In recent years, the number of scientific publications on artificial intelligence (AI), primarily on machine learning, with respect to neurosurgery, has increased.The aim of the study was to conduct a systematic literature review and identify the main areas of AI applications in neurosurgery.Using the PubMed search engine, we found and analyzed 327 original articles published in 1996–2019. The key words specific to each topic were identified using topic modeling algorithms LDA and ARTM, which are part of the AI-based natural language processing.Five main areas of neurosurgery, in which research into AI methods are underway, have been identified: neuro-oncology, functional neurosurgery, vascular neurosurgery, spinal neurosurgery, and surgery of traumatic brain injury. Specifics of these studies are characterized.The information presented in this review can be instrumental in planning new research projects in neurosurgery. The concept of “artificial intelligence” is currently widely used in various fields of science and medicine. In society’s minds, the understanding of artificial intelligence (AI) is formed by the mass media, science fiction, and scientific literature. Still, often this perception does not fully reflect the reality . Technicth–19th centuries, the computer “at the patient’s bedside” is expected to speed up clinical decisions, increase their reliability, and improve the quality and safety of medical care. The above humanistic considerations drive researchers to develop and apply AI technologies in medicine  OR  OR “neurosurgical procedures”[All Fields] OR “Neurosurgery”[All Fields] OR “neurosurgery”[MeSH Terms]) AND , and their number was counted. The expert-provided classification of publications by topics was then objectified using topic modeling technologies: the Latent Dirichlet Allocation (LDA) algorithm and the Additive Regularization of Topic Models (ARTM) algorithm , 11. Usi(https://www.ncbi.nlm.nih.gov/books/NBK25501) from the R environment using the rentrez package . The primary selection and statistical analysis of the data were carried out using original software developed by the authors in the R (version 3.5.0) programming language for statistical analysis assisted with the integrated development environment RStudio. The PubMed query was performed through the programming interface We also applied the software packages XML, fulltext, tibble, dplyr, stringr, tidyr, tidytext, and topicmodels to retrieve the data on publications and analyze them in the R environment using the LDA algorithm. The ARTM model was developed using the Python programming language (version 3.6) in the Jupyter Notebook environment.The process of selecting research articles for subsequent analysis of their topics is shown in Most of the analyzed studies were conducted within 5 major areas of neurosurgery and one combined area:neuro-oncology ;functional neurosurgery ;vascular neurosurgery ;spinal neurosurgery ;surgery for trauma brain injury ;other and related areas of neurosurgery .For publications from the first 5 sections, a topic modeling analysis was carried out. The number of topics was initially selected using LDA (so that the topics differ as much as possible when interpreting the key words). Then the ARTM algorithm was applied with the same number of topics. The topics resulted from the LDA and ARTM were compared with each other. In the cases where the ARTM algorithm created two or more similar (and not separable) topics, they were assigned to the same topic under the LDA. The results of topic modeling with the LDA and ARTM algorithms (main specific key words and interpretation of topics) are presented in the As shown in Despite the recent development of AI technologies, machine learning, and related big data analysis methods, these technologies are yet to earn large-scale and systematic applications in neurosurgery. An objective limitation for the rapid progress in this area is, of course, the insufficient volume of high-quality data .Due to the increased interest in this research, the base of evidence on the performance, safety, and economic feasibility of AI methods in neurosurgery is being created. Thus, in a systematic review by Senders et al. , the autAt present, there is no enough evidence to decide on the utility, safety, and economic feasibility of AI techniques in neurosurgery; therefore, one cannot assume that AI technology is now able to replace the traditional, routine methods of medicine totally. However, given the powerful potential of AI, one can definitely suggest the need for the development and widespread testing of these methods in medical science and practice.In the present review, methods of topic modeling are used to identify the key topics in publications. As an example of AI technologies, these methods are used to analyze texts written in a natural language. Using topic modeling, from 4 to 9 major topics (research areas) were identified for each section of neurosurgery. This approach is required for the subsequent automatic tracking of trends in a given research area and can exemplify the use of AI in biomedical science.Below we discuss the limitations of the present work, which are important for interpreting its results. The systematic review is aimed at studying the topics and trends in using the AI solely in neurosurgery. At the same time, in related fields , the range of tasks solvable by AI can be much wider.Here, we do not analyze systematic reviews on the use of AI in neurosurgery published by others since most of these papers were focused on a specific design of original studies or a specific disease and therefore had narrow inclusion criteria.To date, research into the use of AI technologies in neurosurgery has been carried out in five major areas: neuro-oncology, functional, vascular, and spinal neurosurgery, and traumatic brain injury. Using topic modeling, we identified major research topics in each of these areas. In the second part of this review, we will discuss the tasks in neurosurgery approached by AI technologies.


The molecular biomarkers of breast ductal carcinoma in situ (DCIS) have important guiding significance for individualized precision treatment. This study was intended to explore the significance of radiomics based on ultrasound images to predict the expression of molecular biomarkers of mass type of DCIS.116 patients with mass type of DCIS were included in this retrospective study. The radiomics features were extracted based on ultrasound images. According to the ratio of 7:3, the data sets of molecular biomarkers were split into training set and test set. The radiomics models were developed to predict the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67, p16, and p53 by using combination of multiple feature selection and classifiers. The predictive performance of the models were evaluated using the area under the curve (AUC) of the receiver operating curve.The investigators extracted 5234 radiomics features from ultrasound images. 12, 23, 41, 51, 31 and 23 features were important for constructing the models. The radiomics scores were significantly (P < 0.05) in each molecular marker expression of mass type of DCIS. The radiomics models showed predictive performance with AUC greater than 0.7 in the training set and test set: ER (0.94 and 0.84), PR (0.90 and 0.78), HER2 (0.94 and 0.74), Ki67 (0.95 and 0.86), p16 (0.96 and 0.78), and p53 (0.95 and 0.74), respectively.Ultrasonic-based radiomics analysis provided a noninvasive preoperative method for predicting the expression of molecular markers of mass type of DCIS with good accuracy.The online version contains supplementary material available at 10.1186/s12880-021-00610-7. Breast ductal carcinoma in situ (DCIS) is a kind of malignant tumor originated in the ductal epithelial tissue, limited to the basement membrane . DCIS isImmunohistochemistry (IHC) can reflect the expression of molecular biomarkers in tumor tissue, which can further clarify the biological behaviors of tumors. The expression of different molecular biomarkers can lead to different biological behaviors and treatments. Some studies have shown that some molecular biomarkers were important indicators for predicting biological behavior and judging follow-up treatment in patients with DCIS, such as estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki67, p16, and p53. ER and PR are the earliest molecular biomarkers of breast cancer. They are predictors of breast cancer prognosis and endocrine adjuvant therapy . HER2 isCurrently, the preoperative evaluation of the molecular biomarkers of DCIS mainly depends on IHC detection after biopsy. However, because the progression of tumors are dynamic process, there are differences in spatio-temporal evolution. In addition, the evaluation results of a few tissue biopsies do not necessarily represent the expression of the molecular biomarkers of the whole tumor . InvasivWith the breakthrough of imaging technology, mammography is an important examination method for DCIS, which is sensitive to the detection of calcification . UltrasoBreast lesions are diagnosed and screened by various imaging methods, such as mammography, US, and magnetic resonance imaging (MRI). All three examination have some limitations . RadiomiThus, this retrospective study intended to further clarify the relationship between US-radiomics and molecular markers of DCIS. Radiomics models had been developed to noninvasively evaluate the expression of molecular markers to help achieve accurate risk stratification and treatment for patients with DCIS.Clinical data of 400 patients with DCIS who were pathologically confirmed by surgery were retrospectively analyzed by the investigators. The data were based on the pathology reports of the first affiliated hospital of Guangxi medical university from January 2015 to July 2020. Further inclusion and exclusion criteria for this cohort study were as follows. Inclusion criteria: (1) primary breast DCIS, (2) IHC results of molecular biomarkers; and (3) preoperative US data within one month. Exclusion criteria: (1) non-mass DCIS, including manifestations of ductal dilation, diffuse calcification, and diffuse distribution of lesions; (2) unclear image of target lesions; (3) secondary DCIS or postoperative recurrence of DCIS; (4) preoperative treatment history of radiotherapy, chemotherapy and traditional Chinese medicine; and (5) lack of clinical data.This study finally enrolled a total of 116 patients with DCIS. The IHC  conformed to the diagnositic criteria of the department pathology in this hospital, and were classified as positive or negative. The IHC results of Ki67 were positive or high expression (Ki67 >  = 14%) and negative or low expression (Ki67 < 14%) . The numEach US radiologist involved in image collection had over 5 years of experience in the field of breast. Before collecting US data, all radiologists were strictly trained. GE Logiq E9 , Aloka EZU-MT28-S1  and MYLAB CLASS C  medical ultrasound diagnositic instruments were utilized for image collection. The breast probe was selected, and the frequency was set to 7–14 MHz. The patients took the supine position, put their hands on the head, and fully exposed the breast area and armpits on both sides. The lesions were scanned from multiple angles, and the largest clear image of the lesions were selected. The following ultrasonic characteristics of the lesions were recorded: BI-RADS classification, location, size, shape, boundary, internal echo, calcification, posterior echo changes, ductal dilatation, blood flow signal distribution and axillary lymph nodes.These images were imported into the ITKSNAP software (version 3.8.0). To avoid subjective compliance, two radiologists with five years of working experience manually delineated the region of interest (ROI) of the lesions. The radiologists disregarded the diagnosis and pathological results of the patients . After tThe Intelligence Foundry software  was applied for radiomics analysis. Figure To balance the initial distribution of data, each sub-data set was randomly split into training set and test set in a ratio of 7:3. Based on the difference in the image extraction feature quantization caused by different medical ultrasound diagnositic instruments and parameters, the combat method was employed to solve this problem. The combat method could be used to coordinate and correct the differences between different machines and different center images. Some studies had applied this method to the MRI images . In addiThe purpose of the study is difficult to explain with thousands of radiomics features of high-dimensional data. Feature importance analysis helps to explain the importance of features for subsequent model constructing. Multiple combination techniques were applied to explain the importance of features: First, Spearman correlation coefficient test was used to eliminate high correlation features with threshold values . This test was a statistical index to measure the correlation between two variables. Three dimensionality reduction methods (least absolute shrinkage and selection operator (LASSO) , random Machine learning algorithms were developed based on Python environment. Five machine-learning-based classifiers (decision tree (DT), k-nearest neighbors (KNN), logistics regression (LR), naive Bayes (NB), and support vector machine (SVM)) were employed to predict the expression levels of the molecular biomarkers of DCIS , 34, andTo accurately evaluate the predictive ability of radiomics models, the receiver operating curve (ROC), the area under the curve (AUC), accuracy (ACC), precision (PREC), sensitivity (Sn) and specificity (Sp) were adopted for the evaluation. The closer the AUC was to 1, the higher the diagnostic efficiency was. In this study, only the best classification results of the classifier were shown.The mean age of all patients was 48.8 ± 11.1 years, and the age range was 29–84 years. The characteristics parameters were shown in Table The correlation clustering heatmaps among 5234 features of each molecular biomarkers  were shown in Fig. Ninety models were obtained by constructing prediction models with five classifiers, and the performance of the models were presented in Fig. This study was the first non-invasive comprehensive analysis based on US-radiomics to predict the expression of molecular markers of DCIS. The investigators recruited only 116 patients with DCIS for this study, but it was exciting to see that the radiomics models showed more than moderate predictive performance in predicting molecular biomarker expression of DCIS.DCIS is a malignant tumor with good prognosis, but it is heterogeneous in morphology and genetics. Before the imaging examination was performed, the diagnosis of DCIS was only due to the appearance of nipple discharge and/or palpable mass symptoms, which accounted for only 2% of DCIS detected. It showed that DCIS with hidden symptoms were easily missed . With thAbout various imaging technologies, they also have application limitations . MammogrRadiomics mainly studies the quantitative features that are related to biology in medical images. Radiomics features are considered the invisible tissue infrastructure components of the object to be imaged, which can serve as a valuable method for studying cancer by imaging, such as MRI. Radiomics can provide in vivo visualization and quantitative analysis of the imaging features of the whole imaging mass. Therefore, radiomics is a precision medical method for non-invasive diagnosis, evaluation of efficacy, biological behavior . CurrentBreast radiomics studies are mostly applied to the prediction of the molecular classification, lymph node metastasis and molecular markers of invasive ductal carcinoma. For example, Demircioglu A et al.  construchttps://pyradiomics.readthedocs.io/en/latest/features.html); Ipris features capture nodular heterogeneity and differential growth patterns; CoLIAGe features can distinguish disease phenotypes that have similar morphologic appearances [In this study, the first highlight, the first comprehensive analysis of molecular markers of DCIS was conducted based on radiomics. Second highlight, there were thousands of radiomics features, including eight classifications: original feature can reflect the number of voxels in the images, intensity distribution, pixel pair frequency, image average gray value, size and shape of ROI (earances ; waveletThere were also some shortcomings in our study. First, this retrospective study had the problem of small sample size. It was necessary to increase the sample size or multi-center cooperation to construct universal models. Second, when the radiologists manually delineated the ROIs, there were a certain degree of subjectivity to the contours of the lesions, which may lead to poor robustness of the models. In addition, the delineation process was done by only one radiologist. Third, the investigators only investigated the features extracted from the largest section, which could not represent the whole tumor. Due to the limitations of US, it was not possible to conduct three-dimensional studies similar to other imaging studies.The application of machine learning-based radiomics analysis provided a non-invasive method for predicting the expression of multiple molecular biomarkers in DCIS, with good prediction performance. This study also demonstrated the potential of radiomics in pathologic assessment and individualized precision therapy.Additional file 1. 5234 radiomics features matrix file.Additional file 2. Modeling matrix file for molecular biomarkers.


Antimicrobial resistance (AMR) is a global challenge that requires a “One Health” approach to achieve better public health outcomes for people, animals, and the environment. Numerous bibliometric studies were published on AMR in humans. However, none was published in food-producing animals. The current study aimed at assessing and analyzing scientific publications on AMR in food-producing animals.A validated search query was developed and entered in Scopus advanced search function to retrieve and quantitatively analyze relevant documents. Bibliometric indicators and mapping were presented. The study period was from 2000 to 2019.n = 1970). The Journal of Food Protection  ranked first in the number of publications while the Applied and Environmental Microbiology journal ranked first in the number of citations per document. The USA led with 576 (20.2%) documents followed by China . When the number of publications was standardized by income and population size, India (n = 51.5) ranked first followed by China (n = 38.3) and Brazil (n = 13.4). The growth of publications from China exceeded that of the USA in the last 3 years of the study period. Research collaboration in this field was inadequate. Mapping author keywords showed that E. coli, Salmonella, poultry, Campylobacter, chicken, cattle, and resistant genes were most frequent. The retrieved documents existed in five research themes. The largest research theme was about AMR in Salmonella in food-producing animals. The most recent research theme was about the dissemination and molecular transfer of AMR genes into the environment and among different bacterial strains.The search query retrieved 2852 documents. During the period from 2015 to 2019, approximately 48% of the retrieved documents were published. The article about the discovery of plasmid-mediated colistin resistance in pigs received the highest number of citations (Hot spots of research on AMR in food-producing animals match the world regions of reported hot spots of AMR in animals. Research collaboration in this field is of great importance, especially with low- and middle-income countries. Data on AMR need to be collected nationally and internationally to implement the “One Health” approach in the fight against AMR.The online version contains supplementary material available at 10.1186/s13690-021-00572-w. Food-producing animals may get exposed to antimicrobials upon the use of antimicrobials to act as animal growth promoters or as a prophylactic or therapeutic measure . AntimicThe misuse and/or overuse of antimicrobial agents in humans and animals played an important role in developing AMR . The expThe problem of AMR requires a “One Health” approach in which the health of humans is considered closely connected to the health of the animals and the environment . The FooIt was argued that AMR might cause millions of human deaths in the future due to infections caused by resistant microbes  and thatIn the current study, the literature on AMR in food-producing animals published in peer-reviewed journals indexed in SciVerse Scopus was retrieved. The selection of SciVerse Scopus was based on the advantages it has over other databases such as Web of Science and PubMed . Scopus The search query was developed based on terms related to AMR in food-producing animals listed in the OIE report . The terp < 0.01) and strong (r = 0.96) indicative of the validity of the search query. This validation approach was implemented in previously published bibliometric studies [The finalized search query was validated for the absence of false-positive results by ensuring that the top 200 cited documents were relevant to the search topic. The author asked two colleagues who are experts in microbiology to check for false-positive results by reading the title and abstracts of the top-cited documents sent to them as an endnote file. The search query was considered final when the experts confirmed the absence of any false-positive results. To ensure the absence of false-negative, the correlation test between what has been retrieved by the search query and the actual findings for the top ten active researchers was implemented. The result of the correlation test was significant . Active journals in publishing documents on AMR in food-producing animals were presented as top ten list. The number of publications for each country was standardized by the Gross Domestic Product (GDP) per capita . The intn = 2611; 91.5%) and review articles . The remaining types of documents were letters, editorials, notes, and conference papers. The language in the documents was mainly English  followed by Chinese , and Portuguese . Other remaining languages included Germany, Spanish, Turkish, French, Korean, Japanese, and Dutch. In total, 1038 (36.4%) documents were published as open access. The retrieved documents were published in journals categorized in different subject areas, mainly in immunology/microbiology , followed by agriculture and biological sciences , medicine , veterinary , Biochemistry/genetics/molecular biology , environmental sciences , pharmacology/toxicology , and multidisciplinary .The search query found 2852 documents; mostly as research articles  were published in the last 5 years (2015–2019) of the study period. The retrieved documents received 63,443 citations, an average of 22.4 citations per document. The top-cited document in this field was published in The Lancet Infectious Diseases in 2016 and received 1754 citations within less than 4 years, an average of approximately 439 citations per year [Figure Journal of Food Protection  was the most productive in this field followed by the Foodborne Pathogens and Disease  and the Applied and Environmental Microbiology . Despite the Journal of Food Protection ranked first in the number of publications, documents published in the Applied and Environmental Microbiology received the highest number of citations per document followed by those published in the Foodborne Pathogens and Disease journal.Table n = 375; 13.1%) and Canada . When the number of publications was standardized by GDP  per capita, India (n = 51.5) ranked first followed by China (n = 38.3) and Brazil (n = 13.4). Figure n = 1009; 35.4%) followed by the region of the Americas . The contribution of each of the six world regions was shown in Table The top ten active countries were listed in Table Countries with a minimum contribution of 50 documents were presented as a network visualization map Fig.  to assesE. coli, Salmonella, poultry, Campylobacter, chicken, cattle, and resistant genes were most frequent  is a research theme that discussed Enterococcus and vancomycin resistance. The fifth cluster (dark yellow) is a research theme that mainly discussed MRSA and penicillin. The dissemination and molecular mechanisms of antimicrobial resistance genes represent the most recent research themes in the field as shown in the overlay visualization map with yellow color being most recent . The “United States Department of Agriculture”  was the most active institution followed by the “Technical University of Denmark” , “University of Guelph” (Canada) , “Food and Drug Administration” , “Chinese Academy of Sciences” , “Public Health Agency of Canada” , and “Agriculture and Agri-Food Canada” . The active institutions included academic, research, and governmental institutions.Analysis indicated that 1162 (40.7%) documents received funding. The major funding agency in this field was the “The current study was a descriptive study on global research output on AMR in food-producing animals. In May 2015, the World Health Assembly adopted the global and national action plan on AMR. The plan was supported by a manual developed by WHO, in collaboration with the FAO and the OIE to help countries in preparing and developing their national action plans on AMR . TherefoAcinetobacter baumannii or Pseudomonas aeruginosa [Enterobacteriaceae and as a growth promoter. The unregulated use of colistin in animals played a major role in the development of resistant genes in bacteria [Escherichia coli, Klebsiella, Salmonella, Shigella, and Enterobacter in humans and animals [The current study showed that the top-cited document was about a plasmid-mediated resistance gene (MCR-1) isolated from pigs in China . This puruginosa . The bacruginosa . Colistibacteria . The MCR animals .The current study indicated that China, India, Japan, and South Korea were among the top active countries in the field. A recently published research paper indicated that India and China are hot spots of AMR in animals and that Brazil and Kenya are newly emerging hot spots . The autThe AMR is a global problem and therefore international research collaboration in this field is important. The current study showed inadequate global research collaboration in this field. The use and regulations of antibiotics in animals differ from one region to another and therefore research collaboration will help in knowledge transfer and implementing policies to avoid future problems. Furthermore, researchers and academics in developing countries need to collaborate and build research bridges with scientists in hot spots for AMR in animals to transfer the knowledge to their countries.Salmonella, Campylobacter, and E. coli [Salmonella bacteria are prevalent in food animals such as poultry, pigs, and cattle. Salmonellosis affects humans through the consumption of contaminated food of animal origin . A recent study in Brazil investigated the occurrence of resistance in Salmonella spp., isolated from products and raw material of animal origin (swine and poultry) to antimicrobials found that 51 (38%) out of 134 isolates were resistant to at least one of the eight antibiotics used, and 28 (55%) of resistant isolates were multi-resistant [E. coli strains simultaneously isolated from humans, animals, food, and the environment indicated that colistin had the lowest prevalence and amoxicillin the highest in isolated human E. coli strains [E. coli was highest in animals compared to human or environmental/food isolates. A study of the global and regional burden of 22 foodborne diseases indicated that the leading cause of the foodborne illness was norovirus followed by campylobacter. The diarrheal and invasive infections caused by non-typhoidal Salmonella enterica infections caused the largest burden of disease. The authors found that the burden of foodborne illness was highest in WHO’s African region [The current study indicated that resistant pathogens in food-producing animals included both gram-positive and negative ones. The most common drug-resistant foodborne bacteria of relevance to human health were  E. coli . Salmoneesistant . A recen strains . The sysn region .Enterococcus faecalis and Enterococcus faecium were reported in the current study and had been reported to have intrinsic and acquired resistance to a wide range of antibiotics including vancomycin [Staphylococcus aureus is another gram-positive opportunistic pathogen in animals and harbors several AMR genes [Enterococci such as ncomycin . Currentncomycin . The emencomycin . In Nortncomycin . StaphylMR genes .The current study listed B-lactams, aminoglycosides, and Quinolones/fluoroquinolones as the most commonly encountered antibiotics drug classes in the retrieved literature. These drug classes are important therapeutic choices in human health. These drugs were listed as critically important drugs in human medicine . The misThe current study is the first study to analyze AMR literature in food-producing animals hoping to benefit researchers and health policymakers. However, the current study has a few limitations. First, the search query might have missed some documents due to the wide range of animals, birds, and aquatic species as well as the wide range of antibiotics used for food production. Second, the hot spots of the world such as China, Brazil, and India have unindexed journals with publications in the field and, therefore, were missed. Third, the current study focused on scientific literature. However, there are many national and international reports on this field published as governmental reports. Such reports were not included.E. coli and Salmonella were encountered. Research in the field of AMR in food-producing animals was characterized by limited international research collaboration. National and international action plans to “improve” the use of antimicrobials in animals are of paramount importance.There has been great concern about the AMR in the last two decades. The “One Health” platform requires a comprehensive approach for investigating AMR in humans, animals, and the environment. Numerous bibliometric studies were published on AMR in humans , 40; howAdditional file 1: Appendix 1. Search query and keywords used to retrieve documents on antimicrobial resistance associated with food-producing animals.


Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae are the standard proxy species used for indicating AMR-associated nosocomial infections and healthcare-associated infections. Pig feces and wastewater have been suspected as one of the hotspots for spread and circulation of ARB and ARG. As part of AMR surveillance in a One Health approach, clonal typing is used to identify bacterial clonal transmission from the production process to consumers and patients – although to date there have been few published definitive studies about this in SEA. Various alternatives to antibiotics are available to reduce antibiotic use on farms. Certain of these alternatives together with improved disease prevention methods are essential tools to reduce antimicrobial usage in swine farms and to support global policy. This review highlights evidence for potential transfer of resistant bacteria from food animals to humans, and awareness and understanding of AMR through a description of the occurrence of AMR in pig farm food chains under SEA management systems. The latter includes a description of standard pig farming practices, detection of AMR and clonal analysis of bacteria, and AMR in the food chain and associated environments. Finally, the possibility of using alternatives to antibiotics and improving policies for future strategies in combating AMR in a SEA context are outlined.Antimicrobial resistance (AMR) is a critical challenge worldwide as it impacts public health, especially via contamination in the food chain and in healthcare-associated infections. In relation to farming, the systems used, waste management on farms, and the production line process are all determinants reflecting the risk of AMR emergence and rate of contamination of foodstuffs. This review focuses on South East Asia (SEA), which contains diverse regions covering 11 countries, each having different levels of development, customs, laws, and regulations. Routinely, here as elsewhere antimicrobials are still used for three indications: therapy, prevention, and growth promotion, and these are the fundamental drivers of AMR development and persistence. The accuracy of detection of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARG) depends on the laboratory standards applicable in the various institutes and countries, and this affects the consistency of regional data.  Escherichia coli that are resistant to critically important antimicrobials such as colistin, cefotaxime, and ciprofloxacin have been recorded  in bacterial species and strains is a critical global threat, and has been monitored in animals, humans and the environment through international collaborations aimed at AMR reduction . The mairecorded . A study. Nosocomial infections account for 7 and 10% of all infections in developed and developing countries, respectively . Enterobfections . The posfections . WHO empfections . It is imcr-1 conferring colistin resistance was first identified in China in 2014  and whole-genome sequencing . A plasm in 2014 . To datecarriers . Colisti therapy . A 10–22Thailand  and in KMalaysia . The clo in Laos . OverallSalmonella Typhimurium and E. coli have been found in humans and pigs in SEA and in the United States , and within SEA the top three pig producing countries are Myanmar, Vietnam, and the Philippines. In contrast, Thailand exports the most pork raised under a high standard of farming and food safety conditions . Pig proE. coli, Lawsonia intracellularis, and Actinobacillus pleuropneumonia have been commercialized and used worldwide , pig farms should be located in areas with an appropriate clean water source, with physical barriers to reduce the risk of contamination arising from visitors and animal access. Quarantine pens should be located in a separate area and must be prepared for sick pigs and pig carcass to limit pathogen spread. Housing and equipment providing good hygiene and ventilation with easy-to-clean pig manure systems are recommended, along with good personal hygiene management for workers, including a pre-entry farm protocol which includes facilities for showering and hair washing, and changing into protective farm clothes and footwear before accessing the animal housing. Wastewater and manure should be kept in a closed area well away from the animal house, and the farm should possess a treatment system that limits odor and hazards such as biogas. Moreover, a veterinarian must authorize a program of vaccination and antimicrobial and chemical use for disease prevention and treatment. Vaccination is a potential method to prevent certain infectious diseases and is established as an important alternative to antibiotics . In manyorldwide .In 2013 the total amount of antimicrobials used for food-producing animal in SEA was 2,950 tons: antimicrobial classes included penicillin (666 tons), tetracyclines (484 tons), quinolones (321 tons), sulfonamides (317 tons) and macrolides (281 tons). Thailand consumed the largest amount of antimicrobials (531 tons in 2013), and the amount has subsequently increased , probably due to the growing number of food-producing animals . In pracImplementation of standard biosecurity and management systems in pig farms is an essential part of veterinary preventive medicine, and promotes improved pig production, and reduced antimicrobial consumption in pigs, leading to fewer AMR bacteria on pig farms which otherwise might enter the food chain .The key driver of resistance in bacterial population is considered to be the extensive use of antimicrobial agents which created a selection pressure on susceptible bacteria . FrequenEnterobacteriaceae.At present, the main approaches to detect antibiotic resistance bacteria (ARB) and antibiotic resistance genes (ARG) from bacteria in hosts and environments are primarily categorized into the conventional culture-based methods, and molecular biology-based methods. Clone typing by core-gene multilocus sequence typing (MLST) is used to determine the molecular epidemiology of bacteria in the family E-test method and gradient diffusion method), and automated instrument methods (such as Vitek 2 system by bioMérieux and Sensititre ARIS 2X by Trek Diagnostic Systems)  . The resSystems) .Nevertheless, the conventional culture-based methods are time-consuming and somewhat labor-intensive. Investigators are required to constantly attain a reliable and up-to-date interpretation of the resistance susceptibility testing. Besides, only a minority of bacteria are culturable and suitable for the conventional culture-based methods, which are presumed to be only a tiny fraction of the total bacteria present .This approach allows the identification of deoxyribonucleic acid (DNA) targets with and without the requirement to culture individual isolates. Methods such as Polymerase Chain Reaction (PCR) amplification and use of DNA probes are well known for detecting resistance genes and genetic elements. With the application of multiplex PCR, various ARGs can be screened and detected simultaneously . In compMost recently, molecular high throughput (HPT) and next-generation sequencing  are among the techniques that facilitate studies of the microbial community and their diverse genomes and gene expression without a requirement for culture. Moreover, these techniques are very valuable since they can compute numerous target genes without knowledge of the bacteria or genes in the samples, are not limited by specific primer sets, and are even faster to perform than the conventional molecular methods such as PCR and qPCR . They alTherefore, molecular biology-based methods make possible the detection of ARB and ARG that cannot be cultured and express in individual isolates and provide faster detection of ARB and ARG with high specificity and sensitivity compared with conventional culture-based methods. Nevertheless, these methods cannot separate between living and non-living microorganisms. They are also less useful for identifying ARB and resistance patterns compared to the conventional culture-based methods.Salmonella enterica members, are stable clones, whereas in some species, e.g., Helicobacter pylori, these may be transient or genetical diverse without phenotypical change (1). The relatedness threshold of clonality from cgMLST diversity depends on insight of species-specific population genetics  . For AMR, clonal relations are used as a tool to indicate the phenomenon of bacterial transmission or “spillover” between sources: humans to animals, animals to the environment, or environment to humans or vice versa . The divl change . Index gl change . Since tl change . Core gel change . From eal change . The relriation) , as showFor clonal relationships, the horizontal genetic transmission of mobile genetic elements  and their relatedness are important parameters indicating the transmission of AMR characteristics . There aE. coli from pigs to pig farmers, families, municipal communities, and patients with urinary tract infections   . The mcrThailand . On the ingapore . Moreovec health .Staphylococcus aureus (LA-MRSA) is another resistant bacterium of substantial health concern. LA-MRSA has been found worldwide, predominantly among people involved in livestock farming  was related to that of MRSA discovered in a diseased pig in the same area , at a prevalence of 4.8% (n = 59) of MDR E. coli have been recovered from slaughterhouse workers, where the rates in Nigeria were more elevated in butchers than in cleaners , ampicillin (91%), and tetracycline (92.5%). These isolates contained class1 integrons carrying resistance cassette dfrA12-aadA2. Interestingly, five Salmonella isolates from Thai pig carcasses were producers of extended-spectrum □-lactamase (ESBL) and harbored blaCTX–M–14, whereas isolations from Laos were negative. The study reflected differences in the hygienic procedures of slaughterhouses and antibiotics uses in the two countries  were resistant to nitrofurantoin (93.4%), ampicillin (67.8%), and sulfa-trimethoprim (80.3%)  , even thOverall, the risk of bacterial contamination in the slaughtering process and of pig products is critical, and there is still a lack of comprehensive monitoring throughout the system. Operation under HACCP programs and good manufacturing and sanitation practice (GMP) are intended to control meat safety , but a rThe use of antibiotics on farms increase the possibility of the AMR transmission from livestock production systems to consumers. There have been many attempts to replace antibiotic use on farms. This review outlines two applications for reduction of antibiotic use, including for growth promotion and disease prevention. An overview of possible antibiotic alternatives for growth promotion derived from previous studies is presented in Lawsonia intracellularis, which causes severe ileitis, has been reported to reduce oxytetracycline medication in pigs , all eleven countries in the ASEAN region have developed a National action plan (NAP) which the government has approved . The OneReviews of policy interventions that address AMR in food animal production indicate that there are many existing regulations for controlling veterinary medicines, including antimicrobials, in ASEAN countries. However, they are relatively varied across countries . PolicieSurveillance on AMR and antimicrobial consumption is a vital component of GAP-AMR. The WHO Global Antimicrobial Resistance and Use Surveillance System (GLASS) and Organisation for Animal Health global database on antimicrobials in animals were established to help provide evidence on the emergence of resistance and trends in antimicrobial use globally . The 201Despite existing national commitments, implementation of AMR policy remains a significant challenge, particularly with the monitoring of AMR and AMU in the human and animal sectors. The monitoring systems are hampered by lack of institutional capacity, inadequate investment in human resources, and the need to strength data platforms for routine monitoring. Significant financial boosts are required to support these areas.This paper addressed the cross-species transmission of AMR and ARGs in the SEA. The importance of pig production in SEA has encouraged particular attention to this industry, but similar problems occur with other animal industries . Due to the limited number AMR studies, it is difficult to quantify the extent of the problem in the region, although some countries have better data available than others. Certainly, there is reason to believe that transmission of resistant bacteria and ARGs from pigs at the farm and through the slaughtering process provide risks to the human population, either through direct contact or via contaminated environments or pork products. Efforts should be made to reduce antimicrobial use at the farm level by improving farm hygiene and the use of alternatives to antibiotics. The AMR policy in the region has been implemented, although progress in this area has varied considerably between different countries due to different implementation’s capacities. Additional funding to support AMR surveillance and improved control in SEA is required.NP: original idea, study design, and supervision of writing. WS: AMR distribution in food chain, wastewater, and detection. PA and PP: alternatives to antibiotics and data analysis. AL: policy and strategy controlling AMR in SEA. IS and NK: risk of AMR in pig production cycle and slaughtering. KL: molecular epidemiology analysis. DH: study design, supervision, and proofreading of the writing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The anterior cruciate ligament (ACL) reconstruction via a contralateral bone-tendon-bone (C-BTB) autograft was introduced to encourage early return to sports. The purpose of this study is to evaluate whether primary contralateral BTB ACL reconstruction can be adapted for early return-to-sports modification by investigating the chronological changes of muscle strength after surgery.Fifteen patients who had underwent C-BTB ACL reconstruction were compared with a matched group of 15 patients of ipsilateral BTB (I-BTB) ACL reconstruction. The clinical outcomes of the time of return-to-sports, Tegner activity scale and the rate of second ACL injuries, the tibial anterior translation measurement, and knee extension and flexion muscle strength were assessed.p = 0.021). No significant difference was noted with regard to the Tegner activity scale, reinjury rate or mean instrumental anterior tibial translation. The quadriceps muscle strength in the ACL-reconstructed knee compared with the opposite knee in both groups at 5 months after surgery was 120.6% in the C-BTB group and 70.0% in the I-BTB group (p < 0.001). However, the quadriceps muscle strength of the non-reconstructed limb, which instructed the graft harvested knee in the C-BTB and the intact knee in the I-BTB group, compared with that of the preoperative uninjured limb, was 74.5% in the C-BTB group and 118.7% in the I-BTB group (p = 0.0021) 5 months after surgery. Moreover, the quadriceps muscle strength of the reconstructed knee compared with the preoperative normal limb was 88.8% and 81.5% in the C-BTB and I-BTB groups, respectively (p = 0.38).Within 12 months after surgery, 14 of 15 patients from both groups returned to preinjury sports. The median time to return to sports after surgery was 6.5 months in the C-BTB group and 8.0 months in the I-BTB group (ACL reconstruction via the C-BTB autograft indicated better quadriceps muscle strength from early stage after surgery compared with I-BTB ACL reconstruction. However, the ostensible rapid symmetrical muscle strength recovery was attributed to strength deficits compared to the preoperative condition at the donor site limb and ACL-reconstructed limb.Level: Level: 4. Recovery from anterior cruciate ligament (ACL) injuries in athletes, especially at pre-injury levels, is often difficult. The overall return-to-play rate ranges from 60% to 80% in various sports . FurtherEarly return-to-play, that even increases a risk of the rate of sustaining a second ACL injury , is ofteIn the return-to-play criteria, 86% of the studies used isokinetic muscle strength tests and symmetrical quadriceps strength recovery more than 80% of that of the opposite limb set as the goal after ACL reconstruction , 12. AccThe purpose of the study was to evaluate whether primary contralateral BTB ACL reconstruction can be adapted for early return-to-sports modification by investigating the chronological changes of muscle strength after surgery.This study was approved by the institutional review board of Kanto Rosai Hospital. The ID number was 2019–9. Informed consent for responding to treatment was obtained from each patient by the responding surgeon, and participant agreement in the clinical research was conducted with opt-out approval.Between 2011 and 2014, 363 patients underwent ACL reconstruction via the autograft of the bone-patellar tendon-bone in our institution. After excluding 167 revision ACL surgeries, 18 bilateral ACL reconstructions, and 15 knees with multiple ligaments, the remaining 163 primary ACL reconstruction via the transtibial tunnel creation technique were included in the investigation. Of 163 primary BTB reconstruction knees, 15 athletes underwent ACL reconstruction surgeries using the contralateral BTB autograft (C-BTB) and 148 knees underwent ACL reconstruction with the ipsilateral BTB autograft (I-BTB). The selection for the surgical procedure via the contralateral BTB graft was determined under adequate discussions between the surgeon and the patients who wished to return to their previous sports in an earlier period. To compare the two different procedures, 15 knees from 148 primary ipsilateral BTB reconstruction patients were selected as the control matched group to decrease preoperative bias. The groups were matched for sex, age, type of sports activity, Tegner activity scale, and incident of concomitant meniscus injuries , and quadriceps and hamstring muscle strengths between the two groups were investigated. In this study, we defined return to sports as participation in the normal practice of the whole team on their previous team or another team. Muscle strength was compared in three different evaluation methods using the Biodex System 3 isokinetic dynamometer  at anglar velocities of 60°/s. First, the quadriceps and hamstring muscle strength of the reconstructed knee compared with the opposite knee were investigated. Then, the chronological muscle strength change of the reconstructed knee was measured by comparing it with the preoperative uninvolved normal knee. Third, the chronological change in muscle strength of the non-reconstructed knees, including the graft harvested donor knee in the C-BTB group and the uninvolved intact knee in the I-BTB group, was investigated. Preoperative muscle strength was measured at the day before surgery. Muscle strength was measured at the following three periods: preoperative, 5 months after surgery, and 12 months after surgery.Reconstruction surgeries were performed using the central one-third of the bone-patellar tendon-bone autograft. The BTB grafts were harvested from the ipsilateral knee in the I-BTB group and from the contralateral knee in the C-BTB group. A single round tibial tunnel was created first; then, a round femoral tunnel socket was created via a transtibial approach. The bone-patellar tendon-bone autograft was fixed by the suspension device of the ENDOBUTTON  on the femoral cortex and tied to the tibial post fixation screw and washer . All autografts were fixed at the full knee extension position while applying adequate tension to the graft by hand.Postoperative rehabilitation was performed using the same protocol for both groups. Physical therapy was initiated on postoperative day 1, with the patients wearing a hinged knee orthosis. Once tolerated, the patients started walking with full weight bearing. The range of motion exercise was started to aim for an immediate full extension knee from the following day and gradual flexion to obtain full flexion at 4 months after surgery. Jog training began 2 months postoperatively. Agility exercises and open kinetic muscle training were started 4 months after surgery. At 5 months postoperatively, after estimating isokinetic knee extension and flexion muscle strength, the patients participated in sports activities aiming at returning to the competitive level when they have met the goal set for quadriceps and hamstring muscle recovery. We set the goal of muscle strength to be over 80% knee extension and flexion peak torque of the reconstructed knee compared with that of the contralateral extremity using the Biodex System 3 isokinetic dynamometer.p-values of < 0.05 as being statistically significant in the series.For statistical analysis, we used EZR , which is a modified version of R  for 1:1 matching data extraction from the pooled control group and comparison datasets between the two groups. Then, we used the Mann-Whitney U test to compare the groups in ordinal and continuous variables and chi-square test for the categorical variables with Excel statistical analysis . We defined p = 0.021). Clinical outcomes at 1 year after surgery were not significant different according to the Tegner activity scales and the tibial anterior translation measured using the KT-2000 arthrometer. Concerning the occurrence rates of second ACL injuries, graft reinjury was 6.7% (1/15) in both groups, and the contralateral ACL injury was 6.7% (1/15) in the I-BTB group, with none of the patients in the C-BTB group deploying this injury within the follow-up period (Table p = 0.0021) and 12 months (p = 0.023) after surgery in the quadriceps. In contrast, hamstring muscle strength was not significantly different at either 5 months (p = 0.33) or 12 months (p = 0.74) after surgery .The return-to-play time was significantly earlier in the C-BTB group than in the I-BTB group . Rubinstein et al. [With regard to the graft site pain in this study, 20% of the patients in the C-BTB group required anesthetic injections at the donor site to control anterior knee pain when they returned to playing sports; in contrast, none of the patients in the I-BTB group required anesthetic injection therapy. Mastrokalos et al.  evaluaten et al. , referrip = 0.686 in kneeling and p = 0.564 in severity of pain) [In contrast, Shelbourne et al. reported that no difference in kneeling and severity of pain in the International Knee Documentation Committee Subjective Knee Form subscores between the contralateral and ipsilateral BTB groups (of pain) , 15. Theof pain) , 15. AltAs another approach to reduce donor site pain, the technique of refilling with a substitute material into the bony defect after harvesting the BTB graft was introduced , 11. RefAs with all studies, the limitations of this study exist. First, this was a retrospective study with a small number of patients. Fifteen patients apparently lacked power for the analysis. However, because no patients have been performed using this modification technique presently, the study has stopped as a pilot study that had implied the limitation of this technique. Moreover, the small number of patients did not increase the risk of second ACL injuries that should be critically evaluated. Second, with regard to the donor site morbidity as a result of bone-patellar tendon-bone autograft harvesting, graft site pain is evaluated only based on the frequency of the injection treatments at the site. We did not compare the C-BTB group with the I-BTB group using a subjective or objective knee score. However, to the best of our knowledge, no other studies have evaluated quadriceps and hamstring muscle strength in the early period when the patients anticipated going back to their previous sports. This information will guide surgeons and patients when they prefer accelerated rehabilitation after ACL reconstruction via contralateral BTB autografts.ACL reconstruction via the C-BTB autograft indicated better quadriceps muscle strength from early stage after surgery compared with I-BTB ACL reconstruction. However, we should consider that muscle strength symmetry can result from simultaneous bilateral knee muscle weakness compared to the preoperative condition. The contralateral ACL reconstruction has limitations in resolving the early return-to-play issue securely.


The diameter of electrospun nanofibers was also slightly reduced after selective chemical dissolution. Porous PAN nanofibers can be seen as the precursors to the production of highly porous carbon nanofibers.In this study, polyacrylonitrile (PAN) was mixed with a renewable polymer, lignin, to produce electrospun nanofibers by using an electrospinning technique. Lignin was utilized as a soft template that was removed from the nanofibers by using a selective dissolution technique to create porous PAN nanofibers. These nanofibers were characterized with Fourier transform infrared (FTIR), field emission scanning electron microscopy (FESEM), thermogravimetry analysis (TGA), X-ray diffraction (XRD), and Brunauer-Emmett-Teller (BET) to study their properties and morphology. The results showed that lignin can be homogeneously mixed into the PAN solution and successfully electrospun into nanofibers. FESEM results showed a strong relationship between the PAN: lignin ratio and the diameter of the electrospun fibers. Lignin was successfully removed from electrospun nanofibers by a selective chemical dissolution technique, which resulted in roughness and porousness on the surface of the nanofibers. Based on the BET result, the specific surface area of the PAN/lignin nanofibers was more than doubled following the removal of lignin compared to PAN nanofibers. The highest specific surface area of nanofibers after selective chemical dissolution was found at an 8:2 ratio of PAN/lignin, which was 32.42 m In recent years, nanotechnology has become a promising technology for the future. There are many types of nanomaterials, such as nanoparticles, nanofibers, nanotubes, nanowires, and quantum dots, that have garnered extensive attention due to their unique properties and characteristics . Among tAt present, electrospinning techniques have received interest as they are economical and suited to various types of material , good foRecently, a significant number of studies that have used nanofibers as an adsorbent for the removal of pollutants from aqueous solutions, such as drugs ,13 and hPolyacrylonitrile (PAN) is a polymer usually used as the precursor to the formation of carbon fibers due to its excellent mechanical strength, low flammability, good thermal stability and chemical resistance , such asLignin is among the most promising biorenewable raw materials, and it is a natural polymer that acts as a partial matrix within the structure of plants and trees. It is one of the main elements of wood and is the second most abundant natural polymer. Lignin is a highly branched macromolecular network structure, with an aromatic nature and complex compositions. Furthermore, lignin has a lack of cytotoxicity, which proves that lignin is a type of biomaterial . IndustrThe selective chemical dissolution technique is one of the processes to produce a porous structure and higher surface area in a polymer. For porous polymer nanofibers, this can be achieved through the electrospinning of polymer blend solutions to form a nanofiber, followed by the selective chemical dissolution process which involves the removal of one component using an appropriate solvent that only dissolves a certain polymer in the blend’s nanofibers. Another alternative is the addition of additives such as salts or nanoparticles in the polymer solution that are used as a template, followed by their removal by post-electrospinning processes; the elimination of the template is another method to create a porous structure . In a stIn this study, alkali lignin, with a low sulfonate content, was incorporated with PAN to produce nanofibers. A renewable polymer, lignin was used as a soft template to create a porous and rougher surface for the nanofibers through the selective chemical dissolution technique.w = 150,000), and were purchased from Sigma-Aldrich . N,N-dimethylformamide (DMF) was obtained from R&M Chemicals . De-ionized water was used throughout the experiment.The materials used in this experiment were alkali lignin (low sulfonate content) and polyacrylonitrile (PAN)  . The samples were heated from 50 °C to 600 °C, with a heating rate of 10 °C/min under a nitrogen atmosphere. Field emission scanning electron microscopy (FESEM)  was used to examine the morphologies of the nanofibers. A stub was taped with carbon tape and the samples were placed onto it. The samples were then sputtered with a thin layer of gold. The average fiber diameter was determined by using ImageJ Software, with 200 diameter readings taken. X-ray diffraction (XRD)  analyses of the samples occurred to identify the crystalline phase, where the scan started from 2θ range and from 2° to 60°, with a scanning rate of 2°/min. The surface area and porosity of the prepared nanofiber were determined by N2 adsorption measurements at 77K using BELSORP Mini II. The surface characterization of the nanofibers was obtained using the Brunauer-Emmet-Teller  method.FTIR analyses of the samples were conducted to determine the functional groups using an attenuated total reflectance-Fourier transform infrared spectroscopy (ATR–FTIR) spectrometer . The wavelength used to examine the functional groups ranged from 280 to 4000 cm−1 (O–H stretching), 1595 cm−1 , 1430 cm−1 (C–C stretching with C–H deformation), 1134 cm−1 (C–H deformation), and 1040 cm−1 (C–O deformation) [−1, 1134 cm−1, and 1040 cm−1. A small peak at 2920 cm−1 indicates a stretching of the alkyl C–H bond and a stretching of the intermolecular hydrogen bonding of the O–H group, which is associated with the hydroxyl group in the lignin [−1 indicates the C≡N group of PAN; the intensity of the peak was decreased as the ratio of PAN decreased. A peak at around 1450 cm−1 corresponds to the bending of the CH2 scissoring of PAN [−1 was reduced when the ratio of lignin increased. As can be seen in ATR-FTIR technique was used to analyze the PAN, lignin, and PAN/lignin nanofibers before and after selective chemical dissolution. rmation) . In Figug of PAN . The int−1. These peaks indicate the alkyl C–H bond stretching, C≡N stretching, C≡N stretching, and CH2 bending, respectively [−1 and 1040 cm−1, were reduced significantly. This is because the lignin content in the nanofibers was successfully removed through the selective chemical dissolution process.The FTIR spectra of the PAN/lignin nanofibers after the selective chemical dissolution process when compared to PAN and lignin is shown in ectively ,37,38. SThe morphology of the nanofibers was investigated using the FESEM technique. The derivative thermogravimetry (DTG) and TGA analyses of the PAN: lignin nanofibers before and after selective chemical dissolution was carried out to study the thermal stability of the samples. From DTG thermograms, a sharp peak corresponding to a maximum decomposition temperature of PAN nanofibers is observed at 296 °C  and 299 2g−1, 20.94 m2g−1, 32.42 m2g−1, 29.13 m2g−1, and 28.15 m2g−1 for PAN, with 9:1, 8:2, 7:3, and 6:4 ratios, respectively. The PAN: lignin nanofibers of 8:2 ratio showed the highest BET surface area (32.42 m2g−1), followed by 7:3, 6:4, 9:1, and PAN. This shows an increase in specific surface area of up to 50% compared to PAN nanofibers after the removal of lignin. The specific surface area ratio from 7:3 to 6:3 is a slight decrease from 8:2, possibly due to the excess lignin addition to the nanofibers, which creates a bigger pore diameter and consequently reduces the specific surface area. In this study, the increase in the specific surface area is greater than reported elsewhere in the literature. For example, Ji and co-workers [The most frequent approach to the determination of specific surface areas of porous materials is the Brunauer-Emmett-Teller (BET) approach. The pore information of the porous nanofibers, including the BET-specific surface area and the microporous and mesoporous volumes, is summarized in -workers  studied 3g−1).The interrelationship between the average diameter and the BET-specific surface area of nanofibers as a function of a ratio of PAN/lignin nanofibers after selective chemical dissolution is shown in 2g−1 with a pore diameter of 5.02 nm. Additional lignin not only impacts the morphology of the nanofibers, but also the fiber diameter. The higher the ratio of lignin added, the smaller the average fiber diameter. This study showed that lignin and PAN can be homogenously blended and utilized to produce the high surface area and porosity of PAN nanofibers using a selective chemical dissolution technique. This can be used in an extensive variety of applications, for instance, as a precursor to highly porous carbon nanofibers.The highly porous and specific surface area of PAN/lignin electrospun nanofibers was successfully prepared by using lignin as a soft template and through a selective chemical dissolution technique. The morphology showed a significant change in the surface of the nanofibers before and after selective chemical dissolution technique. After selective chemical dissolution, the nanofibers’ surface appeared to be rougher and slightly smaller in average fiber diameter than before selective chemical dissolution. The BET analysis showed a significant increase in specific surface area after the addition of lignin to the PAN/lignin nanofibers, and the pore diameter was varied with the various ratios of lignin in the nanofibers. The optimum specific surface area of PAN/lignin nanofibers was 8:2 ratio, which is 32.42 m


Antimicrobial resistance (AMR) is a high priority across countries as it increases morbidity, mortality and costs. Concerns with AMR have resulted in multiple initiatives internationally, nationally and regionally to enhance appropriate antibiotic utilization across sectors to reduce AMR, with the overuse of antibiotics exacerbated by the COVID-19 pandemic. Effectively tackling AMR is crucial for all countries. Principally a narrative review of ongoing activities across sectors was undertaken to improve antimicrobial use and address issues with vaccines including COVID-19. Point prevalence surveys have been successful in hospitals to identify areas for quality improvement programs, principally centering on antimicrobial stewardship programs. These include reducing prolonged antibiotic use to prevent surgical site infections. Multiple activities centering on education have been successful in reducing inappropriate prescribing and dispensing of antimicrobials in ambulatory care for essentially viral infections such as acute respiratory infections. It is imperative to develop new quality indicators for ambulatory care given current concerns, and instigate programs with clear public health messaging to reduce misinformation, essential for pandemics. Regular access to effective treatments is needed to reduce resistance to treatments for HIV, malaria and tuberculosis. Key stakeholder groups can instigate multiple initiatives to reduce AMR. These need to be followed up. Antimicrobial resistance (AMR) is a high-priority area across all countries, increasing morbidity, mortality and costs ,4,5,6,7,Rising AMR rates are due to a number of factors including rising antimicrobial utilization especially in LMICs ,21, withLow vaccination rates against disease have also enhanced antimicrobial use and AMR, with current concerns that vaccination rates are being further compromised by the COVID-19 pandemic, with its resultant impact on patient movement and available facilities as a result of lockdown and on other measures ,40,41,42The general overuse of antimicrobials has been worsened by the COVID-19 pandemic ,46,47,48Concerns with rising AMR rates and the consequences have resulted in international, regional, national, and local strategies to try and reduce the rises ,66,67,68Alongside this, there are concerns with multi-resistant microorganisms and the implications for patients with TB, human immunodeficiency virus (HIV), malaria, and typhoid, as well as those with co-infections . Early tOverall, we are aware that coordinated activities among all key stakeholders can address over-utilization of antibiotics. Multiple demand-side measures including education of all key stakeholders, prescribing restrictions, and follow-up in pharmacies stabilized or reduced the utilization of antibiotics in former Soviet Union republics including Azerbaijan, the Republic of Srpska, Bosnia and Herzegovina, and Slovenia versus Poland that failed to instigate such measures ,62,81,82We are also aware that there are concerns with high prevalence rates of hospital-associated infections (HAIs) in a number of LMICs, with major challenges surrounding the appropriate use of antibiotics to reduce surgical site infections (SSIs) ,84,85. TWe would like to build on these issues and challenges to discuss potential ways to decrease future AMR rates among LMICs. We have chosen LMICs as they currently have the greatest increase in antimicrobial use, the highest rate of self-purchasing of antibiotics, as well as the highest rate of antimicrobial use in hospitals ,104,105.We undertook a narrative review of published papers to document potential ways to enhance appropriate prescribing and dispensing of antimicrobials. We purposely did not undertake a systematic review as an appreciable number of these have already been conducted on different aspects to improve future prescribing and dispensing of antimicrobials ,133,134.The World Bank classification was used to break countries down into LMICs or upper income countries where applicable . SimilarThere can also be long waiting times for patients to see physicians in primary healthcare centers (PHCs) in LMICs, long distances to travel to PHCs, and pharmacists are typically open later in the day, resulting in patients often seeking their advice as alternatives to physicians ,159,160.When documenting interventions that have been undertaken to enhance appropriate prescribing and dispensing of antimicrobials, we will break these down into the 4Es to enhance understanding and comparisons, namely Education, Engineering, Economics and Enforcement ,166. EduNo ethical approval was required for this review as we were not dealing with patients. This is in line with previous similar papers published by the co-authors ,184,185.There are a number of key issues that need to be addressed to enhance appropriate antimicrobial use in patients and reduce AMR. We will break our findings down into key areas within hospitals and subsequently ambulatory care before concluding with guidance on potential activities that can be undertaken among all key stakeholder groups to reduce AMR.Activities that can be undertaken in hospitals include PPS studies to gain baseline data of current utilization patterns to guide future quality improvement programs as part of ASPs and other activities. Initiatives in ambulatory care center around activities to improve prescribing and dispensing of antimicrobials especially for self-limiting infections such as viral URTIs. These are especially important since, as mentioned, we are aware that up to 100% of pharmacies in LMICs dispense antibiotics without a prescription despite legislation, and this can account for up to 93% to 100% of all dispensed antibiotics ,135,136.The first consideration within hospitals is to ensure that activities to improve antimicrobial prescribing are given a high priority if this is not already the case. This includes initiatives such as instigating active infection, prevention and control committees (IPC committees) ,191,192,However, there can be issues with the instigation of IPC committees and their effectiveness in hospitals , concernBox 1Availability, ready access and subsequent compliance to local or regional treatment guidelines for key infections. This includes the availability of antibiograms within hospitals to guide empiric use whilst waiting for culture and sensitivity test (CST) findings as well as a potential list of restricted antibiotics depending on physician experienceWhether antibiotics prescribed are included in the hospital formulary/national essential medicine listsRationale (indication) for antimicrobial use documented in the patient’s notesWhether therapy was empiric or targeted based on CST findingsDocumentation of the dose in the patient’s notesDocumentation of a stop/review date for given antibiotics in the patient’s notes. This can include the rate of de-escalation to a narrower-spectrum antibiotic where appropriateDocumentation of any missed doses of antibioticsExtent of IV to oral switching Duration of surgical prophylaxisChanges in antibiotic use over time in terms of Defined Daily Doses/100(0) bed days and/or days of therapy/patient-daysWhether active antimicrobial stewardship groups and/or drug and therapeutic committees/Infection Prevention and Control groups in the hospitalMultiple activities to reduce HAIs include encouraging greater hand hygiene, regular reviews surrounding the use and care of catheters, instigating appropriate strategies to reduce ventilator-associated pneumonia including subgluteal space suctioning before each position change, chlorhexidine gluconate bathing as well as active monitoring of agreed guidelines to reduce HAIs ,221,222.Clostridium difficile infections, and AMR as well as increasing costs .,37.10,37This increasing recognition of the role of vaccines in reducing antimicrobial use and AMR is reflected in the recent WHO Action Framework to enhance current vaccination rates, encourage greater knowledge and dissemination on the role of vaccines to reduce AMR as well as encourage the development of new vaccines to further reduce AMR ,359.Addressing mis- and dis-information surrounding vaccines is critical to reduce future morbidity and mortality arising from pandemics ,361. We Potential ways forward, building on the activities of the WHO and Governments, especially with proposed medicines for COVID-19 including hydroxychloroquine, lopinavir/ritonavir and remdesivir that failed to live up to their preceived promise ,372,373,Governments and others working with pertinent patient organizations within countries also need to proactively address misinformation , especiaSuggested strategies to improve the utilization of antimicrobials among LMICs and thereby reduce AMR have been divided into short- and long-term initiatives to provide future guidance . These bEffectively addressing inappropriate antibiotic prescribing is particularly challenging since the majority of antibiotic prescribing in LMICs is undertaken by general clinicians and their assistants who are not experts in infection management and with often influence from pharmaceutical companies in the absence of continual professional development ,378,379.AMR continues to be a high priority across countries in view of its impact on morbidity, mortality and costs ,15,19, dDespite issues of resources including personnel, a number of activities can be undertaken in LMICs to improve future prescribing of antibiotics. These center around the instigation of ASPs in hospitals including PPS studies to identify areas for quality improvement, with a number of quality indicators now developed to monitor the appropriateness of future prescribing . StrategSuccessful strategies have also been implemented among physicians in LMIC to reduce inappropriate prescribing of antibiotics for essentially viral infections , with paHealthcare professionals, including community pharmacists, along with patient organizations have a key role to play to encourage evidence-based approaches to healthcare, thereby reducing the impact of misinformation. Misinformation has been a real concern during the current COVID-19 pandemic resulting in for instance reduced uptake of the vaccines and the implications for this and other vaccines , with a A number of strategies and initiatives have also been identified to reduce levels of multi-drug resistance organisms to HIV, malaria, and TB, given the resultant impact on morbidity and mortality. Key areas include the provision of treatments free of charge, ready access to healthcare facilities as well as initiatives to enhance adherence to prescribed treatments.Potential strategies for all key stakeholders were subsequently consolidated into short-, medium- and long-term activities to provide future direction . The keyWe are aware of a number of limitations with this review paper. These include the fact that we did not undertake a systematic review for the reasons discussed. We also did not break the number of examples down by country or care setting as our objective was to provide pertinent examples to guide others. In addition, we are aware that some developing countries are more pro-active with their research than others, potentially biasing the findings. Despite these limitations, we believe that our findings and suggestions are robust, providing future direction.In conclusion, reducing AMR should be a high priority across countries given its clinical and economic impact. Reducing AMR rates requires multiple coordinated activities across sectors driven by Governments and others. This is essential given limited new antimicrobials being developed, although compensated to some extent by developments in vaccine technologies. This will also require strategies to address high rates of vaccine hesitance that exist in a number of countries as seen in the recent COVID-19 pandemic. A coordinated approach including all key stakeholder groups is also essential to minimize misinformation and maximize the impact of future interventions to reduce AMR rates.


Endometrial carcinoma (EC) is traditionally treated with surgery and adjuvant treatment depending on clinicopathological risk factors. The genomic analysis of EC in 2013 and subsequent studies using immunohistochemistry have led to the current EC molecular classification into: polymerase epsilon mutated (POLEmut), p53 abnormal (p53abn), mismatch repair deficient (MMRd), and no specific molecular profile (NSMP). The four groups have prognostic value and represent a promising tool for clinical decision-making regarding adjuvant treatment. Molecular classification was integrated into the recent European Society of Gynecologic Oncology (ESGO) management guidelines. POLEmut EC has favorable outcomes and retrospective studies found that omitting adjuvant treatment is safe in this group; two prospective clinical trials, PORTEC-4 and TAPER, are ongoing to assess this. p53 abn is associated with increased recurrence, decreased survival, and benefitted from chemotherapy in the PORTEC-3 subgroup molecular analysis. The clinical trials PORTEC-4a and CANSTAMP will prospectively assess this. MMRd and NSMP groups have intermediate prognosis and will likely continue to rely closely on clinicopathological features for adjuvant treatment decisions. In addition, the molecular classification has led to exploring novel treatments such as checkpoint inhibitors. Overall, the molecular perspective on EC and associated clinical trials will likely refine EC risk stratification to optimize care and avoid overtreatment. Endometrial cancer (EC) is the most common gynecological cancer, and the fourth most common malignancy in women in developed countries . The lifA recent important addition for achieving optimal patient selection for adjuvant treatment in the management of EC is the comprehensive genomic analysis by The Cancer Genome Atlas (TCGA) in 2013, dividing EC into four molecular subgroups based on mutational burden and copy number alterations , howeverTraditionally, EC has been classified into low risk, intermediate risk (low-intermediate risk (LIR)/high-intermediate risk (HIR)), and high risk based on histopathological and clinical characteristics . SpecifiThe adjuvant treatment for EC based on the group is also illustrated in For the high risk group, PORTEC-3 looked at the addition of chemotherapy to EBRT and showed an improvement in disease-free survival (DFS) for stage III patients, with no benefit for overall survival (OS) . The GOGAlthough these landmark trials are prospective studies, several aspects limit the ability to draw conclusions on the optimal management based on clinicopathological factors alone. First, the studies had overlapping cohorts, for instance, there were differences between HIR definitions in the GOG and PORTEC trials such as clear cell and serous EC being included in PORTEC-1, but not in GOG-99 ,6. Not oThe 2013 comprehensive genomic analysis of EC by The Cancer Genome Atlas (TCGA) divided 373 cases of serous and endometrioid EC into four molecular subgroups based on mutational burden and copy number alterations: precisely POLE mutated, microsatellite instability (MSI), copy-number low, and copy-number high  [2]. TheTumors where testing was not carried out or was inconclusive were deemed unclassifiable, whereas tumors where all the tests were negative were named as “no specific mutation present” (NSMP). Approximately 3–6% of tumors have characteristics pertaining to two classification criteria, and these tumors are termed multiple-classifier EC . The iniFurthermore, the molecular classification provides an ability to sort tumors that is standardized, highly reproducible, and shows concordance between the initial biopsy and final hysterectomy specimen. These are all advantages compared to historical histological classification ,23,24. IThe POLE mutation is present in 6–9% of EC specimens and presents in younger, thinner women, often associated with the endometrioid histological subtype and early stage ,25. It iIn terms of treatment, a recent meta-analysis looking at the use of adjuvant treatment for POLE-mutated tumors showed no additional survival benefits with therapy, independent of the adjuvant treatment used . As suchThe Cancer Genome Atlas initially established the category of copy-number high, which correlated with serous and high grade endometrioid EC as well as TP53 mutation . Furtherp = 0.019) [In the molecular-based analysis of the PORTEC-3 cohort, EC patients with abnormal p53 were found to have improved outcomes when platinum-based chemotherapy was added to the adjuvant radiation . Specifi= 0.019) . The use= 0.019) . A poten= 0.019) ,34. A sm= 0.019) ,36. Ther= 0.019) .The MMR deficient molecular group represents 20–30% of EC cases, and is analogous to MSI in the initial genomic classification . Tumors In terms of molecularly directed adjuvant treatments, recent retrospective studies have raised the hypothesis that MMRd ECs might have a stronger susceptibility to radiation with improved survival compared to MMR proficient tumors, however, this has not been studied prospectively ,42,43. CThe NSMP profile is p53 wild type, MMR proficient, shows no POLE mutation, and has been found to be associated with 40–50% of ECs . This moNSMP tumors have also been found to be associated with mutations in the PI3K/Akt/mTOR pathway and given their association with positive estrogen and progesterone receptors (ER+ PR+), a few studies have looked at treatments targeting these receptors. The use of eeverolimus and letrozole in a phase II study on recurrent EC showed an ORR of 32% . AnotherAs the introduction of molecular categorization in EC is adding new information regarding the risk of recurrence and survival, a likely transition phase in the treatment of EC will involve refining the clinicopathological risk groups with the addition of molecular risk factors. However, to date, large prospective studies have not been performed to confirm this hypothesis. Nonetheless, in 2020, the European Society of Gynecological Oncology (ESGO), European Society for Radiotherapy and Oncology (ESTRO), and European Society of Pathology (ESP) updated their management guidelines by combining molecular and clinicopathological factors in the risk stratification , while tThe changes in treatment brought along by the introduction of molecular classification have implications on the choice of adjuvant treatment given changes in risk stratification as well as on the choice of novel molecular-based therapies. First, once the molecular characteristics are integrated into a refined risk group classification of EC, the selection of adjuvant treatment would follow the specific risk group assigned adjuvant therapy, as previously established. For low-risk and LIR EC, no adjuvant treatment is required. When molecular classification is known, stage I–II patients with POLE mutation are to omit adjuvant treatment in the new ESGO guidelines . This isSo far, the evidence regarding adjuvant treatment of EC based on molecular classification is limited to retrospective studies and secondary molecular analyses of patients receiving standard adjuvant treatment. There are several clinical trials currently looking at individualizing treatment based on molecular characteristics , of whicTwo additional Canadian-based studies are looking at specific molecular subtypes, namely, POLE and p53 status. The trial entitled TAPER  is a multi-center, single-arm prospective cohort study that will look specifically at de-escalating care in patients with POLE-mutated and p53-wildtype (NSMP) early stage endometrioid EC. The MMRd and p53 abnormal patients will be excluded. Included patients will receive no treatment postoperatively, in order to prospectively confirm the safety of omitting radiotherapy in POLE mutated and p53 wild type EC, as has been retrospectively described . The priThere are currently two phase III trials recruiting patients to assess the effect of pembrolizumab’s addition to standard treatment for MMRd EC. The NRG-GY018 (NCT03914612) is a randomized quadruple blinded trial  looking at the benefit of adding pembrolizumab to standard chemotherapy with carboplatin and paclitaxel . The conCurrent management of early stage EC includes surgical management with adjuvant therapy. The adjuvant treatment depends on clinical and pathological factors that assist in classifying the patients into low risk, low-intermediate, high-intermediate, and high risk groups. The molecular classification and subsequent surrogate classification using IHC and sequencing has brought along a new promising avenue by classifying EC into four molecular subgroups: POLE mutated, p53 abnormal, MMRd, and NSMP. This was a major advance in terms of characterization compared to the historical division into type 1 and type 2 EC histological subtypes. The four groups of EC currently assist with a better understanding of the risk of recurrence, and represent a promising clinical tool to assist in decision-making regarding adjuvant treatment. Specifically, POLE-mutation has low risk of recurrence and will likely transition to no adjuvant treatment required in the early stages. At the opposite end, p53 abnormal tumors have a high risk of recurrence and decreased survival and will lead to a re-classification into a higher risk group requiring chemotherapy. Clinical trials such as PORTEC-4a, RAINBO, CANSTAMP, and TAPER have the potential to provide key information for tailoring EC treatments based on molecular and clinicopathological criteria, thus leading to more optimized and personalized patient care.