The status of research and scientific outputs with regards to bacterial central nervous system (CNS) infection in southeast Asia (SEA) is unknown. This study aimed to analyze and compare bacterial CNS infection research output of SEA countries in terms of bibliometric indices.Clinicaltrials.gov and WPRIM) were searched for studies on bacterial CNS infection in SEA until August 31, 2020. Frequencies, percentages and Spearman’s rho correlations were used.The major electronic databases  and Vietnam  had the highest number of publications. The most common type of research publication was the case report / case series . Tuberculous meningitis/tuberculoma  was the most common topic. This study showed that the %GDP for research and development (R&D) was associated with a higher number of research output. However, the GDP per capita was not associated with any of the bibliometric indices. The total number of neurologists was associated with all of the bibliometric analysis.There was a total of 648 unique studies on bacterial CNS infection in SEA and it was 657 when double-counted (collaborative studies between SEA countries). Thailand (Bacterial CNS infection research output in SEA countries was low in terms of quantity. The %GDP for R&D was associated with the number of research publications. The total number of neurologists was associated with all of the bibliometric indices. Streptococcus pneumonia and Mycobacterium tuberculosis . Studies about non-bacterial causes of CNS infection  were excluded.Clinicaltrials.gov and Western Pacific Regional Index Medicus (WPRIM)] for studies on bacterial CNS infection in SEA until August 2020. We used the following search terms: [ AND ].We searched the major electronic databases [MEDLINE by Pubmed, Scopus, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Two investigators  were involved in the selection of studies for inclusion; if there were any disagreement, a consensus with a third investigator  was conducted. Predetermined screening criteria were used to screen for the titles and abstracts of the searched records. Duplicate studies were immediately discarded. The studies that fulfilled the screening criteria were obtained as full-text articles and these were reviewed for eligibility. Records that fulfilled the eligibility criteria were included in the qualitative analysis. Articles which were collaborations between/among SEA countries were double counted.The bibliometric indices used for this study were the latest journal IF (2020) and PlumX Metrics, which organized five  metrics Information about the population size of each SEA country in 2020 was obtained from the Worldometers website . Data frStatistical analysis was performed using the SPSS version 25 . Frequencies and percentages were presented for the all PlumX and Scopus metrics except for the field weighted citation impact which used averages. To further explore the publications per country, graphical representations were provided using stacked bar charts depending on the category. To assess if there is a relationship between the country profiles and their citations, Spearman’s Rho correlations were done.Clinicaltrials.gov: 50). There were 1306 duplicate articles that were immediately excluded. Of the remaining 9613 articles, 7637 were discarded based on the screening criteria used. The full-text of 1976 articles were assessed for eligibility and 648 articles were then included for analysis , Journal of the Medical Association of Thailand , and Vaccine . It was noticeable that aside from Thailand, Singapore had its own set of journals that made it to the top 16. This included the Annals of the Academy of Medicine Singapore  and the Singapore Medical Journal . Only 6 out of these 16 journals had recent publications in 2020 . Furthermore, Clinical Infectious Diseases had the highest IF (8.313) with 13 articles, when compared to the other journals. The Journal of Infectious Diseases came next, with a 5.022 IF and 10 articles.A total of 648 articles published in 243 journals were included in this review. The top 16 journals, with a share of at least 1% of the total publications, are presented in Table Table n=148, 22.5%) and Vietnam  share most of the publications. Each country owns 22.53 and 21.61% of the total publications, respectively. Aside from Timor-Leste which did not have any publication, Brunei and Myanmar had the lowest number of publications -- only sharing 0.15% (n=1) and 0.76% (n=5) to the total publications, respectively. At least 47% of the total citations, usage, captures, and mentions came from studies in Vietnam. For social media, the top 2 was still shared by Thailand and Vietnam. Nonetheless, it was Vietnam and Indonesia who had the highest average Scopus field weighted citation impact.In terms of total publications, Thailand , usage, captures, social media, and Scopus field weighted citation impact. The budget for R&D (in terms of % GDP) was only associated with the number of publications. Meanwhile, GDP per capita was not found to be significantly associated with any of the bibliometrics Table .Table 4n=160, 24.4%), retrospective cohort , randomized clinical trial  and prospective cohort . Case-control (n=6), non-randomized trials (n=5), and pre-post study designs (n=3) were the least common. There were also some study designs that were unclear . In terms of country profile, the study designs were mixed. Nonetheless, it was evident that cohort designs were popular to almost all countries , tetanus , gram-negative bacterial meningitis/encephalitis/meningoencephalitis , and brain or epidural or spinal cord abscess/subdural empyema . Vietnam had the highest number of publications about tuberculous meningitis/tuberculoma and tetanus while Philippines had the highest number of publications about gram-negative bacterial meningitis. The least common topics (< 5%) were neurosyphilis  and other spirochetal infections  , prevention , and treatment  were the most common research domains. Public health and caregiving were rarely discussed , Malaysia and Singapore (n=2), Thailand and Vietnam (n=1), Brunei and Malaysia (n=1), Vietnam and Indonesia , Malaysia and Thailand (n=1).Nine research publications involved collaborations between the following SEA countries: Laos and Thailand (n=117) had the highest number of collaborations between SEA countries, followed by the United States of America (n=69), and the Netherlands (n=43) (Table n=76) topped the list, followed by Vietnam and the Netherlands (n=22)  supplemented by using the PlumX metrics . It correlated the socioeconomic factors of a SEA nation with research productivity.n=775; epilepsy, n=702; movement disorders, n=1567; stroke, n=2577) [n=549) [n=142) [n=2698; United Kingdom, n =912; Germany, n=749; France, n=620. Africa had lesser publications on this topic (less than 100) compared to SEA [There was a total of 648 research outputs on bacterial CNS infection in the SEA region over a period of 35 years. Among these studies, only 9 published articles had collaborations among authors from SEA. The amount of research outputs on this topic in SEA was lower compared to the other neurologic diseases   but grea [n=549) . It was d to SEA . In thisPopulation per million was found to be positively associated with citations (PlumX and Scopus), usage, captures, social media, and Scopus field weighted citation impact in this study. This finding could be attributed to the presence of more resources in terms of manpower, that can help promote the research content through social media, if there is a higher number of population per million in a country. These manpower resources may not necessarily need to be specialists.The %GDP for R&D was associated with a higher total number of publications. This was seen in countries like Singapore, Malaysia, and Thailand, which had a high %GDP for R&D. This finding was consistent with the other bibliometric studies done in SEA , 11–13. The total number of neurologists in a country was significantly associated with all bibliometric indices. This was also seen in the other bibliometric studies , 10, 12.It is interesting to see that there is an increasing trend of the amount of research publications in this field. However, the numbers may be still be considered to be inadequate and more research outputs may have to be produced to address this preventable neurologic disease.To best of our knowledge, this was the only study that measured the research productivity of bacterial CNS infection in SEA and there were no other data yet in other parts of the world with regards to this topic. The strength of this study was that it used a systematic and extensive method of searching for the relevant publications in the major electronic databases. The full-text articles were carefully screened for inclusion and analysis in this review.ClinicalTrials.gov) were included in this study. We did not include the research outputs, which were difficult to retrieve such as those from non-indexed journals, local databases, proceedings, and unpublished studies. Research articles that were not written in the English language were also eliminated in this bibliometric analysis. These limitations may underestimate and may not reflect the true status and number of research outputs in SEA regarding this subject matter.This study was limited in that it only dealt with the bacterial causes of CNS infection and did not include the other etiologies such as viral, fungal and parasitic causes, which are also important causes of CNS infection . TherefoHaemophilus influenzae vaccine is included in the vaccination schedule in most SEA countries while Streptococcus pneumonia vaccination is included in only a few countries. Since SEA is not endemic for meningococcal meningitis, Neisseria meningitidis vaccination is not routinely recommended [The findings of this study should not be taken negatively, but rather serve to help improve the research status of a SEA nation. It should encourage researchers to produce more research publications in the field of bacterial CNS infection as there are still many areas to be addressed. Currently, SEA has a high incidence of tuberculosis with most of the SEA nations having adequately vaccinated against this disease . The morommended . A bibliommended , 3. ThisBacterial CNS infection research output in SEA countries was low in terms of quantity. The %GDP for R&D was associated with the number of research publications but the GDP per capita was not associated with any of the bibliometric indices. The total number of neurologists was associated with all of the bibliometric indices. This study can encourage more high-quality research publications about bacterial CNS infection and sound healthcare policy formulation.


Trypanosoma cruzi action. It also discusses how proteochemometric (PCM) modeling and microcrystal electron diffraction (MicroED) can help in the case of the lack of a 3D protein structure; more specifically, Trypanosoma cruzi carbonic anhydrase.Chagas disease still has no effective treatment option for all of its phases despite being discovered more than 100 years ago. The development of commercial drugs has been stagnating since the 1960s, a fact that sheds light on the question of how drug discovery research has progressed and taken advantage of technological advances. Could it be that technological advances have not yet been sufficient to resolve this issue or is there a lack of protocol, validation and standardization of the data generated by different research teams? This work presents an overview of commercial drugs and those that have been evaluated in studies and clinical trials so far. A brief review is made of recent target-based and phenotypic studies based on the search for molecules with anti- T. cruzi transmitted by hematophagous triatomine bugs. The disease is endemic in Latin America but it is also found in non-endemic regions such as North America, Europe , Japan and Australia due to international immigration, blood transfusion, organ transplantation, congenital infection and oral transmission through food  had been commercialized by Bayer under the trade name of Lampit. NFZ presents high toxicity and side effects such as hypersensitivity reactions, anorexia, vomiting, polyneuritis and depression. Due to these adverse reactions, this drug has become inconvenient for clinical use and is no longer used in most countries of Central and South America. BZN is the drug available and clinically prescribed for treatment although the occurrence of side effects such as hepatitis, peripheral polyneuropathy, digestive intolerance and anorexia leads to limitations on its use.However, the benefits offset the risk and the treatment is still favorable especially in the acute phase. Benznidazole administration of 5–8 mg/kg/day for children or 5–10 mg/kg/day for adults during 30–60 days was the most frequent protocol of use . This wahttps://clinicaltrials.gov/) and the results are organized by their respective status.The drug discovery process for Chagas disease has been ongoing with thousands of compounds tested annually before finding a promising candidate. High throughput screening (HTS) campaigns, which represent an important approach to identify new sets of leads for treatment, have been carried out . The DNDSeveral targets are being studied for the development of new drugs and a few of them will be cited in this review. In recent years, factors that have hindered the development of new drugs have been extensively discussed in the literature. The lack of accurate biomarkers for treatment, failure in diagnoses, diversity of strains of the parasite, problems with the standardization of methodologies such as in vivo animal models, different host cell culture lines and problems in the translation process among other factors are barriers for the development of new drugs ,13,20,21T. cruzi ergosterol pathway has been extensively studied in the search for new drugs. Ergosterol is essential for the trypanosome membranes and is required for parasite multiplication. The main enzymes of this pathway have already been studied and sterol-14-alpha demethylase (CYP51) proved to be essential for the parasite’s viability. CYP51 was tested as a therapeutic target for CD and in this context anti-fungal triazole derivatives that inhibit this enzyme such as ravuconazole, prodrug E1224 (Fosravuconazole), VNI [(R)-N--2-(1H-imidazol-1-yl)ethyl)-4-benzamide)]   and posazamide)] . Moraes -BS1246) . Villalt/kg/day) ,28. Acco/kg/day) . Until tT. cruzi is characterized as a target for action of new drugs. This enzyme is associated with growth factors and virulence factors for pathogens and are involved in mechanisms including breathing, CO2 and bicarbonate transport, pH regulation, electrolyte secretions and biosynthetic reactions [T. cruzi, an α-CA was identified, cloned and characterized. TcCA has a high catalytic activity for the CO2 hydration reaction [T. cruzi carbonic α-anhydrase were discovered; these compounds with structures containing sulfonamides, thiols and hydroxamates have a high capacity for binding with zinc and the inhibition of its activity [T. cruzi carbonic anhydrase (TcCA) where 10 compounds from 255 were selected for testing against TcCA [T. cruzi epimastigotes and trypomastigotes). As a result, they reported the discovery of new TcCA inhibitors with a poor interaction with human carbonic anhydrase (hCA), of which two molecules are commercial artificial sweeteners that have vast toxicological data available. Finally, the authors reported that further investigations are needed for a deeper understanding of selectivity against TcCA.The carbonic α-anhydrase (TcCA) of eactions ,30,31,32reaction ,34. Althreaction . In the activity ,37,38. Tactivity . Llanos nst TcCA . The autIn this regard, with respect to the interaction between the inhibitor and the enzyme, Clabbers et al. developed a method to visualize the binding interaction of a sulfonamide inhibitor to human carbonic anhydrase isoform II (hCA II) . In thisTherefore, the use of MicroED for the analysis of carbonic anhydrase inhibitors appears to be promising. Due to the successful use of MicroED in hCA II, a new scheme can be proposed as shown in T. cruzi cycle as well as the genetic validation of this target [T. cruzi does not have RNA interference and the traditional genetic knockouts are often not successful [Based on this evidence, it is worth highlighting the work authored by D’Ambrosio et al. . Accordis target . Accordiccessful . Anotherccessful . FinallyT. cruzi using anion compounds, sulfonamides, sulfamates, thiols and hydroxamates. Due to the success of some results, TcCA inhibition represents a new mechanism of action, being a target with few studies on obtaining anti-Chagas disease agents [According to a review by Supuran, several works have studied in detail the inhibition of the enzyme α-carbonic anhydrases  of e agents . More ree agents .T. cruzi, in the infective trypomastigote and replicative intracellular amastigote form, secretes the enzyme prolyl oligopeptidase 80 kDa (Tc80), which apparently is related to the invasion of non-phagocytic cells [ic cells ,46. Tc80ic cells ,48.Cruzipain is a lysosomal cysteine peptidase expressed in all evolutive forms of the parasite. K777 is a vinyl sulfone derivative inhibitor; it is considered the most potent and well-known inhibitor for this enzyme. In vivo, K777 did not promote a parasitological cure but significantly reduced parasite-induced heart damage. A wide range of susceptible and resistant strains was sensible to this inhibitor. Although K777 entered in preclinical development, the study was stopped. An HTS study conducted by GlaxoSmithKline identified new inhibitors against cysteine peptidase and these studies are in progress . TherefoT. cruzi screening hit [T. cruzi proteasome inhibitors using a luminescence-based high throughput screening assay have been identified [The proteasome was identified as a promising drug target for kinetoplast diseases such as leishmaniasis, Chagas Disease and African trypanosomiasis (HAT). It is considered a key component of the ubiquitin-proteasome protein degradation system and plays an important role in many cellular processes. GNF6702 was invented by researchers working at the Genomics Institute of The Novartis Research Foundation in 2013, with activity against these diseases. Another inhibitor, the GSK3494245/DDD01305143, is a preclinical candidate for visceral leishmaniasis developed from a ning hit ,51,52,53The process of developing a drug can take about 12 years or more from development to approval for launching the drug on the market . AccordiStructure-based drug design (SBDD) is an approach  that depThe discovery of an inhibitor to a target that drives the phenotype of a disease is one of the most important phases of a drug discovery campaign . As thishttp://tdrtargets.org) is an open access database focused on identifying and prioritizing molecular targets for the development of drugs for neglected human diseases [T. cruzi enolase inhibitors [The TDR Targets Database  modeling and microcrystal electron diffraction (MicroED), opening up new possibilities in the discovery of molecules of interest. Studies that used target-based and phenotypic-based approaches are increasingly based on computational methods; however, it has been demonstrated that technological advancement must be accompanied by an integration between systems, annotations and data availability so that the community that studies Chagas disease can, in an integrated way, contribute and benefit.


The purpose of this research is to identify the mechanisms of Shen-Qi compound formula (SQC), a traditional Chinese medicine (TCM), for treating diabetes mellitus (DM) using system pharmacology.  The active components and therapeutic targets were identified, and these targets were analyzed using gene ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and protein-protein interaction (PPI) analysis. Finally, an integrated pathway was constructed to show the mechanisms of SQC.  A total of 282 active components and 195 targets were identified through a database search. The component-target network was constructed, and the key components were screened out according to their degree. Through the GO, PPI, and KEGG analyses, the mechanism network of SQC treating DM was constructed.  This study shows that the mechanisms of SQC treating DM are related to various pathways and targets. This study provides a good foundation and basis for further in-depth verification and clinical application. Diabetes mellitus (DM) is an endocrine and metabolic disease characterized by persistent hyperglycemia. Its main clinical manifestations include polydipsia, polyphagia, polyuria, and weight change . Due to Although the treatment of DM has long been researched, the management of DM and its chronic complications are still big challenges in clinical practice –9. At prrén shēn), Radix Astragali Praeparata cum Melle , Radix et Rhizoma Salviae Miltiorrhizae , Radix et Rhizoma Rhei , Rhizoma Dioscoreae , Radix Trichosanthis , Radix Rehmanniae , and Fructus Corni . The composition of SC is shown in β cell function and insulin resistance [In China, the application of traditional Chinese herbal medicine for DM has a long history. Shen-Qi compound formula (SQC) is a traditional Chinese medicine (TCM) formula that is widely used in treating DM in China. It consists of eight herbal medicines: Radix et Rhizoma Ginseng  and SymMap (https://www.symmap.org/). TCMSP is a database that is widely used in the network pharmacology research of TCM. It contains information on 499 herbal medicines, 29384 ingredients, and 837 related diseases [The workflow for this network pharmacology study can be seen in diseases . This dadiseases . To furtOB represents the proportion of drugs that enter the human blood circulation after oral administration . OB playA and B represent the molecular property of the herbal ingredients and average molecular property of all the molecules in the DrugBank database (http://www.drugbank.ca/), respectively. DL ≥ 0.18, which was the average DL index of all the compounds in DrugBank, was applied as the screening criteria for the ingredients. To ensure that the results of the study are comprehensive and reliable, some compounds which do not meet the screening criteria but are reported as the main components in the literature have been retained in our research.DL is a parameter used to evaluate how “drug-like” a prospective compound is . This coAs some components with pharmacological effects may not be included in the database or do not meet the conditions of OB and DL, these components will be missed. To avoid this, we searched the medicine of SQC in PubMed for pharmacological research. MeSH terms and free text words were used as the search strategy. Each search term was connected with a Boolean operator to other terms. The time limitation was from January 1, 2000, to February 5, 2020. The full search strategy can be seen in supplementary material 1.https://www.uniprot.org/) was used to search the corresponding human gene names. UniProt Knowledgebase is a protein database with extensive amount of information and resources. It integrates data from three databases: Swiss-Prot, TrEMBL, and PIR-PSD. Its data mainly come from the protein sequence obtained after the completion of the genome sequencing project. It contains a large amount of information about the biological functions of proteins from the literature. We retrieved information about proteins and replaced the protein targets with corresponding gene targets in this database.We searched the TCMSP database for protein targets of the chemical constituents we collected. Then, the UniProt Knowledgebase (https://www.genecards.org/). GeneCards is a searchable, integrative database that provides comprehensive, user-friendly information on all annotated and predicted human genes. It integrates gene-centric data from about 150 databases, including NCBI, UCSC, and Nsembl [We then searched about the targets for DM. These were retrieved from the Human Gene Database . This database is used for searching and predicting protein interactions. It can be applied to 2031 species and includes 9.6 million protein interactions and 13.8 million protein interactions. In addition to the experimental data, the results of text mining from PubMed abstracts, and the synthesis of other database data, it also uses bioinformatic methods to predict the results. This is one of the most diverse and informative websites for PPI analysis. The line thickness indicates the strength of data support, that is, confidence. The minimum required interaction score is medium confidence (0.400), which is also the default threshold.The protein-protein interaction (PPI) network analysis helps study the molecular mechanism of diseases and discover new drug targets from a systematic perspective. We constructed a PPI network for the protein targets of SQC, which we retrieved in the TCMSP database. This was done using the string database (https://david.ncifcrf.gov/). DAVID is a robust, publicly available database that aims to illuminate how environmental chemicals affect human health [P value indicates whether the pathway is significantly related to SQC, and the count value reflects the number of targets on the pathway. The larger the count value is, the more targets SQC has on the pathway. We filtered according to a P value of <0.01 and arranged the filtered results according to the count. For the GO analysis, we selected the top five results for each item to display. For the KEGG analysis, to provide readers with a more comprehensive understanding of the mechanism of SQC, the top 25 entries in the KEGG pathways were exhibited.To elucidate the mechanism of SQC in treating DM, we collected the intersected target genes for gene ontology (GO) enrichment and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway enrichment analysis. GO enrichment is the description of genes in different dimensions and levels such as the cellular components (CC), biological process (BP), and molecular function (MF). Through the GO analysis, we can get a better understanding of genes . KEGG ann health , 31. In To display the above results more vividly, compound-target (C-T) network and target-pathway (T-P) network diagrams for the above results were constructed. These network diagrams were drawn using Cytoscape version 3.6.1, which can graphically display the network and edit it . In thesWe excluded the pathways that were unrelated to diabetes among the top 25 pathways. The rest of the pathways were considered to be the main mechanisms. Then, we looked up the KEGG database to understand the specific processes of these mechanisms. Due to the complexity of mechanisms, only the most commonly used and representative molecules in pathways and proven interactions were selected in the construction of the signal pathway. Special attention was paid to the interaction between signal pathways. In this way, we integrated the rest of the diabetic signal pathways and constructed the pathway network of SQC in the treatment of DM.rén shēn, 19 in dì huáng, 103 in shān zhū yú, 175 in dān shēn, 52 in huáng qí, 9 in tiān huā fĕn, 154 in huái shān yào, and 19 in dahuang. After a literature search, 30 additional ingredients were added to our study including 10 in RRG , 4 in Roside Re , Lithosposide Re , Magnesioside Re , 78, andoside Re –85), 3 ioside Re , emodin oside Re , 88, andoside Re ), 2 in Roside Re , 91, Diooside Re –94), 1 ioside Re , Iridoidoside Re , Loganinoside Re , 7-O-Galoside Re , 108, tooside Re , iridoidoside Re , and corBased on the above results, we further searched the targets of these ingredients. A total of 5201 targets were retrieved. Four-hundred and forty-eight targets remained after eliminating the duplicate targets. Then, DM-related targets were searched in the platform, Genecards. A total of 1244 targets were retrieved in the database using the keyword “diabetes”. By intersecting the target of SQC with that of DM, a total of 195 overlapping target genes were screened out. The targets of SQC and DM can be viewed in supplementary P value of <0.01 was considered statistically significant. The complete results of the GO enrichment analysis are displayed in supplementary materials To further elucidate the molecular mechanism(s) of SQC in the treatment of DM, GO enrichment and KEGG pathway analyses were performed on the selected candidate targets in the CTD database. The GO analysis describes the function of candidate targets from three aspects: biological process (BP), cellular component (CC), and molecular function (MF). A Subsequently, we analyzed the KEGG pathway of the candidate genes. The results of the KEGG analysis are displayed in supplementary To show the relationship between these 25 pathways and their related genes, we have mapped the T-P network . In thisα (VEGFA), tumor necrosis factor (TNF), tumor protein P53 (TP53), caspase 3 (CASP3), mitogen-activated protein kinase 3 (MAPK3), and mitogen-activated protein kinase 8 (MAPK8). These genes are considered to play an important role in treating of DM  is an important transcription factor, which can regulate the expression of many downstream target genes and participate in hypoxia adaptation, angiogenesis, immune response, apoptosis, and other reactions. It plays an important role in diabetes. The changes of HIF-1 α expression level in DM, together with the structural and functional abnormalities caused by the covalent modification of glyoxal, ultimately lead to disorder of the signal pathway regulation, such as angiogenesis and apoptosis. These are important molecular events in the occurrence and progress of diabetes and its complications. It was found that the TNF, PI3K/Akt, and MAPK signal pathways can interact with the HIF signal pathway, leading to the gradual progress of the disease.Hypoxia-inducible factor-1 κB signal pathway, and MAPK signal pathway downstream of TNF, thus leading to inflammation and apoptosis.Among the signal pathways we obtained through the KEGG analysis, the toll-like receptor and cAMP and Ras pathways are important signal pathways for organisms, which can participate in a variety of biological processes and have mutual relationships with multiple signal pathways. For example, toll-like receptor-mediated pattern recognition can rapidly activate the immune response, NF-The PPI analysis further explored the interaction of these targets. From these results, we can know which targets play a more important role. TNF, Akt, MAPK, and other targets are the most important proteins. This result is consistent with the results of the KEGG analysis.This research systematically investigated the ingredients and targets of SQC in the treatment of DM through the combination of network pharmacology and a literature search. A total of 282 components and 195 targets were obtained. The multitarget mechanisms of SQC were studied using the GO, KEGG, and PPI analyses. This study provides a solid foundation for further experimental verification and clinical application. Further experimental verification is needed to confirm the result of this current study.


Background: Sternal wound infections (SWIs) can be some of the most complex surgical-site infections (SSIs) and pose a considerable risk following coronary artery bypass graft surgery (CABG).Objective: To capture the cost burden of SWIs following CABG across European countries.Methods: We modeled a standardized care pathway for CABG, starting at the point of surgery and extending to 1-year post surgery. The Markov model captures the incidence and cost of an SWI . The cost burden is calculated from a hospital perspective such that the main inputs relating to costs were intensive-care-unit (ICU) and general-ward (GW) days. Outpatient care, not in the hospital setting, has no cost in this analysis. Model input parameters were taken from Eurostat and a review of published, peer-reviewed literature. European countries were included in this analysis when values for 50% of the required input parameters per country were identified. Missing data points were interpolated from available data. The robustness of results was assessed via probabilistic sensitivity analysis.Results: Full required input data were available for 8 European countries; a further 18 countries had sufficient data for analysis. The median (interquartile range) for SWI incidence across the 26 countries was 3.9% (2.9–5.6%). The total burden for all 26 countries of SWIs after CABG was €170.8 million. These costs were made up of 25,751 additional ICU days, 137,588 additional GW days, and 7,704 readmissions. The mean cost of an SWI ranged from €8,924 in Poland to €21,321 in Denmark. Relative to the costs of post-CABG care without an SWI complication, the incremental cost of an SWI was highest in Greece (24.9% increase) and lowest in the UK (3.8% increase) with a median (interquartile range) of 12% (10–16%) across all 26 countries.Conclusions: SWIs following CABG present a considerable burden to healthcare budgets. Surgical-site infections (SSIs) can be a serious complication that may present in the days or weeks following a surgical intervention. In the 50 years since Rene Favaloro pioneered coronary artery bypass graft surgery (CABG), it has become a commonly performed procedure to improve blood flow to the heart in patients suffering from severe coronary heart disease. During CABG, the afflicted part of the coronary artery is replaced by a segment taken from another major blood vessel (the harvest site). Due to the highly invasive nature of CABG procedures, post-surgical infections are especially dangerous. SSIs linked to CABG can occur either at the harvest site or at the sternum, the latter generally being considered more detrimental to patient outcomes. Sternal-wound infections (SWIs) are further divided into superficial, deep, and organ-space SWIs.SWIs can have a substantial negative effect on patients' quality of life, in some cases even leaving them at pre-surgical quality-of-life levels . For hosIn recent years, SSI rates have been going down, largely due to the introduction of antibiotic prophylaxis, which is almost ubiquitous at this point. Still, SSIs are reported to occur in roughly three percent of CABG procedures in Europe . The WHOThe objective of this research is to estimate the overall burden of SWIs related to CABG in Europe. In the cost model, we differentiate between superficial SWIs (SSWIs) and DSWIs to better reflect their differences in care costs. Organ-space SWIs were not considered separately but are regarded for cost computations to be equal to DWSIs. Data on disease burden are required to start taking appropriate action on current discussions and targets for implementing value-based healthcare programmes. More specifically, data on the burden of SWIs could facilitate well-informed, value-based procurement decisions for interventions allowing for incremental improvement in SWI prevention.Eurostat collects data on 34 countries. The 27 European Union countries (EU-27) plus the UK, Iceland, Macedonia, Norway, Serbia, Switzerland, and Turkey. Our target was to utilize standardized reporting methods in the Eurostat to estimate the burden of disease in the EU-27. This could then be extrapolated to the additional reporting countries if sufficient local data were available. To provide estimates, with quantified uncertainty, a published Markov model of the CABG care pathway was adapted to a hospital-cost-only perspective . This peThe choice of settings was based on the 34 countries for which EuroStat gathers and publishes data. This meant that a considerable part of the data underpinning the analysis comes from the same source, hopefully, allowing for a higher level of comparability between settings. Likewise, for consistency, country-specific unit costs provided by the WHO for the general ward (GW) were used for all included countries. These costs are comprised of components such as personnel, capital, and food costs but exclude costs of drugs and diagnostic tests. No such comprehensive source was available for intensive care unit (ICU) costs, therefore, these costs were sourced from published literature. ICU costs were required to be direct hospital costs, but the costs included and their definitions varied across publications. Details on these definitions can be found in the corresponding references provided in A Markov model previously developed and published by two of the current authors was used as the basis of this analysis . It was Patients enter the model once CABG is initiated, that is, entering the surgical suite . On compThe model outputs for analysis are overall costs of care, number of ICU days, number of GW days, and number of readmissions due to SWIs.C), there were 10 country-specific inputs (I) required. Let C = {C1, …, C34} be the set of 34 Eurostat countries and I = {I1, …, I10} be the set of 10 country-specific inputs. The full dataset (X) is thus represented by the parameters C1 has 10 elements and is defined as I1 has 34 elements and is defined as The dataset for the model is made up of countries and inputs. For each country ; the mean length of hospital stay associated with CABG (I3); the cost of an ICU day (I4); cost of a general ward day (I5); the overall SWI incidence following CABG (I6); the number of days of surveillance/follow-up (I7); the ratio of SSWI to DSWI (I8); additional length of stay to treat an SSWI (I9); and additional length of stay to treat a DSWI (I10). An example for these parameters in the UK setting can be seen in To estimate the burden of CABG-related SWIs, the following parameters were required inputs for each country in the model: the number of CABG procedures/year  and instead were held constant for each country. Examples of such input data were the costs for a readmission and the percentage of patients receiving prolonged MV. The assumption that these parameters were consistent between settings was made due to limited data availability, feasibility of data collection, and analysis of drivers of model outcomes.During data collection, only data specifically referenced to be a DSWI, organ-space infection, or mediastinitis was associated with outcomes for DSWI in the model. General reference to an SSI or SWI was assumed to be data with relevance to a SSWI. Similarly, SSWIs and harvest-site SSIs were assumed to require the same level of treatment and costs. These assumptions were required as the necessary detail in reporting of definitions/types of SSI/SWI was not ubiquitous.Eurostat was the primary source of data. When data on required parameters was not available on Eurostat, these were identified through structured searches of PubMed and hand searches of Google scholar. Where data were not from Eurostat, peer-reviewed, published literature was a requirement. A country was included in the final analysis if there were ≥5 (out of 10 possible) country-specific data points identified.In cases where a country had 5–9 country-specific inputs, any missing data points were interpolated from the set of countries with data. Specifically, for those countries with data, the median and interquartile range of available data were calculated. In the base-case analysis, the median value was used as the input for countries without data.X (X' (Cj ∈ C and input IK ∈ I) being randomly drawn from between the upper and lower bound of all known input Ik values for all 34 countries in I, were also randomly drawn for each model run. In this case, a normal distribution around the input was assumed. In total, 1,144 unique model runs were performed (44 per country). The value of 44 was arbitrary and taken because there were 44 parameters to sample each run. Results of these runs are presented as the median and range of the burden of CABG-related SWIs.The overall robustness of model estimates to input data was assessed through a probabilistic sensitivity analysis. Here, multiple model runs were performed with a new, unique set of input parameters used for each run. Specifically, the dataset During our literature review, if studies on the single-hospital burden of post-cardiac surgery SSIs/SWIs were presented, then these were tagged for potential validation and the data extracted were not used in the main model analysis. Where validation studies were identified, the hospital-specific parameters were used in the model and the burden for this hospital estimated. The results are compared to those published, allowing for readers to determine for themselves the validity of our current analysis.Full required data were identified for 8 of our 34 target Eurostat countries: Belgium, France, Germany, Ireland, Netherlands, Norway, Turkey, and the UK. Sufficient data were identified for a further 18 countries: Austria, Czech Republic, Denmark, Estonia, Finland, Greece, Hungary, Iceland, Italy, Lithuania, Malta, Poland, Portugal, Romania, Serbia, Spain, Sweden, and Switzerland. In total, 26 countries had sufficient data . For theFrom a clinical perspective, the SSWI and DSWI rates are the key parameters of interest. Across the 26 countries analyzed, variation in the absolute and relative rates of SSWI and DSWIs was observed. The lowest reported prevalence of sternal wound infections was 1.6% after 30 days , with the highest being 10.4% after 6 months (Netherlands). The median (interquartile range) incidence of SWIs was 3.9% (2.9–5.6%). Of patients with a sternal wound infection, Iceland had the lowest percentage of these as DSWIs (23.3%), whereas Hungary had the highest (76%). For countries with full data, the range in SWI prevalence at 30-days was from 2.0 (UK) to 3.9% Norway, . In thisThe total annual burden of SWIs after CABG for the 26 countries with sufficient data was €170.8 million. These costs are a made up of 25,751 additional ICU days, 137,588 additional GW days, and 7,704 readmissions. The mean cost of an SWI ranged from €8,924 in Poland to €21,321 in Denmark. The country with the highest cost burden was Germany, where each year €31.7 million is lost to SWI following CABG. The lowest cost burden was found in Malta, being €54,410 per year. These results, though, are likely driven by population size. Normalized by the number of CABG procedures, the highest cost burden was found in the Netherlands, with the lowest being in the UK. As healthcare costs vary by country, the cost burden may be most comparable as percentage of overall costs. Relative to the costs of post-CABG care without a SWI complication, the current cost of CABG care was highest in Greece (24.9% increase) and lowest in the UK (3.8% increase). The median (interquartile range) was 12% (10–16%). Among countries with full data, the largest increase was seen for Turkey 15.2%, . The burThe probabilistic sensitivity analysis for the 26 countries with sufficient data revealed a median (range) overall SWI burden of €181.7 million (€108.8 million to €297.8 million). The results by country, normalized by the number of CABG procedures per year, are shown for the eight countries with full data . Europe-Two papers were identified allowing model outcomes to be assessed for validity. In 2018, Findeisen et al. reported on the cost of post-CABG SWIs at the Jena University Hospital, Germany . From 98p < 0.001)  . In the Innovative approaches to reduce the current burden of SSIs are likely to be of benefit to both patients and providers. Although new technology can increase the direct per-procedure cost, this may pay for itself  if the cost of care is reduced through fewer SWIs. This is especially true if there are systems in place that “punish” hospitals for avoidable SSIs, such as in the UK, where hospitals are not reimbursed for avoidable readmissions within 30 days . Areas wOur study provides a first estimate of the cost burden of SWIs in Europe and gives insight into the additional cost-of-care per patient associated with SWIs. Initial comparison to a published costing study suggests that these data are a reasonable estimate for the SWI burden. Results, therefore, could be used as an initial starting point for hospitals and quality-improvement teams considering budgets for improved infection control. In doing this, readers must note the limitations of the analysis. Firstly, reporting and definitions of SSIs and SWIs were not consistent between studies. Secondly, results are from a computational model, which cannot recreate all the complexities of real-life healthcare. Some of the necessary simplifications were the assumption of an identical care pathway across all settings, a single, universal readmission cost, no inter-hospital variation, and no adjustment for patient-level risk factors. As such, results for individual hospitals will likely vary to some degree from those published here. Still, when the model was adjusted to specific published data for individual hospitals, a good fit between model outcomes and published burden was achieved.While most simplifications were needed to create a functional model that could be used across multiple countries, the issue of limited data availability could be improved. During our search for data on this topic, Eurostat was a helpful starting point, providing some general healthcare data for all settings. When looking for more detailed information such as additional length of stay due to SWIs, or the ratio of DSWIs to SSWIs, there was a paucity of published literature. This lack of data necessitated extrapolation based on available data for several settings, which undoubtedly adds more uncertainty to the results. We encourage those working in the field of infection control to engage in surveillance and to publish and communicate their findings.SWIs, and DSWI in particular, remain a considerable problem post CABG. The treatment, additional length of hospital stay, and readmissions associated with SWIs resulted in increased cost of care—generally adding between 10 and 16% to the cost of every CABG. New interventions to further reducing SWIs would likely be of benefit to both patient outcomes and healthcare budgets. As healthcare budgets come under increasing pressure, this may be an opportunity to consider value-based purchasing schemes to offset any risk to hospitals.https://ec.europa.eu/eurostat/de/home. All extracted data used in the analysis is included in the Publicly available datasets were analyzed in this study. This data can be found at: JL and RS conceived the research project. MB, RS, and JL designed the literature searches. Literature review, analyses, and manuscript draft in full was performed by MB and RS. PM and DB reviewed data extracted and updates to the previously published health-economic model. JL, DB, and PM all provided substantial review of the manuscript. Result review and interpretation and manuscript outline approved by all authors. All authors approved the manuscript for submission and publication.RS is the owner and MB is an employee of Coreva Scientific, which received consultancy fees for this work. While working on this project JL was an employee of Cardinal Health (the funder) and is now an employee of Bose. Neither Xavier University nor its affiliated authors received any compensation for participating in this research project. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed a potential conflict of interest.


The results of multiple linear regression, adjusted for sociodemographic and health-related characteristics, indicated that social frailty had the strongest negative association with life satisfaction . However, cognitive function was significantly positively associated with life satisfaction . Social frailty was significantly correlated with physical, psychological, and mental health as well as life satisfaction in community-dwelling older South Koreans. Therefore, accounting for the social aspect of functioning is an essential part of a multidimensional approach to improving health and life satisfaction in communities.Social frailty affects various aspects of health in community-dwelling older adults. This study aimed to identify the prevalence of social frailty and the significance of its association with South Korean older adults’ health status and life satisfaction. This study involved a secondary data analysis of the 2017 National Survey of Older Koreans. From the 10,299 respondents of the survey, 10,081 were selected with no exclusion criteria. Multiple regression analyses were conducted to identify the factors related to life satisfaction. Compared with the robust and social prefrailty groups, the social frailty group had higher nutritional risk (χ² = 312.161,  The median age of the South Korean population is rapidly increasing; in 2019, individuals aged 65 and over accounted for 14.9% of the South Korean population, and this proportion has been projected to exceed 46.5% by 2067 . A high Frailty is defined as a biological syndrome of extreme vulnerability to endogenous and exogenous stressors associated with multisystem decline in physiological reserve, resulting in increased risk of adverse outcomes including disability, hospitalization, and death ,9. This Recently, the concept of “social frailty” has been increasingly emphasized. Based on a scoping review  and usinPrevious studies have reported that social frailty is associated with muscle weakness  and cognThus, this study aims (1) to examine the differences in general and health status characteristics of community-dwelling older adults in South Korea according to social frailty status; (2) to examine the correlations among social frailty status, nutritional status, depression, cognitive function, and life satisfaction; and (3) to explore the health-related predictors associated with life satisfaction.https://data.kihasa.re.kr/). From the 10,299 respondents of the 2017 National Survey of Older Koreans, 10,081 were selected without any exclusion criteria; 218 were excluded for missing responses.This cross-sectional study used secondary data from the 2017 National Survey of Older Koreans . The NatSociodemographic characteristics included age, gender, education level, economic status, and living conditions . Economic status was sorted in ascending order by annual personal income and divided into five categories so that each group contained 20% of the participants. Then, only the bottom 20% of the group were used in the analysis, as they best suited our interests. Health-related characteristics included the number of prescription medications, diagnosis of chronic diseases, subjective health status , lower-extremity muscle (sitting and standing up), and lifestyle .To identify and assess social frailty, we operationalized the concept into five categories based on a previous study : going oNutritional status was measured using “Determine Your Nutritional Health,” a tool developed by the Nutrition Screening Initiative . Used toDepression was measured using the 15-item Geriatric Depression Scale-Short Form Korean Version (GDSSF-K) . The GDSCognitive function was measured using the Mini-Mental State Examination for Dementia Screening (MMSE-DS) . The 19-Life satisfaction was measured using the question “To what extent are you satisfied with the following aspects of your life: health status, economic status, relationship with spouse, relationship with children, leisure and cultural activities, and relationships with friends and society?” The response options were: 1 = very satisfied, 2 = satisfied, 3 = average, 4 = not satisfied, and 5 = not satisfied at all. Responses to all items were reverse coded, so that higher scores indicated higher levels of life satisfaction. The total scores ranged from 6 to 30; Cronbach’s alpha was 0.61 in the present study.The 2017 National Survey of Older Koreans was approved by Statistics Korea . For our study, after obtaining approval from the Korea Institute for Health and Social Affairs, we received raw data without personal identification information. Moreover, the study was approved by the Institutional Review Board (IRB No.: 1044396-202006-HR-110-01) of Gachon University, to which one of the researchers is affiliated.2 test for categorical data and analysis of variance for continuous data. Then, we performed multiple regression analysis to identify the factors related to life satisfaction. Before running the multiple regression analysis, we conducted a correlation analysis, and the independent variables were tested for multicollinearity using tolerance value and variance inflation factor (VIF). Less than 10% of confirmed missing cases were excluded from the analysis by applying listwise deletion [2 test.Sample characteristics were summarized using means and standard deviations (SDs) for continuous variables and proportions for categorical variables. To evaluate the differences in characteristics between participants from the three groups , we used Pearson’s χdeletion . All stadeletion  in analydeletion  in Pearsp = 0.000). Regarding lifestyle, there was a difference in physical activity according to social frailty status (p = 0.000). However, there were no statistically significant differences between the three groups regarding smoking.The sample characteristics are shown in Additionally, the social frailty group had a higher proportion of participants with more than three diagnosed chronic diseases and a higher number of prescribed medications compared to those in the robust and social prefrailty groups.p = 0.000). In addition, life satisfaction, which was the criterion variable, was significantly correlated with all predictors.β = −0.267, p = 0.000) . The variance inflation factor (VIF) of predictors and the tolerance of predictors were 1.427–2.749 and 0.364–0.701 respectively, which suggests the absence of multicollinearity between the predictors.Multiple linear regression analyses revealed that social frailty had the strongest negative association with life satisfaction (= 0.000) . HoweverThe prevalence of social frailty in the sample was 44.7%. Further, the social frailty group displayed the highest prevalence of nutritional risk, depression, low cognitive function, and poor life satisfaction. Additionally, social frailty displayed the strongest negative association with life satisfaction. These findings suggest that social frailty may affect older adults’ physical, cognitive, and psychological functions as well as life satisfaction.The prevalence of social frailty in this study was higher than the rates reported by Tsutsumimoto et al. (11.1%)  and YamaThis study shows that older adults with social frailty tend to be more vulnerable to impairments in cognitive and psychological functions than their robust counterparts. This result is in line with those of several previous studies, which revealed that higher levels of social frailty were associated with cognitive dysfunction ,25 and dTo the best of our knowledge, this is the first study to examine the association between social frailty and life satisfaction in older adults. According to the results, social frailty had a stronger negative association with life satisfaction than with physical, psychological, and cognitive functions. Previous studies have revealed a negative relationship between depression levels and life satisfaction ,32,33. FThe strengths of this study are the large sample size and the use of an operationalized assessment to identify social frailty. On the other hand, the large sample size can cause overpower problems in situations where there is little association between groups. It is necessary to pay attention to the interpretation of the results based on the effect size ,24, whicHowever, this study also has some limitations. First, owing to the use of cross-sectional secondary data, causality could not be explored; this should be clarified in a future prospective study. Second, although Diener et al.’s Satisfaction with Life Scale  is the mSocial frailty and its association with nutritional status, depression, cognitive function, and life satisfaction should be considered as an integrative comprehensive older adult care. Further studies are needed to develop of efficient social frailty intervention strategies to improve and enhance life satisfaction.


Background. To date, there is no specific literature available on the determinants for therapeutic failure (TF) with meglumine antimoniate (MA) in Northwestern-Argentina. This study aimed to identify epidemiological, clinical, and treatment-related factors that could be involved in TF. Methodology/Principal Findings. We performed a case-control study. Cases were represented by patients who showed TF after administration of the first course of MA treatment, whereas, controls were determined as patients who evolved towards healing after the first MA cycle received. Crude Odds Ratios and their corresponding 90% confidence intervals (CI) were calculated, and risk factors were then tested by multivariate analysis using logistic binary regression. Three hundred and eighty-four patients with a presumptive diagnosis of ACL were recruited, and 153 with a positive diagnosis were selected. We included in the study 71 patients, who underwent specific treatment with MA, presented complete data on response to treatment, and had a minimum post-treatment follow-up of 6 months in cutaneous leishmaniasis, and 12 months in mucosal leishmaniasis. Of these, 34 (47.9%) presented TF. In the initial analysis, TF was significantly associated with the geographical area of disease acquisition (p = 0.036), the presence of mucosal lesions (p = 0.042), the presence of concomitant skin and mucosal lesions (p = 0.002), and lesion age ≥ 6 months (p = 0.018). Risk factors influencing TF in the final multivariate model included the geographical area where the disease was acquired , and lesion age ≥ 6 months . Conclusions/Significance. The results of the present study suggest the existence of some risk factors linked to TF in Northwestern-Argentina, which deserve further investigation. Herein we recorded a high percentage of TF and we described clinical and epidemiological characteristics associated with TF that could be taken into account improving the clinical management of patients. Cutaneous leishmaniasis and mucosal leishmaniasis are parasitic diseases characterized by the involvement of skin and mucous membranes, respectively. The first-line drug for the treatment is meglumine antimoniate, but its use presents several limitations, such as an aggressive administration schedule, a wide range of local and systemic side effects, great variability in therapeutic response, and an important number of failed treatments. In this study, we explored epidemiological, clinical, and treatment-related factors that could be involved in treatment failure (TF). We included in the study 71 adult subjects who underwent the first cycle of specific treatment with meglumine antimoniate, and we found that the geographical area where the disease was acquired (Yungas ecoregion), and lesion age ≥ 6 months accounted as risk factors for TF. Knowledge of the high percentage of TF recorded, as well as a description of distinct characteristics associated with these failures, could help to improve the clinical management of patients. Leishmania, which are transmitted to humans through the bite of infected female phlebotomine sandflies. The disease in all its clinical expressions is endemic in 98 countries [Leishmania species and the immune response of the host, leishmaniases can exhibit a disease spectrum which includes visceral leishmaniasis or "kala-azar", affecting mainly the mononuclear phagocytic system; as well as cutaneous  and mucosal forms , which are characterized by involvement of skin and mucous membranes, respectively [The leishmaniases are a group of diseases caused by parasites of the genus ountries , affectiountries . Over onountries , and an ountries . Dependiectively .Leishmania (Viannia) braziliensis, L (V.) guyanensis, and L. (Leishmania) amazonensis are commonly isolated from human ACL cases although L. (V.) braziliensis is the main agent associated with ACL outbreaks and subsequent ML cases. We performed the parasitological and molecular diagnosis (kDNA-PCR) of leishmaniasis for many years in collaboration with hospitals of Salta (Argentina) [In the Americas, leishmaniasis is endemic in eighteen countries, from southern United States to northern-Argentina. CL and ML forms, also referred as American Cutaneous Leishmaniasis (ACL), are endemic in ten provinces of northern-Argentina, where they represent a serious public health problem . Orán angentina) . Most ofgentina) . These sgentina) . The datgentina)  explain gentina) .Currently, the World Health Organization and National Argentinian guidelines for the control of leishmaniasis do not recommend vector control campaigns, as they are not cost-effective. At present early detection of ACL is the main prophylactic measure. Therefore, prevention relies mainly on rapid diagnosis and early treatment .Leishmania (Viannia) braziliensis in the province of Salta (Argentina), 21% exhibited antimony TF [Chemotherapy remains the major control strategy for this group of diseases with MA enduring as the first-line treatment for all clinical forms of ACL . Howeverimony TF .et al. found that TF was associated with the appearance of 3 or more cutaneous lesions, reports of previous leishmaniasis treatment, body weight above 68 kg, and incomplete treatment schedule [et al. [et al. [L. (V.) peruviana, and infection with L. (V.) braziliensis as risk factors for TF. In Colombia, Castro et al. [Many reports on the influence of clinical and epidemiological factors in response to MA treatment in Latin America ,15–17 arschedule . In Peru [et al.  identifiThe study was conducted according to the principles expressed in the Declaration of Helsinki and approved by the Ethical Committee of Medical College of Salta province, Argentina . All adult subjects provided informed written consent, and a parent or guardian child participants provided consent on their behalf.We adopted an observational, case-control design. The reporting of this study conforms to the STROBE statement.  and 30 days after finishing the administration of their treatment. We also cited the patients and performed the follow-up 3, 6, 9, and 12 months after the finalization of treatment. Patients diagnosed on clinical grounds alone and/or by intradermal–Montenegro–skin test (MST) who did not undergo specific treatment with MA and who presented a shorter follow-up of less than six months in CL, or less than 12 months in ML or without post-treatment follow-up, were excluded of the study. For Leishmania species identification, polymorphism-specific PCR (PS-PCR) was performed, as described in a previous publication of the group [All patients with a positive diagnosis of ACL  , or PCR nia spp. , who undhe group .For CL, TF was considered if after three months post-treatment there was the presence of one of the following criteria: A. The lesion progressed 50% or more in size, or tested positive for parasites; B. The lesion progressed after having previously regressed; C. The lesion did not completely re-epithelize and/or exhibited persistent inflammatory signs ; D. A new parasitologically positive lesion appeared in the site of a previously healed lesion, or a satellite lesion around the initial one (without suspicion or evidence of reinfection), or there was development of inflammatory signs, with or without ulceration, on a previously healed lesion . HealingLeishmania species involved, Chagas disease serological status, presence of secondary bacterial or fungal infections, and presence of other infectious comorbidities. B. Characteristics of the administered treatment, according to the PAHO recommendations for the treatment of ACL [A. Epidemiological and clinical characteristics , relevant clinical information . Ancillary testing results to screen for associated infections and their causative agents, as well as clinical data on concomitant pathologies, especially differential diagnoses for ACL were also included. Other data sources included relevant information from clinical charts from other care centers. This information was reviewed in order to complete the data concerning treatment specifications and follow-up.Frequencies and proportions were used to describe categorical variables. For numerical variables, means, medians, standard deviations, and/or ranges were obtained . To establish possible associations between the impact variable (response to treatment) and the different predictive variables, comparisons were made using Pearson’s Chi-Square and Fisher's Tests. To compare a numerical variable  among the studied groups, the Unpaired Student's “T” Test  and Mann-Whitney's “U” Test  were used for independent samples. Crude Odds Ratios (cOR) and their corresponding 90% confidence intervals (CI) were calculated for each dichotomous nominal variable with significance level ≤ 0.10, using simple logistic regression (SLR). Then these variables were tested by multivariate (MV) analysis through logistic binary regression (LBR) using the “intro” method and obtaining Adjusted OR (aOR). An alpha of 0.10 was chosen for SLR analysis to have potential broader inclusion of variables into the final MV model. Potential confounders were controlled in the analysis phase, through their inclusion in the MV regression. Subgroup analysis was performed in patients with CL and ML.The predictability of the final model , and the Hosmer-Lemeshow Goodness of Fit Test were used for model selection. Missing data were not included in the analyses. The final level of significance for LBR was set at p≤ 0.05. The statistical programs GraphPad Prism 6 and SPSS 21 were used.Leishmania species (L. amazonensis and L. braziliensis) was mapped using GIS software [Geographical location and distribution of cases (latitude and longitude) was obtained using Latlong . Spatialsoftware  and plotsoftware .The study was registered in the National Registry of Health Research, , number IS000822 [Of 384 patients with a presumptive diagnosis of ACL recruited from January 2000 to December 2017, 153 patients (39.8%) had a positive leishmaniasis diagnosis. We included in the study 46.4% of the positive patients (71/153), who underwent specific treatment with MA, and presented complete data on response to treatment. The selected patients also had a minimum post-treatment follow-up of 6 months in CL, and 12 months in ML. Of the 71 patients included in the study, 34 (47.9%) presented TF during the first treatment cycle (cases), while the rest of the patients  healed and were considered as controls. The clinical and epidemiological features of most individuals who comprise this population of patients were described in a previous publication from our group . The stuAll variables that remained associated with TF at a significance level of 90% (p≤ 0.1) were included in the analysis. First, the calculation of the cOR was performed through bivariate (BV) analysis using SLR; then, the aOR was obtained through MV analysis using LBR . Gender Four patients were excluded automatically from the final model (because of missing data). Risk factors for TF in the final MV model were the geographical area of exposure/infection (Yungas ecoregion) (p = 0.004) and lesion age ≥ 6 months (p = 0.023). Model specificity and sensitivity values were 75.0 and 67.7, respectively, with a global percentage value of 71.6. Hosmer-Lemeshow Goodness of Fit Test value was 0.826.In the subgroup analysis, we found that for CL patients, trying to find associations among studied variables, none of them remained significantly associated with TF (p> 0.05). However, the p values for the ecoregion were close to being significant, both in the SLR and LBR (p = 0.06). In patients with ML, the ecoregion variable remained associated with TF in the MV analysis (p = 0.031), and the p-value of the lesions age remained close to significance (p = 0.06).Geographic clustering of patients occurred evenly throughout the Dry Chaco and Yungas jungle regions . HoweverL. (V.) braziliensis presented more commonly in a scattered fashion throughout the jungle (Yungas) and piedmont areas; whereas, L. (L.) amazonensis cases seemed to locate more commonly in the Dry Chaco region  of MA TF-cases was found, and the MV analysis model exhibited a significant association of TF with both, the geographical area of exposure/infection (Yungas ecoregion) and lesion age ≥ 6 months, as possible risk factors.To establish possible associations among studied variables, comparisons were made using Pearson’s Chi-Square Test, Fisher's Test, Unpaired Student's “T” Test and Mann-Whitney's “U” Test. All variables that in these analyses remained associated with TF at a significance level of 90% (p≤ 0.1)  were included in the MV analysis using LBR. Gender and age were also included because of their possible influence in the therapeutic response. Risk factors for TF in the final MV model were the geographical area of exposure/infection (Yungas ecoregion) and lesion age ≥ 6 months, as it was exposed at the beginning. These results were obtained including all patients, without discriminating the clinical form , due to the small size of the sample. When we analyzed these groups separately, in the CL subgroup, the p-value of the ecoregion variable remains close to significance, both in the BV and MV analysis. In the ML subgroup, in the MV analysis, the ecoregion variable remains associated with TF, and the p-value of the lesions age remains close to significance. Although the subgroup analysis reduces the statistical power of the tests, we could affirm that the ecoregion would constitute a risk factor associated with TF, regardless of the clinical form. Also the age of the lesions would constitute a risk factor for TF , mainly in the mucous form of the disease.Leishmania against MA, and the host immune system  [Leishmania species could be responsible for this finding. As most of the parasites isolated in our group of patients correspond to L. braziliensis, we believe that therapy outcome is highly influenced by the presence of strain variability within species which are distributed differently within transmission areas across the region. Marco et al. [L. braziliensis from two different zones of the province of Salta: "Jungle of transition", located into Yungas Ecoregion, and "Western Chaco", corresponding to Dry Chaco Ecoregion. Also, Locatelli and cols. [L. braziliensis (Ab1 and Ab2), and one of them (Ab2) was only found in the zone of the Zenta valley (Yungas Ecoregion), which is where we found most cases of TF. Studies from Brazil reported intraspecific differences  in isolates from patients with different responses to treatment [The precise reason related to the different rates of occurrence of TF-cases in Yungas (70.6%) and Dry-Chaco (29.4%) is not clear. It is however assumed that the difference between the two ecoregions might be caused by factors of parasites and host subjects, such as the difference of strains/genotypes, the susceptibility of the trition) ,24 The io et al.  found gend cols.  identifireatment ,28.+ and CD8+ T cells subpopulations together with the elevation of senescence markers and cytolytic molecules, while CL showed a less pronounced phenotype [Regarding the time of lesion evolution, we found that the patients with more than 6 months of disease progression, presented with a higher risk of TF. On this note, in previous work performed by our group, we investigated the evolution of the T cell differentiation profile in ACL, taking into account that early differentiated T cells are considered to confer best protective immunity while highly differentiated T cells present signs of senescence and exhaustion ,30. We ihenotype . The resIn contrast to our results, Llanos-Cuentas et al.  and ValeLeishmania parasites persistence in mucosal tissues after the end of treatment and suggests that mucosal sites could be a privileged niche for parasite persistence after drug treatment, either by pharmacokinetic differences in drug distribution and accumulation and/or immunological divergence between mucosal vs. skin tissues [Concerning initials association analyses between demographic and clinical variables about cure and failure after the first cycle of treatment , we foun tissues .Interestingly we found that the whole group of patients with concomitant mucous and cutaneous lesions presented TF. There is scarce mention in the literature about this clinical manifestation and its treatment response. Boaventura et al.  reportedAnalyzing the characteristics of therapeutic regimens administered, we observed that a high percentage of patients who were under a first incomplete treatment presented TF (59.4%), and all the patients who received an incomplete second cycle of treatment presented TF. Moreover, of the 17 patients who presented interruptions in the administration of the first cycle of treatment, 11/17 (64.7%) presented TF. These considerations are in accordance with the cohort studied by Rodrigues et al.  in BraziViannia genus [Interestingly, we found that 11 out of 16 patients who received the second cycle of antimonial compounds, presented successive TF. Some studies suggested that the association between TF and history of previous treatment might be due, among other factors, to insufficient dosing, promoting the selection of drug-resistant phenotypes to antimonials ,13,37. Nia genus . Despiteet al. [L. (V.) braziliensis is the predominant species. Nevertheless, it should be considered that the percentage of TF found in our population, could be overestimating the real situation. The reason for this is that many of the patients that we care for come from remote areas referred to our center for specialized care given their complicated clinical presentations or refractoriness to treatment. Patients with uncomplicated forms are usually managed and followed at local ambulatory centers. Also, after clinical cure, most patients abandon follow up. This point could be considered a limitation of the present study. A systematic approach of random sampling would have probably shown a much more accurate estimate of the true TF rate.Our results are coincident to those published by Rodrigues et al.  who descAlthough the present study is a preliminary analysis, the results point towards the existence of key factors associated with TF in patients from NWA, and how treatment outcome is distributed differently within transmission areas. Further unraveling the potential factors influencing therapy resistance in the region will allow to better understand the ecology of the disease and to design adequate preventive measures.In Argentina, ACL cases are mostly diagnosed adequately and therefore treated accordingly. However, the factors related to MA TF-cases found in the present ecoregions, Yungas and Dry-Chaco should be investigated precisely, including MA management in the areas. Given the limited resources of antileishmanial drugs available, it is imperative that effective monitoring of their use should be done to prevent the emergence of resistance. In addition to free availability to the drug (which is the case of Argentina) plus directly observed treatment performed to ensure compliance, health education about the disease and the importance of a full treatment-course is essential to control the disease .S1 STROBE Checklist(PDF)Click here for additional data file.


A few papers studying healthy, first-degree relatives of people with borderline personality disorder (BPD) have found that this group presents attention and memory problems. However, current research has not analyzed their social cognition.We designed an age-, gender- and education-level matched case-control study involving 57 people with BPD, 32 of their first-degree relatives, and 57 healthy controls in Spain in 2018–2019. All were assessed for social cognition and functioning using the Movie for Assessment of Social Cognition and the Social Functioning Scale; other potential confounders were also collected .There were differences in the social cognition domain of overmentalizing errors, with the BPD group scoring significantly higher than controls; however, there was no significant difference with relatives; in the social functioning domain of family relationships, with the controls showing the highest scores. Social engagement/withdrawal, interpersonal behavior, independence-competence, prosocial activities, full scale and categorization domains showed the same pattern: the BPD group had lower scores than their relatives and the controls. Relatives were significantly different from BPD patients in family relationships, social engagement/withdrawal and interpersonal behavior, as well as on the full Social Functioning Scale . However, only controls showed differences with relatives in family relationships.All in all, relatives show similar levels of social cognition and functioning compared with controls, and people with BPD show some alterations in different domains of both social cognition and functioning. Epidemi systems .Social cognition refers to the abilities to perceive, interpret, and process social stimuli that guide social interactions . AlteratSocial functioning is a complex and multidimensional construct, encompassing a person’s ability to achieve goals and play defined social roles, as well as to take care of oneself and enjoy leisure time . Some auAlthough few studies have investigated healthy first-degree relatives of people with BPD, these family members present more attention and memory problems than the general population . We haveWe are not aware of any research studying social cognition in healthy, first-degree relatives of people with BPD. Thus, our objective was to determine whether diminished social cognition is a characteristic feature in the first-degree relatives of people with BPD.The study included people with BPD, their first-degree relatives (parents or children), and members of the general population without any mental illness, from health department 20 . The catchment area of this health department is the entire population of Elche and Santa Pola, which had a registered population of 465,119 inhabitants in 2018 .Diagnostic and Statistical Manual of Mental Disorders (DSM-5)  ; 32 healPeople with BPD were chosen from the hospital coding database at the General University Hospital of Elche ; selected patients were those registered with ICD-9-CM code 301.83 and ICD-10-CM code F60.3. Afterwards, a psychiatrist determined whether the patients met the DSM-5 diagnostic criteria , and theSocial cognition was measured by means of the Spanish version of MASC . This isThe scores took into account both the total number of correct answers and the total errors, and the latter were analyzed by subtype . A lowerSocial functioning was measured using the Spanish version of the self-administered Social Functioning Scale SFS, . The SFSIn addition, the following variables were collected: gender, age (in years), highest educational level attained , marital status , occupation  and household composition .Participants were convened in groups of four or fewer in the classroom space at the General University Hospital of Elche. The facilities had a projector, screen, tables, and chairs. Participants received an information sheet on the study and signed informed consent. They then underwent assessments with the MASC and SFS—always in that order and administered by the same professional, a psychiatric occupational therapist with more than 10 years of experience in the service.The sample size was calculated to compare mean scores on the SFS scale among the three groups (ANOVA). To estimate the means in each group, we randomly selected 15% of the total sample, obtaining the following values: 114.4 for the control group; 115.9 for the relatives; and 101.3 for the BPD group. The estimated standard deviation (SD) was 10.9. According to these parameters and using a type I and type II error of 5%, we calculated a minimum number of 15 participants per group .Qualitative variables were described as absolute and relative frequencies, while quantitative variables were expressed as means (SD) or medians (interquartile range). To compare group characteristics, Pearson’s chi-squared and ANOVA tests were applied. To assess differences in the scales administered to the three groups, median or ANOVA tests were used, depending on whether the variable of interest was continuous or discrete. Post-hoc analysis was carried out using the Bonferroni correction. For the multivariable analysis, linear or ordinal quantile (median) regression models were fitted to adjust the results for marital status, occupation, and household composition. All analyses were performed at a significance level of 5%, and confidence intervals (CIs) were calculated for each relevant parameter. The statistical software used was IBM SPSS Statistics 25 and R 3.5.1.Both the Research Commission and the Research Ethics Committee at the General University Hospital of Elche approved the study . All participants were adequately informed of the study aims and methods, and if they agreed to take part, they signed informed consent before their inclusion.p < 0.001 in the total comparison and p = 0.002 when we compared relatives versus controls or patients). Mean age was 33.4 years in the BPD and control groups, and it was 52.9 in the group of first-degree relatives . Cases and controls showed a similar educational level (p > 0.0056), with most having completed secondary school, while the relatives showed a lower level (p = 0.003 versus controls and p = 0.005 versus patients in secondary school). There were also differences in marital status (p = 0.006), occupation (p < 0.001), and household composition (p = 0.004). Specifically, the relatives were less likely to be single than patients (p = 0.002), more likely to be on disability or pension rolls than controls (p < 0.001), and less likely to be living with their family of origin compared with patients (p = 0.001).A total of 146 participants were included: 57 had a diagnosis of BPD, 32 were first-degree relatives of these people, and 57 were healthy controls. p < 0.05) in the number of correct MASC items (p = 0.012) and the MASC Overmentalizing errors (p = 0.006). Controls scored higher on the first and lower on the second; relatives did not present statistical differences with the other groups (p > 0.017). All SFS dimensions showed differences as well (p < 0.05), with the relatives group presenting higher scores than the BPD group. However, the only dimensions reaching statistical differences between relatives and BPD patients (p < 0.017) were social engagement/withdrawal (p < 0.001), independence-performance (p = 0.008) and recreation (p = 0.008). In contrast, relatives showed significantly higher overall scores on the SFS than BPD patients (p < 0.001) and similar scores to the control group (p = 0.198). When the variable was categorized, likewise there was a significantly larger proportion of relatives compared to BPD patients with higher scores (p = 0.001).Bivariable analysis of the questionnaires among the three groups  and 4 shp < 0.001), followed by the relatives (0) and finally the cases . The SFS subscales of social engagement/withdrawal, interpersonal behavior, independence-competence, and prosocial activities, plus the full scale and the categorization, showed the same pattern, with the BPD group achieving lower scores than the relatives and the controls. However, the statistical differences (p < 0.05) were in: social engagement/withdrawal , interpersonal behavior , SFS full scale  and categorized SFS scores .The present study investigated social cognition and functioning in people with BPD, their healthy, first-degree relatives, and a group of healthy controls. Our results show that relatives of people with BPD show some alterations in social cognition; however, results were not statistically significant, so there is insufficient evidence to support that this is a characteristic feature of BPD. With regard to social functioning, first-degree relatives showed a significant deficit on the family relationships subscale compared to controls and BPD patients, and in social engagement/withdrawal and interpersonal behavior compared with patients. We observed similar results when assessing the SFS full scale, as both a linear and categorical variable.The main strength of our study is its novel nature; we did not find any other paper in the literature examining social cognition in first-degree relatives of people with BPD. In addition, the statistical power was over 95% for testing differences in means in the calculation of the sample size, which increases the precision of our results.To minimize selection bias, the sampling frame was the list of patients in the hospital coding database, not those attending the consult, as in previous studies . This isWe did not find any article that assessed social cognition in first-degree family members of people with BPD, although there are similar studies in other mental disorders, like bipolar disorder and schizophrenia, that have reported alterations. In the case of schizophrenics, their relatives did not show important deficits in social cognition, but they did show lower performance than the general population . These rOur results differ from those of other studies that have not found any diminishment of social cognition in people with BPD, for example, in With regard to social functioning, our results differ from We detected diminished social cognition skills in people with BPD, along with limitations in some domains of social functioning in both the people with BPD and in their first-degree relatives. These results could support development of interventions to reduce the deficits identified. In light of our findings, future studies are needed to determine whether a deficit in the domain of family relationships in healthy relatives influences the social functioning, social cognition, and/or the symptomology of people with BPD. Additional research is also needed to understand the pathophysiology of BPD, including the role of genetic and socioenvironmental factors.Our results show that healthy first-degree relatives of people with BPD present similar social cognition skills as healthy controls, with no genetic vulnerability related to BPD. The social cognition of people with this disorder demonstrates greater deficits in the form of overmentalization. Compared to patients, relatives showed significant differences in social functioning with regard to family relationships, social engagement/withdrawal and interpersonal behavior, and compared to controls, relatives showed differences in family relationships. Otherwise, social functioning is quite similar between relatives and controls, while people with BPD show lower social functioning across many domains.10.7717/peerj.10212/supp-1Supplemental Information 1Click here for additional data file.