Aetiology and outcomes of sepsis in sub-Saharan Africa (sSA) are poorly described; we performed a systematic review and meta-analysis to summarise the available data.Systematic searches of PubMed and Scopus were undertaken to identify prospective studies recruiting adults (> 13 years) with community-acquired sepsis in sSA post-2000. Random effects meta-analysis of in-hospital and 30-day mortality was undertaken and available aetiology data also summarised by random effects meta-analysis.Mycobacterium tuberculosis was the most common cause of blood stream infection where sought. Pooled in-hospital mortality for Sepsis-2-defined sepsis and severe sepsis was 19% (95% CI 12–29%) and 39% (95% CI 30–47%) respectively, and sepsis mortality was associated with the proportion of HIV-infected participants. Mortality and morbidity data beyond 30 days were absent.Fifteen studies of 2800 participants were identified. Inclusion criteria were heterogeneous. The majority of patients were HIV-infected, and Sepsis in sSA is dominated by HIV and tuberculosis, with poor outcomes. Optimal antimicrobial strategies, including the role of tuberculosis treatment, are unclear. Long-term outcome data are lacking. Standardised sepsis diagnostic criteria that are easily applied in low-resource settings are needed to establish an evidence base for sepsis management in sSA.The online version of this article (10.1186/s13054-019-2501-y) contains supplementary material, which is available to authorized users. Sepsis, defined most recently as a syndrome of life-threatening organ dysfunction due to a dysregulated host response to infection , is commThe paucity of data presents challenges in proposing sepsis management specific to sSA. Firstly, defining sepsis for clinical practice or research is problematic. Recent Sepsis-3 guidelines  suggest operationalising the diagnosis of sepsis using the sequential organ failure assessment (SOFA) score . ApplyinSecondly, the optimal clinical management of sepsis in sSA is unknown. Early, appropriate antimicrobials improve outcomes in high-income settings , 14, andFinally, sepsis outcomes in sSA are heterogeneous between studies , 21 and We therefore performed a systematic review and meta-analysis of clinical studies from sSA with three aims: to describe the sepsis definitions used, the aetiology of infection, and clinical outcomes.The protocol of this systematic review was pre-registered on PROSPERO, number CRD42019123589, and follows the PRISMA guidelines.Searches of PubMed and Scopus were undertaken using the search terms shown in Box 1, in all fields. Identified abstracts were exported into Endnote X7.8  and screened against inclusion and exclusion criteria.Inclusion criteria were as follows: prospective cohort studies, non-randomised intervention studies, or randomised controlled trials recruiting adults (> 13 years) with community-acquired sepsis from sSA, for which it was possible to disaggregate a total number of adults with sepsis and was possible to extract aetiology or outcome data. Any study-defined definition of sepsis was accepted. Retrospective studies were excluded due to a high risk of bias: we were concerned that in low-resource settings medical records can often be incomplete and this could introduce significant bias. Exclusion criteria were studies published before 2000 and studies recruiting preselected populations, e.g. puerperal sepsis. There was no language restriction.Abstracts were screened by two authors (JL and JR) and disagreements resolved by consensus. All included abstracts underwent independent full-text review by the same authors, and the inclusion and exclusion criteria were again applied, and disagreements resolved by consensus. Data were extracted onto an Excel spreadsheet  for further analysis: study first author, years of recruitment, inclusion and exclusion criteria, number of patients recruited and demographics , in-hospital, 28- or 30-day mortality, and details of any aetiologic investigations undertaken.A modified Newcastle-Ottawa scale was used to assess risk of bias in the domains of selection, comparability, and outcome  and testing for improved model fit by likelihood ratio testing of nested models. A p value of < 0.05 was considered a statistically significantly improved fit. Bubble plots of the meta-regressions were produced with 95% confidence intervals obtained from 1000 bootstrap replicates. Summary estimates of 28- and 30-day mortality, where available, were considered together and were presented in the same way. Pooled prevalence estimates of malaria, bloodstream infection (BSI), and Mycobacterium tuberculosis bloodstream infection (MTB-BSI) were calculated using random effects meta-analysis as above. For these aetiology analyses, we included all studies, regardless of sepsis definition, and included both usual care and intervention arms of RCTs. All analysis was carried out in R V3.5.1 .Because of concerns about meta-analysis of proportions on very heterogeneous populations, we planned meta-analysis of outcome stratified by inclusion criteria where possible: Sepsis-2 sepsis, Sepsis-2 severe sepsis, and Sepsis-3 sepsis, if available. Mortality was presented as a simple proportion with exact binomial confidence intervals, and pooled mortality estimates were calculated using generalised linear mixed models  using the packages The abstract search yielded 3951 unique records on 17 July 2018  and 5/13 studies recruited a population compatible with Sepsis-2 severe sepsis of SIRS plus organ dysfunction . A variety of organ dysfunction criteria were used including hyperlactataemia or poor Karnofsky performance score; the most common organ dysfunction criterion was low systolic blood pressure, applied in all five studies. No study specifically recruited patients with septic shock, and despite the frequent use of low systolic blood pressure as a defining criterion for severe sepsis, only one study  explicitThe one study that used a non-Sepsis 2-based definition defined sepsis as fever plus one severity criterion , adaptedAll studies reported either in-hospital or 28-/30-day mortality, apart from one retrospective of stored samples , leavingp = 0.006 on likelihood ratio testing of nested models), but year of recruitment was not (p = 0.06). Neither year nor proportion of HIV-infected participants (p = 0.51 and p = 0.83) were associated with inpatient mortality in Sepsis-2 severe sepsis studies. Severe sepsis studies in general appeared to have higher proportion of HIV-infected participants than studies recruiting patients with sepsis . Median age was not associated with in-hospital mortality in sepsis or severe sepsis analyses (p = 0.66 and p = 0.50 on likelihood ratio testing of nested models). In view of the small number of studies reporting 28- or 30-day mortality, meta-regression was not undertaken.Heterogeneity was explored with meta-regression. Proportion of HIV-infected participants was significantly associated with inpatient mortality in studies recruiting patients with Sepsis-2-defined sepsis when included as a fixed-effect covariate  patients died.Aetiology data could be extracted from 14 studies: 11/14 reported aerobic blood culture data, 4/14 mycobacterial blood culture and 9/14 malaria data , non-typhoidal Salmonella (75/458 [16%]), and Streptococcus pneumoniae (68/458 [15%]). All studies reporting blood culture results described the microbiologic methods used but only 6/11 reported external quality control procedures during the study period.Diagnosis of malaria was made by smear in all studies except the retrospective PCR study; one  additionSalmonella isolates were resistant to chloramphenicol and trimethoprim-sulfamethoxazole and that none of the Staphylococcus aureus samples were resistant to oxacillin. The second study provided more comprehensive details, but with very small numbers which limit the conclusions that can be drawn; of 20 isolated Gram-negative bacilli , 9/20 (45%) were resistant to third-generation cephalosporins, and this was strongly associated with mortality. All patients with third-generation cephalosporin-resistant BSI died, compared with 1/11 (9%) of those with sensitive infections (p < 0.0001).Data on antimicrobial sensitivity patterns of the aerobic blood culture isolates were available in only 2/11 studies. One study  gave limPlasmodium spp. (35/336 [10%]), and Streptococcus pneumoniae (31/226 [9%]). Bacterial zoonoses or rickettsioses were uncommon (6/336 [2%]).One study  reportedn = 74,453) found considerably lower mortalities for sepsis (as defined by Sepsis-2), at 4%.In-hospital sepsis and severe sepsis mortality in sSA is high. We found pooled in-hospital mortality of 19% 95% CI 12–29%) for Sepsis-2-defined sepsis and 39% (95% 30–47%) for Sepsis-2-defined severe sepsis. Pooled 28-/30-day Sepsis-2-defined severe sepsis mortality was 54% (95% CI 37–70%). Some between-study heterogeneity in sepsis mortality is likely consequent upon heterogeneous inclusion criteria, and some variability may be explained by the proportion of participants who are HIV-infected. Direct comparison of these mortality estimates to outcomes in high-income settings is difficult as estimates of sepsis mortality often derive from administrative databases and are sensitive to coding strategies. A recent meta-analysis [–29% for It is likely that the sepsis outcomes we describe for sSA are worse than in high-income settings. The reasons for this are likely to be multifactorial, including lack of resources. The association of HIV status with mortality highlights the likely role of HIV as a driver of poor sepsis outcomes in sSA. It is also possible that delays in presentation to hospital or delays in processes of care may contribute to high mortality. The majority of studies we have identified provide no data to address these hypotheses, though there is some suggestion that presentation to care may be delayed. In the two Zambian RCTs , 35, 66–Of note, the 30-day mortality of severe sepsis seemed to be higher than the in-hospital mortality, though with overlapping confidence intervals. The reasons for this are not addressed in our study, but could represent uncontrolled primary infection, secondary infection following sepsis-related immunosuppression, non-infection-related mortality, or hospital practices such as palliative discharge of patients with poor prognosis. None of the studies we identified characterised longer-term (post 30-day) sepsis outcomes in sSA, and this highlights a major area for future research in resource-limited settings. Longer-term follow-up of patients in resource-limited settings is logistically difficult, as is matching episodes of care in administrative or clinical databases for individuals across fragmented and under-resourced health systems, which would be necessary to characterise sepsis outcomes from such databases; these factors may contribute to the lack of available data. No identified study characterised morbidity or economic cost either to health systems or individuals, but the combination of poor outcomes in a young adult population—often the most economically productive group in any society—may have significant socio-economic implications.M. tuberculosis, and non-typhoidal Salmonellae and S. pneumoniae were also commonly isolated, both of which have a strong association with HIV [S. aureus is perhaps surprising, given data on incidence of causative agents of BSI in sSA [Staphylococci from our analysis as likely contaminants, determining whether S. aureus bacteraemia represented true BSI was not possible with the available data. Despite the fact that malaria diagnostic data is from studies carried out in malaria-endemic countries—Malawi, Uganda, Tanzania, and Zambia—malaria was less common than bacterial bloodstream infection, highlighting the emerging importance of non-malarial aetiology of fever in malaria-endemic areas. In the single study employing PCR to describe sepsis aetiology beyond bloodstream infection, CMV was extremely commonly isolated. While it may cause illness in the immunocompromised, CMV reactivation in critical illness is recognised in high-income settings. Without viral testing in a non-sepsis control group, the causal role of CMV is therefore not clear [In contrast to high-income settings, the populations recruited to the identified studies are young and predominantly HIV-infected. It is likely that the high HIV prevalence influences the causative pathogens: the commonest cause of bloodstream infection, when sought, was with HIV , 37. ManI in sSA . Though ot clear . Bacteriot clear , though ot clear , 40, 41,The high prevalence of tuberculosis as a cause of sepsis has significant implications for appropriate antimicrobial therapy in sSA. Current sepsis protocols in high-income settings are based on rapid administration of broad-spectrum antimicrobials to cover common Gram-positive and Gram-negative pathogens, rather than Mycobacteria. However, it is far from clear how tuberculosis therapy should be used in this patient population in sSA, and due to lack of data, it is not possible to make any recommendations from the studies we identified. Further studies are needed to guide clinicians in the best use of tuberculosis diagnostic tests or empiric therapy in sepsis, as are pharmacokinetic studies of tuberculosis therapy in the critically unwell.We identified relatively few studies. Existing studies were geographically restricted: Uganda contributed 8/15 studies, for example, and Zambia 3/15. Several institutions—largely tertiary referral centres—contributed multiple studies. Most studies excluded surgical or obstetric patients. The studies largely used a Sepsis-2 definition of sepsis and severe sepsis, though with a number of modifications, making between-study comparisons difficult. Development of easily applicable sepsis definitions for low-resource settings—or pragmatic modification of currently used screening scores such as qSOFA—could significantly increase the generalisability and utility of the evidence base in sSA.There are weaknesses to our review, including that our searches may have missed studies. We excluded studies in preselected populations  to maximise the generalisability of our findings and minimise potential bias. These populations were also excluded a priori by identified studies, leading to lack of generalisability to surgical or pregnant patients. Much of sSA is unrepresented, potentially leading to bias from geographical restriction. Similarly, the results may not generalise to sepsis in district hospitals, or primary health care facilities, given the predominance of studies from tertiary facilities. The heterogeneity in mortality estimates means that the summary estimates should be regarded with caution. As with all meta-regression, there is the possibility of confounding or ecologic bias. Where it was not possible to disaggregate data from identified studies, we did not attempt to access individual participant-level data. Assessing risk of bias for observational studies is difficult, with no recognised gold standard. We chose to use the Newcastle-Ottawa score, a frequently used tool, but one which has recognised problems with reliability and validity , 43 and We have demonstrated that sepsis in sSA is dominated by the high prevalence of advanced HIV, subjecting a younger population to a high risk of sepsis of different microbial aetiology to high-income/low-HIV settings. Short-term outcomes are poor despite the younger age of sepsis patients compared to high-income settings, whilst long-term outcome data and morbidity data are absent. Data on sepsis aetiology beyond bloodstream infection and malaria are lacking though tuberculosis clearly plays an important role, which has implications for selection of appropriate antimicrobial therapy, though further studies are needed to develop an evidence base for the treatment of tuberculosis in the critically ill. Development and deployment of easily applicable sepsis definitions would help improve our understanding of the burden of sepsis in sSA and intervention studies aimed at the distinct population in sSA are urgently needed.Box 1: Systematic review search termsSepsis AND  OR Africa)Additional file 1:Modified Newcastle-Ottawa Quality Assessment Scale. (PDF 31 kb)Additional file 2:Results of quality assessment using modified Newcastle-Ottawa scale. Numbers are a normalised score for a given domain between 0  and 1 . (PDF 5 kb)Additional file 3:Inclusion and exclusion criteria for included studies. (DOCX 16 kb)Additional file 4:Availability of diagnostic testing by study. (DOCX 15 kb)Additional file 5:Species of pathogenic bacteria isolated from aerobic blood culture. NTS = non-typhoidal Salmonellae (PDF 5 kb)


In addition to histopathological parameters, evaluation of associated hematological factors is essential for devising a sensitive prognostic scale in glioma. Increased neutrophil-lymphocyte ratio (NLR), a marker of systemic inflammatory response, has recently been associated with worse outcome in various cancers. Given that glioma progression is characterized by inflammation, aggressive angiogenesis, and invasion, increased levels of systemic human-chitinase-3-like-one protein (YKL-40) have also been linked to poor prognosis. The aim of the present study was to assess the plausible association of YKL-40, NLR, and platelet count with increasing tumor grade, and evaluate their status as independent prognostic factors in terms of overall survival (OS) in treatment naive patients with diffuse glioma. Plasma levels of both biochemical markers in 72 diffuse gliomas, median age 42 years, were compared with 36 controls. Comparison of YKL-40, NLR, and PC with respect to tumor grade was found to be significant for each of the markers (P <0.0001) while an inverse significant correlation was seen for YKL-40 and NLR with OS . NLR was the best performing marker with AUC 0.9417 at 97% specificity. In addition, YKL-40 had a positive correlation with NLR , indicating that expression of both markers was linked to inflammation and tumor progression as they were significantly correlated with tumor grade. Expression of YKL-40 and NLR was independently associated with worse survival , thus establishing their clinical utility as prognosticators for diffuse gliomas. Gliomas are aggressive and lethal brain cancers  with a mCHI3L1 expression appears to be an important hallmark of inflammation and cancer has been frequently observed in patients with poor prognosis , an acute-phase glycoprotein, is elevated in cancers and inflammatory diseases  but its rognosis .O-methylguanine-DNA methyltransferase (MGMT)  status  is linked to vessel wall integrity and upon activation; these cells release factors which affect angiogenic activity . The prePatientsA total of 72 patients admitted for surgery with an initial radiological diagnosis of suspected glioma were considered for this study. Inclusion criteria were- both symptomatic males and females with neurological deficit and no prior chemotherapy or radiotherapy. Glioma grade  as confirmed by histopathological report, and control subjects without any recent clinical history of inflammation as indicated by their biochemical profile, were taken up for analysis. Exclusion criteria was low grade I glioma (pilocytic).Variable factors such as age, site of tumor  and extent of resection in terms of gross total resection (GTR) and subtotal resection (STR) were tabulated from surgical records. The identified biomarkers were compared with baseline values of 36 healthy subjects which served as controls. The study was a part of the project approved by the institutional ethics committee (IEC/21/Res/11) and all subjects provided written informed consent.All patients were on steroids 24 h prior to surgery. Computed tomography (CT) or magnetic resonance imaging (MRI) was used for initial identification and localization of the tumor. OS time was calculated as the length of time from the start of treatment for glioma till the date of death for a deceased patient, or up to the last follow-up for a surviving patient.Sample collection and storageUpon obtaining informed consent, 3 ml of peripheral blood was collected from each pre-surgery patient and also from healthy volunteers. Samples were processed at 12 ᵒC, plasma was separated and divided into aliquots, then frozen at -80 °C for further experimentation.Blood CountThe pre-operative total WBC count along with the percentage of neutrophils and lymphocytes were provided by the pathologist to estimate the absolute neutrophils and lymphocyte counts. NLR and PC were then calculated from this full blood count performed before intervention.YKL-40 evaluationPlasma YKL-40 concentrations (ng/mL) were determined by a sandwich ELISA assay using the commercial kit from R&D Systems, USA . The protocol was executed according to the manufacturer’s instructions. All samples were analyzed in duplicate. YKL-40 levels were measured as absorbance at 450 nm with the correction wavelength set at 540 nm.IgE assessmentSerum IgE levels were recorded from the clinical profile of the patients to confirm that they had no infection at the time of blood sampling. Values were compared within study groups to demarcate that elevated levels of YKL-40 and NLR were due to inflammation on tumor initiation.Statistical analysis -rank analysis. Patients who were still alive at last contact were treated as censored events in the analysis. Multivariate Cox regression was performed to calculate hazards ratio (HR) with 95% confidence interval (CI) for each biomarker as a continuous variable. A 2-sided P < 0.05 was taken as statistically significant.Kruskal-Wallis test was applied to assess the significance of preoperative levels of each biomarker YKL-40, NLR and PC with tumor grade. Mann-Whitney test was performed to compare YKL-40, NLR and PC with OS, when the patients were stratified into 2 groups based on OS of ≤ 15 and >15 months. Spearman’s correlation coefficient was used to calculate the strength of the relationship of markers with tumor grade and OS. With respect to YKL-40, NLR and PC, receiving operating characteristic (ROC) curve analysis was performed to determine the cut-off value of each biomarker for predicting survival with high sensitivity and specificity. Survival curves were made using Kaplan-Meier method, and compared using logPatients profileThis is the first cross-sectional study on treatment-naive patients with diffuse glioma  to assess preoperative YKL 40, NLR, and PC as independent prognostic indicators. The reported tumor grade was taken as a base criterion, and the samples were further stratified on the basis of WHO classification, 2016 . 23 caseStatistical analysis using Kruskal-Wallis test (non-parametric) for comparison of YKL-40, NLR and PC with respect to tumor-grade was found to be significant for YKL-40 (P < 0.0001), NLR (P < 0.0001), and PC (P <0.0001)  indicatiMann-Whitney test revealed that all three parameters, YKL-40, NLR, and PC were significantly different in patients with OS of ≤ 15 and >15 months .CorrelationThe correlation of preoperative YKL-40, NLR, and PC with OS was analyzed using Spearman’s rho correlation coefficient. A significant positive correlation of YKL-40 , NLR  and PC  was obtained with respect to tumor grade while a significant inverse correlation of YKL-40 , NLR , and PC  was reached with OS. These statistics indicated that all the three markers were significantly correlated with tumor grade and OS. In addition, YKL-40 had a positive significant correlation with NLR , indicating that expression of both markers was linked to inflammation. Since YKL-40 and NLR had a positive correlation with tumor grade, it indicates that as the tumor progresses, the levels of YKL-40 and NLR would increase concomitantly. Hence, both markers can be taken to connote the tumor load of a glioma patient.ROC curve analysis The AUROC analysis provided an optimal cut-off value for YKL-40, NLR, and PC to differentiate between control and glioma patients. Area under the curve (AUC) for YKL-40, NLR, and PC was 0.8792 (P<0.0001), 0.9417 (P<0.0001), and 0.7508 (P<0.0001), respectively at >80% sensitivity and specificity for all markers .Kaplan-Meier method and log-rank testIn lieu of the above results, comparison of survival curves between control and glioma patients with optimal cut-off value to best predict survival using log-rank (Mante-Cox) test was undertaken. Patients with a value of YKL-40 exceeding 42.55 were found to differ significantly from those with values <42.55 and had a decreased survival time . Value of NLR exceeding 2.775 was found to differ significantly from those with an NLR quotient of < 2.775, and could even distinguish low grade glioma. A decreased survival time   was recoMultivariate Cox proportional hazards ratioIncrease in systemic levels of YKL-40 and NLR was independently associated with worse survival in glioma. When these markers were analyzed as continuous variables, Cox proportional hazards analysis demonstrated a trend towards significantly worse OS for both the prognostic markers YKL-40 and NLR .We also performed multivariate analysis of the established confounding factors i.e. age, site of tumor, and extent of surgical resection; which showed that higher plasma levels of YKL-40 and NLR were not associated with age , site , and extent of resection .The effect of chronic inflammation that develops in the glial tumor microenvironment has far reaching consequences beyond its tumor initiating effect, as it adds on to glioma progression, a stage of the disease that loops back, adding to the intensity of the underlying inflammation.Experimental studies suggest that inflammation has an important place in the carcinogenesis of high grade gliomas , 21 whicHigher serum levels of inflammatory marker YKL-40 are associated with poor prognosis as ascertained in studies on cancer , and alsIn this reference, Schultz et al. have shown that repetitive freezing and thawing of plasma samples up to nine times has no effect on plasma YKL-40 levels (36). They documented YKL-40 in plasma to increase by more than 25% following an inflammatory stimulus, thus making it easily detectable. Since plasma reﬂects the biology of not only tumor cells but also the microenvironment, it becomes a more reliable sample type to evaluate YKL-40 in combination with a panel of other biomarkers for monitoring progress of disease activity.A significant inverse correlation of PC with OS (P <0.0001) and positive association with tumor grade (P =0.002) was found in test group. In support is the study of 24 glioblastoma patients (37), stating that elevated preoperative platelet counts are associated with significantly shorter survival (38). But our comparison of PC with OS based on AUROC analysis cut-off was non-significant, thereby indicating that PC cannot be taken as a prognostic indicator; which is supported by two earlier negative studies in glioblastoma patients .Our findings demonstrate that values of markers of inflammation, that is YKL-40 and NLR, correlate with tumor grade and OS in therapy-naive diffuse glioma. Comparison of IgE levels within study groups confirmed that elevated values of YKL-40 and NLR were due to tumor burden, establishing the credibility of these circulating markers.The present investigation clearly delineates that preoperative YKL-40 and NLR can be efficaciously used to follow up diffuse glioma to assess the disease outcome, after adjusting for associated variables of age, tumor site, and extent of resection. The result of this study further identifies the need for validation of these easily accessible, cost-effective, minimally invasive parameters in larger multicentric cohorts; before they can be incorporated into clinical care.


Klebsiella pneumoniae (CRKP) strains that also exhibit resistance to tigecycline and colistin have become a major clinical concern, as these two agents are the last-resort antibiotics used for treatment of CRKP infections. A leukemia patient infected with CRKP was subjected to follow-up analysis of variation in phenotypic and genotypic characteristics of CRKP strains isolated from various specimens at different stages of treatment over a period of 3 years. Our data showed that (1) carbapenem treatment led to the emergence of CRKP in the gastrointestinal (GI) tract of the patient, which subsequently caused infections at other body sites as well as septicemia; (2) treatment with tigecycline led to the emergence of tigecycline-resistant CRKP, possibly through induction of the expression of a variant tet(A) gene located in a conjugative plasmid; (3) colistin treatment was effective in clearing CRKP from the bloodstream but led to the emergence of mcr-1-positive Enterobacteriaceae strains as well as colistin-resistant CRKP in the GI tract due to inactivation of the mgrB gene; and (4) tigecycline- and colistin-resistant CRKP could persist in the human GI tract for a prolonged period even without antibiotic selection pressure. In conclusion, clinical CRKP strains carrying a conjugative plasmid that harbors the blaKPC-2 and tet(A) variant genes readily evolve into tigecycline- and colistin-resistant CRKP upon treatment with these two antibiotics and persist in the human GI tract.Emergence of carbapenem-resistant  Widespread dissemination of carbapenem-resistant Enterobacteriaceae (CRE) in clinical settings threatens to take medicine back to the preantibiotic era, and current efforts to invent and discover new antibiotics apparently have failed to reverse this ominous trend. To address this problem, there has been renewed interest in antibiotics such as the polymyxins, which have not been used clinically due to their relatively high toxicity3. However, this last hope has been tarnished by the recent discovery of a transmissible element that encodes resistance to polymyxins4. This element, a plasmid-borne mcr-1 gene, was found to encode an enzyme that can modify the structure of lipid A in the molecule of lipopolysaccharide in Gram-negative bacteria, enabling them to exhibit resistance to polymyxins such as colistin. However, the potential risk of dissemination of the mcr-1 gene among clinical strains is not clear. Apart from colistin, most clinical CRE strains exhibited high sensitivity to tigecycline. Although the exact molecular mechanism that renders tigecycline effective in treating infections caused by CRE is not well-defined, the drug has been widely used in combination with other antibiotics such as carbapenems to treat CRE infections in clinical settings, particularly in China, where colistin was not approved for clinical use and ceftazidime/avibactam was not available. In this study, we reported a comprehensive microbiological follow-up study of clinical strains recovered from a leukemia patient at various stages of treatment, including chemotherapy, hematopoietic stem cell transplantation, and recovery, over a period of 3 years. The data obtained provide insightful information on the evolution events that lead to the emergence of colistin- and tigecycline-resistant CRKP and the persistence of such strains in the gastrointestinal (GI) tract of the patient.Multidrug-resistant bacterial pathogens that have emerged in the past decade are characterized by possession of extrachromosomal resistance elements that can undergo cross-species transmission, as well as expression of resistance mechanisms that render last-resort antibiotics, such as the carbapenems, ineffective for clinical applicationsA 29-year-old male patient was admitted to the second affiliated hospital of Zhejiang University, Hangzhou, China, in August 2014 with complaints of toothache and fever for over 1 week. A diagnosis of acute monocytic leukemia was made and the patient received chemotherapy and antimicrobial treatment with meropenem and vancomycin. Exhibiting signs of a lung infection on September 6, 2014, he was given a combination of meropenem and isepamicin for 5 days before being discharged from the hospital. The patient was readmitted for a second round of chemotherapy on September 29 and developed a fever, but was discharged upon treatment with meropenem, isepamicin, and vancomycin for 2 weeks. Blood and sputum cultures remained negative during this period  strain, KP2, was isolated for the first time from a fecal sample  and diarrhea and was again given a combination of meropenem and isepamicin. One The patient underwent hematopoietic stem cell transplantation in April 2015 and received prophylactic treatment with piperacillin-sulbactam. With fever and diarrhea developing soon afterwards, the treatment was reinforced by teicoplanin and posaconazole. A CRKP strain, KP3, was recoverable from a fecal sample. Diarrhea symptoms soon worsened, resulting in bloody stool and tenesmus. Meropenem treatment continued for 3 days before switching back to piperacillin-sulbactam and tigecycline. KP3 type strains remained detectable in stool, and a CRKP strain, designated as KP4, was isolated for the first time from blood in May 2015. The patient developed a high fever that reached 40 °C and was given high doses of tigecycline, isepamicin, and fosfomycin. Two more isolates, KP5 and KP6, were isolated from blood samples on the 18th and 24th of May 2015, respectively. A right liver lobe abscess was observed on May 29 when another fecal CRKP strain, designated KP7, was isolated , indicating that colistin selected its own resistance during the treatment process . Two mcr-1 positive E. coli isolates, which were recovered from fecal samples collected in November 2015 and designated EC-Y9 and EC-Y10, respectively, were also subjected to microbiological and genetic characterization , and then polymyxin B (IV). Colistin treatment was started with polymyxin B with 1 million units IV every 8 h and then changed to colistin with the same dose from June 3, 2015 to November 30, 2015. During treatment, CRKP was detectable in sputum, and both CRKP and mcr-1-positive Enterobacteriaceae and CRKP persisted in his GI tract, we performed fecal isolation for these organisms in October 2016. CRKP strains, but not mcr-1-positive Enterobacteriaceae, were recoverable from fecal samples. We designated these CRKP strains as KP12–KP17, respectively. Another seven follow-up procedures were performed, and similar results were obtained , PFGE pattern, and carriage of antibiotic resistance genes. The first K. pneumoniae strain isolated from the patient, KP1, was found to be susceptible to carbapenems and belong to ST1. However, strains KP2 through KP17 were all resistant to carbapenems and found to belong to ST11, the most common ST of CRKP in the hospital environment, indicating that such strains were likely to be hospital-acquired upon treatment with carbapenems. All CRKP strains tested exhibit highly similar PFGE profiles and harbored the blaKPC-2 and blaCTX-M-9 elements, confirming that a single strain was responsible for the infection. S1-PFGE and Southern hybridization confirmed that the blaKPC-2 gene was located in a ~ 60-kb plasmid. Our findings show that once emerged in the GI tract, the CRKP strains were already resistant to multiple antibiotics and not readily eradicated even with intensive and prolonged antimicrobial treatment, which resulted in further enrichment of CRKP strains within the gut microbiome and enhancement of the risk of untreatable opportunistic infections in the immunocompromised patient.7. The use of colistin treatment indeed cleared CRKP from the bloodstream, however, such a strain remained detectable in fecal samples from the patient. Interestingly, upon the use of colistin, the tigecycline-resistant CRKP strain further evolved to become resistant to colistin, with KP10 being the first such strain recovered from the patient. This tigecycline- and colistin-resistant CRKP strain has persisted in the GI tract of the patient for more than 2 years  6 months later when the patient was subjected to hematopoietic stem cell transplantation, suggesting that CRKP in the GI tract would readily cause infections in other sites of the body when the host defense system is weakened Table . Upon trmcr-1-positive Enterobacteriaceae strains became detectable in fecal samples, presumably due to selection of a preexisting resistant subpopulation or acquisition of these strains from other resources , as well as other plasmids derived from E. coli of animal origin (pECJC-B65-33), whereas the ~60-kb, mcr-1-bearing plasmid was similar to the original mcr-1-bearing plasmid pHNSHP454. The data suggested that these two mcr-1-carrying plasmids were readily transmitted among Enterobacteriaceae. Nine months after the discharge of the patient (from December 2015 until September 2016), the mcr-1-positive Enterobacteriaceae strains could not be recovered from the GI tract of the patient, suggesting that without colistin selective pressure, mcr-1-positive Enterobacteriaceae could be reduced to an undetectable level.Another interesting observation is that 4 weeks after continuous treatment with colistin, es Table . Since tdy Table . ConjugaK. pneumoniae was due to carriage of a tet(A) variant in a conjugative plasmid, pKPC-CR-HvKP267 (MG053313), which also contained a blaKPC-2-bearing element9. Alignment of the Illumina reads of these strains against this plasmid demonstrated that these strains all carried a similar type of plasmid that lacked a fragment containing the an aac(3)-IId gene when compared to pKPC-CR-HvKP267. Several plasmids also lacked the mer gene cluster. However, all plasmids were found to carry the blaKCP-2 gene and a tet(A) variant identical to that harbored by pKPC-CR-HvKP267. Interestingly, strains KP4 and KP7 were susceptible to tigecycline, yet harbored the same plasmid and the tet(A) variant, suggesting that the tet(A) gene was not expressed under normal conditions but inducible upon prolonged treatment with tigecycline  was performed on eight strains collected at different stages, namely KP4 (Accession no.: SAMN08725539), KP7 (Accession no.: SAMN08725538), KP10 (Accession no.: SAMN08725534), KP11 (Accession no.: SAMN08725535), KP12 (Accession no.: SAMN08725536), KP13 (Accession no.: SAMN08725537), KP16 (Accession no.: SAMN08725533), and KP17 (Accession no.: SAMN08725532) Table . Pairwisine Fig. .Fig. 2PhK. pneumoniae can be mediated by inactivation of the mgrB gene through insertion of insertion sequence (IS)10. Genome analysis of these strains showed that strains KP10 through KP17 carried an IS903B element between the 13th and 14th base pair of mgrB, yet the mgrB gene in strains KP4 and KP7, which were susceptible to colistin, was not inactivated by an IS element. These findings show that prolonged use of colistin could induce colistin resistance through inactivation of the mgrB gene .CRKP strain KP10 and subsequently recovered strains became colistin resistant due to the prolonged use of colistin in the patient. It has been reported that colistin resistance in ene Fig. . All CRK13. Such strains are readily acquired in the hospital environment and further selected upon antibiotic treatment, thereby contributing to further transmission of CRKP in clinical settings. The GI tract of patients could be considered as a reservoir and incubator of CRKP, and should therefore be regarded as a target of intervention in the development of novel hospital infection control policies. Most importantly, the CRKP strains located in the GI tract could be transmitted to other organs such as the lungs, and cause infection or even septicemia under various circumstances such as during surgery or chemotherapy.This report, which describes a long battle against a series of bacterial infections that occurred in an immunocompromised patient, provides insightful information regarding the choice of antibiotics in the management of infections caused by CRKP and the possible treatment outcomes. Our data indicate that colonization and enrichment of CRKP in the human GI tract have become common events, presumably due to frequent episodes of antibiotic treatment, which results in a significantly higher risk of untreatable opportunistic and systemic infections in cases in which the host defense system has weakened. To date, carriage of CRKP in the GI tract of hospitalized patients has become commonplace15. Furthermore, treatment with tigecycline could lead to induction of tet(A) gene expression in tigecycline-susceptible CRKP strains that carry the tet(A) variant, leading to the development of tigecycline resistance. The tet(A) gene was found in a conjugative plasmid that also harbored the blaKPC-2 gene. This plasmid is commonly harbored by clinical CRKP strains; hence, development of tigecycline resistance readily occurs among such strains upon tigecycline treatment. On the other hand, our data showed that intravenous treatment with colistin could effectively eradicate CRKP from blood. However, the use of colistin could also lead to the development of colistin-resistant CRKP strains through IS element-mediated inactivation of the mgrB gene. These tigecycline- and colistin-resistant CRKP strains cannot be cleared by colistin in the human GI tract and can persist for a long period even without antibiotic selection pressure. The role of colistin in treating CRKP infections was limited as resistance to this antibiotic readily develops and persists. In China, the colistin resistance rate among clinical CRKP strains remains relatively low, presumably because colistin has not been approved for clinical use in China until recently. The rate of colistin resistance in clinical CRKP is worthy of close monitoring as colistin was approved for clinical use in early 2018. Although prolonged usage of colistin could lead to selection of mcr-1-positive, colistin-resistant Enterobacteriaceae strains, such strains appear to be confined to the GI tract and rarely cause infections in other organs; this idea is consistent with findings in the current study in that septicemia caused by mcr-1-bearing Enterobacteriaceae strains is rare16. Nevertheless, since mcr-1-bearing CRKP strains have been reported by other studies20, the clinical value of colistin as a last-resort antimicrobial agent is expected to erode rapidly. Another choice of treatment for CRKP is ceftazidime-avibactam, which has been shown to be effective in treating CRKP infection22. However, this antibiotic is currently unavailable in China and its efficacy in clearing CRKP in this patient was not tested.Choices for treatment of CRKP infections are extremely limited. A high dose of carbapenems is still considered as one therapeutic option despite minimal effectiveness. As most clinical CRKP strains exhibit sensitivity to tigecycline in in vitro minimum inhibitory concentration (MIC) tests, this drug is widely used in combination with carbapenem in the treatment of CRKP infections. However, our data showed that combined treatment of CRKP bloodstream infection with tigecycline and other antibiotics such as carbapenems was not particularly effective in clearing CRKP from the bloodstream, which was consistent with several earlier reportstet(A) and blaKPC-2 genes, suggesting that tigecycline or colistin treatment of infections caused by these strains would significantly enhance development of tigecycline and/or colistin resistance among these strains. A comprehensive surveillance program also needs to be established to monitor the variation of the prevalence of these CRKP strains and their impact on human health. New therapeutics to combat infections caused by these types of strains are also urgently required.Phylogenetic analysis showed that the majority of CRKP strains tested in this study were genetically related. A significant proportion of such strains were also found to harbor structurally similar conjugative plasmids that contained the mcr-1-bearing Enterobacteriaceae strains from fecal samples was performed as described previously23. The isolation of carbapenem-resistant Enterobacteriaceae from fecal samples was performed as follows. Approximately, 5 g of feces from the patient was spread onto Salmonella-Shigella agar plates supplemented with 0.5 μg/ml meropenem for 18 h; more than 20 single colonies were picked for further purification and detection of carbapenemase genes by polymerase chain reaction (PCR) as previously described24. All mcr-1-positive and carbapenem-resistant Enterobacteriaceae isolates were identified using the Vitek 2 system  and confirmed by a MALDI-TOF MS apparatus .Bacteria in blood and sputum samples were isolated according to standard procedures. The isolation of 25. MICs for colistin and tigecycline were determined using the broth dilution method. The 2014 EUCAST breakpoints were used  for tigecycline.The MICs for indicated antibiotics, as shown in Tables blaVIM, blaIMP, blaKPC, blaOXA-48, and blaNDM-1 as well as the extended-spectrum β-lactamase genes blaCTX-M, blaTEM and blaSHV, as described previously26. Screening of mcr-1 was performed as previously described23.PCR and nucleotide sequencing were employed to screen for the carbapenemase-encoding genes 27. Conjugation experiments, S1-PFGE and Southern hybridization were performed as previously described24. MLST targeting seven housekeeping genes was performed in blaNDM-1-bearing E. coli, K. pneumoniae, and E. cloacae isolates, using primers listed in online databases . The resultant PCR products were purified and sequenced. STs were assigned using online database tools.Pulsed-field gel electrophoresis  was used to assess the genetic relatedness between the test isolates and the corresponding transconjugants as described previouslyde novo by the SPAdes Genome Assembler v3.9.128. The draft genomes were annotated with the RAST tool29 and Prokka30. Genome sequence comparison was performed using the BLAST Ring Image Generator (BRIG)31. Pangenome analysis was conducted using the Roary Pangenome analysis pipeline based on the Prokka annotation32. SNPs were determined by the CSI Phylogeny 1.4 [www.genomicepidemiology.org), using default settings and WGS raw reads. Capsular typing was performed on the assembled sequences using Kaptive33. The genome sequences were deposited into GenBank.Genomic sequencing was performed by means of the Illumina NextSeq 500 sequencing platform. Raw Illumina reads were trimmed or filtered to remove low-quality sequences and adapters, and assembled


Facilitating patients’ involvement with 12-step self-help organizations, such as Alcoholics Anonymous (AA) and Narcotics Anonymous (NA), is often a goal of substance abuse treatment. Twelve-step-facilitation (TSF) interventions have been found to be more effective than comparison treatments in increasing patients’ 12-step group involvement and in promoting abstinence. Future TSF evaluation research should address the effectiveness of incorporating TSF interventions with cognitive-behavioral treatment methods, the relative impact of brief versus extended TSF interventions, and the cost-effectiveness and health care cost-offset of TSF interventions within managed health care systems. Although the United States has developed an extensive array of professional alcohol treatment services over the past 30 years, the peer-led, voluntary fellowship known as Alcoholics Anonymous (AA) continues to be the most widely accessed resource for people with alcohol problems . This arThe rationale for facilitating patients’ involvement in 12-step self-help groups stems primarily from recent AA outcome research and from developments in the management and organization of health care in the United States. From the 1940s through the 1980s, most studies on AA did not directly evaluate AA’s effectiveness. Rather, researchers examined AA’s organizational structure and functioning; its history; and the ways in which AA participation changed members’ values, sense of identity, and spiritual outlook -sponsored conference on AA , the IntThe other major factor that has enhanced interest in 12-step facilitation (TSF) interventions is the growth of managed health care. In both the public and private sectors, managed care has reduced the length and intensity of professional addiction treatment services  and incrOne large study, known as Project MATCH, compared a TSF intervention with cognitive-behavioral (CB) therapy and motivational enhancement therapy (MET) among 1,726 patients  diagnosed with either alcohol abuse or dependence, including 774 inpatients who were beginning outpatient aftercare and 952 patients receiving outpatient care as their primary treatment , 1998. CThe TSF intervention in the Project MATCH study was a form of one-on-one professional counseling explicitly designed to work synergistically with AA and other 12-step groups . ConsistAcceptanceAcceptance by patients that they suffer from the chronic and progressive illness of alcoholismAcceptance by patients that they have lost the ability to control their drinkingAcceptance by patients that because there is no effective cure for alcoholism, the only viable alternative is complete abstinence from the use of alcoholSurrenderAcknowledgment on the part of the patient that hope for recovery  exists, but only by accepting the reality of loss of control and by having faith that some higher power can help the patient, whose own willpower has been defeated by alcoholismAcknowledgment by the patient that the fellowship of Alcoholics Anonymous (AA) has helped millions of alcoholics sustain their sobriety and that the patient’s best chances for success are to follow the AA pathSOURCE: Adapted from At both 1- and 3-year followups, patients in all three conditions  had improved significantly on drinking-related , psychological , and life-functioning  outcomes. As predicted, TSF therapy was significantly more effective than either CB therapy or MET in increasing AA involvement, as indicated by the frequency of such patient behaviors as attending meetings, having and serving as a sponsor, following the 12 steps, and considering oneself an AA member . In addiSome Project MATCH participants who had received MET or CB therapy attended AA on their own, even though AA was not a focus of their treatment. The Project MATCH team examined whether those patients benefited less from AA affiliation than did those patients who had received TSF therapy . Among tConcurrent with Project MATCH, the Department of Veterans Affairs (VA) conducted a nationwide treatment evaluation with more than 3,000 male substance abuse inpatients, who provided data when they entered treatment, when they were discharged, and 1 year later.  and other AA/NA literature, and accepting the identity of alcoholic/addict. Staff members in these programs strongly endorsed the disease model of addiction and reported spending most of their time on 12-step treatment activities. The study’s five CB treatment programs required that patients participate in relapse prevention groups, cognitive skills training, and cognitive-behavioral group therapy. Analysis of program schedules showed that CB programs spent less than 5 percent of treatment time on activities based on 12-step principles.The VA study included five 12-step-oriented inpatient programs, which emphasized treatment activities such as attending 12-step group meetings in the community and onsite, following the 12 steps, reading the The study participants  were treated in either a 12-step-oriented or a CB inpatient program and were followed up 1 year after discharge. Thirty-six percent of the participants had either an alcohol abuse or dependence diagnosis only, 13 percent had only a drug abuse or dependence diagnosis, and 51 percent had both drug and alcohol diagnoses.Before treatment, patients in 12-step-oriented and CB programs had similar levels of self-help group involvement. However, 1 year after treatment, the patients who had received 12-step-oriented treatment reported substantially greater involvement in AA/NA during the previous 3 months than did patients who had received CB treatment. Patients in 12-step-oriented treatment were significantly more likely than those in CB treatment to have attended 12-step meetings, to have a sponsor, to have read 12-step literature, and to have a friend who attends meetings see , above, The results of the VA study closely parallel those of Project MATCH. In both 12-step-oriented and CB treatment, patients experienced substantial reductions in substance use, substance abuse-related problems, psychological problems, criminal behavior, and unemployment . The redLike Project MATCH, the VA study also found some evidence suggesting that 12-step self-help group involvement after treatment may be more beneficial for patients who have received 12-step-oriented treatment, compared with patients who have received CB treatment. Among patients who received 12-step-oriented treatment, abstinence rates 1 year after treatment varied from 19 percent for patients with low involvement with self-help groups after treatment to 75 percent for patients with high involvement. Among patients who received CB treatment, abstinence rates ranged from 25 percent for patients with low involvement in self-help groups after treatment to 65 percent for patients with high involvement. This difference was statistically significant, indicating that 12-step self-help group involvement after treatment seems to benefit patients treated in 12-step-oriented programs more than it does patients treated in CB programs .A third study comparing a TSF intervention with other treatment focused on 60 heterosexual couples in which the men were diagnosed with either alcohol abuse or dependence and their female partners were not. As part of a larger study, the couples received either outpatient, alcohol-focused, CB marital therapy only (MT-only), or the MT intervention supplemented with counseling designed to facilitate involvement in 12-step self-help groups (MT+TSF) . The TSFPatients in both the MT-only condition and the MT+TSF condition attended an average of approximately 10 outpatient sessions. Patients in the MT+TSF condition were more likely than those in the MT-only group to attend 12-step group meetings during treatment. Eighty-two percent of MT+ TSF patients attended AA meetings, and 58 percent attended Al-Anon meetings, compared with attendance rates of 15 percent and 5 percent, respectively, among patients in the MT-only group. At 6 months after treatment, however, about half the patients in both groups were either abstinent or engaged in nonproblem drinking, indicating that supplementing CB marital therapy with TSF did not appear to enhance the effectiveness of the intervention.When analyzed together, the results from Project MATCH, the VA study, and the couples study  simply an indicator of patient motivation; rather, it is a behavior that clinicians can influence. The optimistic implication is that by incorporating 12-step facilitation into treatment, providers can increase the likelihood that patients will continue to improve even after professional treatment has ended.Twelve-step-oriented treatments that increase involvement in 12-step self-help groups generally produce outcomes comparable with those of CB treatments and are somewhat more effective in promoting abstinence. Project MATCH and the VA study provide strong evidence that 12-step-oriented treatments are as effective as more heavily researched CB interventions. This finding increases confidence in the U.S. substance abuse treatment system, because many of the prevalent treatment modalities in the United States draw heavily on 12-step principles .Combining CB treatments with AA/NA affiliation may be less helpful to patients than combining 12-step treatment with AA/NA affiliation. None of the studies discussed were specifically designed to address whether positive results are maximized when treatment and self-help groups operate from a similar orientation; thus, this statement is more a working hypothesis than a firm conclusion. Perhaps patients who hear contradictory messages about substance abuse from treatment providers and self-help groups have more difficulty understanding and practicing treatment regimens. To evaluate this possibility, CB treatment providers could develop interventions that promote involvement in CB-oriented self-help groups  and determine whether such interventions enhance outcomes more than do TSF interventions. An alternative explanation for the findings to date is that the subset of patients who switch from CB treatment to 12-step self-help groups do so because they find CB treatment ineffective and seek an alternative that is better matched to their needs.This hypothesis would be an excellent one for future research. Other potential research directions are presented in the following section.The studies reviewed above clearly demonstrate that TSF interventions that engage patients for a significant period .A third key priority for future research is to more fully understand the health care cost offset and cost-effectiveness of TSF interventions. One study of 227 industrial plant workers with alcohol problems  found that patients assigned directly to AA had similar work-related outcomes but more relapses than did patients assigned to inpatient treatment followed by AA. At the same time, patients initially assigned to AA had 10-percent lower alcohol-related health care costs over a 2-year period than did patients initially assigned to inpatient treatment . SimilarThanks in part to support from Federal agencies, research on TSF interventions and AA has expanded significantly in recent years. The next decade will offer researchers and clinicians the opportunity to build on this foundation. AA and other self-help organizations are the most commonly sought resource for substance abuse problems in the United States, currently reaching more than 1 million Americans ; determi


This study aimed to examine association between perioperative uses of aspirin and long-term survival in patients undergoing CABG. A retrospective cohort study was performed in 9,584 consecutive patients receiving cardiac surgery from three tertiary hospitals. Of all the patients, 4,132 patients undergoing CABG met inclusion criteria and were divided into four groups: with or without preoperative or postoperative aspirin respectively. 30-day postoperative and long-term mortality were compared with the use of propensity scores and inverse probability weighting adjustment to reduce the treatment-selection bias. The patients taking preoperative aspirin presented significantly more with comorbidities. However, the results of this study showed that preoperative aspirin (vs. no preoperative aspirin) was associated with significantly reduced the risk of 30-day mortality in the patients undergoing CABG. Further, the results of long-term mortality showed that the patients taking preoperative aspirin and postoperative aspirin (vs. not taking) were associated with significantly reduced the risk of 4-year mortality . In conclusion, this cohort study showed that perioperative (before and after surgery) use of aspirin was associated with significant reduction in 30-day mortality without significant bleeding complications, also improved long-term survival in patients undergoing CABG. Concerning aspirin use in patients with CABG, however, the outcome results from randomized clinical trials (RCTs) and observational studies have been mixed and inconsistent4. Several meta-analyses in the area have showed that preoperative aspirin reduced perioperative MI, but was associated with an increased risk of reoperation, transfusion and bleeding. However, these meta-analyses were based upon early RCTs that were small and underpowered for efficacy outcomes4. The observational studies in the area showed that preoperative aspirin was associated with a decreased risk of perioperative complications and death, with or without an increased risk of bleeding9. In 2011, the American Heart Association and American College of Cardiology (AHA/ACC) recommended that aspirin (100 mg-325 mg daily) should be administered to CABG patients preoperatively10, although conflicting guidelines existed concerning preoperative aspirin and cardiac surgery12. In 2016, a large RCT led by Myles et al. showed that among 2,100 patients undergoing CABG with or without valve surgery, preoperative aspirin (100 mg) given on the day of surgery did not reduce risk of primary outcome including 30-day death, MI, stroke, renal failure, pulmonary embolism or bowel infarction, nor did increase the risk of bleeding13.Aspirin is one of the most common used drugs in preventing and treating cardiovascular disease (CVD) and its complications. In 2002, Antiplatelet Trialists’ Collaboration led by Baigent 16. Thus, this study aimed to examine association between perioperative (before and after surgery) use of aspirin and long-term survival in patients undergoing CABG.The length of follow-up is one of major limitations in most previous studies in the area of aspirin effects on cardiac surgery. Moreover, it remains unknown about perioperative aspirin’s effect on the long-term survival in patients undergoing CABG surgery. Thus far, a few studies have showed that aspirin started before or after surgery, improved vein graft patency up to 1 year after CABGAmong 4132 included patients, 76.5% received preoperative aspirin (PreASA), 23.5% did not (no-PreASA), 92.3% received postoperative aspirin (PostASA) and 7.7% did not (no-PostASA) respectively . As the value of C statistic showed, the multivariate regression analysis for preoperative aspirin, achieved an acceptable discrimination between two groups .The mean, median, and interquartile range of the follow-up time for 4132 patients were 4.49 years, 3.77 years, and 1.39 to 7.16 years, respectively. Figure Based on discharge prescriptions after surgery, 3972 patients were divided into two groups: those prescribed (3665) or not prescribed (307) postoperative aspirin Fig. . The folWith the use of the Cox model analysis, the estimated average covariate-adjusted hazard ratio with preoperative aspirin as compared with non-preoperative aspirin was 0.801 , slightly larger than the estimated 4-year risk ratio (0.78) with obtained with wider 95% CI (0.71–0.85) via the use of IPW approach. Similarly, for postoperative aspirin as compared with non-postoperative aspirin, the estimated average covariate-adjusted hazard ratio was 0.643 (95% CI: 0.58–0.71).et al.17 we obtained the hazard ratios for the unmeasured confounder to explain the observed decreased risk with non-preoperative aspirin would be 5.83, 4.17, and 2.08, respectively.The impact of an unmeasured confounding is shown in Fig. 9 in patients undergoing CABG. Overall, the findings reveal that benefits of perioperative uses of aspirin exceed hazards in patients undergoing CABG, in particular, perioperative uses of aspirin showed a strong association with improved long-term survival in the real world practice.The results of this cohort study showed that preoperative and postoperative aspirin therapy was associated with a significant long-term survival benefit among the patients undergoing CABG. In addition, preoperative aspirin was associated with a reduced risk of postoperative 30-day mortality without increased bleeding complications16. The SYNTAX18 and ASCERT19 trial demonstrated that the benefits of CABG vs PCI did not occur until 3–5 years later after the operation. The longitude of this study is extended from immediate postoperative time to an average of 4-years. The results of the present study revealed that the treatment effect with preoperative aspirin regarding the primary outcome – the long term survival (15–20% improvement) was similar to that observed in Antiplatelet Trialists’ Collaboration1 and also other proven medical treatments21, indicating that aspirin is an effective drug in improving long-term survival of patients with CABG.In the area of the research on aspirin and cardiac surgery, it is still uncertain and controversial about aspirin’s effects in patients with CABG, partially because it has been lacking of the hard-endpoint result–long term mortality. It was difficult to appreciate the overall picture of aspirin’s effects on cardiac surgery patients due to lacking of clinical evidence: long-term survival. Previous clinical studies have clearly showed that the treatment effect on chronic CVD takes a long time to emerge. For example, early clinical studies of vein grafts have shown that perioperative administration of aspirin improves the graft patency up to 12 month after the operation13 showed that among patients undergoing CABG with or without valve surgery or another procedure, the administration of preoperative aspirin resulted in neither a lower risk of death or thrombotic complications nor a higher risk of bleeding than that with placebo. The absence of an adverse bleeding effect in this trial is in line with previous clinical studies9 adding new evidence that a low-dose aspirin does not have significant effect on bleeding in patients undergoing cardiac surgery. The study should be commended for their strength of randomization. Nonetheless, the hard end-point - the event rate of death in this study was very low: there were only 14 vs 9 deaths in the treated (n = 1047) and placebo (n = 1053) groups, indicating a low-risk cohort of patients included in the study.With regard to aspirin’s short term effects, a recent RCT, ATACAS trial22. The underlying rationale for this study was that aspirin, for the long-term use, would prevent events related to its anti-inflammation and pleiotropic effects, in addition to those related to anti-platelet and anti-thrombosis.The beneficial effects of aspirin, in particular, its anti-inflammatory and/or pleiotropic effects most likely take time to occur. On this front, recent studies on potential mechanisms for aspirin in preventing atherothrombosis and chemoprevention on cancer have showed that, apart from suppressing thromboxane (TX) A2 production and TXA2-mediated platelet activation and aggregation, aspirin may play its multifaceted clinical effects via acetylating proteins in blood coagulation, inhibiting COX-2 activity and a variety of COX-independent mechanisms23. In addition, in a separate study9, we examined preoperative aspirin and bleeding complications in patients undergoing cardiac surgery. The results showed that preoperative aspirin did not significantly increase bleeding complications, including chest tube drainage, reoperation for bleeding. As it is known, CABG surgery frequently provokes an extreme and complex stress and hypercoagulable state, with an increased predisposition to long-term vascular morbidity and mortality. Perioperative aspirin may provide cardiovascular protection with potential short- and long-term benefits for survival.The present study provided additional findings regarding effects of preoperative aspirin, including the association with reducing 30-day mortality without significant bleeding complications; the findings complement those of previous studies25. Third, clinically it would be appropriate to group the patients based on whether they were taking aspirin during both the pre- and post-operative period (continuing aspirin) compared with patients they were not on aspirin at any point during the perioperative period (no aspirin). However, a timespan of the cohort follow-up between preoperative aspirin and postoperative aspirin prescription is “immortal” since exposed patients who received their first prescription (preoperative aspirin) had to survive until their second prescription (postoperative aspirin), which introduces an immortal time. Thus, classifying aspirin into 2 groups (continuation vs. none) has a problem due to the difference exposure  of the groups26. Fourth, we lacked data on the dose and adherence of aspirin in this cohort of patients (due to lack of refill records and aspirin being an over-the-counter drug). However, the discharge prescription of aspirin often is indicated for patients with CABG and it should be continued indefinitely and the usual doses are 81 mg–325 mg daily, except for ones with contraindications. In addition, the reported rates of patient aspirin adherence for cardiovascular protection are high, range from 72% to 92% in the literature27. The association we found in this study suggests that perioperative aspirin may provide cardiovascular protection with potential long-term benefits for survival. The results of this study also indicate that further studies, including basic mechanistic studies and large clinical studies, both RCTs and pragmatic studies are still needed to assess aspirin effectiveness in patients undergoing cardiac surgery.First, we have applied the propensity scores, IPW and other methods in this study to minimize biases and control confounding, however, the potential flaws of a non-randomized study may still exist. Second, other unknown confounding factors may exist which could affect the outcomes, thus we did an analysis as described in Fig. Among patients undergoing CABG, taking aspirin before and after surgery was associated with a significant reduced mortality risk during 4-years of follow-up.28, approved by the local Institutional Review Board (IRB) including Thomas Jefferson University IRB and UC Davis IRB, and individual consent was waived in compliance with the HIPAA regulations and the waiver criteria. Preoperative and postoperative uses of aspirin are defined as within 5 days preceding surgery and on the discharge respectively. Of all patients, 4,132 patients undergoing CABG with or without valve surgery met the inclusion criteria and were divided into four groups: with or without preoperative (within 5 days preceding surgery) or postoperative (on discharge) aspirin respectively  undergoing cardiac surgery at three teaching hospitals . The study was in accordance with the Declaration of Helsinki29.The following data were collected: patient demographics, history, medical record information, preoperative risk factors, preoperative medications, intraoperative data, postoperative 30-day all-cause mortality, discharge medicines and long-term all-cause mortality. For missing at completely random and low missing rate variables, missing data values will be imputed using multiple multivariate imputation by chained equations for continuous variables , and the most frequent value for categorical variables. For missing at random, each missing value was replaced with multiple imputation procedure, which used a set of plausible values to impute30. The survival time (time-to-event) of the subject began when the subject had CABG, and ended when the end-point (the death) was reached or the subject was censored from the study31.Primary endpoints were 30-day and long-term mortality, which were based on the data Registry of our three hospitals and the Social Security Death Index32. The performance of propensity model was verified by comparing the distribution of covariates and propensity scores between groups both before and after the IPW33.As anticipated, patients with or without preoperative or postoperative aspirin would differ significantly regarding baseline (before surgery) characteristics. Using multilevel logistic regression, a propensity score was derived on the patient characteristics, reflecting the probability that a patient would receive preoperative aspirin. The individual variables included in the propensity model are listed in Table 34, then re-estimated with using the IPW approach (adjusted) by Cole and Hernan35. For each group with or without preoperative or postoperative aspirin, the survival curves adjusted with the use of IPW represent the expected rate of survival if the treatment of interest were applied to all study patients. Risk ratios at specific time points were calculated with estimated rates of survival among patients receiving CABG with or without preoperative and postoperative aspirin, 95% confidence intervals were obtained with bootstrap methods.The Pearson chi-square test and Wilcoxon rank-sum test were used for analyzing continuous or categorical variables respectively. For long-term survival, survival curves were estimated with using the Kaplan-Meier method (unadjusted)36. The same covariates were used in each model as those used in the propensity model above. Further, to examine the impact of potential unmeasured confounders, we conducted covariate-adjusted Cox modelling to estimate average hazard rations for preoperative aspirin group vs. non-preoperative aspirin, as well as post-operative aspirin vs. non-aspirin. Additionally, we evaluated if the observed differences in the mortality rate could be thoroughly explained via an unmeasured confounder on the basis of the method outlined by Lin et al.17. Percentages, relative risk (RR), hazard ratio (HR), 95% confidence intervals (CI) and P values (2-sided) <0.05 were given in the results. SAS version 9.4  and SPSS 17.0 software for Windows  were used for the statistical analysis.To conduct sensitivity analysis, survival curves were re-estimated separately for patients with or without preoperative and postoperative aspirin with the use of Cox proportional-hazard models without propensity scores


Hip arthroscopy is a common surgical intervention for young and middle-aged adults with hip-related pain and dysfunction, who have high expectations for returning to physical activity following surgery. The purpose of this review was to evaluate the impact of hip arthroscopy on physical activity post-arthroscopy.A systematic search of electronic databases was undertaken in identifying studies from January 1st 1990 to December 5th 2019. The search included English language articles reporting physical activity as an outcome following hip arthroscopy in adults aged 18-50 years. Quality assessment, data extraction and synthesis of included studies were undertaken.n = 234) were assessed for eligibility following screening of titles and abstracts (n = 2086), yielding 120 studies for inclusion. The majority (86%) of the studies were level 4 evidence. One study reported objective activity data. The most frequently occurring patient-reported outcome measure was the Hip Outcome Score-sport-specific subscale . Post--arthroscopy improvement was indicated by large effect sizes for patient-reported outcome measures ; however, the majority of outcome scores for the HOS-SS did not meet the defined level for a patient-acceptable symptom state.Full text articles (The current level of available information regarding physical activity for post arthroscopy patients is limited in scope. Outcomes have focused on patients’ perceived difficulties with sport-related activities with a paucity of information on the type, quality and quantity of activity undertaken.Level IV, systematic review of Level 2 through to Level 4 studies The systematic collection of a range of physical activity outcomes is required in both clinical and research settings to effectively monitor and support post-arthroscopy recovery, building a more comprehensive activity profile of patients that moves beyond athletic classification.Physical activity outcomes are important but diverse and poorly captured in the current literature. The appropriateness of the patient-reported outcomes most commonly employed to measure physical activity is questionable and the range limited.The majority of patients feel better in relation to their ability to undertake physically active tasks including sports, but fail to progress to ‘feeling good’ or a patient-acceptable symptom state.Hip arthroscopy is an increasingly common surgical intervention for young and middle-aged adults with hip-related pain or dysfunction –4. IndicClinicalTrials.gov , 3433, 3To accommodate heterogeneity in the reporting of duration of follow-up, data collection points were collated under the following time frames: ≤ 6 months, 7–12 months, 13–18 months, 19–24 months, ≥ 25 months. Improvements in activity-specific subscales are known to be limited beyond 2 years post-arthroscopy , 35.Reported outcomes were assessed to identify the direction and consistency of effect, and where appropriate data were available, standard paired differences (SPD) were calculated to present a magnitude of effect between time points. This was determined by the within-group difference between time points, divided by the pre-score standard deviation (SD). Where standard errors (SE) were reported, SD was calculated (SD = SE*√number of participants). The magnitude of SPDs was interpreted as large effect (≥ 0.8), moderate effect (0.5–0.79) and weak effect (0.2–0.49) . The 95%To provide a visual representation of HOS-SS outcome scores, all data points from study groups were plotted against the minimal clinically important difference (MCID) and patient-acceptable symptom state (PASS) for this subscale Pooling of data was undertaken where outcomes were statistically and clinically homogeneous. Any studies with potential replication of participants were excluded from this analysis. Where no responses were offered from authors to enable discrete cohorts to be identified, the study encompassing the widest time frame with the greatest number of participants was chosen from studies generated within the same research setting, utilising the same outcome measures and database. Where more than one outcome was reported in a study, the most frequently occurring outcome score across all studies was chosen to be reported in pooled data. Studies reporting number of participants or number of hips were included in the pooled data. Where reporting was unclear, a conservative approach was taken with calculations being made in relation to the lowest number of potential participants. Pooled data were examined using forest plots (Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). Duration of follow-up categories were further merged to provide pooled data for the following time frames: 6 to 12 months, 13 to 24 months and ≥ 25 months. Studies were only reported once in each time frame.The number of records considered at each stage of the review and the reason for exclusions are shown in Fig. The included studies , 40–154 One hundred and twelve 93%) studies were conducted on a single site and/or involved the patients of one surgeon , the remainder recording 1,446 hips/procedures. We were unable to exclude the possibility of participants appearing in more than one study due to the high number of studies retrospectively reviewing databases. The number of participants in studies ranged from 11 to 1835. The mean (± SD) age of participants was 34 ± 7 years with 58% of the data pertaining to women. Seventy-two percent of studies specified FAI/FAIS as the primary inclusion pathology.n = 99, 83%) presented the Hip Outcome Score-sport-specific subscale . A summary of inclusion/exclusion criteria for each study, arthroscopic intervention and findings are given in Additional file Thirty four 28%) of the reviewed studies included some assessment of physical activity attributes of the cohort such as type of activity  with a similar proportion providing sufficient data to enable categorisation of activity type , where All studies employed PROMs; however, the reporting of validity and reliability of these outcomes was deemed adequate in only 26 (22%) of the studies. Complete quality assessment scores are provided in Additional file Large effect sizes for patient-reported physical activity  were seen in all studies at latest follow-up for the HOS, HOOS, HAGOS and iHOT33 subscales, with the exception of ten study groups for the HOS , 147; anPre- to post-arthroscopy change in the HSAS was assessed in four studies , 131. NoA visual representation of all HOS-SS outcome scores is presented in Fig. I2 79% to 92%).Data were pooled for HOS-SS, HOOS-SR, HAGOS SR and iHOT-33 SR and grouped according to time frame  and sport frequency [Eight studies , 154 reprequency  pre-injuThis systematic review evaluated the impact of hip arthroscopy, undertaken for hip-related pain and dysfunction, on the physical activity of young and middle-aged adults. A limited range of relevant outcomes were reported, with PROMs, specifically the HOS-SS predominating, and one study using objective measures to monitor physical activity. Consistency was seen across PROMs for improvements post-arthroscopy; however, the majority of HOS-SS scores did not reflect a patient-acceptable symptom state. In interpreting the evidence, it should be noted that considerable heterogeneity was evident between study designs and eligibility criteria. The majority of studies (78%) were retrospective, the preponderance of level 4 evidence, thus having the potential to inflate positive outcomes and effect sizes.Pooled data showed large effect sizes for the PROM subscales included in the analysis , depicting improvements in patients’ perceived difficulties with sport-related activities. This was consistent within each time frame for data covering 6 to ≥ 25 months post-arthroscopy. Across all pooled data, four studies demonstrated extreme positive effects. Three of these studies , 120 invOur findings indicate the need for more in-depth analysis of the impact of surgery on sport and activity involvement at an individual level. The limited range of outcomes utilised within studies was insufficient to answer questions about how much activity patients are undertaking and at what level of involvement. Despite the rising interest in and accessibility of wearable technology in health and fitness , and theThe limited range of frequently used PROMs identified in the current review reflects the findings of Reiman et al.  and RenoThis study offers insights into the effect of hip arthroscopy on physical activity, based on a comprehensive search strategy across eight databases utilising a rigorous screening and review process; however, there are a number of limitations that should be acknowledged. The methodological quality of the included studies was variable, many being retrospective studies with low participant numbers. This may increase potential for bias and magnification of positive effects . AdditioThe current level of information regarding physical activity for post-arthroscopy patients is limited in scope. Within the framework of patients’ perceived difficulties with sport-related activities, there is a consistent trend of post-arthroscopy improvement. However, the limited percentage of study participants achieving a score commensurate with ‘feeling good’, rather than ’feeling better’, indicates a need for more in-depth analysis to identify potential barriers and facilitators, both physical and psychological, to achieving a more satisfactory return to physical activity.Although the HOS-SS was the most frequently utilised PROM in this review, questions remain regarding its utility for this cohort. A greater range of outcome measures is needed to identify changes in other domains of physical activity. The use of objective measures, such as step count data, is currently a resource that is rarely utilised in studies, despite its use in contemporary practice, and warrants further investigation.This review generates a compelling case for higher quality, sufficiently powered observational studies and RCTs. While RCTs remain the gold standard, purposefully designed, quality controlled, multicentre or population-level databases offer the opportunity for large-scale, comprehensive data collection. However, a more expansive view of physical activity profiles needs to be established with the routine collection of data about type and volume of physical activity undertaken beyond the traditional focus on ‘sport’-related physical activity.Additional file 1: Example search strategy.Additional file 2: Study quality assessment forms.Additional file 3: Studies excluded at full text screen.Additional file 4: Characteristics and outcomes of included studies.Additional file 5: Overview of patient-reported outcomes identified in the review.Additional file 6: Data from intermediate time points.Additional file 7: Inclusion criteria, exclusion criteria, arthroscopic findings and interventions.Additional file 8: Risk of bias assessment.