evaluating effectiveness of a food immunotherapy, however, there remain many methodological limitations to their use and interpretation. Given the limitations of food challenges in predicting reactions outside of a controlled clinical setting , additioHaving standardized definitions and measurement approaches for adverse events, severe reactions and clinical outcomes would also significantly aid comparability and allow for more targeted patient support and regulatory guidance . Given tBy considering the timing and selection of patient-centered outcome measures, trial investigators would be able to generate data that can inform and guide clinical practice. It is vital that outcomes are captured in the real world beyond the tightly controlled clinical trial environment, both through long-term follow-up and Phase 4 trials. A peanut oral immunotherapy is now approved for use in clinical practice in the US, Europe and UK , 60, andOur understanding of HRQL in food allergy is improving but there is much more to learn regarding the impact of different interventions on patient wellbeing during treatment and over the longer term. High quality interventional trials that consistently measure these outcomes in a standardized way are vital to fully evaluate the real-world benefit to patients of novel treatments.This article was conceived jointly by ML and MT. ML led the development of the preliminary draft. All authors reviewed the content for accuracy and completeness. All authors contributed to the article and approved the submitted version.The Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Programme.AD reports having received consultant fees from Aimmune Therapeutics, DBV Technologies, and Nestle (research grant and advisory panel). MT declares consultant fees from Pfizer and Abbott Nutrition; inventorship on patents covering PPOIT; employee and scientific founder of, and holds share interest and options in, Prota Therapeutics; membership of the Medical Advisory Board of Anaphylaxis & Anaphylaxis Australia and past membership of the Board of Directors of the World Allergy Organization ; membership of expert committees of the American Academy of Allergy Asthma and Immunology, Asia Pacific Association of Allergy Asthma and Clinical Immunology, Australasian Society of Clinical Immunology and Allergy, WHO, and past membership of the International Union of Immunological Societies (ended 2019). The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The inflammatory response is an adaptive mechanism that evolved to fight against infections and tissue damage. This complex mechanism is vital for the proper function of the organism, and because of that, is under tight regulation involving a complex network of factors, cells, and systems. Physiological inflammation is perfectly orchestrated to allow the mobilization of leukocytes from the circulation to the injured tissues for the removal of pathogens, tissue repair, and return to homeostasis. However, when the self-limited nature of the inflammatory response and the mechanisms of resolution fail, inflammation might become chronic, leading to the development of many disabling serious diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or psoriasis.Knowledge of the molecular and cellular processes underlying chronic inflammation has substantially increased in recent decades. This resulted in enormous improvements in the treatments for immune-mediated inflammatory diseases, but also revealed the complexity of the cytokine networks and immune cell subtypes involved in non-resolving inflammatory responses. This fact could explain, in part, why certain groups of patients are totally or partially refractory to current therapies. Therefore, we cannot be satisfied with the available drugs, and more research focusing on deciphering the precise molecular pathways behind uncontrolled inflammation is mandatory for developing novel therapeutic approaches.The 34 original and review articles included in this Special Issue contributed to the aim of describing and understanding new mechanisms that trigger inflammation and highlighted new putative treatments for different inflammatory conditions.2 and reduced the activation of pro-inflammatory signalling pathways [Neuroinflammation is a perfect example of the two faces of inflammation. While an acute inflammatory response is protective, chronic neuroinflammation leads to inflammatory conditions such as multiple sclerosis, and it also contributes to other neurological  and psycpathways . In linepathways . These dpathways , angiotepathways , or tollpathways  is beingFocusing on autoimmune responses, Amend et al.  and CarvInflammation significantly contributes to skin malignancies, as reviewed by Ansary et al.  and Razi6-methylguanine-DNA methyltransferase is commonly observed in brain tumours. However, Teuber-Hanselmann et al. [Historically, inflammation-related research mainly comprised studies related to immune cells and inflammatory mediators. However, in recent years, more multidisciplinary and integrative approaches have been applied for the dissection of the inflammatory process . This isn et al.  reportedn et al. ,19 and tn et al.  have alsn et al.  demonstrThe impact of environmental factors such as pollutants, microparticles, or endocrine disruptors is gaining interest. The latter is not only relevant for their interference with the normal function of the endocrine system, but endocrine disruptors can also participate in the pathophysiology of non-alcoholic fatty liver disease (NAFLD)  by modulating liver metabolism . In the This Special Issue also contains translational studies demonstrating the association between high concentrations of IL-6 receptor antagonist and reduced carbohydrate disorders and NAFLD progression in obese individuals , the impFinally, in this compilation of articles, we find very interesting reviews updating a wide variety of topics such as hypoalbuminemia as a surrogate of infections , the resWe hope the lectors will appreciate reading these papers. We thank all the authors and reviewers for their dedication and proactive participation that made the realisation of this remarkable Special Issue possible.