Adult patients with atopic dermatitis (AD) present relatively higher rates of major depressive disorder (MDD). However, the underlying mechanism is largely unknown. Here, we first conducted a systematic literature-based data mining to identify entities linking AD and MDD, including proteins, cells, functional classes, and small molecules. Then we conducted an AD-RNA expression data-based mega-analysis to test the expression variance of the genes that were regulators of MDD. After that, a Fisher Exact test-based pathway enrichment analysis (PEA) was performed to explore the AD-driven MDD-genetic regulators’ functionality. We identified 22 AD-driven entities that were up-stream MDD regulators, including 11 genes, seven small molecules, three functional classes, and one cell. AD could exert a promoting effect on the development of MDD. Four of the 11 genes demonstrated significant expression changes in AD patients in favor of the development of MDD. PEA results showed that AD mainly drives cytokine/chemokine regulation and neuroinflammatory response-related pathways to influence the pathological development of MDD. Our results supported the promotion role of AD in the pathological development of MDD, including the regulation of multiple genetic regulators of MDD involved in cytokine/chemokine regulation and inflammatory response. Atopic dermatitis (AD), also known as atopic eczema, is long-term inflammation of the skin. AD is characterized by pruritic erythema lesions, commonly located in curved areas, face, and hands . AD is nThe relationship between AD symptoms and the prevalence of depression was reported, such as major depressive disorder . Major dAlthough there have been concerns about MDD among patients with AD, the underlying mechanism that AD promotes the development of MDD is largely unknown. Here, we hypothesize that the AD-driven molecule changes in patients may promote the development of MDD. We first conducted a systematic literature data mining to uncover connections between AD and MDD at different levels. Then, we performed a mega-analysis to test the expression levels of MDD regulators (genes) in the case of AD. At last, a gene set enrichment analysis was conducted to explore the functional profile of the genetic regulators of MDD that was also driven by AD. Our results enabled us to uncover functional networks and pathways that may partially explain AD’s influences on MDD.To explore the underlying mechanism of increased MDD risk for patients with AD, we first conducted a systematic literature-based data mining to identify entities linking AD and MDD, including proteins, cells, functional classes, and small molecules. Then we conducted an AD-RNA expression data-based mega-analysis to test the expression variance of the genes that were regulators of MDD. After that, we performed pathway analysis to explore the functionality of the AD-driven MDD-genetic regulators. We provide the workflow diagram of this study in https://supportcontent.elsevier.com/Support%20Hub/Pathway%20Studio/7680_Network_Builder.pdf. Then, following the same process, we identified the items that were regulated by AD. All relationships without polarity (positive or negative) were filtered out. Then the overlapped items were used to construct the network that connects AD and MDD. The definition of different entities and relationships within the network were presented in https://supportcontent.elsevier.com/RightNow%20Next%20Gen/Pathway%20Studio/2683_PS_QuickStartGuide_2020.pdf.Predominant molecular pathways and networks are becoming a common aid in inferring novel pathophysiological insights from changes in the levels of various biomolecules profiled in a high-throughput fashion . Here, aFollowing the initial search with ‘atopic dermatitis’, 103 microarray expression datasets were identified on gene expression omnibus (GEO).Homo sapiens.1) The organism used in the study was 2) The data type was microarray expression profiling.3) The studies were limited to a comparison between AD and healthy controls.4) The original data and the corresponding format file were downloadable.A total of nine datasets satisfied the mega-analysis’ inclusion criteria. We provided the information of these datasets in For the 203 genes that were upstream regulators of MDD see  using thThe heterogeneity of the mega-analysis was analyzed to study the variance within and between different studies. In the case that the total variance (Q) was equal to or smaller than the expected between-study variance (df), the within-study variance percentage (ISq) = 100% * (Q-df)/Q was set at 0, and a fixed-effect model was selected for the mega-analysis. Otherwise, a random-effects model was selected. Q-p represents the probability that the total variance was only due to within-study variance. The current study presented all the mega-analysis results identified in AD_MDD→Mega-analysis. All analyses were performed using Matlab  model was employed to investigate the possible influence of sample size, country of origin, and study date on the gene expression in the case of AD. p-value was used to determine the overlap between an input gene list and a GO term.To test the functional profile of the genes involved in the AD-driven MDD genetic regulators, a Pathway Enrichment Analysis (PEA) was conducted using Pathway Studio (version 12.1.0.16)Through large-scale literature data mining, we identified 18 AD-driven entities that were up-stream MDD regulators, as shown in Mega-analysis showed six genes presented significant expression changes in AD patients, as shown in Pathway Studio assisted literature data mining results showed that, among these genes that presented the significant expression variations in AD, the expression changes of four genes favored the development of MDD, as shown in p-value < 5.18E-5, q = 0.001 for FDR) are presented in p-value < 0.001) have been listed in The PEA was conducted to test the functional profile of the 11 genes identified in the AD-driven pathways in p-value: ; GO ID: 0002822; 0002819; and 0002700]. These pathways were previously implicated in the development of MDD  network, as shown in We also used HuRI (Human Reference Interactome) to explore the physical interactions of genes identified in both function networks , 3, as sIn this study, we integrated literature data mining results and RNA expression data-based mega-analysis results to construct functional networks revealing potential mechanisms underlying the MDD promoting-effect of AD. Our results showed that AD could influence multiple MDD regulators at different levels and drive cytokine/chemokine regulation and inflammatory response-related pathways that play important roles in the development of MDD.Literature data mining showed that AD could impact seven genes, seven small molecules, three functional classes, and one cell, which are upstream regulators of MDD. AD patients present accumulated inflammatory cells , which mAD patients demonstrated increased acetylcholine levels , while cAt the genetic level, there were 11 genes which have been shown as AD-driven regulators of MDD, including eight MDD promoters  and three MDD inhibitors , as shown in We also noted that the expression changes of the other two genes (CCL22 and CC2D1A) in AD patients might not favor the development of MDD. Therefore, further study is needed to test the genetic regulators of MDD in AD patients.PEA results showed that most of the AD-driven genes regulating MDD were enriched within cytokine/chemokine regulation and neuroinflammatory response-related pathways, as shown in Our study indicated that AD might drive multiple molecules that were implicated as upstream regulators of MDD, including genes involved in cytokine/chemokine regulation and inflammatory response.The original contributions presented in the study are included in the article/TY and XH developed the study design, analyzed the data, and wrote the original paper. 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.


The reference lists of these manuscripts were manually searched for additional studies. Twelve studies were included in the final analysis, seven of which have investigated the antimicrobial efficacy of SDF/KI, and the rest have examined the anti-staining potential of KI. The exploratory findings from the reviewed articles revealed the promising antimicrobial potential of SDF/KI on cariogenic microbes associated with dentine caries. There is, however, contradictory evidence on the effect of SDF/KI on tooth color. The reviewed in-vitro studies indicated significant effectiveness of KI in preventing staining. A clinical trial on primary dentition showed 25% reduction in the incidence of staining by SDF after applying KI, while a clinical study on root caries in adults showed no significant effect. Within the methodological limitations of this review, we conclude that for arresting dental caries, SDF could be combined with KI, as there may be a lower likelihood of staining. Further, well-designed clinical trials on the antimicrobial and anti-staining effect of SDF/KI are needed to obtain more robust evidence.Silver diamine fluoride (SDF) is used in minimally invasive dentistry for arresting dental caries. However, discoloration of teeth is a significant side effect that has limited the use of SDF. Hence, the application of potassium iodide (KI) following SDF has been proposed to ameliorate the staining. Although antimicrobial activity is one of the major mechanisms of the caries-arresting effect of SDF, the antimicrobial potency of SDF/KI combination is unclear. Thus, the primary objective of this systematic review was to appraise the studies on the antimicrobial efficacy of SDF/KI combination on cariogenic microbes. The secondary objective was to summarize the evidence on the potential of KI in reducing the discoloration associated with the application of SDF. Electronic databases of Medline via PubMed, Cochrane Library, Web of Science, and EBSCO host were searched for English language manuscripts from January 2005 to 15 Minimal Intervention Dentistry (MID), which emphasizes the critical importance of preserving the integrity of the natural tooth structure and adopts a biological approach in the management of caries lesions [The management philosophy of dental caries has gone through an evolutionary reckoning over the last century. Traditionally this process entailed a purely surgical “drill and fill” approach, with the G.V. Black cavity design and the “extension for prevention” paradigms as its cornerstone . However lesions –4. One s lesions , who des lesions –19 as we lesions –25.Sreptococcus mutans, Actinomyces naeslundii, Sreptococcus sobrinus and Lactobacillus acidophilus [S. mutans, S. sobrinus, Lactobacillus rhamnosus, L. acidophilus, and A. naeslundii on SDF-treated dentine samples [A primary mechanism of the caries-arresting effect of SDF is its microbicidal effect on cariogenic biofilm , 27. Labdophilus , 29. One samples .Candida species, silver ions bind to vital functional groups of cytoplasmic or membrane-bound enzymes, rendering them inactive [Pseudomonas aeruginosa, they inhibit cell division and damage cell envelope and cellular contents [The antimicrobial activity of SDF is mainly attributed to its elemental silver content. Historically, silver has been used as an antimicrobial compound in the treatment of ulcers . Today, inactive . In bactcontents . Additiocontents . Howevercontents .Despite such a convincing database on the antimicrobial efficacy of SDF in arresting dental caries, the clinical application of SDF has been rather limited to date. Although this may partly be due to the fact that SDF has not been formally licensed for the management of dental caries in many jurisdictions , the mai3PO4) [The staining that follows application of SDF is due to the precipitation of silver phosphate (Ag3PO4) , 43. To 3PO4) . This en3PO4) –47 have 3PO4)  observed−) in aqueous potassium iodide (KI) is under debate [Although iodine solutions have been used in the past as an antiseptic for managing wounds and wound infections , and iodr debate . On the r debate  have sugin-vitro and in-vivo evidence on the antimicrobial efficacy of SDF/KI on cariogenic microbes. Furthermore, several studies have demonstrated the aesthetic advantage of potassium iodide in preventing stains that ensue SDF treatment. Hence, our secondary objective was to summarize and appraise the available evidence on the efficacy of potassium iodide in reduction or prevention of the staining associated with SDF.To the best of our knowledge, no systematic review or meta-analysis on the antimicrobial efficacy of SDF/KI combination against cariogenic microbes has been conducted previously. Thus, the primary objective of this present study was to systematically review the th November 2020. Twelve studies were selected, seven of which have investigated the antimicrobial efficacy of SDF/KI, and five studies examined the anti-staining potential of KI following SDF application.Two investigators (AH and KSF) performed an electronic search of Medline via PubMed, Cochrane Library, Web of Science, and EBSCO host databases for English language manuscripts published between January 2005 and 15Two specific review questions were formulated using the PICO framework as follows:Does SDF/KI (I) have an effective antimicrobial action (O) compared to distilled water/saline/chlorhexidine (C) against cariogenic microorganisms (P)?Does the post-SDF application of KI (I) reduce or prevent staining (O) compared to water/no KI application (C) in carious lesions in primary and permanent dentition (P)?A particular search string was structured for each of the databases, which included the following search terms:Silver diamine fluoride AND (caries OR carious lesion OR biofilm) AND ; potassium iodide AND (caries OR carious lesion OR biofilm) AND ; silver diamine fluoride AND (potassium iodide OR KI) AND (staining OR discoloration); silver diamine fluoride AND .in-vitro, in-vivo, ex-vivo, in situ oral-biofilm model, asymptomatic dentine/dentinal caries, human dentine/dentin block of primary/permanent teeth, cariogenic microbe/bacteria, cariogenic yeasts/Candida/Candida species, SDF/SDF-KI antimicrobial effect (caries arrest), SDF/SDF-KI pre-post bacterial reduction (caries arrest), SDF/SDF-KI pre-post cariogenic, yeast/Candida/Candida species reduction (caries arrest)English language articles, dentine biofilm, in-vivo/in-vitro study design, human dentine/dentin blocks, dentine/dentinal caries lesion, post-SDF application of KI and stain reduction, post-SDF application of KI and stain reduction, qualitative/quantitative assessment of silver stain reductionEnglish language articles, Incomplete outcome data, bovine dentine, enamel caries, child or adult patient on an antibiotic, conference/poster presentation, abstracts, case reports, unpublished information/grey literature, opinion articles, scoping reviews, systematic reviews, umbrella reviewsIncomplete outcome data, bovine dentine, enamel, conference/poster presentation, abstracts, case reports, unpublished information/grey literature, opinion articles, scoping reviews, systematic reviews, umbrella reviewsThe combined antimicrobial effect of SDF/KI on dentine biofilm and the anti-staining potential of KI, post-SDF application on dentine caries.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines , 54 wereTo answer the clinically relevant question, a three-step approach of evidence-based analysis was employed. In stage one, two reviewers (AH and KSF) independently screened the studies’ titles and abstracts using the defined inclusion and exclusion criteria. In cases where it was challenging to gather sufficient information from an abstract, the full text was assessed for study validity and clinical importance. In the second stage, appraisal and selection of articles were performed by AH and KSF. In cases where there was disagreement between the reviewers, a third reviewer (HCN) was consulted. Finally, another reviewer (LPS) reassessed and validated the articles to be included in the review. A spreadsheet method was employed to extract information from the included studies and ensure that the eligibility criteria were met. At this stage, the studies’ reference lists were manually searched to identify potential additional studies that could be considered. The identified articles were compiled using a bibliographic software tool, Endnote version 9 .in-vitro studies have the lowest level of evidence due to the possible risk of “false-positive” results, lack of external validity, and generalizability to real clinical situations [in-vitro studies [in-vitro studies is somewhat similar, taking leads from the consolidated standards of reporting trials (CONSORT), we checked the transparency and quality of included in-vitro trials [In the third stage, the Cochrane Collaboration risk of the bias assessment tool  was usedtuations . However studies . Since to trials . Items sThe results of the included studies are summarized in Tables in-situ biofilms. Five participants were instructed to wear a maxillary intraoral appliance, each having six removable wells for biofilm collection, which were removed after 6 hours. The experiment was repeated three times for each participant, yielding 90 biofilm samples divided into the six test groups of 38% SDF, 31.3% SDF, KI, 31.3% SDF/KI, sterile distilled water, and 2% CHX. They found that KI did not have any antibacterial effect while both SDF and SDF/KI had potent antibacterial efficacy without any statistically significant difference between the two. Thus, they concluded that KI does not modulate the antibacterial efficacy of SDF.Abdullah et al.  tested tin-vivo study by Karched et al. [S. mutans and 90% reduction of total anaerobic bacteria in laboratory culture without any statistically significant difference between the two groups.An d et al.  evaluatein-vitro studies [S. mutans on dentin blocks prepared from extracted non-carious human teeth. Hamama et al. [S. mutans isolated from caries lesions. They demonstrated the antimicrobial potency of SDF/KI compared to control groups by counting the live/dead mass ratio of S. mutans in the dentinal tubules of the dentin blocks.Four  studies –64 have a et al.  utilizedS. mutans over the dentin disks placed over vials. Measurements of the optical density of the solution in the vials were taken. A lower optical density in the vials corresponding to dentin disks treated by SDF and SDF/KI compared to control groups was observed. They concluded that SDF and SDF/KI had significantly prevented the penetration of S. mutans into the dentin disks. In another trial, they examined the outer surfaces of dentin disks with scanning electron microscopy [S. mutans biofilm, whereas KI alone did not show this capacity.Contrastingly, the bacterial supply source in experiments by Knight and colleagues –64 is noS. mutans (ATCC) in tissue culture plates and measured the effects of SDF, SDF/KI, and KI on the biofilms by assessing the colony-forming units. Their findings indicated that all three groups of SDF, SDF/KI, and KI significantly reduced the viability of established S. mutans biofilms. However, SDF alone showed the most significant overall disruption of the biofilm.Vinson et al.  incubateTurton et al.  comparedThe effects of SDF/KI on arresting dental root caries, as well as on the aesthetic outcomes were investigated by Li et al., using a RCT on an elderly population . The stuZhao et al.  investigin-vitro anti-staining efficacy of KI on extracted carious primary molars. Teeth were photographed at baseline and regular intervals up to seven days after applying SDF or SDF/KI, and mean grey values (MGV) of the carious lesions were calculated. They demonstrated that MGV of lesions that had received KI was not statistically different from the baseline values. In contrast, with SDF application alone, the MGV of the lesions steadily decreased over time, indicating a gradual darkening of the lesion.Patel et al.  tested tex-vivo experiment on extracted human molars, unspecified whether they were from primary or permanent dentition. The samples were divided into ten different test groups, each receiving either SDF or SDF/KI treatment. Only two groups had teeth with existing caries, while the others had minimal decay. Six groups of non-carious teeth received different types of cavity preparations and restorative materials, and two groups received SDF and SDF/KI without any previous modifications. Color assessments were done at baseline and after four weeks with a colorimeter using the CIELAB system. They revealed that all groups with SDF/KI treatment, irrespective of whether they received a restoration or not, had minimal to no changes in the lightness value, resulting in no darkening as opposed to groups treated with SDF.Nguyen et al.  conductein-vitro studies in this systematic review mentioned whether a sample size calculation was conducted before the experiment. The RCTs on the anti-staining effect of KI [Having an appropriate sample size calculated based on sound assumptions is essential to ensure a high study power , 71. Nonct of KI , 67, stact of KI  and Abduct of KI  were alsLoss to follow-up can lead to the exclusion of patients from a clinical trial. Evaluation errors can result if data is analyzed without adjustment for the unequal loss of patients from the various treatment groups, as the lost patients may not be representative of the remaining patients in the study . The stup-value [p-values, thus creating difficulty in the precise interpretation of their clinical significance. In particular, Li et al. [The outcome of the study in each group should be reported with adequate statistical measures such as effect size and confidence intervals in addition to the p-value , 73. Thei et al.  communici et al.  did not Another limitation pertaining to the reviewed studies relates to the protocol of the application of KI. In a clinical study, the intervention must be replicable , meaningin-vitro and in-vivo studies on the antimicrobial efficacy of SDF/KI on plaque biofilm, and the effect of KI on prevention of tooth discoloration in primary and permanent dentition.Numerous clinical studies have shown that SDF is an effective caries-arresting agent –25. The in-vitro and clinical studies reviewed here clearly demonstrate that both SDF/KI, and SDF have potent anti-cariogenic activity. While it has previously been hypothesized that application of KI may reduce the antimicrobial efficacy of SDF by reducing the concentration of silver ions [All the ver ions , studiesver ions , 62, 64 ver ions  showed sin-vitro studies inevitably have shortcomings in their ability to replicate the complex intra-oral ecosystem. Five in-vitro studies [Streptococcus mutans. Nevertheless, the oral plaque microflora causing dental caries is a complex microbial consortium [Streptococcus mutans from human caries lesions to mitigate this problem, these are likely to exhibit pathogenic attributes that differ from natural, in-situ biofilms.The  studies –65 used nsortium . While Hnsortium  used a win-vitro study has thus far used a natural in-situ biofilm [in-vitro studies discussed above, is that the viability count of the biofilm flora was performed using real-time PCR, leading to the quantification of both the cultivable and uncultivable flora [A single  biofilm  to evalu biofilm . Anotherle flora .in-vivo clinical study by Karched et al. [in-vivo antimicrobial effect of SDF/KI. Moreover, novel methods such as next generation sequencing (NGS) [In contrast, the d et al.  analyzedd et al.  and Karcd et al.  is the sng (NGS)  could bein-vitro studies reviewed clearly imply that the application of KI to varying degrees prevented tooth discoloration associated with SDF [in-vitro studies evaluated the color of the lesions for periods of less than one month. In contrast, the reassessment of the lesions in the studies by Li et al. [in-vitro may have resulted in more significant dissociation of the silver iodide present.In general, the with SDF , 69. In with SDF  reportedwith SDF  recordedi et al.  and Turti et al.  was condi et al. . Althougi et al.  and Turti et al.  comparedin-vitro studies were also conducted under varying experimental conditions not mimicking the natural oral ecosystem, limiting their generalizability and extrapolation. Two of these studies [On the other hand, the  studies , 69 were studies  used an Furthermore, the RCTs , 67 alsoin-vitro study by Li et al. [In terms of color assessment of the SDF/KI treated teeth, it is noteworthy that the i et al.  subjectii et al. . Intra ai et al. . It has i et al. . Also, tin-vitro studies by Nguyen et al. [Additionally, Li et al.  only hadn et al.  and Zhaon et al.  used a cn et al. , 87. On n et al.  used a mFinally, it should be mentioned that one factor which can affect the antimicrobial efficacy and the aesthetic outcome of SDF/KI treatment is the amount of KI applied. As indicated in a study by Sorkhdini et al. , an excein-vitro and clinical studies in the present review have indicated the promising antimicrobial potential of SDF/KI against the cariogenic microflora in dentine caries.The available in-vitro studies on both primary and permanent teeth have indicated significant effectiveness of KI in preventing tooth staining. In contrast, a single clinical study on root caries in the elderly suggested no effect whatsoever. A clinical trial on primary dentition demonstrated 25% reduction in staining incidence by SDF after applying KI.There is contradictory evidence on the effect of SDF/KI on tooth color. All the reviewed However, it should be noted that there is a scarcity of studies on SDF/KI, and the manuscripts reviewed in this systematic review had numerous methodological limitations, as discussed previously. Further, well-designed clinical trials on the antimicrobial and anti-staining effect of SDF/KI are needed to obtain more robust data and address the gaps in our knowledge, particularly on the optimum therapeutic regimen of SDF/KI application for the management of dental caries.S1 Fig(TIFF)Click here for additional data file.S1 File(DOC)Click here for additional data file.


The increasing incidence of carbapenem-nonsusceptible Enterobacterales as major pathogens in healthcare associated infections (HAIs) is of paramount concern. To implement effective prevention strategies against carbapenem-nonsusceptible Enterobacterales (CnSE) HAIs, it is crucial to identify modifiable factors associated with these infections. We identified risk factors for CnSE-HAIs, and compared clinical outcomes of CnSE-HAI and carbapenem-sensitive Enterobacterales (CSE)-HAI patients.We conducted a multi-centre parallel matched case-control study in two 1700-bedded Singapore acute-care hospitals from 2014–2016. Patients with CnSE-HAIs and CSE-HAIs were compared to a common control group without HAIs (1:1:3 ratio), matched by time-at-risk and patient ward. Carbapenem nonsusceptible was defined as non-susceptibility to either meropenem or imipenem. Presence of healthcare associated infections were defined by the criteria provided by the European Centre for Disease Prevention and Control. Outcomes of CnSE-HAI and CSE-HAI patients were compared using multivariable logistic and cox regression; the models were adjusted for infection and treatment characteristics.Klebsiella spp. (63.8%). In the risk factor analysis, presence of drainage devices  and prior carbapenem exposure  independently predicted CnSE-HAIs. In the crude outcomes analysis, CnSE-HAI patients had higher all-cause in-hospital mortality and longer time to discharge compared to CSE-HAI patients. After adjusting for differences in receipt of antibiotics with reported susceptibility to the Enterobacterales, there was no significant difference in all-cause in-hospital mortality between the two groups . Time to discharge remained significantly longer in patients with CnSE-HAI  after adjusting for disease severity, receipt of antibiotics with reported susceptibility and receipt of appropriate source control.Eighty CnSE-HAI and 80 CSE-HAI patients were matched to 240 patients without HAIs. All CRE-HAIs patients had prior antibiotic exposure, with 44 (55.0%) with prior carbapenem exposure. The most common CnSE-HAIs were intra-abdominal infections (28.8%) and pneumonia (23.8%). The most common CnSE species was Appropriate management of deep-seated Enterobacterales infections and reducing exposure to carbapenems may reduce risk of CnSE-HAIs in Singapore. Efforts to improve antimicrobial therapy in CnSE-HAI patients may improve patient outcomes. Modern medical care has evolved with increasingly invasive procedures and complex patients. This has contributed to the risk of healthcare-associated infections (HAIs) . HAIs arAgainst severe HAIs caused by Enterobacterales, carbapenems are a class of broad-spectrum antibiotics typically used as last-resort option . HoweverIt has been estimated that approximately 20% to 70% of all HAIs are preventable . To estaA multicentre retrospective matched case-case-control study was conducted from 2014 – 2016 at a 1,700-bed tertiary and a 1,700-bed secondary acute-care public hospital in Singapore. The study was conducted in accordance to the methods for identifying risk factors for antimicrobial-resistant pathogens, detailed by Kaye E. coli, Enterobacter spp., and Klebsiella spp. were included as they were the most common Enterobacterales species associated with HAIs in Singapore  who acquired a HAI attributed to one or more microbiologically-confirmed CnSE. Only the first CnSE-HAI episode in the study period was included. The second case group consisted of adult inpatients (≥21 years old) who acquired a HAI attributed to one or more microbiologically-confirmed CSE. Patients who have both CSE- and CnSE-HAIs within a single admission were excluded from the second case group as inclusion of these patients in the second case group would have led to an overlap with patients in the first case group. Both CnSE-HAIs and CSE-HAIs were defined according to the European Centre for Disease Prevention and Control (ECDC) definition for HAIs; patients who did not meet the criteria for an active HAI as per ECDC were excluded from the study as they were deemed to be either community-acquired infection or colonised . The folingapore . Carbapeingapore . The twoAll data was sought from electronic medical records. Potential risk factors collected were: 1) patient demographics; 2) comorbidities (Charlsons co-morbidity index); 3) previous hospitalisations and length of stay; 4) previous admissions to intensive care unit (ICU) and ICU length of stay; 5) exposure to invasive devices , indwelling urinary catheters (IDCs), or drainage devices); 6) exposure to non-surgical invasive procedures; 7) exposure to surgical interventions; 8) exposure to surgical implants; 9) receipt of immunosuppressive therapy; and 10) receipt of antibiotics and duration . Receiptde novo genome assembly using SPAdes (v.3.11.1). STs were determined by performing a basic local alignment search tool (BLAST) search of the assembled contigs against multilocus sequence typing (MLST) database (https://pubmlst.org/databases/). The SRST2 software tool were used to detect acquired antimicrobial resistance genes using ARGannot database . Categorical susceptibility was determined according to the CLSI breakpoints . Whole gdatabase .Clinical outcomes were collected for the case groups. The primary outcome was all-cause 30-day mortality. The secondary outcomes were all-cause in-hospital mortality, and time to discharge after infection for all patients and for patients discharged alive from the admission from interest. To adjust for factors that may confound the outcomes, details pertaining to severity of infection [as determined by the Sequential Organ Failure Assessment (SOFA) score], infection type, receipt of antibiotic with reported susceptibility, and presence of source control were collected. Source control was deemed to be appropriate when devices associated with the infection of interest were removed, or when interventions were made to remove the infected tissue (e.g. amputation). Patients were deemed to have received appropriate antibiotics for the infection if at least one antibiotic with reported susceptibility to the Enterobacterales based on the 2017 CLSI guidelines was prescribed for ≥48 hours .All statistical analyses were performed using Stata 14.0 . Sample size calculations were informed by Klebsiella spp., 15 (18.8%) were Enterobacter spp., and 9 (11.3%) were E. coli. The demographics, comorbidities, prior healthcare and antibiotic exposure, and results of the univariate analysis are shown in rd/4th generation cephalosporins, carbapenems, fluoroquinolones, and aminoglycosides.A total of 80 patients with CnSE-HAIs and 80 patients with CSE-HAIs were matched to 240 patients with no HAIs. Out of 80 Enterobacterales in CSE-HAI group, 56 (70.0%) were Klebsiella spp., 13 Enterobacter spp., and 9 E. coli) were available for phenotypic and genotypic characterisation  and ST43 (n=4) being the most prevalent. CnS-Enterobacter spp. and CnS-E. coli belong to 10 and 8 different STs respectively, with ST93 (n=3) being the most prevalent for CnS-Enterobacter spp.The most common HAIs caused by CnSE were intra-abdominal infections , followed by respiratory infections  and skin and soft tissue infections . Out of the 80 patients with CnSE-HAIs, 23 (28.8%) were also identified as CRE carriers, by rectal swabs and/or stool samples. A total of 68 CnSE isolates . All-cause in-hospital mortality rates in CnSE-HAI patients were significantly higher in the crude comparison (40.0% vs. 23.8%); however, this difference was not observed after accounting for differences in the receipt of antimicrobials with reported susceptibility Table 4.This study investigated the predictors and outcomes of CnSE-HAIs in Singapore. We found that use of drainage devices and carbapenem exposure were associated with CnSE-HAIs in Singapore hospitals. Compared to patients with CSE-HAIs, patients with CnSE-HAIs had a higher crude rate of in-hospital all-cause mortality and longer length of stay. The observed higher in-hospital all-cause mortality rates appeared to be independently associated to the lower rates of receipt of antibiotics with reported susceptibility in CnSE-HAI patients.Studies on CRE risk factors, even when done in the same setting, can be challenging to compare. This is because subtle differences in design and definitions can cause findings to vary . In locaA key finding in our study is any prior receipt of carbapenems (as opposed to duration of carbapenem use) is significant risk factor for development of CnSE-HAIs. This is most likely associated with the selective pressure on the microbial environment upon carbapenem exposure. Carbapenems kills beneficial flora and susceptible bacteria while bacteria resistant to carbapenems survive, multiply and become predominant, predisposing the host to a greater risk of infection by carbapenem-resistant organisms . CurrentPrior use of drainage devices was another significant risk factor associated with CnSE-HAIs in our study. We postulate two possible explanations for this finding. Firstly, the drainage device could have acted as a portal of entry or source of infection, either from endogenous organisms present on the skin or exogenous bacteria from the environment. However, we believe that infections from the exogenous environment is less likely as most of the CnSE strains in our study were non-clonal, reducing the likelihood that development of CnSE-HAIs due to horizontal transmission from the environment. Endogenous infections from organisms present on the skin is also unlikely given that none of the other instrumentation/devices in our study were associated with increased risk of CnSE-HAIs. A second and more likely explanation is that the presence of drainage devices represents the presence of high microbial burdens at collection sites with limited antimicrobial penetration. This could have resulted in failure to eradicate the infection, leading to the selection of the resistant subpopulations present within the microbial collection .in vitro activity against the CnSE-HAI, especially in patients where existing comorbidities may have precluded the limited remaining effective antibiotic armamentarium (e.g. tigecycline cannot be prescribed to patients with severe hepatic dysfunction). Our results suggest that there is a need to evaluate the utility of new or resurrected agents such as ceftazidime (or aztreonam)/avibactam, imipenem/relebactam, meropenem/vaborbactam, plazomicin and intravenous fosfomycin as potential empiric therapy in patients with high risk of CnSE-HAIs in our local setting . However, our results here indicate a diversity of sequence types and carbapenemases, suggesting that CnSEs observed in our study is less likely due to clonal expansion. In our MSLT analysis, we were unable to conduct in-depth plasmid analyses to detect carbapenemase dissemination In conclusion, nosocomial infections caused by CRE constitute a significant clinical and public health threat due to their propensity for spread and limited treatment options . Our stuThe sequencing data has been deposited in the NCBI Sequence Read Archive (SRA) under study accession numbers PRJNA577535 and PRJNA751707.The studies involving human participants were reviewed and approved by SingHealth and National Healthcare Group ethics review board (CIRB/2016/2388). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.GH: Methodology, Investigation, Data curation, Writing – original draft. YC: Conceptualisation, Methodology, Formal analysis, Writing – review and editing, Project administration. YQ: Investigation, Data curation. JT: Resources, Writing – review and editing. SC: Resources, Writing – review and editing. TK: Resources Writing – review and editing. TL: Resources, Writing – review and editing. KM: Resources, Writing – review and editing. ON: Resources, Writing – review and editing. AK: Conceptualisation, Resources, Writing – review and editing, Supervision, Funding acquisition. All authors contributed to the article and approved the submitted version.This study was supported by the National Medical Research Council Centre Grant (NMRC/CG/M011/2017), the National Medical Research Council Centre Grant (NMRC/CG/C005B/2017), and the Singapore General Hospital Research Grant (SRG-AN#01/2016).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.


No study is available that explores the association of dietary phytochemical index (DPI) with glioma. The objective of the current study was to assess this association in Iranian adults.This hospital-based case-control study included 128 newly-diagnosed cases of glioma and 256 age- and sex-matched controls. Data collection on dietary intakes was done using a 123-item validated food frequency questionnaire. Calculation of DPI was done as /total daily energy intake ) × 100. Logistic regression models were used to examine the association between DPI and glioma.P = 0.06). After controlling for age, sex, energy intake, several demographic variables and dietary intakes, the association between DPI and glioma became strengthened .Individuals in the top tertile of DPI were more likely to be older and female. Before taking potential confounders into account, subjects in the top tertile of DPI tended to have a 40% reduced chance of glioma than those in the bottom tertile (OR: 0.60; 95% CI: 0.35–1.02, .High intakes of phytochemical-rich foods were associated with a lower risk of glioma in adults. High consumption of phytochemical-rich foods might be recommended to prevent glioma. However, further studies with a prospective design are needed to confirm our findings Glioma, the most prevalent brain tumor, refers to all tumors that are supposed to originate from neuroglial cells . About 7Earlier studies have reported some risk factors for glioma. For instance, farming was considered a high-risk job for glioma  because Detailed information about study design, inclusion and exclusion criteria of this hospital-based case-control study have been reported previously . BrieflyQualified cases for taking part in our project were those who met the following inclusion criteria (1) individuals with pathologically confirmed glioma with a maximum one-month interval after diagnosis of glioma, (2) aged between 20 and 75 years old. Controls were healthy subjects that had the same age and sex as cases.The following items were regarded as exclusion criteria: 1) being pregnant or lactating, (2) having a history of some disorders including cancer (only in control groups), neurological, gastrointestinal, hepatic, endocrine, immune, kidney and cardiovascular diseases in medical records, (3) being on special diets, which might result in changes in routine dietary intakes, (4) having any history of chemotherapy or radiation therapy, and (5) use of nitrosamine-enhancing drugs  to evaluate dietary intakes of subjects over the past year . Each paWe estimated DPI using McCarty equation :\documeThe phytochemical-rich foods we considered in the current study were as follows: Whole grains ; fruits ; vegetables ; soy products (soybean); nuts ; legumes ; olives; olive oil; natural fruit and vegetable juices . Potato, as a food item in the vegetable group, was not considered in DPI calculation due to its low content of phytochemicals.Detection of glioma was performed based on the pathological test ICD-O-2 and morphology codes 9380–948 . Glioma A pretested questionnaire including several variables of sociodemographic status such as age (years), gender , the status of marriage (married/unmarried), residence place , occupation (farmer/non-farmer), education (university graduated/non-university graduated) and family history of glioma and any other cancer (yes/no), a history of trauma, hypertension and allergy (yes/no), dealing with chemicals during the past ten years (yes/no), methods of cooking (barbecue/microwave/canned foods/fried foods), drug use (yes/no), use of hair dye (yes/no), cell phone use duration (years), exposure to the radiographic x-ray (yes/no); was applied to collect general information of participants. Measurement of participants’ physical activity was done using a short form of the International Physical Activity Questionnaire (IPAQ). Data from IPAQ were stated as Metabolic Equivalent per week (METs/week). Anthropometric measurements were quantified via standard methods. Considering weight and height, body mass index (BMI) was calculated for each participant.P-values was considered at < 0.05.All subjects were classified based on the DPI score into tertile ranges. The distribution of study participants in terms of general characteristics across tertiles of DPI was assessed using the Chi-square test. Differences in continuous variables across DPI tertiles were determined using one-way analysis of variance (ANOVA), followed by pairwise post hoc tests with Bonferroni correction. Binary logistic regression was used to evaluate the association of DPI with glioma. Age (continuous), sex , energy intake , physical activity (continues), family history of cancers (yes/no), family history of glioma (yes/no), marital status (yes/no), education (university graduated/ non-university graduated), high-risk occupation (farmer/non-farmer), high-risk residential area (yes/no), duration of cell phone use (continues), supplement use (yes/no), history of exposure to the radiographic X-ray (yes/no), history of head trauma (yes/no), history of allergy (yes/no), history of hypertension (yes/no), smoking status (smoker/non-smoker), exposure to chemicals (yes/no), drug use (yes/no), personal hair dye (yes/no), frequent fried food intake (yes/no), frequent use of barbecue (yes/no), canned foods and microwave (yes/no), dietary intakes of red and processed meat, fish, tea, coffee, sugar-sweetened beverages, egg, total fat, dietary fiber, cholesterol, calcium, SFA, folate, and selenium were adjusted in the multivariable-adjusted model. The selection of these confounders was made based on previous publications , 32–34. Table Cases and controls were not significantly different in terms of mean age, BMI and physical activity. The comparison of general characteristics of study participants across DPI tertiles revealed that individuals in the highest tertile were more likely to be physically active, use hair dye and drugs than those in the lowest tertile. A higher percentage of subjects in the highest category of DPI were married than those in the lowest category. Higher DPI was associated with older age and less frequent fried food intake. A lower percentage of individuals in the highest category of DPI were males. Subjects in the highest category of DPI had shorter cell phone use duration compared with those in the lowest category. No other significant differences were seen in terms of other general characteristics across tertiles of DPI Table .Table 2Table P = 0.06). After controlling for age, sex, energy intake, several demographic variables and dietary intakes, the association between DPI and glioma became strengthened . The Hosmer-Lemeshow goodness-of-fit test suggested an excellent calibration for the multivariable regression model .Crude and multivariable-adjusted ORs for glioma across tertiles of the DPI are presented in Table Our findings from this hospital-based case-control study revealed an inverse association between DPI and the odds of glioma after adjusting for a wide range of potential confounders. Although several studies have suggested fruits, vegetables, nuts and legumes as prophylactic agents with respect to the diet-glioma link , 35–37, Because nearly 90 % of glioma patients die within three years after detection, it stands among the most lethal malignancies in the world . TherefoIn the current study, subjects in the top tertile of DPI had 57% lower odds of glioma than those in the bottom tertile. Food groups that are considered phytochemical-rich sources have previously been investigated regarding glioma risk , 41, 42.Various mechanisms have been hypothesized linking phytochemical-rich foods with glioma. Anticancer property has been attributed to the main phytochemicals in these sources. It is well-known that oxidative stress is a process by which produced reactive oxygen species take part in glioma pathogenesis and antioxidant intake can prevent the development of glioma . PhytochSeveral strengths of the present study worth noting. To the best of our knowledge, this study is the first to examine the association between DPI and glioma risk. Adjustment for a wide range of potential confounders indicated an independent link between DPI and odds of glioma. In addition, cases were selected from newly-diagnosed glioma patients due to the possibility of altering their dietary habits after glioma detection. Finally, previous investigations proved the effect of energy intake on all foods and nutrients; therefore, energy-adjusted DPI was used to remove energy from other foods and nutrients. This can help reducing misclassification of study participants in terms of DRI. Limitations of our study include the following: (a) lack of containing all the dietary items of phytochemical-rich foods like spices in the DPI calculation, (b) the inherent limitations in the calculation of DPI; for instance, non-caloric phytochemical-rich foods like green and black tea were not included in the calculation. In addition, lack of differentiation between consumed phytochemicals’ type in DPI score, to elaborate, a diet with more legumes and nuts may have the same DPI score as a diet with more fruits and vegetables; therefore, the various quality of dietary phytochemicals among people with the same DPI score affects the risk of glioma differently, (c) the U.S. Department of Agriculture FCT was applied to calculate energy and nutrient intakes due to incompetence Iranian FCT, (d) the nature of case-control design with its inherent possibility of selection and recall bias would not allow us to confer causality, (e) using FFQ for dietary assessment results in misclassification which is unavoidable in epidemiologic studies, (f) lack of the use of molecular parameters along with tumors’ morphology to identify the tumors, and (g) as eating habits of Iranians are different from other countries in the world, the generalizability of our findings must be done cautiously. Although the results cannot be extrapolated to populations of other countries, it must be kept in mind that phytochemicals exist in various dietary sources. Based on the current study’s findings, taking these dietary components from any food source might help prevent glioma even in other populations.In conclusion, this case-control study’s findings indicate that a diet with a high amount of phytochemical-rich foods was associated with a lower odds of glioma in Iranian adults. Although our findings support the current recommendations of consumption of phytochemical-rich foods in the daily diet, it seems that adherence to popular diets that include high amounts of fruit and vegetables, including the Mediterranean diet or the vegetarian diets with low refined grains, potato products, hard liquors, added sugars and oils might help preventing glioma. Of note, the DPI of most current diets, especially in developed countries, would be unlikely to be as high as 20, which means that there would be quite ample room for improvement. Considering that such modification would result in increased intakes of potassium, fiber, vitamins, trace minerals and plant proteins and increase dietary phytochemical intake, the contribution of such diets to human health would be enormous.


Conclusion: Long-term tramadol analgesic use prior to breast cancer diagnosis might be associated with poor overall survival in patients with chronic pain compared with such patients that did not receive long-term tramadol analgesic treatment.Purpose: The impact of tramadol analgesic use before breast cancer diagnosis on survival in patients with chronic pain is unclear. Therefore, we designed a propensity score-matched population-based cohort study to compare the breast cancer-related survival of patients with chronic pain who received long-term tramadol analgesic treatment with that of those who did not receive such treatment. Patients and Methods: We included patients with chronic pain and categorized them into two groups according to their analgesic use, comparing their breast cancer-related survival; patients with breast cancer and chronic pain who were prescribed ≥180 defined daily doses (DDDs) of tramadol analgesics per year >3 months before breast cancer diagnosis comprised the case group, and those who were prescribed non-tramadol analgesics before breast cancer diagnosis comprised the control group. Patients in both groups were matched at a ratio of 1:5. Results: The matching process yielded a final cohort of 624 patients  who were eligible for further analysis. According to both univariate and multivariate Cox regression analyses, the adjusted hazard ratio for all-cause death in the case group compared with in the control group was 3.45 (95% confidence interval = 2.36–5.04;  Chronic pain is one of the most common reasons that patients seek medical attention . ChronicThere have been some conflicting data of tramadol use for non-cancer pain and cancer pain and all-cause mortality ,14,15,16Therefore, we conducted a head-to-head propensity score matching (PSM) study to clarify the tramadol use for non-cancer pain patients before cancer diagnosis. Our study could clarify the influence of survival in long-term tramadol analgesic users and nonusers for non-cancer pain patients who would have breast cancers in the future. The long-term tramadol analgesic use for chronic pain patients before breast cancer diagnosis might be associated with survival impact in breast cancer patients based on the previous conflicting data ,8,9,10. From the Taiwan Cancer Registry database (TCRD), we identified patients with chronic pain who had received a diagnosis of breast cancer between 1 January 2008, and 31 December 2017. The index date was the date of breast cancer diagnosis. The follow-up duration was from the index date to 31 December 2019. The study protocols were reviewed and approved by the Institutional Review Board of Tzu-Chi Medical Foundation (IRB109-015-B). Data from the cancer registry database of the Collaboration Center of Health Information Application, which contains detailed cancer-related information regarding pathological types, cancer stages, and treatments, were also used ,19,20.Inclusion criteria were a diagnosis of chronic pain, aged >20 years, receiving analgesics, and having breast cancer without metastasis. Chronic pain was defined as originating from one of the following: osteoarthritis : 715), spinal disorders , peripheral vascular diseases (ICD-9-CM: 443.8–444.9), osteoporosis (ICD-9-CM: 733.0), gout (ICD-9-CM: 274), headache , diabetic neuropathy , rheumatoid arthritis (ICD-9-CM: 714), pressure ulcer (ICD-9-CM: 707), or herpes zoster (ICD-9-CM: 053). The exclusion criterion was a history of cancer before diagnosis of breast cancer. Long-term tramadol analgesia use was defined as use of tramadol on most days for >3 months with a mean tramadol dose of ≥180 defined daily doses (DDDs) per year ,22. PatiAfter adjustment for confounders, we used a time-dependent Cox proportional hazards model to model the time from the index date to all-cause death for patients with chronic pain and breast cancer. To reduce the effects of potential confounders when comparing all-cause death between the long-term tramadol analgesic user and nonuser groups before breast cancer treatments, participants were matched based on propensity scores. The matching variables used were sex, age, comorbidities, income levels, urbanization, menopausal status, Human Epidermal Growth factor Receptor-2 (HER2) status, nodal surgical types (sentinel lymph node biopsy or axillary lymph node dissection), American Joint Committee on Cancer (AJCC) clinical stage, hormone receptor status, breast surgical types , differentiation of tumor, chemotherapy, and adjuvant radiotherapy. Definition of clinical cancer stages in our study was based on the clinical AJCC, 7th Edition for breast cancer stages. Comorbidities were determined according to ICD-9-CM codes in the main diagnosis of inpatient records or if the number of outpatient visits was ≥2 within 1 year. Comorbidities onset at 12 months before the index date were recorded. Continuous variables are presented as means ± standard deviations or medians , where appropriate. Hormone receptor positivity was defined as ≥1% of tumor cells demonstrating positive nuclear staining through immunohistochemistry , and HERp < 0.05 was considered significant. Overall survival (OS) was estimated using the Kaplan–Meier method, and differences between the long-term tramadol users and nonusers were determined using the stratified log-rank test to compare survival curves (stratified according to matched sets) .,45.44,45The strength of our study is that it is the first long-term follow-up cohort study to estimate the primary endpoint of OS for patients with chronic pain receiving tramadol analgesia and non-tramadol analgesia before they received a breast cancer diagnosis. The covariates between the groups in the study were homogenous for patients with chronic pain, and no selection bias was identified through PSM . No otheThis study has some limitations. First, because all patients with cancer were enrolled from an Asian population, the corresponding ethnic susceptibility compared with the non-Asian population remains unclear; hence, our results should be cautiously extrapolated to non-Asian populations. However, there is no evidence to demonstrate significant differences in oncologic outcomes for breast cancer survivors between Asian and non-Asian patients. Second, the diagnoses of all comorbid conditions were based on ICD-9-CM codes. Nevertheless, the Taiwan Cancer Registry Administration randomly reviews charts and interviews patients to verify the accuracy of the diagnoses, and hospitals with outlier chargers or practices may be audited and, subsequently, heavily penalized if malpractice or discrepancies are identified. Accordingly, to obtain crucial information on population specificity and disease occurrence, a large-scale randomized trial comparing carefully selected patients undergoing tramadol analgesia use and non-tramadol analgesia use before breast cancer diagnosis should be carried out. Nevertheless, it is very difficult to perform this kind of RTC to estimate the effects of tramadol use for patients without breast cancer. Finally, the TCRD does not contain information regarding dietary habits or body mass index, all of which may be risk factors for OS. Despite these limitations, a major strength of this study is the use of a nationwide population-based registry with detailed baseline information. Lifelong follow-up was possible through the linkage of the registry with the national Cause of Death database. Considering the magnitude and statistical significance of the observed effects in the current study, the limitations are unlikely to affect our conclusions.Long-term tramadol analgesia use before breast cancer diagnosis might be associated with a reduction in OS for patients with chronic pain compared with non-tramadol analgesia use. Although some studies have demonstrated the survival benefits of postoperative short-term tramadol use for patients with breast cancer, physicians should consider the risk of mortality when prescribing long-term tramadol analgesic use for chronic pain, especially in patients at a high risk of breast cancer.


Anorexia nervosa (AN) is associated with structural brain abnormalities. Studies have reported less cerebral tissue and more cerebrospinal fluid (CSF) in individuals with AN relative to healthy controls, although findings are variable and inconsistent due to variations in sample size, age, and disease state . Further, it remains unclear if structural brain abnormalities observed in AN are a consequence of specific brain pathologies or malnutrition, as very few longitudinal neuroimaging studies in AN have been completed.To overcome this issue, this comprehensive meta-analysis will combine region-of-interest (ROI) and voxel-based morphometry (VBM) approaches to understand how regional and global structural brain abnormalities differ among individuals with AN and healthy controls (HCs). Additionally, we aim to understand how clinical characteristics and physiological changes during the course of illness, including acute illness vs. weight recovery, may moderate these structural abnormalities. We will create an online database of studies that have investigated structural brain abnormalities in AN. Data will be reviewed independently by two members of our team using MEDLINE databases, Web of Science, PsycINFO, EMBASE, and CINAHL. We will conduct ROI and VBM meta-analysis using seed-based d mapping in AN and HCs. We will include all studies that include structural neuroimaging of individuals with AN (both acute and weight-recovered) and HCs between January 1997 and 2020.This systematic review will assess the effects of AN compared to HC on brain structure. Futhermore, it will explore the role of acute AN and weight-recovered AN on brain structure. Findings will help researchers and clinicians to better understand the course of illness in AN and the nature of recovery, in terms of weight, malnutrition, and the state of the brain.CRD42020180921PROSPERO The online version contains supplementary material available at 10.1186/s13643-021-01799-y. Anorexia nervosa (AN) is a severe and lethal psychiatric disorder, with a mortality rate of 10% . AlthougPrevious meta-analyses investigating structural brain changes in AN from 2010 to 2018 demonstrate that individuals with AN have lower grey –16 and wPresently, there are two common methods to investigate structural brain changes in AN: voxel-based morphometry (VBM) and region-of-interest (ROI). VBM is a coordinate-based approach that surveys the entire brain to examine regional changes in volume. The ROI approach focuses on specified regions-of-interest only. The small number of meta-analyses in AN to date have focused on studies using a VBM approach. VBM approaches are effective in summarizing consistently reported peaks, but tend to ignore nonsignificant data. To circumvent this challenge, new Seed-based Mapping (SDM) methods  allow for the inclusion of 3D-statistical maps to increase accuracy. To date, only one meta-analysis has used SDM-effect size in acute AN  and no mA meta-analysis utilizing ROI and VBM image analysis to examine grey matter in individuals with actute AN and individuals who are weight-recovered will provide an opportunity to increase statistical power. This meta-analysis will differ from previous meta-analytic work, which restricted investigation to only one of these measurement approaches. For the purposes of this study, we will be looking at individuals with acute AN vs. weight-recovered AN (rather than including other definitions of recovery). This will help uncover which brain regions may be most sensitive to weight loss. We would expect regions most sensitive to weight-loss  to be remitted in those with weight-recovered AN because most other medical complications of AN remit with weight restoration . On the This comprehensive meta-analysis of grey matter imaging studies comparing AN to control subjects will aim to answer the following questions: (1) How do global and regional structural brain abnormalities differ between individuals with acute AN versus healthy controls (HC), weight-recovered AN versus HC, and acute AN vs. weight-recovered AN? (2) How do clinical characteristics and physiological differences moderate structural brain abnormalities in individuals with AN and weight-recovered AN? To answer these questions, we will (1) collectively analyze key findings from all structural volumetric studies comparing AN to HC using both ROI and VBM and (2) use meta-regression analyses to explore key neuroradiological, study quality, demographic, clinical, and metabolic variables to explore potential moderators of the cross-sectional effects detected. We will include sub-group analyses to compare those with AN to HC and AN to weight-recovered AN cross-sectinoally. We will also compare those with weight-recovered AN individuals to HC, to make inferences on the site and timing of cortical grey matter changes in AN.The proposed systematic review will be reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), and this protocol was reported in accordance with the PRISMA guidelines for systematic review protocols (PRISMA-P). This meta-analysis has been registered in PROSPERO.This review will consider structural magnetic resonance imaging (MRI) studies that include participants with acute AN, weight-recovered AN, and/or healthy controls. Since AN is more prevalent in females than males , we willThis review will consider both experimental and observational studies that report data on cross-sectional and longitudinal structural MRI in individuals with acute AN and weight-restored AN, compared to healthy controls. Studies will be included only if they were published in English. Studies will be included from 1997 to the present, because this represents the timeframe in which structural MRI has been applied to study anorexia nervosa , 24.We will initially identify articles using MEDLINE databases. A literature search for papers related to structural neuroimaging in anorexia nervosa will be conducted using the RISMED package in R  searching for the terms “MRI” and “anorexia nervosa” in the ProQuest Dissertations and Theses electronic database, and (2) emailing requests for unpublished or in-press studies over prominent listservs in the clinical psychology and clinical neuroscience communities . We will conduct this final search method to address the potential misrepresentation of population effect sizes due to the greater likelihood that significant (vs. nonsignificant) findings will be accepted for publication .Two review authors will independently extract data. Discrepancies will be identified and resolved through discussion with a third reviewer. Missing data will be requested from study authors via email.We will record the following data: (1) sample size , (2) diagnostic classification system used , (3) participant demographics , (4) participant clinical characteristics , type of treatment (if in treatment), duration of illness, mean score from eating disorder symptom measures given , lowest reported weight, highest reported weight, and type of control group used, (5) medication information  MRI acquisition .We aim to expand on prior work using a VBM approach by using a technique called SDM . SDM is 1) How do global and regional structural brain abnormalities differ between individuals with acute AN versus healthy controls (HC), weight-recovered AN versus HC, and acute AN vs. weight-recovered AN? We will conduct a voxel-based and regional meta-analysis to probe differences in grey matter between individuals with acute AN and HC, weight-recovered AN and HC, and acute versus weight-recovered AN. Statistical analyses will be performed using random-effects inverse-weighted variance models. Subgroup analyses will be conducted where there is sufficient data to investigate. Where statistical pooling is not possible, the findings will be presented in narrative form including tables and figures to aid in data presentation, where appropriate. We will conduct sensitivity analysis to test how robust our results are relative to variations in meta-analytic method, using effect sizes and Hedges’ g for each brain region in our analyses for ROI and VBM. To reduce the number of comparisons in the ROI analysis, we will focus on brain regions that are significantly different from those of control subjects in either the acute-AN or weight-recovered-AN meta-analysis.I2 tests. For continuous outcome measures, we will use Hedges’ g ([Effect sizes will be expressed as either odds ratios (for dichotomous data), weighted, or standardized final post-intervention mean differences (for continuous data), and their 95% confidence intervals will be calculated for analysis. Heterogeneity will be assessed statistically using the standard chi-squared and dges’ g  How do clinical characteristics and physiological differences moderate structural brain abnormalities in individuals with AN and weight-recovered AN? Meta-regression will be employed to explore the potential effects of clinical characteristics, neuroradiological, and study quality. To reduce type I errors, we will select clinical variables based on key clinical questions as well as the availability of the variables in the studies. The following moderators will be considered: duration of illness, age of onset, body mass index (BMI), amount of weight gain from treatment , levels of depression, shape and weight concerns, body image, restriction severity, drive for thinness, frequency of binge and purge behaviors, percentage of females, and percentage of medicated participants. To explore the effects of neuroradiological techniques, we will consider the following variables: MRI slice thickness, image smoothing level, MRI field strength (Tesla), and inclusion of motion correction.To assess whether the findings in our analysis will be related to different presentations of extreme restrictive eating: AN binge/purge subtype and AN restricting subtype AN, we will complete a supplementary set of meta-analyses in subjects based on diagnostic categories. These subgroup analyses will be exploratory in nature and will be completed to generate hypotheses to be tested in new primary studies. We will use diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5). Table Our proposed method includes VBM and ROI analysis to reduce risk of bias. We will compare results from the VBM and ROI analysis to assess agreement, which has broader implications for neuroimaging meta-analysis of other disorders and has not been done in eating disorders. VBM and ROI results often differ for the following reasons: (1) VBM involves smoothing, which biases sensitivity to brain regions dependent on the size of the kernel, (2) ROI analyses only report on a subset of brain regions and are likely to be impacted by publication bias, (3) SDM (used for VBM studies) uses coordinate data; thus, the effect size is biased toward zero in brain regions where there are no significant clusters, and (4) VBM adjusts for total global brain volumes, whereas ROI studies use absolute volumes.We anticipate that some studies will report measures from subgroups of patients and matched controls. For example, studies may compare short-term versus long-term recovery. We will incorporate these results in the meta-analysis as two different studies, which is consistent with other meta-analyses , 15. As The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for grading the certainty of evidence will be followed to assess estimates of relative risk and a ranking of the quality of the evidence based on the risk of bias, directness, heterogeneity, precision, and risk of bias of the review results.Our comprehensive meta-analysis will provide a detailed summary of structural brain abnormalities and their associations with clinical variables in AN and weight-recovered AN.Findings from this eventual meta-analysis should be considered in light of some limitations. First, our findings will be limited by the fact that we are only able to include studies published in English, as we do not have study team members who are native speakers of other languages. Second, due to power considerations, we anticipate that we may not be able to examine all subgroups of interest. Nonetheless, this study will provide more precise insight into structural brain changes in AN that are most sensitive to weight loss versus those that may be more sensitive to psychological disturbances of the illnesses.Additional file 1. R code describing our search of MEDLINE databases.


Despite evidence that stress relates negatively to cognitive functioning in older adults, little is known how appraisal of stress and socioeconomic meso-level factors influence different types of cognitive functions in older adults. Here, we assess the relationship between perceived stress  and a battery of cognitive functions, including prospective memory in 1054 older adults (65+). A moderator analysis assessed whether this relationship varies with neighborhood socioeconomic status using an area-based measure of Socioeconomic Position (SEP). Perceived stress was associated with worse processing speed, verbal fluency, and inductive reasoning. The perceived self-efficacy subscale of the PSS is related to better performance in these measures. Higher self-efficacy was also associated with better prospective memory; this relationship was more pronounced for people with high neighborhood SEP. These findings indicate that not only do perceived stress and perceived self-efficacy relate to cognitive functioning in older age but also that neighborhood SEP is a moderator of this relationship. Evidence from experimental studies indicates that stress modulates cognition, with the brain being most sensitive to stress during childhood and older age ,2. As suThereby, the effects of stress on cognition vary depending on the appraisal of stressful events and the type of cognitive function under study ,11. ApprConcerning the type of cognitive function, memory performance in episodic or semantic memory tasks relates negatively to the PSS sum score ,22. In cStress-related effects on an additional cognitive domain, prospective memory, have only recently received more attention. Prospective memory refers to the capacity to remember to carry out an intended action at an appropriate point in the future while being engaged in an ongoing activity ,24. As sHence, the first aim of our study was to examine the relationship between perceived stress and cognitive performance in a comprehensive battery of cognitive tests, including prospective memory, testing a large sample of older adults. Hereby, we aimed to replicate previous findings showing that perceived stress, particularly the PSS-PW self-efficacy subscale, relates to multiple domains of cognitive functioning. Furthermore, we examined how perceived stress relates to prospective memory.In a recent conceptual framework on life course stress effects and vulnerability in old age, we suggested that (cognitive) vulnerability in older age may stem from a lack of sufficient reserves across multiple domains, notably including social and economic resources . In thatMore recently, it was argued that important additional information is captured when meso-level context factors are taken into account, and socioeconomic position (SEP) is assessed at a community or area level . Indeed,2 = 0.032, similar to previous studies examining the relationship between perceived stress and cognitive functions [The Vivre–Leben–Vivere study is a large interdisciplinary survey of the life and health conditions of older adults living in Switzerland ,44,45. Tunctions , with 80All participants provided written informed consent before participation. The study protocol was in accordance with the Declaration of Helsinki and was approved by the local ethics committee.Perceived Stress was assessed with the 4-item version of the Perceived Stress Scale (PSS). The PSS measures how stressful individuals appraise situations in their life that occurred during the previous month . The 4-iFace-to-face interviews assessed cognitive functioning with the Mini Mental State Exam, the Trail Making Test Part A and B (TMT A and TMT B), prospective memory, and the six subtests of the Cognitive Telephone Screening Instrument (COGTEL) ,49.The Mini Mental State Exam assesses global cognitive functioning and is commonly used as a screening tool for cognitive impairment .The Trail Making Test (TMT) consists of two parts, which measure processing speed (TMT A) and cognitive flexibility (TMT B). For TMT A, participants were instructed to connect a sequence of numbers from 1 to 25 as fast as possible without errors, after practicing the task once with a sequence from 1 to 8. To measure cognitive flexibility with TMT B, participants were given one practice trial alternating connecting numbers and letters, i.e., connecting 1-A-2-B-3-C-4-D. They were then instructed to alternate in connecting the numbers 1 to 13 in ascending and the letters A to L in alphabetic order, i.e., 1-A-2-B-3-C until 12-L-13, without making any error .Prospective memory was assessed with four event-based tasks, i.e., a task in which the execution of the intended action is triggered by the presentation of a specific external target event. At the beginning of the interview, the experimenter instructed the participants to be unsolicited (1) say red pen at the time of the interview that the interviewer talked about a red pen, (2) knock twice on the table when the interviewer talked about physical activities, (3) tell the interviewer the year of birth when talking about activities in the course of the participant’s life, and (4) remind the interviewer to switch on their mobile phone at the end of the interview.The COGTEL assesses verbal short-term and long-term memory, working memory, verbal fluency, inductive reasoning, and prospective memory.For verbal short-term and long-term memory, participants learned four pairs of un-related words read aloud for 3 s each. After a short break, the experimenter cued the participants with the first words, in a different order than the word pairs had been learned. Participants recalled the second pair of words in the following 5 s (short-term memory scores ranging from 0 to 4) . For corWorking memory was assessed with the backward digit span test of the WAIS-R . ParticiVerbal fluency was assessed with a letter fluency and a category fluency task . ParticiInductive reasoning was assessed with a subtest of the WAIS-R : ParticiAs an indication of socioeconomic position, we used the Swiss neighborhood index of socioeconomic position (Swiss-SEP). The Swiss neighborhood SEP is an area-based measure of socioeconomic position based on data on income, education, occupation, and housing conditions obtained from the 2000 census and provided by the Swiss National Cohort (SNC) . The SwiMean scores and standard deviations were computed for age, years of education, perceived stress , and all cognitive tests. Two-tailed t-tests specified whether the subgroup of participants that underwent the COGTEL differed from the one-third of participants that did not undergo the COGTEL. Bivariate correlations between age, education, perceived stress, and all domains of cognitive functions and neighborhood SEP were computed. Linear regression analyses were performed separately for the PSS-PW subscale, the PSS-NW subscale, and the total PSS scales as independent variables, and the different cognitive measures as the dependent variable. All regression analyses controlled for age, sex, and years of education. Last, we examined whether the relationship of perceived stress  on cognition varied as a function of socioeconomic position. To do so, we followed the guidelines by Hayes and used the PROCESS macro in SPSS to test for moderation effects . SpecifiThe sample is described in Authors should discuss the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted.p < 0.001), higher values of PSS sum score (p < 0.001), PSS-NW subscale (p < 0.01), and lower values of the PSS-PW scale (p < 0.001). Years of education correlated positively with all measures of cognitive functions (p < 0.001) other than TMT A short-term and long-term memory . Higher education was related to a lower PSS sum score (p < 0.05) and a higher score on the self-efficacy scale (p < 0.05).Age and education correlated significantly with perceived stress and cognitive functions. In particular, higher age was correlated with lower cognitive functioning . The total score of the PSS correlated negatively with performance in the COGTEL tests for working memory, inductive reasoning, verbal fluency, and prospective memory, but negatively with performance in TMT A and TMT B. Similarly, the PSS-NW scale was correlated negatively with COGTEL tests for inductive reasoning and verbal fluency, but positively with TMT A and B. In contrast, the PSS-PW scale was correlated positively with Mini-Mental State Exam scores and all cognitive measures of the COGTEL , except for short-term memory (p = 0.065), but negatively with TMT A and TMT B  and PSS-PW were correlated with neighborhood SEP , but not PSS-NW scale (p > 0.05). Neighborhood SEP was correlated with the Mini-Mental State Exam , working memory , and prospective memory , but no other cognitive variables .In addition, PSS sum score  and the cognitive tests of COGTEL and TMT.This population-based cross-sectional study examined how perceived stress (PSS questionnaire) relates to cognitive functioning in older adults (>65 years). Perceived stress was related to decreased global cognition assessed with Mini-Mental State Exam, slower processing speed/flexibility assessed with TMT, and poorer verbal fluency and inductive reasoning assessed with COGTEL. These results were mainly driven by lower perceived self-efficacy . In particular, the PSS-PW scale was positively related to global cognition, verbal fluency, inductive reasoning, and reduced processing speed. Furthermore, perceived self-efficacy was positively related to prospective memory. Importantly, neighborhood socioeconomic position (SEP) moderated the relationship between perceived self-efficacy and prospective memory. Perceived self-efficacy had a more pronounced positive impact on prospective memory in people with high neighborhood SEP than those with low and medium neighborhood SEP.The finding of an association between perceived stress and global cognition, processing speed, and verbal fluency in old adults is consistent with previous findings ,19,20,58p < 0.001). This finding is in accordance with previous findings [Considering the two subscales of the PSS, we found that the perceived self-efficacy subscale PSS-PW and the perceived helplessness subscale PSS-NW were moderately correlated , although SEP and self-efficacy were not strongly correlated . A potential explanation for our novel finding that perceived self-efficacy and prospective memory was moderated by neighborhood SEP is that adverse socioeconomic neighborhood conditions are less likely to enable older adults to have sufficiently frequent experiences of successful coping with stressful events, especially in relation to cognitive challenges under stress, which would allow building up of higher levels of self-efficacy. This might be of particular significance for prospective memory tasks, in which the challenge is to self-initiate an intended action at the right target moment without being prompted by the experimenter. With a build-up of higher self-efficacy through high neighborhood SEP, these participants might have more successfully coped with the key challenge of a prospective memory task .Interestingly the relationship between perceived self-efficacy and prospective memory was moderated by neighborhood SEP: The positive relationship between perceived self-efficacy and prospective memory was only reliable for older adults with high neighborhood SEP, while this relationship was eliminated in older adults with low and medium neighborhood SEP. A link between perceived control and socioeconomic status was well-established in previous studies, with people with higher socioeconomic status displaying higher perceived control ,60,61. SFuture studies should test whether improving perceived self-efficacy in older age could be a means of reducing perceived stress, especially in the lower SEP groups, and thus maintaining prospective memory function. Such an intervention may potentially be effective, given that previous studies have demonstrated that experimental interventions can result in changes in one’s perceived level of control, suggesting that perceived self-efficacy is modifiable . Other sA limitation of the present study is that we took cross-sectional data from the Vivre–Leben–Vivere 2 survey. As such, we are unable to determine the causality for the relationship between perceived stress and cognitive function. In addition, only one measure of perceived stress was acquired. The PSS questionnaire assesses stress perceived within the month prior to the survey but does not ask for intensity or duration of stressors. Consequently, we are not able to assess the relationship between chronic stress and cognitive function, nor cognitive decline. In addition, our effects are small to moderate, yet in a similar range as previous findings ,5,20. DeOur data from a large population-based sample provides important scientific evidence for an association between perceived stress/perceived self-efficacy and cognitive functioning in older adults. For our prospective memory, this relationship is moderated by neighborhood SEP. Understanding how perceived stress/perceived self-efficacy is related to cognition is crucial for future interventions studies that should test whether altering perceived stress/perceived self-efficacy levels could help to prevent cognitive decline, an issue of major individual and public health importance.


This study aimed to track development assistance for trauma care (DAH-TC), uncover funding trends and gaps, and compare DAH-TC to development assistance for other health conditions.A systematic search of the OECD Creditor Reporting System (CRS) and Development Assistance Committee (DAC) databases was performed to capture projects related to trauma care. Reports from large foundations and public-private partnerships were also searched. DAH-TC was described, and comparisons were made between DAH-TC and other health conditions.The search yielded 1754 records; after applying exclusion criteria, 301 records were included for analysis. During the 25-year period, US$93.7M of DAH-TC was disbursed to low- and middle-income countries (LMICs) . Contributions were dominated by a few donors and fluctuated dramatically over time. A sizable portion of DAH-TC came in the form of investments to build infrastructure (38% of DAH-TC); information and research activities (17%); and training (16%). Nearly US$58M (62% of DAH-TC) was funneled to projects that targeted victims of war. Trauma care received US$0.04 per DALY incurred, while malaria, TB, HIV and MCH received US$9.62 per DALY, US$25.09 per DALY, US$4.05 per DALY and US$45.75 per DALY, respectively.DAH-TC is critically underfunded, particularly compared to other health foci. To improve the DAH-TC landscape, stakeholders can better mobilize domestic resources; use advocacy more effectively by catalyzing network convergence, grafting trauma care onto related high-priority issues, and seeking broader coalitions; and develop partners within the donor and channel communities to promote strategic DAH-TC disbursements. Nearly five million people die from injury each year, and tens of millions more are left with disability; nearly 90% of this burden occurs in low- and middle-income countries (LMICs) . DespiteDevelopment assistance represents financial and in-kind contributions by donors  to recipient LMICs . Monies Much is known about the DAH landscape in general, and for high profile global health conditions  . HoweverTo address the lack of DAH-TC landscape data and promote transparency around global health funding, this study aimed to track DAH-TC, uncover funding trends and shortfalls, and compare DAH-TC to development assistance for other high-profile global health conditions, both in absolute terms and relative to disease burden. We hypothesized that DAH-TC will have a vulnerable financial landscape  and have markedly less DAH compared to other high-profile global health conditions, both in absolute terms and relative to disease burden.Financing Global Health 2015 Report [A systematic search of the Institute of Health Metrics and Evaluation (IHME) Financing for Global Health 2015 DAH Database (IHME DAH Database), which draws from the Creditor Reporting System (CRS) and Development Assistance Committee (DAC) databases of the Organization for Economic Cooperation and Development (OECD), was performed to capture all OECD-reported projects related to trauma care, and their corresponding financial disbursements from 1990-2015 (most recent database update) , Emergen5 Report .All records retrieved by the keyword search underwent a fully-crossed review by two independent coders  to target only projects related to trauma care and to exclude irrelevant records – namely, projects focusing on non-trauma emergency care, system-wide approaches, psychosocial trauma or injury prevention. Although the importance of injury prevention is recognized, it was excluded here as the related development assistance involves a number of non-health sectors with established DAH funding streams that are only partially represented in health funding databases. Records of DAH-TC before 1990 were excluded since the CRS was not well established until that year, as were projects with an unclear description. For any non-English entries, Google Translate  was used to translate project descriptions. Any discrepancies were resolved by a third reviewer (BS), and the overall inter-rater agreement was less than 5%.Using project descriptions, identified trauma care projects were categorized into various themes  and sites where the intervention occurred along the trauma system  related to trauma care from 1990 to 2015. After screening, only 301 records were related to trauma care (Seventy percent of DAH-TC flowed through a channel (Fifty-seven countries received DAH-TC (The most sizable portion of DAH-TC (38% of DAH-TC) came in the form of investments to build infrastructure . The next largest target categories were information and research  followed by human resources and training  at 17% and 16% of total DAH-TC, respectively. Nearly US$58M (62% of DAH-TC) was funneled to projects that targeted victims of war. Notably, war incurs only 3% of the global injury burden.DAH-TC constitutes only a small fraction of total DAH  is critically underfunded, and far from commensurate to the disease burden attributable to injury, particularly when compared to other high-profile global health foci. Second, the donor and channel landscapes are sparse, creating vulnerability to temporal economic trends  or shifts in donor priorities. Third, current DAH-TC appears tied to geopolitical priorities, instead of being driven by the health burdens of populations in need and the limited resources currently available to address them in LMICs.Although DAH-TC increased nearly 900% between 1990 and 2015, this generally followed the overall trend in DAH, and remains grossly inadequate relative to the anticipated costs of trauma care capacity improvements needed in LMICs . FurtherDomestic financing has increased in many countries with high burdens of injury, and in many cases, is no longer inconsequential compared to DAH . TherefoSuccessful examples of domestic resource mobilization for health sector improvements exist. El Salvador raised tax revenues a total of 4% of GDP between 2005 and 2013 and used that increased revenue to cut child mortality by 75% through sustainable system-wide improvements . SimilarHowever, additional domestic resources will continue to be unavailable for some LMICs and inadequate for many others. Therefore, dramatic increases in DAH-TC will be necessary to meet global demand and will require substantial advocacy efforts to alter the funding portfolios of donors. As is often the case when dealing with overlooked issues, advocacy and politics will become all the more important in crafting an improved agenda. Brief examination into the ways in which maternal and child mortality became a global health priority, through the lens of Schiffman and Smith’s policy framework, is useful for considering approaches to advocate for improving trauma care . Early aThe DAH-TC donor and channel landscape is sparse compared to other global health foci; as a result, DAH-TC is particularly vulnerable to temporal economic trends and shifts in donor foreign or development policy. As an example, the 2008 global financial crisis significantly impacted DAH. In the two years preceding the crisis, DAH grew by 17% per year; DAH grew only 4% per year from 2009 to 2011 . FurtherAlthough war and collective violence are small contributors to the global burden of injury, 62% of DAH-TC flowed to recipients in conflict. This highlights the geopolitical drivers of DAH, and again demonstrates the importance of a diverse donor landscape to damper the effects of shifting geopolitical and developmental policy . CertainAlthough this study provides an understanding of the DAH-TC landscape, several limitations merit discussion prior to interpreting the results. First, there may have been projects that indirectly result in improvements to trauma care that were not included due to our search criteria. However, we used a broad and widely inclusive list of keywords generated from landmark documents and guidelines in the realms of global health and trauma care. Given that the majority of the records retrieved by the search were excluded due to not being related to trauma care and due to the fact that the entire disbursement amount was counted for any tagged trauma care projects , it is more likely that our search was over-inclusive . Second,DAH-TC is critically underfunded and receives a disproportionately low amount of funding compared to other global health foci with smaller burdens of disease. Additionally, the limited donor and channel landscape creates vulnerability with regard to economic trends and changing developmental policy. To improve trauma care in LMICs and the DAH-TC landscape, stakeholders might:Work with LMIC governments to mobilize domestic resources to bolster DAH-TC and foster national ownership of trauma care;Use advocacy more effectively by catalyzing network convergence, identifying related issues, and seeking partners both in and beyond the health sector; andSeek partners within the donor and channel communities to provide and direct more strategic DAH-TC disbursements.