Increasing knowledge of the microbiome has led to significant advancements in the agrifood system. Case studies based on microbiome applications have been reported worldwide and, in this review, we have selected 14 success stories that showcase the importance of microbiome research in advancing the agrifood system. The selected case studies describe products, methodologies, applications, tools, and processes that created an economic and societal impact. Additionally, they cover a broad range of fields within the agrifood chain: the management of diseases and putative pathogens; the use of microorganism as soil fertilizers and plant strengtheners; the investigation of the microbial dynamics occurring during food fermentation; the presence of microorganisms and/or genes associated with hazards for animal and human health  in feeds, foods, and their processing environments; applications to improve HACCP systems; and the identification of novel probiotics and prebiotics to improve the animal gut microbiome or to prevent chronic non-communicable diseases in humans . The microbiomes of soil, plants, and animals are pivotal for ensuring human and environmental health and this review highlights the impact that microbiome applications have with this regard. Microbiome research has been intensifying in recent years in terms of the numbers of publications, research programs and complexity. A query performed using the PubMed repository (visited on 4 April 2022)In the last years, the application of high-throughput DNA sequencing (HTS) approaches has revolutionized the way microbes are investigated. Different sequencing platforms are available and their constant improvement allows the generation of billions of base pairs of data in a reasonable time and price . The sucIn this collection of case studies, we provide an overview of agrifood success stories based on microbiome research that meet one or more of the following criteria: (i) Microbiome-based innovations in the agrifood chain context that led to commercialization, (ii) Microbiome-based mitigation strategies implemented by the industry to increase product yield and quality or decrease economic losses during production, (iii) Microbiome-based innovations in the agrifood sector that helped improve plant, animal, and human health, (iv) Microbiome-based knowledge that led to improved food safety management systems, or (v) Amendments of legal regulations based on microbiome research. For the purpose of this review, the MicrobiomeSupport consortium members have selected 14 example case studies matching at least one of the above-mentioned criteria from different sectors, including plant health, feed products and livestock health, food production and human health .One of the greatest challenges for agriculture in the upcoming decades is to meet the demand for food production caused by a growing human population, which is expected to reach 10 billion in 2050 . Food prPlant pathogens are causing substantial losses in the production of plant-based food products globally. Crop protection against pests and diseases has been mainly achieved by pesticides that are harmful to the environment and non-target organisms. However, an increased number of recent studies targeting the seed microbiome have demonstrated their ability to improve crop sustainability and production without the need of chemical substances . DiffereSphingomonas were accumulated and transmitted across successive generations in disease-resistant rice seeds and conferred resistance to disease-susceptible phenotypes against the plant pathogen Burkholderia plantarii. Using culture-based approaches, Sphingomonas melonis strain (ZJ26) as the core constituent of the seed-endophytic bacterial community in disease-resistant phenotypes. More profoundly, S. melonis ZJ26 restored the phenotypic plasticity in disease-susceptible rice seeds upon exposure to B. plantarii. The identification of S. melonis ZJ26 as the resistance-conferring agent by the integration of HTS data, gene mutagenesis, and molecular interaction assays facilitated the discovery of its principal mode of action that underlies pathogen inhibition by S. melonis ZJ26 -fixing bacteria (diazotrophs) have been effectively shown to partially or completely replace chemical N fertilizers in agricultural systems (2 into ammonia (NH3), which can be easily assimilated by plants (Azotobacter spp.), associative bacteria , and symbiotic bacteria  is one of the most limiting nutrients affecting crop yield, and thus applied in large quantities worldwide . However systems . Diazotry plants . Diazotrhe plant .−1  that secrete organic acids in concentrations required for dissolving inorganic P in the soil . Furthermore, the vulnerable phase (from inoculum to active growth in the rhizosphere) can be overcome by the rapid germination of a high percentage of the conidia typical of Penicillium spp. The species found to perform best for this type of application by the biotech industry was Penicillium bilaiae, which does not produce metabolites toxic to humans or other animals. Notably, the first reported producer of oxalic acid in Penicillium, Penicillium oxalicum  to sufficient phosphorus (P) in soil is a well-known and widespread limiting factor for the establishment and growth of crop plants . Phosphathe soil . Therefothe soil . This isthe soil , which s disease . This inoxalicum  producesoxalicum , but hasoxalicum . Similar as well .P. bilaiae to increase the availability and accessibility of soil P to plant roots through the colonization of the root system and production of organic acid exudates. It stimulates vigorous root growth, shoot development, increases draught tolerance, and improves yield potential. Furthermore, higher seedling vigor is known to give increased tolerance to pests and diseases, an additional indirect effect of the use of such a “BioAg” product. The BioAg term covers a group of new bio-based products, derived from microorganisms, microbial metabolites or enzymes or that are produced by converting side-streams and residues from biorefineries into higher-value products . This product is an inoculant that contains organism . DevelopB. simplex (Bacillus sp. S4) strain repeatedly showed efficacy in improving seedling vigor under water and N deficit in winter wheat as well as reproducible PGP in corn under N stress. In parallel, genome analysis revealed a range of genes important for plant-association and potential PGP in the B. simplex strain, such as the pathway for the synthesis of the siderophore aerobactin or methylthiolated cytokinins. Following the in vitro analysis, the B. simplex strain was tested extensively in field trials over 3 years and proved efficiency to enhance drought stress resilience in crops by improving root architecture  the optimization and development of methods for delivering microbes; (2) the use of co-adjuvants or other molecules that are synergistic with the effects of bacterial or fungal inoculation; and (3) the creation of products containing a consortia of microbes capable of delivering multiple beneficial traits to plants. It has been recently shown in several studies that an improved rhizosphere microbiome can provide disease suppression and strengthen plant growth; however, only a small fraction of the available knowledge has been translated into the field. Therefore, additional research into the dynamic interactions between crop plants, the rhizosphere microbiome, and the environment are necessary to better guide the harnessing of the microbiome to increase crop yield, quality, and sustainability.Omics-based technological advances have also revolutionized our understanding of host-associated microbial communities in livestock health. Animal microbiome research often focuses on the microbial populations that inhabit the gastrointestinal tract (GIT) of animals, in order to determine their role in the animal’s growth, health and disease . FunctioGlobally, feed production uses approximately 75% of all arable land. Further, responsible industrial animal production is struggling to solve issues regarding animal welfare, diseases and zoonosis, and find means to cut down the use of antimicrobials and reduce GHG emissions. Thus, it is essential to identify sustainably resourced feed materials  and select feedstocks with high potential to provide the basis for stabilizing and sustaining a healthy GIT microbiome .The fermentation process has been used to improve the nutritional quality and stability of various foods . MicrobiAscophyllum nodossum  were found between non-treated and XOS-treated samples. Differences were also found between the lengths of XOS. These results showed an improvement in porcine gut health after such prebiotic oligosaccharide treatments  or Lavipan® .Among the poultry-borne pathogens, e humans . Controldulation . Bacteriathogens . Yeast sathogens . The in  effects . CommercMicrobiome modulation in the GIT is an innovative and emerging approach to control farm animal disease and foodborne pathogens. A customized combination of microbial-based therapies could promote animal health and contribute to the practice of sustainable husbandry.Microbiome-based innovations have the potential to improve food processing and human health. The microbiological analysis of foods continues to be heavily reliant on the use of classical culture-based approaches involving agar plates and incubators. While these have value, they are laborious, time-consuming and require the selection of specific growth media based on the microorganisms predicted to be present, or cause for concern, with respect to that specific food . This meThe meat microbiome has an important role in the conversion of the components of meat into several metabolites, with a consequential major impact on physical and organoleptic properties, and the quality and safety of the final products . The iniMediterranean countries produce numerous Protected Geographical Indication (PGI), Protected Designation of Origin (PDO), or Traditional Specialty Guaranteed (TSG) fermented sausages . TraditiLactilactobacillus sakei and Staphylococcus xylosus strains; L. sakei, ensured rapid microbial growth, a high acidification rate and fast consumption of fermentable substrates. A decline in the relative abundance of Enterobacteriaceae was observed, as well as in the microbial diversity. Metagenomic analysis of the sausages made with the starter showed higher level of acidity and the resulting taste was characterized as pungent, vinegary, cheesy, and weedy. On the other hand, the indigenous microbiome from spontaneous fermentation  displayed higher counts of genes involved in fatty acid biosynthesis and amino acid metabolism. From the metabolome dataset, higher amounts of medium- and long-chain fatty esters enhanced the sensory profile of these sausages conferring the sausages a “fruity wine, waxy sweet apricot, and banana brandy” flavor. As a result, consumers preferred the spontaneous fermented sausages due to their flavor and odor characteristics. In contrast, products made with the starter culture that boosted the production of acetic acid were found to be unacceptable by the consumers .Current estimations of global food loss and waste lie at around 1.3 billion tons every year . This coThermus in defect cheeses. These microorganisms had not previously been found in cheese, most likely due to difficulties in cultivating them. The role for Thermus in the pinking defect phenomenon was subsequently confirmed when a strain of Thermus thermophilus was spiked into cheese and “recreated” the pinking defect  without affecting cell viability. L. casei W56 was then used for the enrichment and stepwise chemical characterization of candidate metabolites, revealing tryptophan as the responsible compound for the immunomodulatory effect. Enantiomeric separation of the purified subfraction confirmed the presence of D- and L-tryptophan, whereas the corresponding growth medium used as a control contained only L-tryptophan. Oral supplementation of D-tryptophan in mice with induced asthma  increased D-tryptophan serum levels significantly, indicating enteric uptake and systemic distribution. Pretreatment of mice with D-tryptophan for 3 days and throughout experimental asthma induced significant shifts in the gut microbiome of the treated mice resulting in an increase of overall diversity. At the same time, supplementation improved airway hyperreactivity in response to methacholine. Allergic airway inflammation reduced gut microbial diversity, but when fed to mice, D-tryptophan increased gut microbial diversity and ameliorated the disease, demonstrating the importance of the gut-lung axis in health  has estimated that the absence of effective preventive measures for obesity will severely increase the percentage of new cases of diabetes (60%), cardiovascular diseases (18%), dementia (11%), and cancers (8%) between 2020 and 2050, with the consequent increase of premature deaths and the reduction of life expectancy . The intParabacteroides distasonis population, a gut bacteria documented for its anti-inflammatory and anti-obesity properties  cannot solve the problem alone but, together with dietary counselling, could help to reduce inflammation and the risk of developing chronic metabolic complications more effectively than dietary changes alone  during the evaluation process should be considered at the very beginning of the research program . For approval of a microorganism to be used as a drug, the regulatory framework is not as well established, but both the Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines and Health Care (EDQM) codified these as live biotherapeutic products. The approval of these innovative products is promising but also constitute a challenge due to the limited experience of both applicants and regulators in defining quality and safety criteria and developing suitable study designs to demonstrate efficacy. Despite this, collaboration between the Pharmabiotic Research Institute (PRI) and industrial partners and scientists provides a roadmap .Agrifood companies recognize the potential in understanding the microbiome and translating this knowledge into products. Interested parties range from food ingredient producers, consumer goods companies and medical device companies to biotech firms and technology service providers. The food industry is further preparing to develop personalized diets and specific foods for particular target groups in order to prevent or treat certain chronic conditions. Meanwhile, industrial and academic partners are calling for public–private partnerships to stimulate the translation of scientific knowledge into new products and treatments.Microbiome research has benefited greatly from the improvement in different multi-omics technologies, such as DNA HTS . HTS of While the relevance of these approaches to food and food chain microbiology is clear, challenges remain with respect to simplifying sequencing and bioinformatics approaches so that they can be employed by non-experts within agrifood companies. Additionally, regulation and standards will need to be put in place to facilitate their application for routine quality and safety testing. Despite this, the all-important first steps have been made to facilitate the more widespread application of HTS as a powerful tool for agrifood chain applications.To conclude, it is important to remark that the case studies presented here are a subset of examples of potential applications of microbiome-based research in the agrifood field selected within the MicrobiomeSupport consortium members and their partners. The microbiomes of soil, plants and animals are pivotal for ensuring human and environmental health. Research and innovation on microbiomes in the agrifood system are constantly advancing, and a better understanding of these microbiomes will be a key factor in producing highly nutritious, affordable, safe, and sustainable food.RO, SUW, TK, AS, ES, and MW: conceptualization. All authors substantially contributed to collecting and writing the case studies. RO and SUW drafted the manuscript. RO edited and prepared the submitted version of the manuscript. All authors made a substantial, direct, and intellectual contribution to the work, and revised and approved the last version of the manuscript for its publication.This work was supported by the European Union’s Horizon 2020 R&I programme under grant agreement No. 818116 (MicrobiomeSupport).Bifidobacterium strain for obesity licensed (WO2012/076739A1). AS and BM had a patent on the plant-endophyte combinations and uses therefor (US9364005B2).At the time of writing, SS was employed by Indigo Ag. RdS and JA was employed by Symbiomics Microbiome Solutions. YS had a patent on a The remaining 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.The handling editor BM declared a shared affiliation with the authors MO, MR-P, and YS at the time of review.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.


Optical coherence tomography (OCT) has changed the standard of care for diagnosis and management of macular diseases in adults. Current commercially available OCT systems, including handheld OCT for pediatric use, have a relatively narrow field of view (FOV), which has limited the potential application of OCT to retinal diseases with primarily peripheral pathology, including many of the most common pediatric retinal conditions. More broadly, diagnosis of all types of retinal detachment  may be improved with OCT-based assessment of retinal breaks, identification of proliferative vitreoretinopathy (PVR) membranes, and the pattern of subretinal fluid. Intraocular tumors both benign and malignant often occur outside of the central macula and may be associated with exudation, subretinal and intraretinal fluid, and vitreoretinal traction. The development of wider field OCT systems thus has the potential to improve the diagnosis and management of myriad diseases in both adult and pediatric retina. In this paper, we present a case series of pediatric patients with complex vitreoretinal pathology undergoing examinations under anesthesia (EUA) using a portable widefield (WF) swept-source (SS)-OCT device. Optical coherence tomography (OCT) is an essential diagnostic tool in the management of retinal disease. There are trade-offs in the acquisition of OCT images between speed of acquisition, field of view (FOV), and image resolution and quality. Over the last two decades, despite significant advances in imaging speed and the transition from time-domain to spectral domain (SD)-OCT, the vast majority of OCT applications are for macular diseases in adults. OCT has proven ability to detect subclinical disease, often resulting in new disease classifications and earlier treatment, facilitate objective assessment of macular thickness and pathologic fluid, and improve visualization of the vitreoretinal interface. As a result, it is not possible to provide the standard of care for many adult retinal diseases without OCT.These same advances in clinical diagnosis and management would likely benefit pediatric retina patients. In retinopathy of prematurity (ROP), the most common pediatric retinal disease, OCT has revealed the normal spectrum of macular development in prematurely born infants , 2, idenen face visualization to allow the physician to position the probe optimally for image acquisition. The 105° FOV system has potential to provide objective diagnosis in pediatric retinal diseases with predominantly extramacular pathology, like ROP, and contribute to new insight in these disease processes. We recently described our experience using these devices for ROP screening in the neonatal intensive care unit (NICU) in awake infants  at Oregon Health and Science University (OHSU) and adheres to all tenets of the Declaration of Helsinki. Consent for imaging was obtained from parents. Pupils were pharmacologically dilated per routine clinical care. Infants were imaged in the operating room (OR) after the induction of general anesthesia and placement of an eyelid speculum with a 400-kHz portable handheld SS-OCT system, shown in he probe –17. The en face projections were calculated with custom software coded in MATLAB . TRDs are most commonly related to peripheral epiretinal neovascularization with fibrosis, with the resulting vitreoretinal traction leading to macular dragging  retinal detachments (RDs) in children. The most common visualization of OCT is the cross-sectional scan (B-scan) that reveals axial anatomy within a single imaging slice. However, SS-OCT can facilitate real-time en face visualization with topographic volume rendering. There are many previous publications focusing on the role of OCT in pediatric macular disease , retinal hemangioblastoma as part of Von-Hippel Lindau (VHL) disease, vasoproliferative tumor, and a variety of benign hamartomas such as choroidal hemangioma and congenital hypertrophy of the retina and RPE. The most serious of these is RB, which is both vision- and life-threatening. The current standard of care requires careful documentation of all tumors in the retina, including their size, location and the presence of any associated vitreous seeding, and subretinal fluid. Fundus photos are used to document these findings. Commercially available OCT systems are also widely used in retinoblastoma care, but have significant limitations due to their narrow field of view and narrow depth of focus –26. RetiChanges at the vitreoretinal interface are better diagnosed with OCT than ophthalmoscopy and are common in pediatric proliferative retinopathies, some inherited retinal degenerations, and disorders of ocular development. en face OCT and OCTA.Obtaining high quality OCTA is challenging even in cooperative adults, more so in children, and even more so with wider field of view. Nontheless, particularly under anesthesia, it is possible to explore the potential role OCTA may play in the diagnosis of pediatric retinal diseases when used in conjunction with structural OCT . Figure en face and cross-sectional AS-OCT in several patients with both preoperative and post-operative abnormalities of the anterior segment.Anterior segment (AS)-OCT has demonstrated a number of potential uses in adults, including evaluation of corneal curvature and pathology, angle structures, and iris and lens abnormalities . We haveIn this paper, we reviewed our experience using WF-OCT in the management of patients with a variety of pediatric retinal diseases undergoing EUA. Compared to the highest resolution commercially available adult OCT devices, our prototype uses a faster, swept-source laser, which facilitates efficient imaging of the retina even in awake neonates and children. These results demonstrate the tradeoff between FOV and resolution, which is necessary when trying to keep imaging time to a minimum.en face visualization, objective assessment of the peripheral stage, longitudinal monitoring of disease progression and regression, and detection of early vitreoretinal interface abnormalities  who presented shortly after birth with bilateral retinal folds and tractional-exudative RDs. Post-operative scans reveal improved exudation and subretinal fluid.Differentiating the cause of retinal detachment is key for proper management of retinal detachments in children, and OCT may be a pivotal tool. RRD repair depends on accurate identification of breaks, and the identification and management of proliferative vitreoretinopathy (PVR) membranes, which may be above or below the retinal surface. The standard of care is to carefully observe the entire retina with ophthalmoscopy and scleral depression for the presence of breaks. However, clinical diagnosis is not perfect and OCT may be superior for identification of peripheral pathology , 33. In In retinoblastoma (RB), the most common primary intraocular malignancy in children, the value of OCT has been demonstrated, however, there are known challenges with commercially available OCT systems –26. The In the realm of inherited retinal dystrophies (IRDs), OCT has been useful in identifying prognostic indicators, such as foveal cavitation , and theAs mentioned throughout, there is a tradeoff between FOV, resolution, and acquisition speed, therefore the transverse resolution is lower for a given laser when expanding the FOV for a given amount of imaging time. Practically speaking, that means that individual B-scans may be lower resolution using this approach compared to commercially available systems with narrower FOV, such as the Heidelberg Flex system, although the acquisition time is faster . Other lEn face visualization can provide the same benefit as fundus photography, but with volumetric structural and angiographic information as well. Finally, OCT facilitates objective assessment of retinal structures that can be used to monitor disease stability. The challenges to widespread adoption of this technology remain the lack of commercially available OCT devices of sufficient speed and FOV to be effective in capturing images outside of the macula. As the costs of lasers come down with time, our hope is that the market will facilitate the routine use of this technology in the care of children with retinal disease.In summary, the use of WF-OCT has several potential advantages compared to the clinical exam and fundus photography in the setting of pediatric retinal diseases. As in adults, the axial resolution is superior to what our eyes can see, enabling earlier detection of retinal abnormalities in multiple diseases. The original contributions presented in this study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by the Oregon Health and Science University Institutional Review Board. Written informed consent was obtained from the minor(s)’ legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article.JC, MC, DH, YaJ, and YiJ designed the study and obtained the funding. SO developed and maintained the patient database and consented all patients. AS contributed to the data and critically reviewed the manuscript. T-TN, GL, SN, SK, and XW identified, processed, and contributed to the images to the final manuscript. All authors reviewed and approved of the final version of the manuscript.Oregon Health and Science University (OHSU), DH, and YaJ have significant financial interests in Optovue, a company that may have a commercial interest in the results of this research and technology. These potential conflicts of interest have been reviewed and managed by OHSU. DH and YaJ have received royalties for patent files through OHSU, as well as loaned equipment for research from Optovue. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The purpose of this Research Topic, a continuation of Workplace Health promotion Volume 1, was to understand issues connected to population health from a workplace perspective such as factors mitigating against the health of workers, barriers to occupational health promotion, and other emerging problems . The aimA total of 88 researchers from across the globe contributed to 13 articles in this volume. The study participants were from sectors such as health and social welfare and include doctors, medical students, social workers, and the Police, to name a few. Several of the articles explored the impact of workplace issues on mental health and wellbeing; some examples include working conditions, gossip, feelings of exclusion at the workplace, and social media usage. One study investigated the outcome of an intervention to address depression among workers. Articles in this volume also highlight the role of social support, leadership, and supervision in addressing health-related workplace challenges. Other key features include, alcohol and sick leave, shift work and insomnia, performance, and work culture, fall accidents and supervision as well as burnout and the role of sleep quality, workplace violence and shift work. Each of the articles are summarized below.Chang et al. WHP performance was significantly related to workplace health culture, especially health policies, healthy climate, and peer and supervisor support. In their study, the Workplace Health Scorecard was administered to WHP representatives at each workplace, while a personal questionnaire was used to measure workplace health culture, healthy lifestyles, and health statuses at the individual level. A total of 27 enterprises and 1,732 individuals participated in the cross-sectional study, and data analyzed using a hierarchical linear model.According to Huang et al. studied the relationship between work conditions and outcomes like psychological distress among social workers in Chengdu, China. The study also investigated the mediational effects of positive affect (PA) and negative affect (NA) among the 897 participants. Results suggest that JR has a greater effect on PA and NA relative to the effects of JD on PA and NA. The authors conclude by suggesting interventions to promote PA in order to buffer against the effects of JD among social workers.Using the job demands and resources (JD-R) model, Emsing et al. using the SCL-90-R survey, aimed to find if there are differences in the mental health of two cohorts of Swedish police recruits totaling 376 from 2009 and 2020. The mental health of both cohorts was also compared to that of the general population using data from 2002. Multivariate analysis of variance (MANOVA) and bivariate analyses were conducted. Results showed that recruits from 2020 fared better, and that while some recruits scored above the Swedish patient mean, the prevalence and intensity of mental health disorders among recruits were generally low. Findings also showed that gender, educational level and relationship status were important predictors of mental health.Sim et al. attempted to answer by using e.g., multivariate logistic regression to analyze night shift profiles and baseline demographics data of three hospitals between January 2015 to December 2017 . Findings showed that the prevalence of insomnia was 38.7%, and that there was a significant relationship between consecutive night shifts and insomnia. The authors conclude that findings from the study could be a basis for developing policies and guidelines to improve the health of night shift workers.What is the prevalence of insomnia caused by consecutive night shifts? What night shift duration worsens insomnia the most? These were the questions which Yan et al. the aim was to investigate the prevalence of burnout among emergency physicians and its associated factors using a nationally representative cross-sectional survey of 15,243 emergency physicians between July and September 2019 in 31 provinces across China. The prevalence of burnout was 14.9%. Associated factors were depression, shift work, workplace violence, having poor self-perceived health status and sleep quality, working in developed regions and governmental hospitals, and having an intermediate professional title. Recommendations for prevention are discussed.In the study by Luo et al. propose a modification of the human factor classification analysis system (HFACS) framework. They also construct a Bayesian network (BN) topology based on the dependence between human factors and organizational factors, as well as determine the sensitivity of causal factors. Findings show that the most important reason for falling accidents is unsafe on-site supervision, the BN risk assessment model suggests that the most likely causes are loopholes in site management work, lack of safety culture, insufficient safety inspections and acceptance, amongst others.Given findings from a literature review and the characteristics of fall accidents in construction, Kanwal and Isha social media activities among office workers in the oil and gas industry significantly moderate the effect of effort-reward imbalance on health and wellbeing and impact job rewards. The conclusions are based on exploratory factor analysis and confirmatory factor analysis of data from 424 participants using an online questionnaire. Findings showed among others, that social media activities related to work-life decreased health and wellbeing by 11%, and social media activities related to personal life negatively affected job rewards by about 55%.According to Cheng et al. studied the effect of workplace gossip on employees' mental health using data collected in three waves from 222 full-time employees of a Taiwanese tourism company. Results suggest that workplace gossip is associated with employees' mental health through psychological capital, and that the relationships among workplace gossip, psychological capital, and mental health are moderated by developmental job experience.Hashemi et al. linked data from the WIRUS study  to company-registered sick leave data. The study included a total of 2,560 employees from 95 different work units in 9 public companies and 5 private companies in Norway. Negative binomial regression models were used, adjusted for gender, age, cohabitation status, educational attainment, work position, and employment sector. Findings show that although there were variations of 1-day, short-term, and overall sick leave days between companies than between work units within companies, neither alcohol-related problems nor drinking attitudes were associated with sick leave.To understand the relationship between alcohol-related problems and drinking attitudes with sick leave, Stassen et al. conducted a systematic review to investigate the attention to principles of resistance training (RT) progression and variables of RT exercise prescription in workplace-related RT interventions. The databases searched were LIVIVO, PubMed, SPORTDiscus, and Web of Science for publications between 2000 and 2020. Results from 21 articles  revealed that interventions showed different positive effects on strength- or performance-related and/or health- or complaint-related outcomes. However, several key RT principles and variables were reported inconsistently, thus reducing reproducibility, suggesting the need for standardized RT intervention reporting in workplace-related interventions.Xu et al. aimed to investigate medical residents' levels of social support, psychological resilience, and coping style, and explore the mediating role of psychological resilience. An online questionnaire was administered to a total of 577 medical residents from China recruited via convenience sampling, and the data were analyzed using Pearson correlation analysis. Findings show positive correlations between social support, psychological resilience and coping style and a significant mediating effect of psychological resilience in the relationship between social support and coping styles. The importance of paying attention to the psychological status of medical residents, as well as the need for increasing enthusiasm for coping style and promoting their mental health using social support and psychological flexibility, are discussed.The study by Frank et al. investigated whether employees with a mental illness become socially excluded at the workplace and if they have more days of sick leave. A total of 86 employees diagnosed with a mental disorder were interviewed and completed online-surveys, and Path analyses were conducted. Results show that the interview-rated severity of the mental disorder had an indirect effect on the days of sick leave, and that this was mediated by the symptomatic burden and social exclusion at the workplace. The need for organizations, especially supervisors, to be attentive for signs of exclusion and address same is discussed as important given the financial implications of employee absenteeism on organizations.Building on the stereotype content model and allostatic load theory, Gwain et al. conducted a pre-intervention and post-intervention study to assess an intervention which they developed to reduce depression among workers at the Outpatient Mental Health Clinic in Washington District of Columbia, United States. In order to determine the pre-intervention prevalence of depression, a survey was conducted on 43 employees using the Patient Health Questionnaire depression scale (PHQ-9). Thereafter, the WHO Healthy Workplace Model was adopted to design an instrument for determinants of depression at the workplace, followed by the development and implementation of a mHealth intervention. Finally, a post-intervention survey was conducted among the cohort, and the data was analyzed using descriptive and inferential statistics in STATA. Findings show that the prevalence of depression went from 30.2%, pre-intervention, to 12.6% post-intervention. The findings suggest that improving employee mental health can be achieved using cheap mhealth solutions.The need for clear policys and routines, as well as increase in wellness packages offered and strategies to improve their uptake thus remains . In concLO-E was responsible for project idea, design, implementation, manuscript drafting, and final version of the manuscript. DG and SA contributed to project implementation and manuscript final version. All authors contributed to the article and approved the submitted version.


Current clinical literature and supporting animal literature have shown that repeated and profound early-life adversity, especially when experienced within the caregiver–infant dyad, disrupts the trajectory of brain development to induce later-life expression of maladaptive behavior and pathology. What is less well understood is the immediate impact of repeated adversity during early life with the caregiver, especially since attachment to the caregiver occurs regardless of the quality of care the infant received including experiences of trauma. The focus of the present manuscript is to review the current literature on infant trauma within attachment, with an emphasis on animal research to define mechanisms and translate developmental child research. Across species, the effects of repeated trauma with the attachment figure, are subtle in early life, but the presence of acute stress can uncover some pathology, as was highlighted by Bowlby and Ainsworth in the 1950s. Through rodent neurobehavioral literature we discuss the important role of repeated elevations in stress hormone corticosterone (CORT) in infancy, especially if paired with the mother  as targeting the amygdala and causal in infant pathology. We also show that following induced alterations, at baseline infants appear stable, although acute stress hormone elevation uncovers pathology in brain circuits important in emotion, social behavior, and fear. We suggest that a comprehensive understanding of the role of stress hormones during infant typical development and elevated CORT disruption of this typical development will provide insight into age-specific identification of trauma effects, as well as a better understanding of early markers of later-life pathology. We have known for decades that early-life adversity during a sensitive period robustly increases vulnerability to physical and mental disorders, as has been replicated in other animal species . Since tAs first noted by Bowlby, attachment forms regardless of the quality of caregiving. However, trauma associated with the attachment figure has been emphasized as particularly influential in vulnerable contexts associated with later-life pathology . Indeed,The delayed onset of psychopathology induced by early-life trauma has presented the challenge of identifying the early-life roots of later-life psychiatric disorders. However, more recently, an emphasis on the subtle age-specific expression of later-life psychiatric disorders suggests there are earlier symptoms of dysfunction that serve as markers of later-life pathology . For exaTo further tease apart the correlations between early-life adversity and a social context with later-life pathology, we look to animal research with a translational approach. While some may suggest that parent–infant attachment is unique to humans, John Bowlby, the father of Attachment Theory, was strongly influenced by animal research on attachment. Bowlby’s discussions with animal researchers, specifically with ethologists studying rodents, non-human primates, and avian imprinting , led himIn Attachment Theory, Bowlby highlights that the quality of care an infant receives establishes the quality of attachment, and thus consequently the infants’ social interaction with the parent . While iWhile this mechanism of attachment in imprinting may seem counterintuitive, from an evolutionary viewpoint, selection pressure likely favored robust features of the attachment figure and increased the probability of a chick’s survival. Overall, this research supports the notion that regardless of the quality of parental care received, an infant will form an attachment. As will be discussed in more detail below, this association of pain and attachment in infants can also be seen in rodents, dogs, non-human primates, and children, where abusive parental care supports robust attachment . In humaIn summary, research on both human and non-human animals describes a sensitive period in early life when attachment learning occurs regardless of the quality of care the infant receives, including nurturing and maltreatment. This attachment system has short-term benefits in that infants will always attach . Yet earThe most notable impacts of this adversity are within a social context where children display heightened separation anxiety, decreased ability to soothe, and altered fear, all of which are associated with acute increase in stress hormones. Indeed, increased levels of stress hormones have consistently been shown to negatively impact neurobehavioral development . HoweverTo further investigate the role of stress in modulating response to adversity, experiments on experiences of adversity within varying caregiving contexts were conducted. Early research within child development showed that increasing stress could uncover disrupted behavior toward the caregiver, and this was capitalized upon by Ainsworth in the development of the Strange Situation Procedure (SSP) . SSP wasAn additional category was later added to Ainsworth’s attachment styles and termed disorganized attachment, a form of attachment in which the child exhibits intense parent-directed social behaviors that are contradictory, combined with expressions of confusion and apprehension, and immobility/freezing . DisorgaThe rodent literature has shown that in the natural nest with the mother, adversity-reared pups still show typical social behavior with the mother, at least when not being actively maltreated , suggest(CORT) during SSP’s last reunion with the mother see , but theIt is important to note that prolonged adversity-rearing impacts many processes throughout the brain, and depending on the level of analysis indicated, it can either potentiate or attenuate the response to the mother (or caregiver). For example, imaging and optogenetic manipulation of pups following adversity-rearing suggest that pups’ amygdala is altered in a myriad of ways, including increases and decreases in the functionality of the basolateral amygdala (BLA) and the central amygdala (CeA), changes in neurogenesis, and an increase in neural activity as indicated by c-Fos, 2-DG autoradiograph and LTP/Ltd. .Furthermore, CORT during infancy has a role in switching the amygdala on and off. For example, young rats cannot be fear conditioned until they are about PN10 , which iIn summary, CORT has a unique role in infant rats that gates emotional expression and learning, this is best observed by the slowly increasing levels during typical development and its permissive role in amygdala expression of fear around PN10. A precocious increase of CORT induced by adversity-rearing can derail this typical developmental trajectory through at least a few ways. First, atypically high levels of CORT in pups < PN10 permits the early expression of amygdala-dependent fear. Second, elevated CORT also engages the amygdala in young preweaning pups, a process that disrupts social behavior . OverallThe ability of the parent to reduce their child’s response to a threat was first highlighted by Bowlby, who noted a child was more likely to explore a novel environment if the parent was present , 1965. SAnimal research has been helpful in defining causal mechanisms of social buffering, highlighting that maternal presence blocks the amygdala response to threat in infant rats, thus blocking plasticity in the brains’ core fear processing center as seen in Specifically, around PN16, while the mother continues to decrease pups’ threat-induced stress hormone increase, the mother can no longer suppress the amygdala’s plasticity . FurtherMore recently, maternal suppression of fear learning has been replicated in children; 4-year-old children can learn fear, but fear learning is suppressed in the presence of the parent . ImportaIn summary, within typical development across species, the presence of the caregiver reduces infants’ response to trauma by reducing the stress hormone release. Animal research suggests that the mother blocks the release of stress hormones by blocking activation of the HPA axis and depriving the amygdala of an age-specific dependence on the stress hormone CORT. CORT is required to engage plasticity mechanisms within the amygdala during the transitional sensitive period see , with thThe child development literature suggests that the parent–infant social buffering system is degraded with repeated trauma-parent associations, which can occur in maltreatment , and hasTo better understand how the quality of caregiving can alter the infant’s neurobehavioral response to trauma, we again can look to research on rodents. As illustrated in via brain programming. Non-human animal research fills a gap in our understanding of the child’s brain when clinically relevant questions are addressed and often builds bridges between basic and clinical domains that can transcend jargon and biases within research domains.Research in children is the gold standard for understanding neurobehavioral development and a critical benchmark for understanding the neurobehavioral expression of pathology. However, while brain imaging techniques are powerful tools, resolution is low and models of inferential causation are frequently used instead of defining causal mechanisms within the brain, the organ of behavior. This combined with ethical limitations exploring the infant’s response to trauma limit our understanding of the developing brain. However, the emergence of robust animal research in brain networks to define neural circuits and extracellular and intracellular events, shows infants’ brains are indeed immediately altered in response to trauma and further altered by repeated trauma Within typical development, our current literature on bi-directional translational research in children and other infants of altricial species shows that frequent stress produces an increase in stress hormones, which is reduced by parental presence to inhibit responses to the threat. Animal models have shown the neural basis of this, highlighting a brain network involving suppression of the hypothalamic control of stress hormone release and inhibition of VTA dopamine (DA) release, to suppress amygdala plasticity molecules, and halting fear expression and learning , 2021. MFor atypical development, we reviewed the rodent literature with repeated infant adversity experiences illustrating this system of parental suppression of stress hormones, where the amygdala is greatly attenuated, and fear learning is not blocked. Furthermore, this dysfunctional system that is preserving high levels of stress in the infant when with the mother , also disrupts social behavior with the mother.Ultimately, this system initiates a pathological pathway of brain development that specifically targets and disrupts amygdala development to produce enduring dysfunctional processing of the mother within infant brain networks. We suggest that a better understanding of these age-specific roles of CORT and its dysfunction provides insight into age-specific identification of trauma effects related to elevated CORT, and potentially a better understanding of early markers of later-life pathology and mechanisms initiating the pathway to pathology.The presence of the mother, even without exhibiting any form of behavior , reduced threat-induced stress increase in infants with adversity-rearing, and this is known as social buffering. The ability of the caregiver to socially buffer highlights the instrumental role of social context of adversity and how attachment to a caregiver can impact how an infant will react to trauma.Deepening the understanding of typical and atypical development induced by repeated early-life adversity, especially within a social context, is crucial for designing age-specific interventional treatments that have efficacy in alleviating deleterious impacts of trauma during infancy on mental and physical health that are known to continue into adulthood. Early-life trauma, especially within the family, is emerging as one of the more potent factors of later-life psychopathology, and it is important to understand the mechanisms of action among risk factors that increase vulnerability to psychopathology. For reviews of this translational approach, please see NN, RMS, and RMZ: conceptualization, research, writing—original draft preparation, editing, and creating figures. SW, AU, BY, and AS: editing, research, and drawing figures. 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.


Precision medicine for cancer affords a new way for the most accurate and effective treatment to each individual cancer. Given the high time-evolving intertumor and intratumor heterogeneity features of personal medicine, there are still several obstacles hindering its diagnosis and treatment in clinical practice regardless of extensive exploration on it over the past years. This paper is to investigate radiogenomics methods in the literature for precision medicine for cancer focusing on the heterogeneity analysis of tumors. Based on integrative analysis of multimodal (parametric) imaging and molecular data in bulk tumors, a comprehensive analysis and discussion involving the characterization of tumor heterogeneity in imaging and molecular expression are conducted. These investigations are intended to (i) fully excavate the multidimensional spatial, temporal, and semantic related information regarding high-dimensional breast magnetic resonance imaging data, with integration of the highly specific structured data of genomics and combination of the diagnosis and cognitive process of doctors, and (ii) establish a radiogenomics data representation model based on multidimensional consistency analysis with multilevel spatial-temporal correlations. Quantitative description of tumor heterogeneity may lead to one-sided or even erroneous diagnosis, affecting the treatment options, and leading to drug resistance and disease recurrence in patients.Tumor heterogeneity, one of the main characteristics of malignant tumors, poses great challenges to its accurate diagnosis and treatment, which is also manifested by multiple genotypes and multiple gene expression patterns in the same tumor cells . The samGenome analysis technology attempts to solve the problem of tissue sampling and analysis under tumor heterogeneity, such as the multiregion sampling strategy for spatial heterogeneity, and the micro-cutting of different tumor tissues for the isolation of small tissue fragments. DNA of these fragments has been analyzed . HoweverBroadly speaking, tumors are made of evolved and heterogeneous populations of cells that are resistant to matched targeting therapy. Thus, it is not enough reliable to evaluate effects of tumor treatment and diagnosis only from the perspective of tumor abnormality , 11. TumThis paper was aimed at reviewing the methods in literature regarding the precise diagnosis and prognosis prediction of neoadjuvant chemotherapy for tumors, using breast MRIs, for example. Taking tumor heterogeneity as the core issue, the deep learning-based radiogenomics analysis of breast tumor heterogeneity was studied, and the relationship between the imaging characteristics of heterogeneous tumors and molecular expression features was correspondingly explored as well. At the same time, geometric algebra was applied to design a framework for analyzing dynamic contrast enhanced MRI radiogenomics, and fully mining the rich spatial images, spatial signals, and semantic features in breast multidimensional magnetic resonance imaging. According to the heterogeneity of different tumors, an individualized model of neoadjuvant chemotherapy efficacy prediction was established by combining MRI information, molecular typing information, and clinical information of patients suffering from breast cancer, which provided scientific guidance for accurate diagnosis, treatment, and prognosis of patients, improved the survival rate of tumor patients, enhanced the life quality of patients after surgery, and achieved effective and rational utilization of medical resources.The remainder of the paper is structured as follows: In biomedical analysis, tumor heterogeneity characteristics and multiple physiological tumor characteristics are not combined, and multimodal (parametric) imaging technology is not widely used . VariousAt present, this method is only applied for two-dimensional analysis of DCE-MRIs –29, and In recent years, there have been several researches concerning the radiomics research of tumor stroma. For example, King et al. found that the increase in the dynamic enhancement rate of fibroglandular mammary glands was associated with higher mammary cancer morbidity , who divAs a noninvasive modality, the multidimensional radiogenomics analysis based on Magnetic Resonance Imaging (MRI) has become a special field of study on the tumor grading. The field of radiogenomics has been advanced substantially by novel MR imaging sequences that reflect underlying oncogenic processes. MRI-based radiogenomics combines a mass of quantitative data extracted from multidimensional MR images with individual genomic phenotypes and builds a prediction model through deep learning, which aims to make a diagnosis for patients, offer guidance for therapeutic strategies, and make an evaluation on clinical outcomes . AdditioRadiogenomics, as an important application, reveals and reflects the molecular pathological characteristics of tumor tissues, such as dynamic enhancement characteristics for tumor and mammary-gland tissue , 34 and Tumor molecular classification is an important index in clinical diagnosis. In several studies, quantitative image features, such as the dynamic enhancement ratio of the lesion to the background area, gray-scale histogram features, and 66texture, are used to predict these molecular indicators , 41. It Currently, a large amount of research regarding radiogenomics focuses on exploring the relationship between imaging group and molecular features. Some work bypasses the association between imaging and molecular information and directly uses imaging features to predict treatment results.It has been investigated that the imaging phenotype of the tumor can be used to provide information on the outcome of tumor treatment, such as chemotherapy efficacy and prognosis. Fan et al. extracted 156 image features of breast tumors and background regions using DCE-MRIs and selected several distinguishing heterogeneous features reflecting gray-scale unevenness, such as kurtosis and skewness, to predict the effectiveness of NAC for breast cancer . Huang eWith the use of perfusion magnetic resonance (MR) imaging, Wu et al. characterized intratumoral spatial heterogeneity and studied the tumor homogeneity to predicate the recurrence-free survival (RFS) of the patients with breast cancer .  FigureApart from the mentioned analysis of imaging group features, some researchers have also attempted to establish a multiomics approach for tumor diagnosis and treatment by combining image features and molecular features. For example, it was found that imaging methods exhibited different prediction results for patients with different molecular subtypes of breast cancer. Specifically, HER2-positive breast cancer was found to have a higher accuracy rate for its NAC treatment, while human epidermal growth factor receptor 2 (HER2) and triple-negative breast cancer (TNBC) had a lower accuracy rate , since pIt was revealed that imaged tumor features and patient symptoms could be complementary, and the combination of the two could improve the accuracy of the prediction model. Although researchers have made considerable efforts on tumor diagnosis and treatment based on the analysis of clinical and molecular pathology information and image characteristics, there are few results in the research of precision diagnosis and treatment models combining the two features, and the methods and technologies in this area shall be studied and resolved. Besides, repeatability and reproducibility are the two relatively major problems  regardinTumor heterogeneity poses challenges to the precise diagnosis and treatment of breast tumors. Its systematic analysis provides extensive information for the characterization of breast tumors, and effective application of this information is of great significance to improve the accuracy of breast cancer diagnosis and treatment. Fan et al.  exploredBesides, a modelling framework was proposed by Fan et al. , as showBased on the radiogenomics techniques, this section aims to develop novel multidimensional mining algorithms, focusing on the key core issue of tumor heterogeneity. The proposed algorithms will lead to the identification of tumor patterns in complex geometric spaces. Through the analysis of multimodal images and molecular information reflecting different functional characteristics of tumors, we aim (1) to deeply mine the spatial, temporal, and semantic features of breast multidimensional images across scales; (2) to reveal the relationship between the overall and regional imaging phenotypes of tumors and recognize their joint functional characteristics with gene expression together with molecular typing; (3) to provide new intelligent solutions for breast tumor clinical diagnosis and neoadjuvant chemotherapy efficacy prediction, which can effectively assist doctors to make correct treatment decisions and improve patients' health.According to different description methods for tumor heterogeneity, the analysis on tumor radiogenomic correlation is to be carried out at three levels, that is, analysis of the whole tumor region, tumor subregions, and tumor subcomponents; regarding a single time point; and longitudinal time axis. Different levels of tumor heterogeneity can be mapped using geometry algebraic decomposition in relation to the multidimensional image space, image subspaces in different directions corresponding to the same dimensional image vector, and the cross-dimensional image signal vector features in different directions.It is a crucial basis for accurate analysis of radiogenomics to realize the rapid and automatic parameter extraction of unstructured breast radiomics data and the effective fusion of unstructured feature vectors with diagnostic value found in structured data.Based on the theory of geometric algebra, tumor images with different structures are transformed from complex geometric objects to straightforward geometries like dots, lines, and polygons that can be directly expressed in Euclidean space, so as to realize the hierarchical decomposition of the complex geometric data of breast tumors. Appropriate image segmentation and deep clustering methods should be adopted to analyze multiple geometric vectors in different dimensions. The final aim is to achieve deep learning and feature extraction of tumor heterogeneity based on multidimensional uniformity analysis in a multivector space and achieve the transition from unstructured imaging to structured genomics data.As discussed in , it is eThere are three parts proposed below for further realization of the deep association learning between MRI radiomics and genomics, as illustrated in Weak supervision can facilitate the acquisition of the datasets marked manually. Weak supervision learning enables the application of inexpensive weak labels, and such labels can be exploited to build a powerful prediction model. The overall heterogeneity of tumors can be measured, analyzed, and classified using weakly supervised learning –69 of imi) “omics” features, and this process for all tumor images (j) can be sorted out to obtain an i × j matrix, so that feature calculation and classification research can be performed on the same time signal dimension.Taking DCE-MRI as an example, the clustering results of the initial enhancement speed and the later decline speed of the enhancement curve can be sorted out to obtain several  image features and molecular analysis features. In order to comprehensively analyze the heterogeneity of different functional characteristics of tumors, image registration –73 is peTo fully analyze the correlation between heterogeneous image features and molecular features, the mixed images and gene molecular expression signals are suggested to be decomposed separately. This practice is to realize high- and multidimensional vector analysis in an integral space, also the multidimensional subspace region analysis, and spatial-temporal consistency analysis of heterogeneous subcomponents. The goal is to establish correlation models at different levels and achieve more accurate relationship to highlight key entities for the image or signal processes and the relationship between multiple entities  in multidimensional vector space or subspace.Simultaneously, the gene expression data can be analyzed using subpathways, submodules, and enrichment methods, thereby dividing them into several representative pathways, marked modules, and gene clusters. The expression signal is expected to break down according to different tissue and cell characteristics using the signal decomposition method, which will in turn constitute a “convex hull,” each containing some “marked” genes .In order to study the correlation between characteristic components in terms of different tissues, the correlation between the subregions (components) of the tumor heterogeneity should be analyzed and sorted by the spatial-temporal consistency-based algorithm after the decomposition of the image group and gene expression data, as shown in Each sample is decomposed into these three types of subcomponents, and then the radiogenomic association of each subcomponent  is analyzed separately for all samples. Unlike traditional analysis methods, the attention-based deep learning network aims to study and analyze the correspondence between high-dimensional image vectors and gene expression subcomponents and try to obtain more accurate map of relationships based on the relationship between “pure” subcomponents with the directions of themselves.The effective embedding of radiomics and genomics information plays a key role in establishing spatial-temporal consistent model of radiogenomics. The genomics information of breast multi-dimensional dynamic imaging is intricate, including image sequence information, and time series information, both unstructured data of magnetic resonance imaging and structured vector of genomics. The design of gated loop unit with memory mechanism is important not only for timing information, but also for the memory and integration of image and genomics information.Therefore, the two-way activation embedding method of the gated cyclic unit is designed based on the lightweight Bi-GRU, and the activation gate is introduced to process the genomics data of breast cancer patients with individual differences. The AuGRU model enables effective fusion of the genome sequence-related output and tumor heterogeneity analysis via radiogenomics, along with molecular typing for classification.Additionally, it is of importance to design a bidirectional threshold recurrent neural network (BiGRU-RNN) model based on memory and attention mechanism, which highlights tissue-level radiomics feature input and molecular typing feature vector and encodes the contextual interaction mechanism of the genomics feature vector of tumor. Such a model plays a key role in carrying out the effective correlation of the spatiotemporal features of dynamic images and constructing a joint representation model of image data and genomics data. The schematic diagram summarizing the proposed attention-based BiGRU-RNN network model is shown in Radiogenomics characteristics reveal multiscale intratumoral heterogeneity concerning biological functions and survival in breast cancer. These studies performed diagnosis and treatment analysis by measuring the characteristics of overall tumor heterogeneity. For example, the research group of Huang et al. used 132 texture features of CT images to forecast the Disease-Free Survival (DFS) of non–small cell lung cancer (NSCLC) , and GohIn order to accurately locate and describe the imaging heterogeneity of tumor subregions, researchers around the world have made some preliminary attempts to describe the heterogeneity of different tissue characteristics using different imaging modalities , 77, 79.As mentioned previously, malignant tumor has become one of the most common diseases harmful to human health, whose precise diagnosis and treatment are studied internationally, but remains unsettled. This paper focused on the precise diagnosis and prognosis prediction of neoadjuvant chemotherapy for cancer disease. Centering the tumor heterogeneity, this paper investigated radiogenomic methods for tumor heterogeneity analysis based on machine learning and explored the relationship between the imaging characteristics and molecular expression characteristics of heterogeneous tumors. A multidimensional MRI radiogenomics data analysis framework was designed based on geometric algebraic representation model to comprehensively explore the rich spatial images, spatial signals, and semantic features in multidimensional multimode MRIs. Besides, a spatial-temporal representation model was designed by focusing on both local and the global feature spaces in different hierarchy, and diversified self-attention mechanisms were implemented. Regarding the heterogeneity of different tumors, this paper proposed an individualized radiogenomic model combining the information about tumor imaging, molecular classification, and tumor clinical treatment for predicting the curative effect of neoadjuvant chemotherapy. It provides scientific guidance for accurate diagnosis, treatment, and prognosis of breast tumor patients, for the purpose of improving the cure rate of the patients with tumor, enhancing the well-being of patients after surgery, and using medical resources effectively and reasonably.Tumor heterogeneity is a determinant playing a key role in therapeutic effect and is scarcely known from the perspective of molecular . This pa


Molecularly imprinted polymer (MIP)-based luminescent chemosensors combine the advantages of the highly specific molecular recognition of the imprinting sites and the high sensitivity with the luminescence detection. These advantages have drawn great attention during the past two decades. Luminescent molecularly imprinted polymers (luminescent MIPs) towards different targeted analytes are constructed with different strategies, such as the incorporation of luminescent functional monomers, physical entrapment, covalent attachment of luminescent signaling elements on the MIPs, and surface-imprinting polymerization on the luminescent nanomaterials. In this review, we will discuss the design strategies and sensing approaches of luminescent MIP-based chemosensors, as well as their selected applications in biosensing, bioimaging, food safety, and clinical diagnosis. The limitations and prospects for the future development of MIP-based luminescent chemosensors will also be discussed. Chemosensors are composed of a receptor functional moiety and a reporter, which can produce a detectable signal response, such as absorption, luminescent or electrical, to reflect the binding of an analyte with the receptor via non-covalent host-guest interactions. For an ideal chemosensor, the host-guest interaction must be highly specific to the targeted analyte and preferably with high binding affinity to achieve high selectivity and sensitivity ,2,3,4. AThe extensive developments of molecularly imprinted polymers (MIPs) have provided an effective way for preparing materials with receptor sites, which are highly specific to the molecular template used in the preparation of the MIPs or molecules with high structural similarity, including the distributions of the functional group moieties, hydrophobicity, and polarity. In addition to the highly selective binding receptors, MIPs are also well-known for their inherent mechanical and chemical stability, strong binding affinity, short development time, and low cost with well-developed preparation strategies ,10,11. GThe use of MIPs in the development of chemosensors offers another advantage, as the polymeric systems are well-known to provide collective responses to enhance their sensitivity by “amplifying” the signals compared to single molecular systems . The ampGiven the ease of developing highly selective receptors from MIPs, the amplification effect in polymer-based sensors as well as the highly sensitive luminescent detection, the recent advances in luminescent MIP-based sensors and devices are reviewed in this article. The design strategies and classifications of luminescent MIP-based chemosensors and their selected applications in biosensing, bioimaging, food safety, and clinical diagnosis  will alsAs mentioned above, MIPs, as selective sorbents, are prepared from a mixture containing at least two essential components, namely functional monomers for interacting with the template or structurally-related molecule that acts as a template. The design concept of MIP was first reported and demonstrated using silica matrices by Polyakov’s seminal work ninety years ago. Different strategies for preparing MIP have been rapidly developed over the past few decades due to the exponential growth and development of organic polymers .In the syntheses of MIPs, the template-monomer(s) adduct was formed in the reaction mixture via one or more intermolecular interactions, such as reversible covalent bond formation, semi-covalent or non-covalent interactions . The subsequent polymerization is performed in the presence of an initiator and crosslinker in the solvent. With crosslinking polymerization, the orientation of monomers and the functional sites that bound with the template molecule are fixed and rigidified by crosslinking units in a three-dimensional network to avoid their random movement. Subsequent removal of the template molecules from the MIP matrix leaves robust binding sites that are highly selective to the template molecule and structurally similar molecules having the same functional groups . These hIn general, MIPs can be prepared by copolymerization reactions of a combination of the most commonly used building blocks (monomer and crosslinker) in the presence of template molecules, initiators, and solvents, as summarized in With the highly selective binding sites, MIPs have found a wide range of applications such as solid-phase extraction (SPE), sensors, membranes, catalysis, synthesis, and drug delivery ,36. MoreLuminescence detection has been providing a significant and attractive approach for numerous chemical, biological, and environmental species because of its high sensitivity, non-destructive nature, and stability ,5,6,7,8.For emissive analytes, their MIP-based chemosensors can be non-emissive and thus are generally prepared using the standard method for MIPs using the analyte as the template. As the luminescent properties of the analytes would change upon binding with the imprinted sites of the MIP due to the changes in the micro-environment and the electronic properties resulting from the binding interactions, such changes can be used for the qualitative and quantitative determination of the analyte. Selected examples include MIP-based sensors for enrofloxacin and fluoroquinolone analogs  and rhodFor non-emissive analytes, luminescent chemosensing can be achieved by displacement or competitive assay using a non-emissive MIP with a luminescent-labeled analyte as the template ,50. HoweEarly design of luminescent MIPs is mainly based on the physical entrapment or chemical modification of the MIPs through the addition of luminescent dye or polymerizable organic fluorescent-dye-containing monomers in the preparation of MIPs, respectively ,55. HoweThrough the copolymerization of luminescent monomer in the preparation of MIPs, emissive MIPs with the emission properties derived from the luminophore of the monomer can be obtained. This method has been extensively explored in the past decade for the development of luminescent chemosensors. For example, Rurack and coworkers  designedAnother example is illustrated in fluorescent tetracycline-imprinted polymers reported by Zhang and coworkers . By copoAlthough wide varieties of organic fluorescent functional monomers are observed to have good compatibility with polymeric materials and relatively high fluorescent intensities, their universal applications are hindered by the broad and tailing emission peaks. These limitations are more pronounced in MIPs with fluorophores and receptors derived from two separated monomers, in which the emission of some of the fluorophores is unaffected by the binding event. Moreover, poor photostability and photobleaching of these MIPs have also been reported .MIPs can be made luminescent through immobilization strategies by attaching luminescent signaling elements. Chemical surface functionalization methods are applied to provide covalent binding sites for exterior luminescent moieties. The commonly used functional groups for covalent immobilization include thiol, amino, carboxyl, hydroxyl, vinyl, and azide groups ,62,63. WWang and coworkers  developeWith luminophores attached through covalent bonding, a chemical surface functionalization is a promising tool for translating recognition events into luminescent signals. However, maintaining the integrity of the binding cavities after chemical surface functionalization so as not to weaken the selectivity remains a challenging issue.Since the first report of luminescent lanthanide-based copolymer sensors by Murray and coworkers ,68, lant3phen] into poly(amidoamine) dendrimer to serve as a luminescent additive dispersing on the surface of the molecularly imprinted membrane for the selective recognition of salicylic acid  and photosensitizer chlorin e6, and surface imprinted polymer with an anticancer drug doxorubicin (DOX) and the epitope peptide of CD59 protein as the templates. With this multifunctional core-shell MIP, the epitope peptides lead to precisely reaching the cancer cells; the emission and magnetic properties of SiGdQDs in the core facilitate the fluorescence and magnetic resonance imaging dual modality; the photosensitizer chlorin e6 can function as a photodynamic therapeutic reagent to generate toxic 1O2 upon irradiation; and DOX is released to kill the cancer cells  with different functional molecules for simultaneous fluorescence imaging-guided target recognition and chemo-photodynamic therapy . The MIPer cells .The detection of food contaminants and spoilage are important food safety issues. Luminescent MIP-based sensors allow for real-time monitoring of food spoilage. For example, the spoilage of seafood can be monitored by volatile amines, particularly trimethylamine (TMA) vapor. Through surface chemical immobilization of phosphorescent cyclometalated Ir(III) complex on TMA-imprinted polymer (PTMA-Ir), Ko and coworkers have developed luminescent MIP for the quantification of TMA vapor. The surface chemical immobilization strategy was inspired by the method reported by the same research group for the preparation of iridium-based polymer-supported photocatalysts . After tLuminescent MIPs have also been developed for the detection of food contaminants. This is exemplified in the luminescent MIP-based tetracycline sensor, which is designed by doping luminescent carbon-QD-containing monomer in the preparation of the tetracycline-imprinted polymer . The lumIn recent years, the development of luminescent MIPs has provided a promising sensing platform for point-of-care diagnostic applications. The fast, sensitive, high specificity, and simple sampling requirement of luminescent MIP-based sensors have overcome several drawbacks of traditional diagnostic methods, including time-consuming sample preparation and the use of sophisticated instrumentation. Based on the biomarker identified for disease diagnosis, luminescent MIPs for biomarker detection with optical readout signals for simple detection is of great significance for clinical screening ,144. ForIn this review, the recent design strategies, development, and representative applications of luminescent MIP-based chemosensors over the past ten years have been described and emphasized. Based on the well-developed methodologies, the progress of synthetic MIPs with cavities capable of serving as the synthetic receptors for wide varieties of targeted molecules/ions ranging from metal ions and simple molecules to macromolecules have been discussed. Using various design strategies, different types of luminophores, including organic fluorescent dyes, transition metal complexes, lanthanide complexes, and nanomaterials, can be incorporated onto the surface or backbone of the MIPs to serve as the emissive reporters for the binding events of the cavities in the MIPs. Based on the emissive responses towards the target analyte, these luminescent MIPs can serve as the chemosensors to detect and quantify the analyte. With the robustness and compatibility of the luminescent MIPs to different conditions, they have found promising applications in different areas, including environmental monitoring, biotechnology, biomedical sciences, clinical diagnosis, and the food industry. It is expected that parallel to the growing demands of analytical tools for different analytes. Extensive research works to develop new luminescent MIPs for novel applications will be reported.Despite outstanding performance and potential applications, the limitations of each strategy in designing luminescent MIPs for chemosensors should be noted for the successful development of luminescent MIP-based sensors with drastic optical responses. In addition to the performance, biocompatibility, and toxicity must be considered when designing MIP-based chemosensors, in particular those aimed at biotechnological and biomedical applications. On the other hand, the long-term chemical inertness of these luminescent MIPs might become an environmental threat when these MIPs are commercialized and widely used. This issue can be tackled by developing biodegradable MIPs, which have received growing attention in recent years. However, biodegradable MIP-based luminescent chemosensors are almost unexplored.


Positive visual phenomena, although reported in lesions of visual cortex, are often overlooked in patients with acute neurological conditions. Yet, their occurrence without structural abnormalities or other underlying neurological disorders represents a unique observation. This report aims to raise awareness of these phenomena, their implications for understanding visual consciousness and to propose a practical, structured algorithm for the clinical assessment of visual hallucinations related to neurological conditions.We describe the clinical presentation and imaging findings in two patients with isolated visual hallucinosis secondary to transitory hypoperfusion.One patient presented with subocclusion of the right posterior cerebral artery and the other with multifocal arterial abnormalities suggestive of reversible cerebral vasoconstriction syndrome (RCVS). Both presented isolated visual hallucinations and hypoperfusion of the right mesial occipito-temporal cortex. Hallucinated images exhibited peculiarities of certain attributes that were recognized only through guided perceptual analysis performed during their occurrence.Dysfunctions in the visual and attentional networks due to the uneven impact of hypoperfusion on the regions of the mesial occipito-temporal cortex likely contributed to the occurrence of visual hallucinations. The initial impaired awareness of certain image attributes obscured an altered, non-realistic rendering of the hallucinated images. Enhancement of awareness through clinical guidance indicates improved attentional deployment, modulation of visual information processing and hallucination–background integration. These features of the hallucinatory phenomena highlight the critical role of semiological analysis during their occurrence and question the validity of post hoc inquiries. Visual sensory deprivation (e.g. Charles Bonnet syndrome) and several brain disorders, including strokes in visual areas, may induce hallucinations –5. TheirWe report two cases with visual hallucinosis and hypoperfusion of the right occipito-temporal cortex, without infarction of the visual cortex, and we propose a practical and structured algorithm for the evaluation of visual hallucinations related to neurological conditions. This algorithm allows an organized exploration of the hallucinatory phenomena and the localization of the involved brain networks. It includes the classification of the hallucinations, the context of their appearance, their chronology, the assessment of insight and of the attributes of the hallucinated images  and subocclusion of the P2 segment of the right posterior cerebral artery . Her complex hallucinations were clear wall writings, people and plants smaller than real (micropsia), clear and brightly colored. All had neutral emotional impact. Through guided analysis, patient noticed that all hallucinations manifested in her left visual field. The writings were illegible and appeared static. The people and the plants showed depth and lateral shifting without biological movement, resulting in an ellipsoid trajectory, and the transition between the hallucinations and the background was blurred. Noteworthy, lateral component of the translational movement was present during steady fixation and was also influenced by the eye movements (e.g. changes in the perceived trajectory or speed).A 55-year-old woman with history of untreated essential tremor was admitted following a third episode of thunderclap headache. Neurological exam was normal. MRI showed multifocal arterial irregularities suggestive of RCVS Fig. C, D. No Several hours later, on the evening of the admission day, patient reported isolated simple and complex visual hallucinations with preserved insight. A repeat MRI showed hypoperfusion of the right occipito-temporal cortex without parenchymal lesions Fig. A, B. EEGPatient's hallucinations were assessed soon after their first appearance, when they were manifest, and their progress was monitored daily until they resolved. Simple visual hallucinations included a bright equilateral triangle sliding from the left towards the center of the visual field, replaced several hours later by complex hallucinations of people, animals and plants. Her complex hallucinations were normal-sized, clear, vividly colored, well integrated into background, “moving” and emotionally neutral, except for one reported as a “scary head with holes in its face, large red cheeks and small black eyes”. Through guided visual analysis, patient noted that all hallucinations manifested in the left visual field and that hallucinations of people, animals and plants had in-depth and lateral shifting without biological movement resulting in an ellipsoid trajectory, and a blurred transition with the background. As with the first patient, the lateral component of translational motion was present during steady fixation and was further impacted by eye movements (e.g. changes in the perceived trajectory or speed).The occurrence of visual hallucinations during cerebral hypoperfusion in the ventral visual stream without infarction or underlying neurodegenerative disorder suggests dysfunctions in the visual networks , 11. ThiWhile in the first patient, simple and complex hallucinations were intermingled in the course of the hallucinatory phenomena, in the second patient there was a progression from simple to complex hallucinations. Insight was preserved and the hallucinations were spontaneously perceived as real and natural. To emphasize the veracity of the perceived images, patients focused on aspects like the high resolution of certain parts of the image  while disregarding others  and the guided analysis performed during the phenomenology pointed out peculiarities of certain attributes (see Table In our patients, hypoperfusion could have induced an aura-like, cortical spreading depression phenomenon similar to the one described in the penumbra region of ischemic stroke –14. MoreThe change in the perception of the hallucinations following the guided analysis could be due to several reasons. One possibility is that the hallucinations are intrinsically defective and that the analysis helped the patients become aware of the image flaws. Another possibility is that the hallucinations are inherently real when the patient focuses on them but their perception is altered by the guided redeployment of attention towards a global picture integrating the hallucinations into the environment. Indeed, this last hypothesis is endorsed by the fact that most of the flaws detected in the hallucinated images concerned attributes that interact or are impacted by the visual context, such as the type of movement, the relative size and the interface with the background. In physiological conditions, the detection of image boundaries is paramount in figure–background segregation , the segHallucinated images, although spontaneously reported as “completely natural”, presented structural and kinetic anomalies revealing an altered, non-realistic rendering. Noteworthy, the impaired awareness of peculiarities in the attributes of the hallucinated images questions the accuracy of post hoc inquiries and points to the crucial role of detailed, structured semiological analysis in the acute phase, while visual hallucinations are actually occurring. This should be considered by future studies exploring positive perceptual phenomena.


The activated eNSCs can proliferate, migrate and differentiate into neuron, oligodendrocyte and astrocyte, and play an important role in brain injury repair and neural plasticity. The roles of eNSCs in the repair of brain injury include but are not limited to ameliorating cognitive function, improving learning and memory function, and promoting functional gait behaviors. The activation and mobilization of eNSCs is important to the repair of injured brain. In this review we describe the current knowledge of the common character of brain injury, the roles and mechanism of eNSCs in brain injury. And then we discuss the current mobilization strategy of eNSCs following brain injury. We hope that a comprehensive awareness of the roles and mobilization strategy of eNSCs in the repair of cerebral ischemia may help to find some new therapeutic targets and strategy for treatment of stroke.Brain injury poses a heavy disease burden in the world, resulting in chronic deficits. Therapies for brain injuries have been focused on pharmacologic, small molecule, endocrine and cell-based therapies. Endogenous neural stem cells (eNSCs) are a group of stem cells which can be activated  The brain is the center of the nervous system and controls all of our functions, including voluntary and involuntary movement, the secretion of hormones, study and memory formation, and so on. The damage and impairment of the brain directly brings about dysfunction in the body. The neural networks composed with neurons and their microenvironment is the functional foundation of the brain. And the destruction of neural networks is the common character of brain injury, such as stroke, trauma, cerebral palsy, neurodegenerative disorder, et al. . Thus thThe key components in the reconstruction and repairmen of the neural network are neurogenesis and synaptogenesis . The neuThus a thorough clarification of the molecular mechanisms is essential for the application of eNSCs biology to promote repair strategies for brain injury. In this review, we firstly describe the current knowledge of the common character of brain injury, the roles and mechanism of eNSCs in brain injury. And then we discuss the current mobilization strategy of eNSCs following brain injury.Brain injury refers to injuries to the cerebral hemispheres, cerebellum, and brain stem. According to the tree structure of brain injuries in Medical Subject Headings (MeSH) in National Library of Medicine (NLM), the major categories of brain injuries include brain trauma , cerebral ischemia/hemorrhagic injury, degenerative injury.Ischemic stroke caused by a disruption of blood flow to brain tissue leads to a lot of neuron loss and dysfunction, such as necrosis, apoptosis, autophagic cell death and synapse loss. The irreversible cerebral infarction is the primary lesion of ischemic stroke, which occurs within minutes in infarct core area, and gradually extends to the surrounding area of the lesion within a few hours . IschemiNon-traumatic intracerebral hemorrhage (ICH) caused by rupture of blood vessel in brain and extravasation of blood into the brain parenchyma. ICH is the subtype of stroke with the greatest mortality . AccordiTraumatic brain injury (TBI) is one of the most serious acute injuries with high incidence, high disability rate, and high mortality rate . The TBIDiffering from the TBI and cerebral stroke, the neurodegenerative disease without significant loss of brain tissue is not caused by a sudden injury or cerebrovascular accident. The typical neurodegenerative diseases are Alzheimer’s and Parkinson’s disease. Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that accounts for 70–80% of dementia . The symRecently, frontotemporal lobe degeneration (FTD) has been attracted great attention. FTD present with a spectrum of syndromes characterized by neuronal degeneration in the frontal and anterior temporal lobes. FTD often leads to motor, language and memory disorders, it is the third most common cause of dementia. Some neurologists think that Parkinsonism is a manifestation of FTD, but some FTD patients are negative in the presynaptic dopaminergic deficiency when they are detected by dopamine transporter-single photon emission computed tomography (DaTSPECT). These finding implied that FTD is a neurodegenerative disease differentiated to the PD, although both of them lead to dementia . The undIn summary, although the causes of these brain injuries are different in pathology and etiology, all of these brain injuries involves the loss of neurons and nerve tissue. This loss eventually leads to the dysfunction and destruction of neural networks. Thus the treatment of brain injury is not only to protect the neuron and its network in the early stage but also to repair the injured neural networks in the late stage.in vitro  that consists of physical, social and sensory stimuli are effective treatment measures for the normal and injured brain through promoting neurogenesis and plasticity . There iIn vitro, mallotus oblongifolius was observed to activate the Wnt/β-catenin signaling pathway, increase the proliferation of neural stem cells, and enhance the protein expression levels of β-catenin and CyclinD1 in the oxygen-glucose deprivation and reperfusion (OGD/R) treated cell model. EGb761, one of the ginkgo biloba extracts, enhanced the proliferation of neural stem cells in the subventricular zone and DG in a rat model of vascular dementia , polycomb group (PcG) proteins and other chromatin remodeling factors play important roles in neural stem and progenitor cell biology, and can be applied to potentially promote eNSCs- mediated brain repair . The ant neurons . Control neurons . The non neurons . In the  neurons . In feta neurons . The adm neurons . Using a neurons . Dibutyr neurons .+), bromodeoxyuridine/glial fibrillary acidic protein (BrdU+/GFAP+), BrdU/S100 calcium-binding protein B, BrdU/microtubule-associated protein 2- and BrdU/galactocerebrosidase-positive cells (In addition, electro-acupuncture was identified to promote the differentiation of eNSCs. Electro-acupuncture was reported to promote the differentiation of eNSCs via exosomal microRNA 146b after ischemic stroke in rats . Electrove cells . The resve cells .Transplantation of exogenous cells was found to improve the proliferation of eNSCs. After transplanted into the subventricular zone, human neural stem cells in the brain of a rat model of focal cerebral ischemia triggered the proliferation of eNSCs and their differentiation into mature neural-like cells, and improved angiogenesis . UmbilicThere are also some factors reported to curb the proliferation of eNSCs. Gli1 is a gene that encodes a member of the Kruppel family of zinc finger proteins. The encoded transcription factor is activated by the sonic hedgehog signal transduction cascade and regulates stem cell proliferation . eNSCs cNeural stem cells have proven strikingly valuable to the repair in brain injury. Although exogenous neural stem cells are a potential strategy for repairing brain injuries, it is not popular because of tumorigenic, immunological, and ethical problems. As a result, eNSCs appear to be more practical in brain repair. However, there are still lots of unsolved difficulties which limit the maximum therapeutic effect of eNSCs. Firstly, although the brain injury and some exogenous medicines can trigger neurogenesis in SVZ and hippocampus DG, even some of them can migrate to the site of ischemic area, most of them die during the next few weeks after stroke. Thus we need to explore some strategies to enhance the number of surviving neurons, increased cell survival rate. Secondly, in addition to the role of nutrient factor secretion, the differentiation of eNSCs into mature neurons is more important for repair of brain injury. The new-formed neurons can replace the injured neurons and repair the disrupted neural network. However, at present the mechanisms that affected differentiation of eNSCs is not understood clearly and the effective promotion strategies is still lack. Finally, a single treatment strategy may not be enough to maximize the effect of eNSCs. Some strategies are better at promoting eNSCs proliferation, while others are better at promoting eNSCs migration or differentiation. The comprehensive treatment program that integrated small drugs, neurotrophic factor and growth factor, rehabilitation, electro-acupuncture, and so on may lead to a better outcomes. Thus we need to further investigate the optimal combination of treatment options and the optimum application time window of every option.PZ and KY developed the idea and revised the manuscript. QH, WL, YY, YJ, and DW reviewed the literature and prepared the tables. HL and TW prepared and revised the manuscript. All authors have read and approved the final manuscript.