As pan-genome approaches are largely employed for bacterial comparative genomics and evolution analyses, but still difficult to be carried out by non-bioinformatician biologists, there is a need for an innovative tool facilitating the exploration of bacterial pan-genomes.Anaplasmataceae strains .PanExplorer is a web application providing various genomic analyses and reports, giving intuitive views that enable a better understanding of bacterial pan-genomes. As an example, we produced the pan-genome for 121 http://panexplorer.southgreen.fr. The source code has been released in a GitHub repository https://github.com/SouthGreenPlatform/PanExplorer. A documentation section is available on PanExplorer website.PanExplorer is written in Perl CGI and relies on several JavaScript libraries for visualization . It is freely available at  In the past decade, the pan-genome concept has been largely employed to investigate the bacterial comparative genomics and evolution analyses . Many prhttps://github.com/nconrad/hotmap), MauveViewer (https://github.com/PATRIC3/mauve-viewer), CircosJS (https://github.com/nicgirault/circosJS), MSAViewer (The application takes a list of GenBank identifiers as input and the server will execute successively: (i) retrieval of the corresponding published complete genome sequences and their annotations, (ii) gene clustering and pan-genome analysis using PGAP . The PanAs a presence/absence variation (PAV) matrix  using thThe physical map of core-genes and strain-specific genes can be displayed as a circular genomic representation , for eacThe conservation of gene order between genomes can be investigated using two graphical representations . A Hive PanExplorer offers the possibility to focus on any cluster of the pan-genome, and get access to its composition in terms of protein or DNA sequences, to their alignment using Muscle . This exThe application allows to reduce the PAV matrix after the selection of a subset of strains from the original collection of genomes (e.g. for focusing on one species or one particular phenotype), which finally results to a different list of genes defined as core-genes.PanExplorer offers broad-spectrum of tools for easily exploring pan-genomes for scientists without programing skills . Thanks to a connection to NCBI ftp server, the application guarantees an up-to-date availability of public genomes, to be analyzed on-the-fly, and represents a versatile tool for genome exploration filling a need for bacteriologist community. Among perspectives and further development, new functionalities might be implemented shortly such as online pan-Genome Wide Association Studies (pan-GWAS) based on Scoary software (


The status of epidermal growth factor receptor (EGFR) mutation is a critical signal for the treatment strategies of patients with NSCLC. Higher response rates and prolonged progression-free survival could be obtained in patients with NSCLC harboring EGFR mutations treated with tyrosine kinase inhibitors (TKIs) when compared with traditional cytotoxic chemotherapy. However, patients with EGFR mutation treated with TKIs inevitably develop drug resistance, so predicting the duration of resistance is of great importance for selecting individual treatment strategies. Several semiquantitative metabolic parameters, e.g., maximum standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), measured by PET/CT to reflect 18F-FDG metabolic activity, have been demonstrated to be powerful in predicting the status of EGFR mutation, monitoring treatment response of TKIs, and assessing the outcome of patients with NSCLC. In this review, we summarize the biological and clinical correlations between EGFR mutation status and 18F-FDG metabolic activity in NSCLC. The metabolic activity of 18F-FDG, as an extrinsic manifestation of NSCLC, could reflect the mutation status of intrinsic factor EGFR. Both of them play a critical role in guiding the implementation of treatment modalities and evaluating therapy efficacy and outcome for patients with NSCLC.PET/CT with  In 2020, it was estimated that there were approximately 228,820 newly diagnosed lung cancer cases and 135,720 deaths from lung cancer in the United States . In addi18F-2-fluoro-2-deoxyglucose (18F-FDG) has been widely used for pretreatment staging and restaging, monitoring treatment response, and evaluating prognosis for patients with NSCLC (max), total lesion glycolysis (TLG), and metabolic tumor volume (MTV), have been demonstrated to be promising PET/CT indices to reflect the metabolic activity and/or tumor burden  for patients with NSCLC  of the primary tumor was more likely to have EGFR mutations in NSCLC  and phosphorylated to 18F-FDG-6-phosphate by hexokinase (HK). It is trapped inside cells and dephosphorylated slowly because 18F-FDG-6-phosphate is not a substrate of glycolysis or pentose phosphate pathway (PPP) and is unable to diffuse outside cells  were determined to obtain a relatively high receiver operating characteristic (ROC) curve area   , 24, 50.ype EGFR . The comaccuracy , 51.18F-FDG  in NSCLC EGFR-mutant patients was significantly higher than that of wild-type patients  but also based on radiomics of PET/CT. The combination of clinical features, laboratory results, conventional PET/CT parameters, and PET/CT radiomics would provide higher accuracy in predicting EGFR mutation status. However, there are still many contradictory reports, so 18F-FDG PET/CT should be used with caution when predicting EGFR mutations in patients with NSCLC. More prospective cohort studies are needed to further verify the role of 18F-FDG PET/CT in predicting EGFR mutations.In short, detection of EGFR mutation status in NSCLC plays a major role in the daily management of individual patients, especially in the selection of TKI targeted therapy. Most patients with NSCLC develop late in the course of the disease, which is inoperable , 71. The18F-FDG PET/CT, a molecular and functional imaging method, has emerged as a powerful ability in diagnosing, staging, and evaluating outcomes for patients with NSCLC  for classification , 77. Howth NSCLC . In addied NSCLC –85.18F-FDG PET/CT could be used to monitor response , SUV3Dpeak (3D peak SUV), SUVA50 , SUVA41 , SUV50 , MTV, and TLG; these parameters have been demonstrated to be useful in monitoring response for patients with TKI-treated NSCLC  classification is a measure to specify the disease extent for patients with NSCLC and plays a vital role in choosing a treatment strategy . 18F-FDGth NSCLC . PatientIn the past two decades, EGFR is a well-known predictive marker of outcome for patients with NSCLC who were treated with TKIs . TKIs ha18F-FDG PET and high-resolution CT in predicting the prognosis for patients with clinical stage-IA NSCLC has been assessed, which showed that SUVmax of the primary tumor and ground-glass opacity ratios on high-resolution CT images were significant prognosticators of these patients, which should be kept in mind before selecting therapeutic strategies  and late (6 weeks) 18F-FDG PET/CT scans after initiation of erlotinib therapy  on 18F-FDG PET/CT can be used to reflect metabolic activity and tumor burden. EGFR mutation status, as an intrinsic factor, plays a vital role in guiding the implementation of treatment modalities  and evaluating therapy efficacy and outcome for patients with NSCLC. Significant correlations are observed between 18F-FDG metabolic activity and EGFR mutation status, not only in biology but also in clinical practice. However, at present, there is still a lack of comprehensive evaluation of the association between 18F-FDG PET/CT and EGFR mutations in patients with NSCLC, e.g., using 18F-FDG PET/CT to predict EGFR mutation status and then monitor treatment response and evaluate the outcome, which needs to be carried out simultaneously in a large sample retrospective or prospective study.In summary, the MJ and JJZ were responsible for the conception of this review. All authors contributed to the article and approved the submitted version.This work was supported by the Medical Scientific Research Foundation of Zhejiang Province, China (Grant no. 2021KY1014), Research Foundation of Hwa Mei Hospital, University of Chinese Academy of Sciences, China (Grant no. 2022HMKY27), Ningbo Public Service Technology Foundation, China (Grant No. 2021S176), and Medical Science and Technology Project of Ningbo, China (Grant no. 2020Y10), Ningbo Clinical Medical Research Center of Imaging Medicine (Grant No. 2021L003), and Provincial and Municipal Co-construction Key Discipline of Medical Imaging (Grant No. 2022-S02).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.


Background: Tight junctions are transmembrane proteins that regulate the permeability of water, solutes including ions, and water-soluble molecules. The objective of this systematic review is to focus on the current knowledge regarding the role of tight junctions in atopic dermatitis and the possible impact on their therapeutic potential. Methods: A literature search was performed in PubMed, Google Scholar, and Cochrane library between 2009 and 2022. After evaluation of the literature and taking into consideration their content, 55 articles were finally included. Results: TJs’ role in atopic dermatitis extends from a microscopic scale to having macroscopic effects, such as increased susceptibility to pathogens and infections and worsening of atopic dermatitis features. Impaired TJ barrier function and skin permeability in AD lesions is correlated with cldn-1 levels. Th2 inflammation inhibits the expression of cldn-1 and cldn-23. Scratching has also been reported to decrease cldn-1 expression. Dysfunctional TJs’ interaction with Langerhans cells could increase allergen penetration. Susceptibility to cutaneous infections in AD patients could also be affected by TJ cohesion. Conclusions: Dysfunction of TJs and their components, especially claudins, have a significant role in the pathogenesis and vicious circle of inflammation in AD. Discovering more basic science data regarding TJ functionality may be the key for the use of specific/targeted therapies in order to improve epidermal barrier function in AD. Atopic dermatitis (AD) or atopic eczema is an inflammatory pruritic dermatosis with long-standing course and relapses. Allergic rhinitis, food allergy, and asthma are Th2-driven atopic comorbidities of AD. AD affects up to 20% of children and up to 14% of adults with variations in different ethnicities and geographical regions . This reThis systematic review has been performed using the PRISMA guidelines for Systematic Reviews and Meta-Analysis 2020 checklist. Literature indexed from 2009 to 2022, describing the role of tight junctions in atopic dermatitis, was searched. We identified eligible studies using the following inclusion criterion: (1) written in English. The exclusion criteria were: (1) articles focused on other diseases, such as psoriasis or ichthyosis vulgaris, in which AD was merely mentioned; (2) articles whose full-text version was not available to us; and (3) articles written in a language other than English. We performed the literature search between 2009 and 2022 in the PubMed, Cochrane Library, and Google Scholar databases, using the following terms: “atopic dermatitis” OR “atopic eczema” AND “tight junctions” OR “claudins”. Two authors individually reviewed the database search results, assessing the titles, evaluating the abstracts, and considering or not the study for full review. Any disagreements in either the title/abstract or the full manuscript review phases were resolved by consensus. All eligible studies were evaluated and included in this systematic review .TJs are connection structures between cells that exist in simple, multi-layered epithelia and endothelia, and consist of transmembrane proteins (claudins (Cldns), junctional adhesion molecule A (JAM-A), TJ-associated marvel proteins (TAMP) (occludin (Ocln), and tricellulin) and TJ plaque proteins  ,5 Figur.Tjs are present in human skin, as well as in other human epithelia, such as the small intestine and blood–brain barrier. Tjs are located between endothelial cells of the cerebral microvasculature in the blood–brain barrier, controlling the homeostasis of the central nervous system. Alterations in the functionality of Tjs could lead to neurological disorders . In the Tight junctions in the human epidermis are composed of sets of continuous intramembranous strands, as has been revealed by freeze-fracture replica electron microscopy studies, and are found directly below the SC on opposing membranes of granular layer corneocytes ,9. They Cldns family proteins include 27 members , and oclThe expression of cldn-4 is high in the SG between the four levels of the epidermis, and is regulated by ΔNp63, a p53 family transcription factor, which plays a key role in epithelial differentiation. In healthy human epidermis, ΔNp63 and cldn-4 expression are inversely correlated. Distinct types of cldns and other TJ-associated molecules are expressed in all epidermis layers. Nevertheless, an effective TJ form is found only in SG, where cldn-4 is more prominently expressed .Functional TJs are also found in hairy skin and form an effective seal between the hair and the dermis all around the keratinized club hair. TJs in human anagen hair follicles (HF) form barriers that are less dense than the scalp and cheek epidermal barriers. TJ proteins in the infundibulum and isthmus of club HF and in the outer root sheath surrounding the club hair shaft, are located in the outermost epithelial layer. Functional TJs also exist in the external layers of the outer root sheath and circle the club hair close to the keratinous rootlets. The removal of extracellular calcium leads to TJ opening and to disruption of the HF barrier. Cldn-1 is more abundant than other TJ proteins in anagen and club HF, and its expression in HFs is crucial for the HF barrier functionality and for hair growth . A TJ stTJ-regulated permeability also affects the selective diffusion of molecules from deeper layers to the surface of the barrier. Injecting a 557 Da molecular weight tracer subcutaneously in a rat model of normal and cldn-1-deficient mice revealed that the tracer could only pass through TJs to the skin surface in the cldn-1-deficient mice. This supports the hypothesis that Tjs control the paracellular movement of multiple molecules and in multiple directions within the barrier .TJs contribute to many cellular functions, such as differentiation, polarity, proliferation and signaling cascade processes . Their rDysfunctional TJs contribute to irregular function of the skin barrier in AD. Disrupted TJs appear to impede SC formation through an increase in the SC potential of hydrogen (pH), failure to mature lamellar structures, and degradation of keratohyalin granules. Damaged TJ barriers can affect the processing of polar lipids and profillagrin by disturbing the pH condition of SC . The TJ Studies show that hereditary or acquired cldn-1 defects can be seen in AD subjects . A studyCldn-1 has been suggested to control AD features time- and dose-dependently . A reducIn AD, cldn-1 is downregulated in both lesional and non-lesional skin. However, cldn-1 downregulation is not observed in healthy skin. Downregulation of cldn-1 has been reported to be caused by inflammation and the degree of downregulation is analogous to the density of the inflammatory infiltrate in the lower and upper levels of the epidermis . De BeneImpaired TJ barrier function and skin permeability in AD lesions is correlated with cldn-1 levels . Cldn-1 Regarding ZO-1, reduced synthesis is found in non-lesional and lesional AD skin . Cldn-1 TJ damage is significant in the vicious cycle of itching and scratching. Scratching has also been reported to decrease the cldn-1 expression without affecting ZO-1 or ocldn expression, and to increase Akt phosphorylation in AD . The ErkP63 is a regulator with multiple roles in cutaneous development and differentiation, including regulation of the junction complexes between cells within the epidermis. In AD, p63 is overexpressed and this is related to pruritus, dry skin, and high IgE. P63 can directly lead to the activation of IL-31 and IL-33, which are the main components of Th2 inflammation . The ΔNpHost defense peptides, or antimicrobial peptides, are involved in various biological procedures, such as chemotaxis promotion, the production of cytokines and chemokines, dendritic cell and macrophage differentiation, neutrophil and epithelial cell apoptosis, pro-inflammatory response suppression, angiogenesis, and wound healing induction. Cathelicidin LL-37, human β-defensins, and S100 protein psoriasin (S100A7) participate in skin defense. In skin, keratinocytes and neutrophils transport LL-37 when they infiltrate infected or wounded skin. Normally, the expression of LL-37 is scarcely detectable in keratinocytes. On the other hand, during infection or injury, its production is strongly increased. Human cathelicidin LL-37 is overexpressed in lesional psoriasis, but decreased in lesional AD. It has been found that LL-37 selectively increases the expression and membrane distribution of TJ proteins and is involved in enhancing TJ barrier function through the activation of aPKC, Rac1, GSK-3, and PI3K signaling pathways. Thus, in addition to its antimicrobial and immunomodulatory activities, LL-37 contributes to skin immunity through regulation of the skin barrier function .AD patients are more vulnerable to cutaneous infections than non-AD patients. Widespread HSV-1 infections may be associated with a reduced cldn-1 expression and a subsequently destroyed TJ function . VirusesS. aureus than normal skin. This colonization leads to reduced functionality of coagulase-negative staphylococci, which are part of the normal skin microbiota spectrum and exert a protective effect against pathogens. S. aureus expresses proteins that contribute to epidermal barrier dysfunction and superantigens that promote pro-inflammatory cytokine production [S. aureus, the TJ barrier function increases. Later, however, the TJ barrier function decreases. This biphasic effect causes TJ protein relocation but not quotative TJ protein level alterations [AD skin is significantly more colonized by oduction . Howeveroduction . Normallerations .Dendritic cells (DCs) are white blood cells that mediate antigen presentation and protection against microbes. Langerhans cells (LCs), which are a DCs’ subclass, function in the human epidermis beneath the TJ barrier, establishing a complex system. Activated LCs have dendrites that invade into the TJs of the healthy human epidermis . During TJ activity changes depending on the external environment, showing a dynamic management in order to protect against the invasion of external microorganisms . AlthougS. aureus is strongly associated with skin inflammation in AD [Langerin is a type of pattern recognition receptor and more specifically a C-type lectin receptor that is expressed only in LCs and takes part in host defense against many viruses, fungi, and bacteria. Dendrites of activated LCs present Langerin in AD skin, while DCs do not . Langerion in AD .Inflammation, especially Th2 inflammation, inhibits the expression of important cldns (cldn-1 and cldn-23). A negative correlation exists between epidermal cldn-1 expression and markers of Th2 polarity . Th17 ceThe literature suggests that several agents could exert pharmacological modification of TJs. Spirodela polyrhiza extract (SPE) and OLE (Olea europaea leaf extract) have positive effects on AD symptoms. Treatment with both OLE and SPE as a combined mixture has been reported to improve pruritus and epidermal hyperplasia, stabilize the immune response , reduce the levels of IgE and histamine, and restore skin barrier function (up-regulation of expression of skin barrier proteins) . AquaphiAs more data on TJs role in AD become available, unanswered questions to be further investigated emerge. The effect of filaggrin expression downregulation on TJs functionality is an area that needs further investigation. Exploring the crosstalk between TJs and the immune system is also on the forefront of current research. Developing topical agents that improve TJ functionality, among other action modes, is an emerging therapeutic field. Pivotal clinical trials now include genomics data, which might help to illuminate basic unanswered science questions on AD pathogenesis, including the potential of TJs.TJs in AD is an emerging subject in the literature. This means that the publication of new data could possibly change our current knowledge as presented in this review in the near future. In addition, only literature written in English was considered. As a result, literature written in another language may have been skipped.


Background: Obesity, and in particular extreme obesity, as a global health problem is an important risk factor for many diseases, including atherosclerotic cardiovascular disease (ACVD). Bariatric surgery might stop or slow atherogenesis by decreasing excessive weight in the early stages of atherogenesis, by suppressing low-grade systemic inflammation as well as by inhibiting oxidative stress and endothelial dysfunction. The aim of this meta-analysis was to provide an answer to whether bariatric surgery has a significant effect on intima-media thickness (IMT) which is a surrogate marker of early atherosclerosis and has a good correlation with atherosclerotic coronary heart disease. Methods: A systematic literature search in PubMed, Scopus, Embase, and Web of Science as well as grey literature was performed from inception to 1 July 2022. The meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V3 software. Overall, the estimate of effect size was measured by a random effects meta-analysis. To account for the heterogeneity of studies regarding study design, characteristics of the populations, and treatment duration, a random-effects model (using the DerSimonian–Laird method) and the generic inverse variance weighting approach were used. To assess the existence of publication bias in the meta-analysis, the funnel plot, Begg’s rank correlation, and Egger’s weighted regression tests were used. Results: The meta-analysis of 30 trials, including 1488 subjects, demonstrated a significant decrease in IMT after bariatric surgery. The reduction in IMT was also robust in the leave-one-out sensitivity analysis. It must be stressed that the results of the random-effects meta-regression did not suggest any relationship between the changes in IMT and delta body mass index (BMI) or duration of follow-up after the bariatric surgery. However, the subgroup analyses showed a better IMT reduction after laparoscopic sleeve gastrectomy (LSG) when compared to Roux-en-Y gastric bypass (RYGB). Within a year, the IMT follow-up values showed a further improvement. Conclusions: Bariatric surgery significantly reduced IMT. Significant associations were found between the surgery type and IMT changes, as well as a significant effect of follow-up duration on the changes of IMT after bariatric surgery. Almost all countries are witnessing a pandemic of overweight and obesity with a devastating trend, which is best illustrated by the fact that obesity has nearly tripled since 1975. In 2016, more than 1.9 billion adults aged 18 years and older were overweight and 3% of the world’s population, or more than 650 million people, were obese with an increasing prevalence ,5,6,7,8.No matter how it is achieved, weight reduction decreases the risk of ACVD, cardiovascular events, as well as cardiovascular and total mortality. Bariatric surgery is a surgical treatment, which is used primarily for patients who are severely obese to decrease their excessive weight. The types of bariatric surgery are sleeve gastrectomy (SG), laparoscopic adjustable gastric band (LAGB), Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion/duodenal switch (BPD/DS), and one anastomosis gastric bypass/mini gastric bypass (OAGB/MGB) . There aMeasuring intima-media thickness (IMT), particularly carotid IMT (CIMT), by ultrasonography is considered to be a surrogate marker of early atherosclerotic changes in the arteries. This could help to improve the prediction of cardiovascular events in different arterial territories because of the positive correlation between increased IMT and atherosclerotic changes in coronary arteries, i.e., with coronary heart disease (CHD) ,18,19,20Following bariatric surgery, several cardiovascular-related risk factors can be improved, including insulin resistance, type 2 diabetes, hypertension, and hyperlipidemia; however, it is worth mentioning that these improvements are not the only effect of weight loss ,22. SincSince the data concerning the effects of bariatric surgery on IMT are conflicting, the aim of this systematic review and meta-analysis is to provide a clear answer as to whether bariatric surgery can decrease IMT or not.The 2009 preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines were used to prepare this systematic review and meta-analysis . PubMed,All studies investigating the effects of bariatric surgery on carotid intima media thickness (CIMT) were included, based upon our pre-determined inclusion criteria. Case studies, non-English studies, reviews, and animal studies were not considered. A study had to provide documented CIMT data before surgery and after a post-operative observation period to be included in this meta-analysis. This systematic review and meta-analysis was not registered in any registry.All titles and abstracts were separately screened by two authors (TJ and MA). When there was a disagreement concerning the eligibility of a study, the paper was examined collaboratively, and a decision was reached. Study characteristics  were extracted from each study.The Newcastle–Ottawa Scale (NOS) was used to estimate the quality of the studies included in this meta-analysis ,28. ThisThe meta-analysis was performed using Comprehensive Meta-Analysis (CMA) V3 software  . The weiTo investigate the association between BMI change and follow-up duration after surgery with the estimated effect size, these parameters were included into a random-effect meta-regression model.A subgroup analysis was completed to describe heterogeneity, and to further characterize outcomes for the type of surgery and follow-up period.p-value non-significant was determined using the “fail-safe N” approach as another evidence of publication bias [The funnel plot, Egger’s weighted regression, as well as Begg’s rank correlation tests were used to examine the presence of publication bias in the meta-analysis. The “trim and fill” approach was used to insert potentially missing studies when there were indications of funnel plot asymmetry. In the case of a significant result, the number of potentially missing studies needed to make the ion bias .Among 356 published studies identified by a systematic databases search, 173 were directly related to the topic of this study. In total, 143 studies were excluded after careful evaluation . Therefore, 30 studies which evaluated IMT after bariatric surgery were included . Figure In cohort studies, although most of the selected studies ,58,59,60p < 0.001)  A. The re< 0.001) B. In othp = 0.670) or duration of follow-up    A,B.p < 0.001). The improvement of IMT in patients who had laparoscopic sleeve gastrectomy (LSG) surgery was better than in those who had Roux-en-Y gastric bypass (RYGB). Furthermore, a significant effect of follow-up duration on the changes of IMT after bariatric surgery was observed with further improvement in IMT in the follow-up period of less than 12 months . The subgroup analyses demonstrated significant associations between surgery types and IMT changes  suggested that publication bias existed in the meta-analysis concerning the effect of bariatric surgery on IMT, Begg’s rank correlation test  did not indicate the presence of publication bias. The trim and fill test showed three “missing” studies in order to adjust publication bias. The “fail-safe N” test showed that 39 missing studies would be needed to reduce the effect size to a non-significant (p < 0.001) level  level .The results of this meta-analysis of 30 trials, including 1488 subjects, showed a significant decrease in IMT after bariatric surgery, and the reduction in IMT was also robust in the leave-one-out sensitivity analysis. It must be stressed that the results of the random-effects meta-regression did not suggest any relationship between the changes in IMT and delta BMI or duration of follow-up after the bariatric surgery. However, the subgroup analyses showed significant associations between the surgery types and IMT changes and a significant effect of follow-up duration on the changes of IMT after bariatric surgery.One important question which might theoretically influence the results of this meta-analysis is a sex difference in obese subjects concerning IMT. However, this issue was clarified in a recent study showing that IMT was significantly higher in men than in women but this difference disappeared after adjustment for covariables, such as waist circumference, age, HDL-cholesterol, and mean arterial blood pressure . It has As already mentioned, it has been previously shown that obesity is associated with thicker arterial walls, i.e., increased IMT which seems to be independent of other cardiovascular risk factors ,63. It hSimilar to our meta-analysis, a previously published small meta-analysis showed a significant reduction in IMT after bariatric surgery and indicated that the percentage of changes in BMI were associated with changes in IMT . The resThe present study has some limitations. Perhaps the most important one is the fact that until relatively recently there was a lack of IMT measurement standardization  which could influence the predictive value in CHD risk estimation in different studies; therefore, this might also have an impact on the results of this meta-analysis . In addiThe results of this meta-analysis suggest that bariatric surgery significantly reduced IMT. Since increased IMT reflecting early structural atherosclerotic changes in patients with severe obesity seems to be independently associated with ACVD, the results of this study may have clinical implications for individuals with severe obesity and high cardiovascular risk. This suggests a beneficial antiatherosclerotic effect of bariatric surgery. Future prospective studies with a precise follow-up, bigger sample size, and different markers that could predict the outcomes of bariatric surgery regarding elimination of co-morbidities should add more objective data to the spectrum of benefits of weight loss surgery.


Surface-enhanced Raman spectroscopy (SERS) technology has been regarded as a most efficient and sensitive strategy for the detection of pollutants at ultra-low concentrations. Fabrication of SERS substrates is of key importance in obtaining the homogeneous and sensitive SERS signals. Cellulose filter papers loaded with plasmonic metal NPs are well known as cost-effective and efficient paper-based SERS substrates. In this manuscript, face-to-face assembly of silver nanoplates via solvent-evaporation strategies on the cellulose filter papers has been developed for the SERS substrates. Furthermore, these developed paper-based SERS substrates are utilized for the ultra-sensitive detection of the rhodamine 6G dye and thiram pesticides. Our theoretical studies reveal the creation of high density hotspots, with a huge localized and enhanced electromagnetic field, near the corners of the assembled structures, which justifies the ultrasensitive SERS signal in the fabricated paper-based SERS platform. This work provides an excellent paper-based SERS substrate for practical applications, and one which can also be beneficial to human health and environmental safety. Surface-enhanced Raman spectroscopy (SERS) is one promising surface precautionary technology for the selective and sensitive detection of analytic molecules in the field of human health and environmental safety . Even anThe unique morphology features of plasmonic metal NPs exhibit excellent localized surface plasmon resonance (LSPR) properties, especially in anisotropic metal NPs ,7,8,9,102 NPs coated filter paper. These substrates exhibit sensitive detection of thiram, and their LODs are 4.6261 ng/cm2, 1 nM, and 1 nM, respectively. We have previously developed a general fabrication methodology for cellulose filter paper nanocomposites for SERS sensing and chemical catalysis . . −8 M. I−4 M to 10−7 M, and the peak position is consistent with the theoretical calculation result. Compared with thiram in acetone, −1, but still with a good recognition. In general, the self-assembled substrate can sensitively detect thiram concentration, where the limitation of detection is far lower than the national standard.We observed the same peaks in the calculated Raman spectrum  as in thIn summary, we have achieved the ultra-sensitive chemical sensors for the R6G molecules and thiram molecules. A simple fabrication approach for the paper-based SERS substrates has been developed via the controllable face-to-face assembly of Ag nanoplates on filter papers. Our theoretical simulations showed that, high density of hot spots was distributed nearby the assembled nanostructures. Therefore, the paper-based SERS substrates showed efficient and homogeneous distribution of SERS spectra dyes and pesticide. The developed paper-based SERS substrates can be potentially applied in the food safety, environment monitoring, and defense security.


Emotion recognition and social deficits have been previously reported in Parkinson’s disease (PD). However, the extent of these impairments is still unclear and social cognition is excluded from the cognitive domains considered in the current criteria for PD mild cognitive impairment (MCI). This study aims to analyze emotion recognition, affective and cognitive theory of mind in early PD patients classified according to Level II MCI criteria, and to evaluate the prevalence of socio-cognitive deficits in this sample.n = 32) or MCI (n = 13) based on a standard neuropsychological assessment. Social cognitive skills were evaluated through validated tests for emotion recognition  and mental states attribution  and compared to a group of 45 healthy controls (HC). Between-group differences in social tasks were performed, as well as correlation analyses to assess the relationship between social, cognitive, and clinical variables. Finally, the number of patients with social cognitive impairments in both MCI and CU subgroups was computed based on Italian normative data.We enrolled 45 participants with PD, classified as cognitively unimpaired (CU; Statistical comparison revealed significant differences among groups in the Ek60 test, with MCI obtaining significantly lower scores than HC and CU, especially for negative emotions. Significant differences were detected also in the SET, with lower performance in emotion and intention attribution for both PD groups compared to HC. A significant correlation emerged between the Ek60 test and emotion attribution. Nine patients showed poor performance at social tasks, five of them being classified as PD-CU.Parkinson’s disease cognitive profile was characterized by emotion recognition and attribution deficits. These results, as well as the detection of CU patients with isolated socio-cognitive impairments, underline the importance of assessing social cognition in PD as a possible early marker of cognitive decline. Parkinson’s disease (PD) is a progressive multisystem neurodegenerative disorder  characteDespite the above-mentioned evidence of socio-cognitive deficits in PD, social cognition is not included among the cognitive domains clinically assessed for the definition of PD cognitive status according to the 2012 Movement Disorder Society (MDS) criteria for the detection of mild cognitive impairment (MCI) . These cForty-five patients with PD diagnosed according to the United Kingdom Parkinson’s Disease Society brain bank criteria  were enrForty-five healthy controls (HC), matched for demographic variables to the patient group, were also enrolled for statistical comparison at social tasks. HC were included based on the absence of positive neuropsychiatric history, neurological disorders, or cognitive impairment evaluated through the Italian version of the Montreal Cognitive Assessment  . The stuAll patients underwent a standard neuropsychological evaluation including a test of global cognitive status , as wellSocio-cognitive abilities have been evaluated through a test of emotion recognition (Ekman 60-faces Test—Ek60)  and a teFirst, preliminary statistical analyses were performed to evaluate data distribution (Shapiro-Wilk test) and to compare demographic variables  between groups  through one-way ANOVA and Chi-squared test.t-student statistics or Mann-Whitney U based on data distribution.Differences in basic neuropsychological tasks were evaluated between PD-MCI and PD-CU using Post-hoc analyses were carried out through the Games-Howell test (for parametric statistics) and Dwass-Steel-Crotchlow-Fligner pairwise comparison (for non-parametric statistics). Since a significant difference between PD-CU and PD-MCI was found in education, analyses were performed on adjusted scores according to normative values. Then, partial correlation analyses controlling for global cognitive status  were performed between the main neuropsychological variables of interest to assess the relationship between socio-cognitive abilities and clinical, cognitive and behavioral functioning in PD. Finally, we evaluated the number of patients with socio-cognitive impairments in both MCI and CU subgroups based on Italian normative cut-off values for Ek60 global score, affective (SET-EA) and cognitive (SET-IA) mental states attribution. Notably, we used the approach of “equivalent scores” proposed by Performances at social tasks (Ek60 Test and SET adjusted scores) were compared between PD-CU, PD-MCI, and HC using parametric or non-parametric  one-way ANOVA. 2(2) = 1.15, p = 0.6; one-way ANOVA on age variable: F = 0.11, p = 0.9], apart from education  , attention  executive functions , language  and visuo-spatial abilities .According to level II PD-MCI criteria, 32 patients classified as PD-CU and 13 patients as PD-MCI . All PD- = 0.03] . At cognp < 0.001) compared to PD-CU (p = 0.009) and HC (p = 0.003). In particular, PD-MCI patients showed lower scores than HC in the recognition of fear (p = 0.02), surprise (p = 0.002) and sadness (p < 0.001). Anger (p = 0.04) and sadness (p < 0.001) recognition was reduced in PD-MCI compared to PD-CU patients. Together with emotion recognition deficits, PD-MCI showed worse performance than HC in SET scores of emotion  and intention  attribution, as well as in the control condition of causal inference . Notably, SET-EA (p = 0.002) and SET-IA (p = 0.02) were also reduced in PD-CU compared to HC, while only a trend emerged in SET-CI (p = 0.05).The analysis of social performance between PD-MCI, PD-CU, and HC showed significant differences in both emotion recognition and attribution tasks . Global s) results are reported in s = 0.48, p < 0.004), while no significant correlations emerged with SET-IA or SET-CI sub-scores. Executive functions  were significantly associated to the performance at both SET  and Ek60  tasks. SET-EA performance was also associated to language functions . Finally, scores at the Ek60 test were positively associated with the performance at the unknown face recognition task .Partial correlation  and sadness (n = 4)  was finally evaluated according to Italian normative data , 2015 toFinally, when considering social cognition among the cognitive domains for MCI criteria, two patients originally classified as PD-CU were re-classified as PD-MCI multiple domains, presenting a significant impairment in two neuropsychological tasks .Increasing evidence reports significant socio-cognitive dysfunctions in PD. However, the extent of these deficits according to the disease stage, as well as their clinical relevance, is still unclear. Thus, in this study, we adopted two social tasks clinically standardized for the Italian population in order to assess emotion recognition and ToM in PD, with the final aim of investigating the prevalence of socio-cognitive deficits in a sample of non-demented patients classified according to MDS Level II criteria for MCI .Emotion recognition and ToM represent two core components of social cognition, driving social interaction through automatic and voluntary processes . NotablyTogether with mentalizing deficits, PD-MCI showed a significant impairment in negative emotion recognition in agreement with previous quantitative and qualitative literature reviews . NotablyMeta-analytical evidence concurs however in reporting a major impairment in the recognition of negative emotions rather than of positive ones, and this deficit has been previously associated with amygdalar  and mesoDespite the significant results at group level, when evaluating socio-cognitive performance in single subjects according to normative data we found a limited number of patients showing a deficitary performance. This possibly suggests in the PD group the presence of subtle alterations in socio-cognitive tasks, still below the threshold of clinical relevance. This hypothesis is further supported by the presence of patients showing a borderline performance in both emotion recognition and mental states attribution. When considering normative cut-off scores, 20% of patients showed a significant clinical deficit in global emotion recognition or mental state processing. This percentage is similar to what has been previously reported  . The misWhen we included social cognition among the cognitive domains for MCI criteria, two PD-CU patients were re-classified as PD-MCI multiple domains. Considering the contribution of MCI classification in predicting the hazard of PD dementia , this reThe main limitations of this study are represented by the small sample size that might affect the statistical power of the analyses, and by the lack of a detailed neuropsychological characterization of healthy controls, which does not allow to exclude the presence in this sample of subtle deficits in single cognitive domains. Despite the MoCA cut-off score used to include healthy participants is lower than the one suggested by international meta-analytic results e.g., , this isIn conclusion, the results of the present study support that alterations in affective recognition and attribution may occur in PD from the earliest stages of the disease. In agreement with previous evidence , we highThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by University of Trento Ethical Committee. The patients/participants provided their written informed consent to participate in this study.AD, CP, LT, and FZ: conception and organization of the project. MP, CL, MM, and RD: data acquisition. AD, CM, and GF: data interpretation and data analyses. AD and GF: first drafting of the work. All authors revised the manuscript and provided the approval of the work.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.


This study evaluated the accuracy of DUS in predicting the development of respiratory failure in patients with CAP, as well as the feasibility of its use in the emergency department (ED) setting.Early recognition of patients with community-acquired pneumonia (CAP) at risk of poor outcomes is crucial. However, there is no effective assessment tool for predicting the development of respiratory failure in patients with CAP. Diaphragmatic ultrasonography (DUS) is a novel technique developed for evaluating diaphragmatic function T-tests, while categorical variables were analyzed using chi-square tests. Further logistic regression and receiver operating characteristic curve analyses were performed to examine the ability to predict the development of respiratory failure. Intra- and inter-rater reliability was examined with intraclass correlation coefficients (ICCs).This was a single-center prospective cohort study. We invited all patients with ED aged ≥ 20 years who were diagnosed with CAP of pneumonia severity index (PSI) SIe diagnosed with CAP of pneumonia severe with respiratory failure or septic shock were excluded. Two emergency physicians performed DUS to obtain DTF and DE measurements. Data were collected to calculate PSI, CURB-65 score, and Infectious Diseases Society of America/American Thoracic Society severity criteria. Study endpoints were taken at the development of respiratory failure or 30 days post-ED presentation. Continuous variables were analyzed using p = 0.0416). At the optimal cut-off point of 23.95%, DTF had 69.23% of sensitivity, 83.78% of specificity, 88.57% of negative predictive value, and 80% of accuracy. Intra- and inter-rater analysis demonstrated good consistency .In this study, 13 of 50 patients with CAP enrolled developed respiratory failure. DTF was found to be an independent predictor  may reliably predict the development of respiratory failure in community-acquired pneumonia patients presenting to the emergency department.  Patients with CAP have a wide-ranging clinical presentation, varying from fever and cough to severe respiratory distress, acute respiratory distress syndrome, and even multiple organ dysfunction syndromes.Early recognition of patients with the potential to deteriorate during their admission is important in the emergency department (ED) . To thisOther scoring systems have been developed to identify patients with CAP who are critically ill and consequently require admission to the intensive care unit (ICU). These scores include the severe community-acquired pneumonia score , SMART-Cvia the abovementioned prognostic scores was performed by evaluating the risks of mortality of patients with CAP. Nevertheless, given that CAP imposes significant morbidity in addition to mortality, such risk assessment can also be performed through consideration of the morbidity risks of developing severe disease sequelae. One important complication of CAP would be respiratory failure, though there has yet to be any established evaluation method to predict its development in patients with CAP.Risk stratification The diaphragm is a major inspiratory muscle and as such plays a critical role in the work of respiration . Diaphravia 2 main ultrasonography techniques. The first technique, diaphragm thickening fraction (DTF), is a measurement of the difference in end-inspiratory and end-expiratory diaphragmatic thickness, expressed as a fraction with the denominator of the end-expiratory thickness. The second method is to measure diaphragm excursion (DE), the diaphragmatic altitude difference between expiration and inspiration  outside the ICU, demonstrating good intra- and inter-rater reproducibility of right-sided DE measurements in the ED –34. Its In this study, we aimed to evaluate the two DUS techniques of DTF and DE in predicting the development of respiratory failure in patients with CAP presenting to the ED. These results will assist emergency physicians (EPs) and intensivists in the early identification of patients with CAP at risk of deteriorating rapidly and subsequently enable clinicians to make necessary arrangements in advance for mechanical ventilation and ICU admission.This was a single-center, prospective cohort study of all patients who visited the ED of Linkou Chang Gung Memorial hospital from December 2018 to March 2019 and were diagnosed with CAP. Linkou Chang Gung Memorial Hospital is one of the largest tertiary medical centers in the world with 3,406 beds and approximately 15,000 monthly ED visits in 2019 . This stAll patients aged 20 years or older who visited our ED and were diagnosed with CAP of moderate-to-high severity (PSI class ≥ 4) were invited to participate in this study, except for those who fulfilled the following exclusion criteria: [1] history of prior admission to any healthcare facility in the preceding 48 h; [2] patients who meet the IDSA/ATS severity major criteria  on ED prAll patients diagnosed with CAP in our ED were managed by EP-led teams in accordance with the 2018 Taiwanese guidelines, endorsed by the Infectious Diseases Society of Taiwan and the Taiwan Society of Pulmonary and Critical Care Medicine . ApproprAfter eligible patients had consented to participate in our study, DUS was performed immediately by two board-certified EPs (raters A and B) who had been trained in emergency ultrasonography and are accredited by both the Taiwan Society of Emergency Medicine and the Taiwan Society of Ultrasound in Medicine. These two raters were blinded to the patients’ full diagnoses and treatment courses, while patients and attending clinical teams were blinded to the ultrasonography findings.Diaphragmatic ultrasonography was performed at the bedside using the Mindray M7 portable ultrasound machine. Each examination comprised measurements, which were repeated for three consecutive respiratory cycles and subsequently averaged. Both raters took turns performing the DUS examination twice on the right hemidiaphragm. The right hemidiaphragm was opted over the left hemidiaphragm since the latter was often obscured by gastric contents with a less-favorable spleen window , 32, 37.The clinical progress of all recruited patients was followed. Study endpoints were taken at either development of respiratory failure or 30 days post-ED presentation.The diaphragm thickening fraction is calculated using the following formula:via ultrasound through the 7th to 9th intercostal spaces at the right mid-axillary line using M-mode while the patients lay in the supine position. The evaluation was performed using a high-frequency linear probe  in the longitudinal plane  while the patients lay in the supine position. The evaluation was performed using a low-frequency linear probe  in the sagittal plane, with cranial angulation to produce a perpendicular cross-sectional image of the posterior diaphragm using the liver as an acoustic window .T-tests, while categorical variables were expressed as frequencies with their corresponding percentages and evaluated via chi-square tests. The averages of the 4 DTF and 4 DE measurements recorded for each patient with CAP were used for statistical analysis between patients who developed respiratory failure vs. those who did not. Logistic regression models were also constructed to assess the association between the variables and study outcomes. Receiver operating characteristic (ROC) curve analysis with c-statistics was performed, with optimal cut-off points identified for DTF and DE. Areas under the ROC curve (AUROC) were plotted for DTF, DE, PSI, CURB-65, and the IDSA/ATF minor criteria to compare their abilities to predict the development of respiratory failure in patients with CAP.Continuous variables were recorded as means ± standard deviation and analyzed using k = 2), single-measure, and 2-way mixed effects model  with 95% confidence intervals were calculated, based on a mean-rating . Notably, 13 of these 50 patients with CAP (26%) eventually developed respiratory failure during hospitalization, approximately 7 days after presenting to the ED (165.6 ± 143.3 h). In comparison with patients who did not develop respiratory failure, patients with CAP who progressed into respiratory failure were found to be more anemic (p = 0.0087) with higher blood urea nitrogen levels (p = 0.0264). There were no statistically significant differences in patient demographics, underlying comorbidities, initial vital signs, and other laboratory investigation results between both groups  and fulfilled more IDSA/ATS minor criteria (p = 0.0185). DUS examination revealed that DTF in patients who developed respiratory failure was lower at 26 ± 15% vs. 41 ± 17% in those who did not (p = 0.0094), while there were no significant differences in DE measurements for both groups , PSI , and IDSA/ATS minor criteria  had significant correlation with the development of respiratory failure. Subsequent multivariate analysis revealed that only DTF and PSI were independent predictors. Each reduction of 1% in DTF increased the odds of developing respiratory failure by 6.1%  curve analysis of the studied risk stratification tools found PSI to be the best performing tool with an area under ROC curve (AUROC) of 0.8565, while DTF ranked second with an AUROC of 0.7796 . Furthery of 80% .Evaluation of DTF’s intra- and inter-rater reliabilities demonstrated good consistency, with 0.774 (95% CI: 0.633 – 0.865) and 0.781 (95% CI: 0.644 – 0.870) inter-rater intraclass correlation coefficients (ICCs) and 0.817 (95% CI: 0.700 – 0.892) and 0.789 (95% CI: 0.657 – 0.874) intra-rater ICCs .Our study demonstrates that the DTF technique of DUS can reliably predict the development of respiratory failure in patients with CAP presenting to the ED. We also found that DE is a poor predictor of the development of respiratory failure. This study is, to the best of our knowledge, the first to describe the association of critical illness-associated diaphragm dysfunction with the development of respiratory failure in patients with CAP.via point-of-care ultrasonography would enable clinicians to make necessary arrangements in advance for mechanical ventilation and ICU admission. This prognostication and risk stratification tool may also allow clinicians to prioritize and optimize the care of these critically ill patients with CAP and facilitate counseling and communication with patients and their families from the very beginning of their hospital admissions. Conversely, patients with a low risk of developing respiratory failure can be considered for outpatient management.Early identification of patients with CAP at risk of deteriorating rapidly During the respiratory cycle, the diaphragm thickens in the inspiratory phase while moving caudally to create negative intrathoracic pressure for drawing air into the lungs; conversely, the diaphragm flattens out during expiration while moving cranially in the expiratory phase to create a positive intrathoracic pressure to expel air out of the lungs. Diaphragmatic weakness is highly prevalent in critically ill patients. Often referred to as “ventilator-induced diaphragmatic dysfunction,” it is a well-recognized pathological entity in the ICU . Recent This direct representation of the diaphragm’s function is perhaps the reason why we found a strong correlation between DTF and the development of respiratory failure in patients with CAP presenting to the ED. Since it provides a preview of diaphragmatic dysfunction, DTF may be used to enable early risk stratification and rapid decision-making at the bedside in the ED – future follow-up studies can be performed to evaluate and validate its clinical application.Stroke, neuromuscular disease, age, and cardiopulmonary diseases such as heart failure and chronic obstructive pulmonary disease have been associated with diaphragmatic dysfunction , 42–46. While the DTF was found to be a valuable risk stratification tool in predicting the development of respiratory failure in patients with CAP at the ED, the same does not hold true for the DE. This is perhaps because DTF directly evaluates the extent of diaphragmatic contractility (and therefore function) by measuring the variability of its thickness during the respiratory cycle, while DE is an indirect evaluation of this contractility by measuring the altitude displacement of the diaphragm between inspiration and expiration. Not only is this DE measurement of altitude displacement influenced by active diaphragmatic contractions, it is also affected by other forces external to the diaphragm . During Univariate logistic regression analysis of the various risk stratification tools found that PSI, IDSA/ATS minor criteria, and DTF were significantly associated with the development of respiratory failure in patients with CAP, while multivariate analysis confirmed that PSI and DTF were independent predictors. Further AUROC analysis revealed that PSI and DTF were comparable in their risk stratification abilities. While statistical analysis had demonstrated that DTF was noninferior to the more established PSI, the former is more clinically feasible and applicable in the ED environment. This is especially so with the increasing ubiquity of point-of-care ultrasonography in the ED, which would allow rapid visualization of the diaphragm and DTF measurements within minutes. In stark contrast, calculating the PSI would require a much longer time to collate the required data on the patient’s comorbidities, clinical history, physical examination, laboratory investigation results, and radiological imaging.At a cut-off point of 23.95%, DTF was found to be 80% accurate in predicting the development of respiratory failure in patients with CAP, with a sensitivity of 69.23% and a specificity of 83.78%. Its high NPV of 88.57% and negative likelihood ratio of 0.3672 mean that patients with DTF > 23.95% are very unlikely to develop respiratory failure; these patients can be considered for outpatient management and follow-up. Patients with DTF < 23.95% have a high likelihood of developing respiratory failure (positive likelihood ratio 4.2692) and therefore would benefit from hospitalization and monitoring by healthcare professionals, especially in the first week of illness .Our study is a single-center observational study with a relatively small sample size. Therefore, further studies should be performed to confirm our findings and validate the use of DUS and DTF assessment in patients with CAP. As with any other ultrasonography-based evaluation, DUS is operator-dependent . NeverthDiaphragmatic ultrasonography assessment of DTF in patients with CAP may be a reliable and accurate risk stratification tool to predict the development of respiratory failure. The short time required by a trained operator to obtain these measurements makes it ideal for the ED setting. Patients with DTF > 23.95% may be considered for outpatient management – further studies are, however, required to validate its use in the clinical management of CAP in the ED.The SPOT includes the following members: Johan Seak, Jia-Qi Xu, Yi-Zhen Chen, Hao-Tsai Cheng, Hsien-Yi Chen, Yu-Shao Chou, Chih-Huang Li, Tzu-Heng Cheng, Chen-Bin Chen, Chia-Hau Chang, Chien-Lin Chen, Wei-Chun Lin, and Chiao-Hsuan Hsieh.The datasets generated and/or analyzed during this current study are available from the corresponding author on reasonable request.The studies involving human participants were reviewed and approved by Institutional Review Board of the Chang Gung Memorial Hospital (IRB no: 201801855B0). The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.K-HH: approve the formal analysis. S-EC, J-XL, and C-JS: conceptualization. S-EC and J-XL: data curation. K-HH and C-JS: formal analysis and supervision. C-JS: funding acquisition and resources. S-CC, ZG, C-KS, JS, and C-JS: methodology. S-EC, J-XL, C-JN, and C-JS: investigation. C-JS and ZG: validation, visualization, and writing – review and editing. S-EC, J-XL, ZG, C-KS, JS, and C-JS: writing – original draft. All authors contributed to the article and approved the submitted version.


Background: Clinical guidelines recommend beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, and statins for the secondary prevention of acute myocardial infarction (AMI). It is not clear whether variation in real-world practice reflects poor quality-of-care or a balance of outcome tradeoffs across patients. Methods: The study cohort included Medicare fee-for-service beneficiaries hospitalized 2007–2008 for AMI. Treatment within 30-days post-discharge was grouped into one of eight possible combinations for the three drug classes. Outcomes included one-year overall survival, one-year cardiovascular-event-free survival, and 90-day adverse events. Treatment effects were estimated using an Instrumental Variables (IV) approach with instruments based on measures of local-area practice style. Pre-specified data elements were abstracted from hospital medical records for a stratified, random sample to create “unmeasured confounders” (per claims data) and assess model assumptions. Results: Each drug combination was observed in the final sample , with 35.7% having all three, and 13.5% having none. Higher rates of guideline-recommended treatment were associated with both better survival and more adverse events. Unmeasured confounders were not associated with instrumental variable values. Conclusions: The results from this study suggest that providers consider both treatment benefits and harms in patients with AMIs. The investigation of estimator assumptions support the validity of the estimates. Evepractice .However, this variation may not be completely unfounded. Almost four decades have passed since the publication of the first BB trials, which themselves preceded the implementation of acute coronary revascularization and widespread ST use ,24,25,26Unfortunately, new RCTs to address these known knowledge gaps are unlikely. Not only are the medications readily available as lower-cost generics, but randomization to any treatment combination other than BB+AA+ST would be contrary to the well-established guidelines, and bring forth ethical questions of equipoise. Considering this reality, observational studies remain as an alternative approach to assessing the effectiveness of alternative combination therapies. Previous research using retrospective data report higher overall survival rates for AMI patients using guideline-recommended treatments ,16,47,48The objective of this study to generate practice-based evidence associated with higher rates of guideline-recommended treatment for AMI patients in real-world practice. One-year overall survival, one-year cardiovascular-event-free survival, and 90-day adverse events were assessed for a sample of Medicare fee-for-service beneficiaries hospitalized in 2007–2008 with AMI. An instrumental variables estimator was used that followed the approaches in previously published studies ,59. The Medicare claims data obtained from the Chronic Condition Data Warehouse were used to identify all Medicare fee-for-service beneficiaries within the continental United States (lower 48 states) hospitalized with an AMI in 2007 or 2008. Data for these beneficiaries included enrollment information, final adjudicated Part A and Part B medical claims, and Part D prescription drug events. The date of acute hospital admission with a principal diagnosis of AMI served as the index admission date for the patient. The index stay was defined to include all contiguous days of care at any/all inpatient institution(s), beginning with the initial acute hospitalization. The end date for the index stay was the date the patient was finally discharged home, and was calculated by combining all Medicare institutional claims  with overlapping admission and discharge dates following the initial admission . PatientThis study focused on 3 medication classes recommended by clinical guidelines for secondary prevention following an AMI: beta-blockers (BB), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (AA), and statins (ST) ,6. From The primary outcomes of interest were one-year overall survival, one-year cardiovascular-event-free (CVE-free) survival, and adverse events occurring within 90 days of discharge. Cardiovascular events included another AMI, unstable angina, or stroke. Adverse events were defined as the presence of an inpatient claim with diagnoses for hypotension, bradycardia, heart block, angioedema, hyperkalemia, serious myopathy, an acute renal event, or an acute hepatic event. The specific medical coding terminology used to identify these outcomes can be found in previously published work ,59.a priori by the study team for the IV analyses. All models controlled for demographic variables ; primary AMI diagnosis for the initial acute hospitalization ; baseline medical history and comorbidity pre-AMI and during hospitalization ; procedures pre-AMI and during hospitalization ; medication use 180-days pre-AMI ; potential contraindications to study drugs pre-AMI and during hospitalization ; healthcare utilization during hospitalization ; insurance variables  and financial burden at time of discharge ; and urbanicity and socioeconomic (SES) variables . The complete list of model covariates is further detailed in Covariates and confounders measurable from Medicare claims and administrative data were identified IV estimators generate unbiased estimates of treatment effects under the assumption that the specified instrumental variables are unrelated to unmeasured confounders ,68,69,70The identification strategy in this study is based on prior research developing instrumental variables from variation in treatment rates across geographic areas ,79. ThisA priori, these assumptions seemed valid to the study team, as there is no reason to believe that patients select their residential ZIP code based on an area’s tendency to use BB+AA+ST for the secondary prevention of AMI. In this study, we provide ex post assessment of these assumptions.As with any modeling framework, there are assumptions that must be made and deemed reasonable. For the identification strategy of this study to be valid as a quasi-natural experiment in treatment choice, the variation in risk-adjusted average-treatment-rates across areas must only reflect differences in provider practice-styles that are not otherwise related to A) outcomes or B) unmeasured patient characteristics that affect outcomes. To create the instruments in this study, an Area Treatment Ratio (ATR) for each of the drug combinations was estimated for the local area surrounding each residential ZIP code of every patient in the study cohort, and was defined as the ratio of the number of patients in their local area who received a particular drug combination over the sum of the predicted probabilities of those same patients receiving that same drug combination. The predicted probabilities were estimated across the entire  study cohort using a logistic regression model adjusting for all measured covariates. “Local area” was defined to include all patients residing in that ZIP code, along with the patients in each of the sequentially nearest ZIP codes (by driving distance) necessary to satisfy the requirement that the local area include a minimum of 150 patients ,95. By cPatients who received guideline-recommended therapy (BB+AA+ST) were set as the reference group for the analyses. First-stage treatment choice regressions were estimated individually for the remaining 7 drug combinations. These first-stage treatment-choice models were specified as a function of the instruments and all measured covariates. F-statistics were used to assess the correlation between the instruments and treatment choice in this first-stage model. For the second-stage model, study outcomes were regressed on the estimated treatment probabilities for each of the 7 drug combinations, along with the same set of measured covariates included in the first-stage model.All models were estimated with robust standard errors. The analytic dataset was created using SAS software , and statistical analyses were performed with Stata . An Institutional Review Board approved this study.This study was designed, from its inception, to include a set of confounders unmeasurable with respect to the Medicare data, but measurable using medical records data, for the express purpose of evaluating IV model assumptions. To complete this task, the study team created a structured data-abstraction tool to capture additional, “unmeasured” clinical-assessment and treatment information. Concepts from validated instruments used in the Cooperative Cardiovascular Project  and WomeBroadly speaking, the unmeasured confounders commonly cited in comparative effectiveness studies of cardiovascular drugs ,52,53,54An Ordinary Least Squares model was fitted to test for trends in these unmeasured confounders across treatment choice and instruments. Statistically significant test statistics across drug combinations would indicate selection bias. Statistically significant test statistics across the ATR quintiles would indicate a possible violation of IV model assumptions and bias in the associated parameter estimates.p-value < 0.001). Unadjusted one-year overall and CVE-free survival were 84.3% and 75.4%, respectively, for the study cohort, and 5.4% experienced an adverse event within 90 days of discharge. Survival tended to increase with the number of drugs, whereas, perhaps paradoxically, adverse events trended lower with the number of drugs.The final cohort included 124,695 hospitalizations for individual patients with an AMI in 2007 or 2008 . The medThe mean treatment rates for local areas grouped by ATR quintiles are reported in and a lower risk of adverse events, compared to BB+AA+ST.IV parameter estimates for the seven non-guideline drug combinations relative to guideline-recommended combination therapy are reported in Of the 1404 patients in the stratified, random sample of the study cohort, 67.0% were overweight (BMI > 25), and 25.7% had difficulty in at least one activity of daily living (ADL), with 7.0% dependent on others for care in two or more domains . Less thp < 0.001). More-intense therapy was also associated with healthier patients, as measured here by lower ACE-27 scores and less difficulty with ADLs, as well as a lower likelihood of having a potential contraindication to the study drugs . In contrast, there was no association between these same unmeasured confounders and the instruments. Statistically significant trends were observed in unmeasured confounders across drug combination groups . More-inGuidelines recommend that patients receive beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers, and statins (BB+AA+ST) for the secondary prevention of AMI ,6. In thand detrimental effects in this population-based sample. Given these tradeoffs, it is possible that existing treatment rates reflect practice-based evidence, where physicians are not only asking “does X cause Y?”, but also “how will adding X alter the complex personalized system of the actual patient before me?” [Our findings suggest that the observed deviation from guideline-recommended treatment in real-world practice may not necessarily indicate poor quality-of-care or physician ignorance. Higher rates of guideline-recommended treatment were associated with both beneficial ore me?” . Such prore me?” ,44,45,46The results from other work also suggest patient-centered treatment decisions and the use of practice-based evidence. In two previous papers, 62% of patients surviving an AMI had a statin available within 30 days of discharge, far below what was recommended by clinical guidelines ,106. In The results from our IV models suggest a tradeoff between survival and adverse events with increased use of BB+AA+ST. It is important to note that these estimates are only generalizable to marginal patients, i.e., those whose treatment choice were sensitive to the values of the instrument. The Local Average Treatment Effect estimate identified by IV estimators reflects the expected treatment effect for the “compliers,” or those whose treatment choice are conditional on the value of the specified instrumental variable(s). As such, the IV estimates found here will likely not generalize to the subset of patients who would have been offered the same medication combination by all providers. ATR-based instruments are particularly well-suited for this study’s research question, as parameter estimates are directly interpreted as the absolute change in outcome rates observed with higher rates of guideline-recommended therapy. In addition, because the treatment effects for these drug combinations are likely heterogeneous across patients, the optimal management strategy for any single individual cannot be directly addressed with these estimates.Further limitations to this work should be acknowledged. As with any observational study, assumptions are required in regard to unmeasured confounders. In this study, hospital medical records were abstracted to assess the assumptions underlying the IV estimator. Although these measures were selected intentionally for this purpose and based upon evidence from the literature and expert input, they are likely not exhaustive of all factors related to treatment choice or patient outcomes. In addition, though no correlation was found between these instruments and the unmeasured confounders, only a finite set were measured.The estimated treatment effects will be biased if other unmeasured and effective treatments are correlated with the study drugs. In McClellan’s seminal instrumental variable study, the authors acknowledged that their estimated effects of invasive surgical treatment on survival for Medicare AMI patients were likely biased high, as hospitals using invasive surgical treatment at higher rates were likely also using unmeasured treatments such as thrombolytics (at the time) at a higher rate . This maAnother limitation is the definition of treatment. The study medications are indicated for the management of a chronic condition, and prescribed to be taken indefinitely (as duration of adherence is correlated with outcomes) ,109,110.In addition, adverse events were defined in this study as the presence of an inpatient claim listing any of the following diagnoses: hypotension, bradycardia, heart block, angioedema, hyperkalemia, serious myopathy, an acute renal event, or an acute hepatic event. These conditions were identified using medical coding terminology, and, although the observation period was limited to the first 90 days post-discharge, some encounters may not have been the direct result of treatment. Additionally, less severe events; other types of adverse events; and symptoms of adverse events reported by patients, but not indicated on inpatient claims, were not included in these measures. Thus, the true prevalence of adverse events is likely under-estimated. Given this, the results of this study likely represent a lower-bound of the true adverse-event rate in this population.Lastly, this study utilized older Medicare data, and the treatment rates reported here may not reflect current practice. There is, however, evidence that the use of secondary-prevention medications for AMI patients has increased only moderately over time, even in cardiology practices . Recent Even with these limitations, this present work is a contribution to the literature. Existing research evaluating the comparative effectiveness of drug combinations after AMI have applied risk-adjustment regression methods to observational data, and found more-intense therapy associated with better health outcomes ,122,123.This retrospective observational study assessed the benefits and detriments of combination therapy in a sample of Medicare beneficiaries hospitalized for AMI relative to guideline care (BB+AA+ST). The results from the instrumental variables (IV) models indicated tradeoffs between survival and adverse events associated with higher rates of guideline care relative to other drug combinations. This suggests that the observed distributions of drug combinations in practice may reflect a balance in treatment benefit and harm for the patient mix within each treatment group. These findings support the notion that decisions to deviate from guideline-recommended therapy do not necessarily signal poor quality-of-care, particularly in the context of polypharmacy for older, vulnerable adults .


Immune checkpoint inhibitors (ICIs) are effective against advanced and even perioperative non-small-cell lung cancer (NSCLC) and result in durable clinical benefit, regardless of programmed death ligand-1 (PD-L1) expression status in cancer. Existing clinical evidence shows that the effect of immunotherapy in patients with EGFR-mutant NSCLC after the development of tyrosine kinase inhibitor (TKI) resistance is not satisfactory. However, compared with monotherapy, ICIs combined with chemotherapy can improve the efficacy. Encouragingly, compared with that of patients with sensitive mutations, the progression-free survival of patients with rare mutations who were treated with ICIs was increased. Adequately maximizing the efficacy of ICIs in EGFR-mutant NSCLC patients is worth exploring. In this review, we described preclinical and clinical studies of ICIs or combined therapy for EGFR-mutant NSCLC. We further focused on EGFR mutations and the cancer immune response, with particular attention given to the role of EGFR activation in the cancer-immunity cycle. The mechanisms for the natural resistance to ICIs were explored to identify corresponding countermeasures that made more EGFR-mutant NSCLC patients benefit from ICIs. Among newly diagnosed patients with lung cancer, non-small-cell lung cancer (NSCLC) patients accounted for the highest proportion, approximately 80 percent of the total . In mostIn research insights of the last few years, immune checkpoint inhibitors (ICIs), represented by programmed cell death receptor-1 (PD-1)/programmed death receptor ligand-1 (PD-L1) inhibitors, have attracted increasing attention due to durable clinical benefit along w1ith low toxicity in patients with NSCLC . PreclinSome reports have noted that tumor immunogenicity –23, the Recent clinical trials had found that ICI monotherapy has few effects on patients with EGFR mutations. However, in existing clinical studies, ICI combined with chemotherapy or anti-angiogenesis had achieved encouraging results. While ensuring the efficacy, the safety also should be guaranteed. Here, we reviewed the clinical efficacy and toxicity of ICIs in EGFR-mutant NSCLC  and OS (19.2 months vs. 14.7 months) of patients in the chemotherapy ± atezolizumab + bevacizumab group (ABCP group) were significantly longer than those of patients in the chemotherapy + bevacizumab group (BCP group) . And the confirmed ORR were 43.9% and 25.2% in group A and group C respectively. The combination of ICI and antiangiogenic therapy creates a new pattern of EGFR-TKIs resistance.In addition to its well-known antiangiogenic effect, bevacizumab has also been found to mediate immune regulation –56. The P group) . UnfortuP group) . ORIENT-P group) . The PFSIn theory, cytotoxic T-lymphocyte antigen-4 (CTLA-4) and PD-1 have a coordinated effect on antitumor immune responses. The combination of ipilimumab and nivolumab was used as the first-line treatment for EGFR-mutant NSCLC, and the ORR was 50% . In a su+ tumor-infiltrating lymphocytes (TILs). The heterogeneity of the TME of distinct EGFR mutations results in different immune responses to ICIs. Further exploration of the pathological and immunological characteristics of different subtypes may help us select the population benefiting from ICIs.In a multicenter retrospective clinical cancer study, 171 NSCLC patients with EGFR mutations were treated with PD-1/PD-L1 ICIs or ICIs combined with a CTLA4 inhibitor . ImmunotFrom existing preclinical and clinical studies, ICIs were generally well tolerated as monotherapy or in combination with chemotherapy or anti-angiogenesis for EGFR-mutant NSCLC patients, and no newly treatment-related adverse events have been observed. However, it is worth noting that ICIs combined with EGFR-TKIs enhanced toxicity among EGFR-mutant NSCLC patients.Some studies have shown that EGFR-TKIs can induce the immunogenic apoptosis of tumor cells, recruit T cells or upregulate the expression of PD1/PD-L1. Therefore, it is logical to combine TKIs with ICIs. Dismally, in clinical trials, the combined application of EGFR-TKIs and ICIs for the treatment of EGFR-mutant NSCLC patients did not provide a significant clinical benefit but increased side effects . MoreoveCollectively, according to preclinical and clinical trials, EGFR-mutant NSCLC patients benefit little from ICIs, especially ICI monotherapy, due to their heterogeneous immune characteristics. Encouragingly, compared with that of patients with sensitive mutations, the PFS of patients with rare mutations who were treated with ICIs was increased. At present, the specific mechanism that causes this phenomenon is not clear and is worth exploring further. Daniel S. Chen et al.  proposedThe T-cell-mediated anticancer response starts with the release of new antigens produced by tumorigenesis that are captured by antigen presenting cells (APCs). Immunogenic cell death (ICD) accompanied by the release of neoantigens is an irritation signal; tolerable or apoptotic cell death is an inhibitory signal . Wu et ain vitro study by Nigro et al.  kinase MEK pathway, which leads to the poor response of NSCLC to immunotherapy. Homoplastically, other studies suggested that in patients with EGFR-TKI resistance, T790 M-negative tumors tended to respond more favorably to the ICI nivolumab than T790 M-positive cells . In T790The T-cell receptor (TCR) lineage consists of thousands of TCR clones, reflecting an individual’s immunity during aging, infection and even malignancy. It is of high clinical value to distinguish the clonality and diversity of TCR  and the overlap index (OLI) of unique TCR chain sequences identified between tissue and blood. One study found that obvious curative effects of ICIs can be seen in patients who had high clonality and high OLI scores –94. The + TILs is, the better the immune effect -targeted T-cell therapy was a promising strategy for the treatment of malignancies . Han’s t+ T (TFH)-B-tissue-resident memory CD8+ T (TRM) cooperation mediated by the CXCL13-CXCR5 axis in EGFR-mutant NSCLC may account for poor responses to ICIs (Increasing evidence has proven that the significant efficacy of B cells may promote both the response and prognosis of ICIs . Compare to ICIs . Patient to ICIs ; therefoIn summary, achieving the goal of complete and safe cancer eradication through ICIs may require only monotherapy in a few patients with EGFR-mutant NSCLC, while most of these patients may need combination therapy, and the major challenge for the latter group is joint toxicity. In addition, current studies suggested that EGFR L858R, a common mutation, and rare mutation still showed superiority in ICIs treatment. More preclinical and clinical studies exploring the combination of ICIs and several other treatments, such as anti-angiogenesis, chemotherapy, novel ICIs, radiotherapy, anti-CD47-SIRP-α, anti-CD73- adenosine axis, and B-cell-associated immunity are urgently needed because most analyses are based on subgroup analysis or retrospective studies. Moreover, the optimal dose, sequence and schedule of the combination should also be included in future studies. However, in basic research, it was challenging to obtain humanized animal models containing EGFR mutations, which seriously restricts the progress of research. We speculated that continued improvement of the mouse preclinical model would accelerate the pace of ICI optimization in EGFR-mutant NSCLC patients.Through the cancer-immunity cycle, immunotherapy has informed promising approaches for EGFR-mutant advanced NSCLC patients. Considering the large population of EGFR-mutant NSCLC patients and low toxicity and durable clinical benefit of ICIs, it is particularly important to explore immunotherapy strategies after TKI resistance.CS wrote the original draft. YW collected and interpreted the data. CS and YW analyzed data, prepared, and reviewed figures. JX offered significant guidance. XZ offered main direction of this manuscript. CS and YW contributed equally to this work. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Additionally, the serum albumin level was significantly higher in the good neurologic outcome group than in the poor neurologic outcome group . Relatively low serum albumin levels in the early phase may be associated with in-hospital mortality of resuscitated patients after cardiac arrest. However, we could not evaluate the association between albumin level and neurologic outcome because of limited included studies and unresolved high heterogeneity.We aimed to evaluate early phase serum albumin levels in and outcomes of resuscitated patients after cardiac arrest. Medline, EMBASE, and the Cochrane Library were systematically searched until 4 July 2022, for studies on post-cardiac arrest patients and involving measurement of early phase albumin levels and assessment of in-hospital mortality or neurologic outcomes. Two reviewers independently assessed the methodological quality of the included studies using the Quality in Prognosis Studies tool. We included 3837 patients from seven observational studies in this systematic review and meta-analysis. The serum albumin level was significantly higher in survivors than in non-survivors, showing a positive association with an overall standardized mean difference (SMD) [/pooled standard deviation] of 0.55 (95% confidence interval [CI], 0.48–0.62; I Ischemia-reperfusion injury that occurs during cardiac arrest (CA) and return of spontaneous circulation (ROSC) after cardiopulmonary resuscitation (CPR) is referred to as post-cardiac arrest syndrome (PCAS) . HypoxicSerum biomarkers as outcome predictors of patients with PCAS have several advantages, including relatively easy access, rapid performance, immediate results, and repeatability . Neuron-Hence, we performed the first systematic review and meta-analysis of previous studies to assess the association between serum albumin levels and outcomes of patients hospitalized after CA. We hypothesized that in resuscitated patients, there would be an association between early phase low serum albumin levels and in-hospital mortality and poor neurologic outcomes (PNO).http://www.crd.york.ac.uk/PROSPERO/, accessed on 20 December 2021), with registration number CRD42022299361.This study was performed according to the principles outlined in the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines ,17. We rA literature search of critical assessments was performed, and eligible studies were selected and evaluated through a systematic review and meta-analysis. The PICO  question was as follows: population (P) = adult patients with ROSC after CA; intervention (I) = serum albumin level; comparator (C) = none; and outcome (O) = in-hospital mortality and neurologic outcome.An extensive database search was performed for studies that assessed the prognostic impact of serum albumin levels in adult patients with ROSC after CA. Two reviewers (H. Lee and J. Lee) performed the literature search on 4 July 2022, using the EMBASE (from 1974 to 1 July 2022) and MEDLINE (from 1946 to 1 July 2022) databases through the Ovid interface and the Cochrane Library . The search terms included “heart arrest” or “cardiac arrest” or “cardiopulmonary resuscitation” or “return of spontaneous circulation” and “albumin” . All artTwo experienced reviewers (H. Lee and J. Lee) independently screened the titles and abstracts of all selected studies, and irrelevant studies were excluded. A full-text review of potentially relevant articles was subsequently performed. The exclusion criteria were as follows: irrelevant outcomes , irrelevant populations (patients who did not experience sustained ROSC), duplicate data or studies, animal studies, reviews, case reports, and conference abstracts. Any disagreement not resolved on discussion was reviewed by a third reviewer (H. Shin), and differences were resolved through discussion until a consensus was reached.Two reviewers (H. Lee and J. Lee) independently extracted relevant data that included study characteristics, main outcomes, and basic characteristics of patients in the included studies. The following study variables were extracted: name of the first author, publication year, country of study, inclusion period, study type, CA type (OHCA or IHCA), sample size, number of patients with in-hospital mortality and PNO, serum albumin measurement time, and time points of outcome measurement. The neurological outcome was classified as good or poor based on the cerebral performance category  scores . The mean (±SD) serum albumin levels of the patients were calculated from the median values with interquartile ranges .Two reviewers (H. Lee and J. Lee) independently assessed the methodological quality of the included studies, with the authorship and journal data blinded. Unresolved disagreements between the reviewers were resolved through a discussion. Six bias domains  were assessed using the Quality in Prognosis Studies (QUIPS) tool in systematic reviews . The QUI2 statistics were used to quantify heterogeneity and estimate the proportion of inter-study inconsistency resulting from the true differences between studies, with values of 25%, 50%, and 75% categorized as low, moderate, and high, respectively [In the main analysis, we identified the prognostic impact of serum albumin levels in predicting in-hospital mortality and PNO in patients with ROSC after CA. The strength of the association between decreased serum albumin levels and in-hospital mortality and PNO was estimated with standardized mean differences (SMD) using a random-effects model . This moectively .We conducted additional analyses, including sensitivity and meta-regression analyses, if the heterogeneity was moderate or high in the main meta-analysis. To interpret the potential causes of inter-study heterogeneity, a sensitivity analysis was conducted by sequentially omitting the studies. Meta-regression analysis was conducted to identify heterogeneity and assess the influence of study characteristics on the results. Funnel plots were used to assess publication bias. The asymmetry of the funnel plot indicates the presence of bias.p < 0.05.The reference management software Endnote X9  was used to organize all studies identified in the literature search. Statistical analysis was performed using Review Manager . Identification of publication bias, sensitivity analysis, and meta-regression were performed using the R packages “meta” and “metafor” . Statistical significance was set at The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework for meta-analysis was used to evaluate the quality of evidence, and the level of evidence was graded as high, moderate, low, or very low . The levA total of 370 studies were identified through a database search along with two additional manual searches ; 43 duplThe main characteristics of the included studies are summarized in The results of the quality assessment of the included observational studies are presented in 2  =  0%; p  <  0.001, The serum albumin level was found to be relatively higher in survivors than in non-survivors, showing a positive association with an overall SMD  of 0.55  of 0.54 .Alternatively, decreased serum albumin levels are associated with mortality and can be used as a prognostic marker in critically ill patients . SeveralIn critically ill patients, blood lactate level has been commonly used as an indication of tissue perfusion changes for decades ,41. HypeExcept for the relationship between albumin levels and in-hospital mortality, high heterogeneity was observed in this meta-analysis. The differences in study characteristics , serum measurement time), and small number of included studies might be the reason for the high heterogeneity. One multicenter observational study that reported on albumin level and outcomes of OHCA patients  was exclThis study had some limitations. First, there are many variables that affect the prognosis of cardiac arrest patients. However, meta-analysis cannot adjust for these variables because different studies have assigned somewhat different meanings to many of the variables. In addition, as stated previously, some statistical and clinical heterogeneities between the studies were not resolved. Despite this, this study was conducted using SMD, a random-effects model that accounts for the variation between studies to reduce heterogeneity. This could have limited the quality and interpretability of the findings. This limitation requires additional analyses such as subgroup analysis or meta-regression. However, this was limited by the lack of included studies. Second, we could not determine diagnostic test accuracy for calculating sensitivity, specificity, odds ratio, or summary ROC curve owing to lack of data. Third, the applicability of our findings is limited because the included research was conducted in three nations and over half of the included studies were conducted in Korea. Fourth, we did not consider confounding variables that could have affected albumin or lactate concentrations, such as underlying diseases, CA duration, nutritional status, drug or alcohol use, and smoking history. To improve the findings of this meta-analysis, a large-scale prospective follow-up investigation with a larger sample size is required. Finally, observational or selection bias could have occurred because we included observational studies in this meta-analysis, not randomized controlled trials. The result of GRADE was rated as “low” in present study. To overcome this limitation, serum albumin level should be evaluated for its predictive value for CA patients by well-designed randomized clinical trials.Serum albumin levels measured in the early phase of post-CA were significantly higher in the survival group than in the non-survival group. However, the present study could not evaluate the association between albumin level and neurologic outcome because of the lack of included studies and unresolved high heterogeneity. The albumin concentration test could be helpful in predicting in-hospital mortality of post-CA patients. Owing to the low level of evidence provided by GRADE, a well-designed, large-scale, prospective trial is required to validate the findings of this study.