They also had higher mortality or hospital readmissions at one year . Additionally, echocardiograms showed thicker walls in these patients  but without functional disorder. Myocardial injury in COVID-19 survivors is associated with poor clinical prognosis at one year, independent of age and sex, but not with echocardiographic functional abnormalities at six months.Myocardial injury, which is present in >20% of patients hospitalized for COVID-19, is associated with increased short-term mortality, but little is known about its mid- and long-term consequences. We evaluated the association between myocardial injury with one-year mortality and readmission in 172 COVID-19 patients discharged alive. Patients were grouped according to the presence or absence of myocardial injury (defined by hs-cTn levels) on admission and matched by age and sex. We report mortality and hospital readmission at one year after admission in all patients and echocardiographic, laboratory and clinical data at six months in a subset of 86 patients. Patients with myocardial injury had a higher prevalence of hypertension (73.3% vs. 50.0%,  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought about the COVID-19 pandemic, which has caused significant mortality and morbidity worldwide. The symptoms of COVID-19 can range from none or mild to a broad spectrum of clinical features, including severe respiratory failure and myocardial injury, and can lead to death , but theAs previously reported by our group and others, more than 20% of patients hospitalized with COVID-19 suffer myocardial injury, defined by elevated high-sensitivity cardiac troponin (hs-cTn) levels ,13,14,15In the present study, patients were classified in two groups according to the presence or absence of myocardial injury during the acute phase of COVID-19 infection and matched for age and sex in an attempt to better understand the effect of myocardial injury on mid- and long-term prognosis, while eliminating the potential confounding effect of age and sex. We report mortality and readmission outcomes in all patients at one year after initial hospitalization and details on echocardiographic, laboratory and clinical characteristics in a subgroup of patients at six months after hospitalization.We designed a two-centre cohort study of 172 survivors of COVID-19 after hospitalization. All 172 patients were classified in two groups according to the presence or absence of myocardial injury during the acute phase of COVID-19 infection and matched for age and sex. We analysed mortality and the need for hospital readmission during the first year after initial admission. A subgroup of 86 patients, also matched for age and sex, were re-examined through interviews, echocardiograms and laboratory tests six months after initial admission.We selected a consecutive series of patients ≥18 years of age with laboratory-confirmed COVID-19 who were admitted to one of two Spanish hospitals  from 27 February to 16 May 2021 and subsequently discharged alive. Of a total of 681 eligible patients, 145 patients had myocardial injury during the acute phase and 86 of these patients with myocardial injury could be paired 1:1 for age (+/−5 years) and sex with another 86 patients without myocardial injury. Patients were excluded if they were unwilling to participate, were lost to follow-up, or could not be matched 1:1 by age and sex .2); and previous history or current treatment in the patient’s medical records for chronic heart failure, coronary heart disease, atrial fibrillation, chronic obstructive pulmonary disease, cerebrovascular disease, or peripheral vascular disease.The acute phase of infection was defined as the time between hospital admission and hospital discharge. Demographic and clinical data were retrieved from electronic medical records. Demographic data included age, sex and smoking history. Clinical data included cardiovascular risk factors, defined as previous history or current treatment for hypertension, dyslipidaemia or diabetes mellitus in the patient’s medical records; chronic kidney disease, defined as a persistent abnormality in kidney function  guidelines , myocardA subset of 86 patients  had a follow-up visit in the outpatient clinic six months after hospital discharge. All patients were interviewed with questionnaires on symptoms and employment situation, and the same laboratory analyses were performed as at admission. A standard echocardiogram was performed using CX 50  by senior expert cardiologists. Left ventricular diameters, interventricular and posterior wall thickness were measured with M Mode. Left ventricular ejection fraction (LVEF) was measured with the biplane Simpson’s method . MeasureAll 172 patients were followed up at one year after initial hospital admission by telephone contact and through electronic medical records. Hospital readmission was defined as a subsequent hospital stay longer than 24 h. Cardiovascular causes of admission were defined as those related to arrhythmia, a cardiac ischemic event or heart failure.The primary outcomes were calculated for all patients at one year from initial hospital admission for COVID-19 and included death and/or hospital readmission due to any cause. The two primary outcomes were calculated both separately and as a composite outcome. Secondary outcomes were calculated for the subset of 86 patients at six months from initial hospital admission and included echocardiographic, laboratory and clinical characteristics.p ≤ 0.05.Continuous variables were described as mean (±standard deviation [SD]) or median (interquartile range [IQR]) according to their distribution. Normal distribution was assessed with the Shapiro–Wilk test and normal Q-Q plot. Categorical variables were presented as percentages. Differences between groups were assessed using the Student’s T-test or Mann–Whitney U test, as appropriate, for continuous variables and the Chi-square test for categorical variables. Curves for deaths and hospital readmissions were generated by the Kaplan–Meier method and compared with the log-rank test. All statistical analyses were performed with R version 3.6.1 . Statistical significance was set at Of 681 eligible patients, a total of 172 patients paired for age and sex  were followed up during a period of 358 days (IQR 350–374) after their initial hospital admission for COVID-19. p = 0.006).At one year after initial admission, one patient with myocardial injury had died due to an unknown cause. Hospital readmission was higher among patients with myocardial injury. The composite primary endpoint (death or readmission) occurred more often in patients with myocardial injury . In addiThe subset of 86 patients  were re-examined at six months after initial admission (median follow-up 229.5 days [IQR 174.5–252.75]). There were no relevant differences in baseline characteristics between these 86 patients and the other 86 patients in the study who were not re-examined at six months .p < 0.001) between initial admission and 6-month follow-up, while approximately half of the patients (48.8%) with myocardial injury showed persistent elevated hs-cTn levels at 6-month follow-up. Patients with myocardial injury also had worse kidney function, less haemoglobin, more lymphopenia and higher NT-proBNP levels at six months. Most of the 86 patients were classified as New York Health Association (NYHA) functional class I or II, and we found no differences in symptoms at six months according to myocardial injury status on admission. However, 11.6% of patients with myocardial injury remained on sick leave at 6 months post-discharge, compared to 2.33% of those without myocardial injury (p = 0.082).We have evaluated mid- and long-term outcomes in a cohort of COVID -19 survivors matched for age and sex. We found that patients with myocardial injury on hospital admission had poorer 1-year prognosis than those without myocardial injury, mainly in terms of hospital readmission. In addition, myocardial injury on admission was related to thicker myocardial walls and higher PAPs on echocardiograms performed six months after initial admission.Myocardial injury, an important pathogenic feature of COVID-19, is associated with elevated in-hospital mortality ,23,24,25p = 0.013). In a previous study that included in-hospital events, Kini et al. also found that myocardial injury was a strong and independent predictor of 6-month mortality [There is evidence of increased short-term mortality associated with myocardial injury, but little is known about its mid- and long-term consequences ,41,42. Iortality . Along tAt six months after initial hospital admission, nearly half of our patients with myocardial injury continued to have elevated serum levels of hs-cTn, potentially indicating chronic myocardial injury . The preA previous study by our group found that high hs-cTn levels predicted worse in-hospital prognosis in COVID-19 patients and that early measurement of troponin levels helped guide patient management during the acute phase of the disease . Our resOur study has several limitations, including the fact that an echocardiogram is not the most sensitive or specific imaging technique to assess myocardial function, so it may not have detected subtle abnormalities that could have impacted future clinical prognosis. However, an echocardiogram is readily accessible and is the most frequently used imaging technique for assessing cardiac function in clinical practice. In addition, some patients did not agree to attend the planned follow-up at six months. However, baseline characteristics were similar in patients who were re-examined at six months and those who were not. Finally, due to the limited number of events in our study, we were not able to adjust the effect of myocardial injury for potential confounding factors. Although we paired patients by age and sex, thus eliminating these potential confounders, this resulted in a more limited number of patients, which, in turn, precluded adjusting for other potential confounders. We cannot rule out the possibility that comorbidities or COVID-19 severity  might have contributed to the worse one-year prognosis in the group of patients with myocardial injury . NeverthThe early presence of myocardial injury in hospitalized COVID-19 patients is associated with worse one-year prognosis, mainly in terms of a higher incidence of hospital readmissions. This association is independent of patient age and sex. However, myocardial injury is not associated with significant echocardiographic functional abnormalities at six months after initial hospital admission.


We evaluated the effects of the coronavirus disease pandemic on diagnosis of and treatment for tuberculosis (TB) in Vietnam. We obtained quarterly notifications for TB and multidrug-resistant/rifampin-resistant (MDR/RR) TB from 2015–2020 and evaluated changes in monthly TB case notifications. We used an interrupted time series to assess the change in notifications and treatment outcomes. Overall, TB case notifications were 8% lower in 2020 than in 2019; MDR/RR TB notifications were 1% lower. TB case notifications decreased by 364  notifications per quarter and MDR/RR TB by 1 (95% CI −129 to 132) notification per quarter. The proportion of successful TB treatment outcomes decreased by 0.1% per quarter (95% CI −1.1% to 0.8%) in 2020 compared with previous years. Our study suggests that Vietnam was able to maintain its TB response in 2020, despite the pandemic. Mycobacterium tuberculosis transmission and consequently higher mortality rates  has been causing a global coronavirus disease (COVID-19) pandemic that has had wide-reaching effects on delivery of care for many other health conditions, including tuberculosis (TB). Each year, ≈10 million TB cases are diagnosed and ≈1.5 million TB deaths occur worldwide (Vietnam is a high-burden TB country and ranks among the top 30 high-burden countries for multidrug-resistant/rifampin-resistant (MDR/RR) TB . Vietnam, located in Southeast Asia, has a population of 96 million and reports ≈100,000 TB cases and >11,000 TB deaths every year  through a separate national database. We included MDR/RR TB case notifications during January 2015–December 2020 , panel BPatient-level data were only available for 2019 and 2020. We summarized TB notifications by age, sex, history of previous treatment, and treatment outcome and reported proportions of missing data , as wellFor quarterly TB notifications during 2015–2020, we used an interrupted time series . PatientFor 2019 and 2020 data, we summarized MDR/RR TB notifications by age, sex, history of previous treatment, smear and culture results, and treatment outcome . We noteFor MDR/RR TB, we calculated the relative risk for cases to have a positive smear diagnosis in 2020 compared with 2019. Similarly, we calculated the relative risk for a positive culture diagnosis in 2020 compared with 2019.https://www.sas.com). The University of Sydney provided ethics approval for this study . The study also was approved by the Vietnam National Lung Hospital.We calculated CIs and performed analyses by using SAS version 9.4  during the year after the onset of the COVID-19 compared with the previous 5 years. Successful TB treatment outcomes decreased by 0.1% per quarter (95% CI −1.1% to 0.8%) for patients completing treatment in 2020, compared with rates for 2016–2019  Table 3.We noted all known MDR/RR TB cases reported in Vietnam during 2015–2020  Table 4.In April 2020, during the first major COVID-19 outbreak and the first nationally implemented social distancing efforts, MDR/RR TB notifications decreased by 27% compared with notifications during April 2019  Table 3.This retrospective cohort study compared the number of notified TB cases and treatment outcomes in Vietnam during the first year of the COVID-19 pandemic with those during the preceding 5 years. We found an 8% decrease in overall TB notifications and a 1% decrease in MDR/RR TB notifications in 2020 compared with the preceding year. We did not observe any difference in TB treatment outcomes in 2020 compared with the period 2016–2019. However, we did see noticeable decreases in TB and MDR/RR TB case notifications in the provinces affected most by COVID-19 in the months in which social distancing measures were enforced. This observation suggests a possible delay in the diagnosis of TB and MDR/RR TB cases. NTP and provincial TB programs in areas most affected by COVID-19 should develop strategies to reduce the delay in diagnosis and prevent community transmission.Our study starkly contrasts findings from other settings during the COVID-19 pandemic. Several countries reported ≤30% fewer TB notifications during the first half of 2020 than before COVID-19 .In 2020, during the first COVID-19 outbreak, Vietnam implemented nationwide physical distancing and public health policies. These restrictions lasted <2 months, after which daily life returned to normal for most of the population  and completed treatment during the pandemic compared with TB patients beginning treatment during 2016–July 2019. In contrast, Italy, a country with low TB incidence, reported a substantial increase in the proportion of patients experiencing poor TB treatment outcomes during the pandemic, including loss to follow-up and death  before the pandemic, which enabled us to account for trends over time; single comparisons might miss previously existing trends, including seasonal variation (Our study is limited by using routinely collected programmatic data, which is limited to key information about patients and only includes the 2020 calendar year. Collection of smear status was missing for ≈30% of cases, and culture status at baseline was missing in ≈70%, limiting the ability to fully appreciate any change in smear or culture status between 2019 and 2020. Furthermore, because the duration of MDR/RR TB treatment is 9 or 20 months, we could only compare treatment outcomes for patients on standard first-line therapy. Finally, the effects on treatment outcomes can only be fully appreciated when all patients who commenced treatment in 2019 and 2020 receive an outcome.Several policy implications arise from this study. Evidence suggests that countries with prolonged control of community transmission of SARS-CoV-2, such as China, Vietnam, and South Korea, have seen only modest impacts on overall TB notifications. Furthermore, evidence also suggests that TB notifications can rebound after COVID-19 has been controlled. Thus, involvement of national and international organizations in the care of TB patients is critical for monitoring and evaluating the interactions between COVID-19 and health priorities, preparing the healthcare sector, and limiting service disruptions. The COVID-19 pandemic is far from over and must be controlled before care to other infectious diseases such as TB can be restored.Future studies could address the effect of a prolonged COVID-19 pandemic on delayed TB diagnosis, especially in settings with a high burden of COVID-19. The COVID-19 pandemic has taken a markedly different course from mid-2021, and Vietnam has experienced major outbreaks nationwide because of the Delta variant. Further research evaluating this period will enable us to contrast the effects of COVID-19 outbreaks on TB notifications over the course of the pandemic. Further evaluation also is needed to assess effects of COVID-19 on TB treatment outcomes, including changes in adverse TB outcomes, such as loss to follow-up due to decreased access to healthcare systems. Ultimately, the extent of the effects of the COVID-19 pandemic on TB care will take many years to fully appreciate, both in Vietnam and globally. Operational research is required to continue to identify these effects and to maintain resources for TB programs despite competing healthcare priorities. Finally, COVID-19–related restrictions, such as social distancing and the use of facemasks, might limit TB transmission; however, the adverse consequences of the COVID-19 pandemic likely are not adequately offset by these beneficial effects, and this requires further exploration.In conclusion, our study demonstrated a very limited decrease in TB notifications in Vietnam during the first year of the COVID-19 pandemic, despite national physical distancing measures. Settings with high rates of community transmission of SARS-CoV-2 are likely to experience a surge in TB notifications when COVID-19 restrictions are eased. These settings should increase healthcare capacity to detect and treat TB cases missed during COVID-19 restrictions.Additional information on the effects of the COVID-19 pandemic on tuberculosis notifications, Vietnam, 2020.


To describe clinical and non-clinical factors associated with receipt of breast conserving surgery (BCS) versus mastectomy and time to surgical intervention.Cross-sectional retrospective study of January 1, 2012 through March 31, 2018 data from the IBM MarketScan Commercial Claims and Encounter and Medicare Supplemental Databases. Area Health Resource Files provided non-clinical characteristics and sociodemographic data. Eligibility: Female sex, claim(s) with ICD-9-CM or ICD-10-CM diagnosis of non-metastatic invasive breast cancer, > 6 months of continuous insurance pre- and post-diagnosis, evidence of BCS or mastectomy following initial ICD9/10 code diagnosis. Logistic and quantile multivariable regression models assessed the association between clinical and non-clinical factors and the outcome of BCS and time to surgery, respectively.p = 0.02) or obstetrics and gynecology  physicians. Shorter time-to-BCS was associated with living in the South . Longer time-to-BCS was associated with residence in more urban , educated , or plastic-surgeon-dense  communities.A total of 53,060 women were included in the study. Compared to mastectomy, BCS was significantly associated with older age  and higher community density of medical genetics (OR: 5.88, 95% CIs 1.38 to 25.00; Clinical and non-clinical factors are associated with adoption of BCS and time to treatment, suggesting opportunities to ensure equitable and timely care.The online version contains supplementary material available at 10.1007/s10549-021-06155-1. Over the last four decades, advances in detection, diagnosis and surgical treatment for non-metastatic breast cancer have resulted in improved survival and health outcomes –4. AmongWhile breast cancer guidelines recommend optimal time from diagnosis to initiation of radiation and chemotherapy, there is no such standard for time to surgery (TTS) . A 2012 Both the use of BCS and TTS have been described as indicative of care quality  in that ® Commercial and Medicare Supplemental Databases to identify eligible patients. The MarketScan Commercial Database contains data on enrollment, select demographics, and the medical (inpatient and outpatient) and prescription-drug (outpatient only) claims of several million employees and their dependents covered under a variety of fee-for-service and capitated health plans. The MarketScan Medicare Supplemental Database contains the same health care experience data for individuals with Medicare supplemental insurance paid for by employers. All study data were obtained using International Classification of Diseases, 9th and 10th Revision, Clinical Modification (ICD-9 and ICD-10) codes, Current Procedural Terminology 4th edition (CPT) codes, Healthcare Common Procedure Coding System (HCPCS) codes, and National Drug Codes (NDCs). All database records were statistically de-identified and certified to be fully compliant with US patient confidentiality requirements set forth in the Health Insurance Portability and Accountability Act of 1996. As this study did not involve the collection, use, or transmittal of individually identifiable data, Institutional Review Board approval to conduct this study was not necessary.This cross-sectional, retrospective, observational study utilized the MarketScanThe Area Health Resource Files (AHRF) were used to capture community-level characteristics on the availability of health care providers or services, income- and education-levels and sociodemographic composition of racial/ethnic groups. The AHRF is a publicly available dataset that aggregates information from more than 50 sources including the American Hospital Association Survey Database and the American Medical Association Physician Master File . The 201in situ (DCIS) diagnosis were included because this diagnosis is not uncommon prior to or at the time of invasive, non-metastatic breast cancer diagnosis. Furthermore, these individuals represent an important proportion of non-metastatic invasive breast cancer patients and the presence of co-existing DCIS may have a prognostic value in this patient population  TTS (in days) increased from 21.0  in 2012 to 25  in 2017 . From the multivariable quantile regression model (Table  TTS (in p < 0.001 to p = 0.001); having a prior DCIS diagnosis ; receiving adjuvant chemotherapy ; receiving adjuvant hormonal therapy ; residing in the Midwest , South , West , or in communities with a higher number of radiation oncologists  , median TTS increased from 31.0 19, 48] in 2012 to 35.5  in 2017. Shorter mastectomy TTS was related to being in an age group 60 and older  as did those enrolled in CDHPs . AIDS was one chronic condition significantly associated with a longer TTS . Lastly, patients residing in communities that had a greater percent urban population had longer TTS for mastectomy .Mastectomy patients in HMO/EPO plans had longer TTS  factors associated with the likelihood of receiving BCS. We also noted multiple factors that correlated with longer TTS across US geographic regions. Between 2012 and 2017, there was a 16% increase in the proportion of patients undergoing BCS relative to mastectomy. Strikingly, older patients were at least 54% more likely than younger patients to undergo BCS. Moreover, patients residing in areas with a higher density of medical geneticists and obstetricians and gynecologists had a significantly higher likelihood of undergoing BCS. The strong association between BCS and receipt of adjuvant radiotherapy was expected since it is a standard treatment after BCS.The gradual increase in the proportion of patients undergoing BCS in our cohort aligns with increasing adherence to guideline-based surgical recommendations . Since tThe reasons for the positive association between BCS and residence in areas with higher numbers of medical geneticists or gynecologists and obstetricians or higher median income cannot be derived from the current retrospective study. Nevertheless, it is plausible that these patients had access to more comprehensive multidisciplinary breast cancer services, including second opinion, and greater information about management options .The increase in TTS we observed could be explained by an increase in preoperative evaluation workup, including MRI, genetic counseling, fertility counseling, and psychosocial assessment for distress , particuOur study results suggest a nuanced approach to considering TTS as a stand-alone quality measure. Patient multidisciplinary evaluation and local–regional treatment planning enhance the quality of non-metastatic invasive breast cancer care  and patiAnalysis data were derived from large national claims databases. Consequently, these results may not be generalizable to patients with Medicaid or no health insurance coverage. Also, these data are collected to facilitate payment for medical services and lack the clinical granularity found in medical records ; therefore, the potential for misclassification and/or coding errors is inherent. Multivariable modeling was limited to characteristics that can be measured from administrative claims. As a cross-sectional study, the results described reflect associations and do not imply causality. Also, various clinical or non-clinical characteristics may have affected the results of this study. For example, patient preference for BCS vs. mastectomy was not assessed. Patients with previously diagnosed/treated DCIS or concurrent breast reconstruction surgery, which may potentially alter their TTS, were not excluded from analyses. Receipt of adjuvant therapy was only captured 2 months post-surgery, potentially underestimating actual utilization.Health care service availability and multiple sociodemographic factors were consistently associated with preferential BCS use and TTS. While treatment planning in non-metastatic invasive breast cancer has become increasingly complex with greater use of imaging, second opinions, clinical decision-support tools, and multidisciplinary tumor boards, this study identified several non-clinical factors associated with BCS and TTS. Understanding the influence of non-clinical factors such as area of residence and patient sociodemographic characteristics on BCS and TTS are important considerations to ensure equitable access to breast cancer care and outcomes.Supplementary file1 (DOCX 2051 KB)Below is the link to the electronic supplementary material.


Smoking tobacco, poor nutrition, risky alcohol use, and physical inactivity (SNAP) behaviors tend to cluster together. Health benefits may be maximized if interventions targeted multiple health risk behaviors together rather than addressing single behaviors. The internet has wide reach and is a sustainable mode for delivery of interventions for multiple health behaviors. However, no systematic reviews have examined the long-term effectiveness of internet-based interventions on any combination of or all SNAP behaviors in adults aged 18 years or older.This systematic review examined, among adults (aged ≥18 years), the effectiveness of internet-based interventions on SNAP behaviors collectively in the long term compared with a control condition.The electronic databases Medline, PsycINFO, Embase, CINAHL, and Scopus were searched to retrieve studies describing the effectiveness of internet-based interventions on ≥2 SNAP behaviors published by November 18, 2019. The reference lists of retrieved articles were also checked to identify eligible publications. The inclusion criteria were randomized controlled trials or cluster randomized controlled trials with adults examining an internet-based intervention measuring the effect on ≥2 SNAP behaviors at least 6 months postrecruitment and published in English in a peer-reviewed journal. Two reviewers independently extracted data from included studies and assessed methodological quality using the Quality Assessment Tool for Quantitative Studies. A robust variance estimation meta-analysis was performed to examine the long-term effectiveness of internet-based interventions on all 4 SNAP risk behavior outcomes. All SNAP outcomes were coded so they were in the same direction, with higher scores equating to worse health risk behaviors.2=1.5%, P=.01). The global methodological quality rating was “moderate” for 1 study, while the remaining 10 studies were rated as “weak.”The inclusion criteria were met by 11 studies: 7 studies measured the effect of an internet-based intervention on nutrition and physical activity; 1 study measured the effect on smoking, nutrition, and physical activity; and 3 studies measured the effect on all SNAP behaviors. Compared with the control group, internet-based interventions achieved an overall significant improvement across all SNAP behaviors in the long term (standardized mean difference –0.12 [improvement as higher scores = worse health risk outcomes], 95% CI –0.19 to –0.05; IInternet-based interventions were found to produce an overall significant improvement across all SNAP behaviors collectively in the long term. Internet-based interventions targeting multiple SNAP behaviors have the potential to maximize long-term improvements to preventive health outcomes. Smoking tobacco, poor nutrition, risky alcohol use, and physical inactivity (SNAP) are modifiable risk factors for chronic diseases such as heart disease, stroke, cancer, and diabetes . IndividThe internet is accessible globally and is a sustainable mode for the delivery of interventions for multiple health behaviors . There aExisting systematic reviews have examined the effectiveness of behavioral interventions on multiple health risk behaviors ,17. A syThis systematic review aimed to examine the effectiveness of internet-based interventions on multiple SNAP health risk behaviors in the long term compared with a control condition.The electronic databases Medline, PsycINFO, Embase, CINAHL, and Scopus were searched to retrieve studies describing the effectiveness of internet-based interventions on 2 or more SNAP behaviors published by November 18, 2019. The following combinations of keywords were used:  AND (internet or web* or online or on-line) AND . The reference lists of retrieved articles were also checked to identify any additional eligible publications.The inclusion criteria were studies (1) that reported randomized controlled trials (RCTs) or cluster RCTs of internet-based interventions for ≥2 SNAP behaviors as either the sole intervention or an adjunct to written materials, (2) with adults aged 18 years or older, (3) that reported outcomes for ≥2 SNAP behaviors at least 6 months postrecruitment, (4) that had a no-intervention control group or the control group received information either in hard copy or information unrelated to SNAP via a website, and (5) in the English language in a peer-reviewed journal.Publications were excluded if (1) they did not report the outcomes of an RCT or cluster RCT ; (2) they examined only 1 SNAP health behavior; (3) they included special populations only such as people with chronic conditions  or pregnant women ; (4) weThis systematic review was conducted in accordance with PRISMA  guidelines . All recData were independently extracted from the included studies by 2 authors (AM and AH or LW). A third author (FT) resolved any inconsistencies in data extraction. The study and sample characteristics extracted from eligible publications included authors and year of publication, country, years that data were collected, setting, sample characteristics , recruitment method, eligibility criteria, treatment conditions , internet-based intervention received , retention rate at follow-up, SNAP measures, SNAP outcomes at 6 months of follow-up or later, and costs.The outcomes extracted for each health behavior were any measure of (1) tobacco smoking , (2) nutrition , (3) alcohol consumption , and (4) physical activity .The Quality Assessment Tool for Quantitative Studies developed by the Effective Public Health Practice Project was used to assess methodological quality . This toThe methodological quality of included studies was rated by 2 authors (FT and AM). Any discrepancies were discussed between these authors until consensus was reached. When rating the data collection methods, the measures for “all” SNAP outcomes needed to be shown to be valid and reliable for the data collection methods to be rated as strong. For instance, if smoking cessation was measured via biochemical validation and physical activity assessed via pedometers, the data collection methods were rated as strong. However, if smoking cessation was measured via a self-reported measure with no information about its psychometric properties and pedometers were used to assess physical activity, the data collection methods were rated as weak because “all” SNAP measures were not shown to be reliable and valid.robumeta. All SNAP behaviors were coded so they were in the same direction, with higher scores equating to worse health risk outcomes. Where a study measured the outcome at multiple time points , data from the longer-term follow-up was included in the meta-analysis. The SNAP outcomes from each study were converted into Cohen d (standardized mean differences [SMDs]) and the corresponding variance [robumeta. A common within-study correlation (rho) of 0.8 was assumed, and sensitivity analyses were performed to determine the sensitivity of the results to this assumption . Heterogeneity was measured using the I2 statistic [A robust variance estimation meta-analysis was performed using the R package variance . Robust tatistic .The PRISMA flow diagram outlining the study selection process is presented in As shown in The interventions included web-based learning activities, modules, or tutorials ,30,32,33As outlined in 2=1.5%, P=.01) [2=1.5%), and the tau-square (the extent of variation due to between-study variance) was low, at <0.001. The sensitivity analysis showed that the model results did not vary greatly across different values of within-study correlation (rho).The robust variance estimation meta-analysis found that, compared with the control group, internet-based interventions achieved an overall significant improvement across all SNAP behaviors in the long-term  ,32,34-37This is the first systematic review to examine the long-term effectiveness of internet-based interventions on SNAP behaviors collectively in adults aged 18 years or older. This systematic review focused on internet-based interventions to increase the homogeneity of included studies. This is similar to other systematic reviews that have focused on a specific digital technology ,39. MoreThe robust variance estimation meta-analysis findings reported that internet-based interventions achieved an overall significant improvement across all SNAP behaviors in the long term. This suggests that internet-based interventions that adopt a holistic approach to behavior change by addressing multiple SNAP behaviors improve these behaviors collectively and consequently may lead to better health outcomes and reduced health care costs. Given no previous systematic reviews have examined the long-term effectiveness of internet-based interventions on multiple SNAP behaviors nor provided an overall effect size across all SNAP behaviors, we cannot compare our findings to previous reviews. To advance the field, further research is needed on the long-term effectiveness of internet-based interventions on multiple SNAP behaviors.The studies in this systematic review recruited participants from a variety of settings, including universities ,30,34-36In terms of methodological quality, 10 of 11 studies had a global rating of “weak” -31,33-37This systematic review had some limitations. First, although we were able to pool the studies to undertake a robust variance estimation meta-analysis to examine the long-term effectiveness of internet-based interventions across all SNAP behaviors, additional analyses examining potential moderators  were not possible due to the relatively small number of studies in this systematic review. Second, the methodological quality assessments were based on the information contained in the articles, and missing details from these articles may have had an impact on the ratings. Finally, all the studies were conducted in high-income countries, which may limit the generalizability of this systematic review’s findings to low- and middle-income countries. In addition to expanding the research in the settings and populations included in this review, future research should assess the long-term effectiveness of internet-based interventions on multiple SNAP behaviors in additional populations , settings , and countries  to strengthen the evidence base and improve the generalizability of the findings.Internet-based interventions were found to produce an overall significant improvement across all SNAP behaviors in the long term. Given the promising findings on the long-term effectiveness of internet-based interventions across all SNAP behaviors collectively, such interventions may maximize improvements to health and prevent chronic diseases.


Enterobacterales (CRE) pathogens, optimally developed for Klebsiella pneumoniae carbapenemase (KPC). The study aims to evaluate the cost-effectiveness of Vaborem versus best available therapy (BAT) for the treatment of patients with CRE-KPC associated infections in the Italian setting.Vaborem is a fixed dose combination of vaborbactam and meropenem with potent activity against target Carbapenem-resistant A cost-effectiveness analysis was conducted based on a decision tree model that simulates the clinical pathway followed by physicians treating patients with a confirmed CRE-KPC infection in a 5-year time horizon. The Italian National Health System perspective was adopted with a 3% discount rate. The clinical inputs were mostly sourced from the phase 3, randomised, clinical trial (TANGO II). Unit costs were retrieved from the Italian official drug pricing list and legislation, while patient resource use was validated by a national expert. Model outcomes included life years (LYs) and quality adjusted life years (QALYs) gained, incremental costs, incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratio (ICUR). Deterministic and probabilistic sensitivity analyses were also performed.Vaborem is expected to decrease the burden associated with treatment failure and reduce the need for chronic renal replacement therapy while costs related to drug acquisition and long-term care  may increase. Treatment with Vaborem versus BAT leads to a gain of 0.475 LYs, 0.384 QALYs, and incremental costs of €3549, resulting in an ICER and ICUR of €7473/LY and €9246/QALY, respectively. Sensitivity analyses proved the robustness of the model and also revealed that the probability of Vaborem being cost-effective reaches 90% when willingness to pay is €15,850/QALY.In the Italian setting, the introduction of Vaborem will lead to a substantial increase in the quality of life together with a minimal cost impact, therefore Vaborem is expected to be a cost-effective strategy compared to BAT.The online version contains supplementary material available at 10.1186/s13561-021-00341-z. Klebsiella pneumoniae Carbapenemase (KPC) producers are a high priority and high risk CRE enlisted by the World Health Organization and represent the fastest growing antibiotic resistance threat in Europe [K. pneumoniae resistant to carbapenems has risen up to six-fold between 2007 and 2015 [Carbapenamases are versatile β-lactamase with an ability to hydrolyse a wide spectrum of β-lactams such as penicillins, cephalosporins, monobactams, and carbapenems –4. Hencen Europe –8. The pn Europe , 10. Theand 2015 , 10.K. pneumoniae include urinary tract infections, lower respiratory tract infections, intra-abdominal infections, and bloodstream infections among others. The CRE-KPC infections are difficult to treat as carbapenem resistance is most often accompanied by multi-drug resistance [, colistin or polymyxin B) or aminoglycoside  classes have been prescribed for CRE infections. However, these antibiotics have some safety concerns associated with toxicity and more importantly the CRE-KPC has developed resistance toward these antibiotics reducing the efficacy of treatment [The infections caused by sistance , 11. Witreatment . Even coreatment . Newer areatment .Enterobacterales producing KPC-type and other class A serine carbapenemases. Meropenem is a broad-spectrum carbapenem antibiotic that has been used worldwide for over two decades for the treatment of serious infections [Meropenem–vaborbactam, with the brand name Vaborem, is the first drug combination that includes a boronic acid-based beta-lactamase inhibitor and a carbapenem , 14. Vabfections , 14.Vaborem has shown positive results in two phase 3 clinical trials. In particular in the TANGO II trial, a randomised, prospective, pathogen-specific multicentre phase 3 clinical trial versus Best Available Treatment (BAT). Vaborem has shown higher clinical cure rates, lower nephrotoxicity and reduction in mortality rates compared to treatments currently used in clinical practice . The impHowever, the economic impact of introducing Vaborem on healthcare expenditure has not yet been investigated. From an Italian perspective, the guidelines published by the Italian Medicines Agency highly recommend performing economic evaluation analyses on any new drugs/active ingredients or drugs with extended indication . Cost-efA cost-effectiveness analysis (CEA) was conducted based on a decision tree model that simulates a scenario with Vaborem and one with BAT (without Vaborem) in the treatment of CRE-KPC infections. Decision tree model was chosen as they are particularly suited to modelling acute care decision problems and medium-term diseases, such as infections. The model structure, presented in Fig. Two cohorts were considered in the model, one for each scenario, with 1000 hospitalised patients, representative of the target population, with confirmed diagnosis of CRE-KPC infection. The model captured short-term outcomes until day 28 (in line with the TANGO II study protocol)  and simun = 47) of TANGO II in which most patients had CRE-KPC associated infections . In particular, patients’ mean age and weight were 62.5 years and 76 kg and 51.1% of patients were male [The target population included adult patients ≥ 18 years with CRE-KPC associated infections. The CRE-KPC infections considered were the same of TANGO II : complicere male .The time horizon of the CEA was 5 years, which was considered sufficient to capture the main differences among the two scenarios in terms of costs and outcomes. This time horizon was also in line with the Italian guidelines’ requirements  and otheIn the analysis, the Italian NHS perspective was adopted. This option was considered conservative because only direct costs borne by the NHS for the management of CRE-KPC associated infections were included. The indirect costs such as loss of productivity of patients and their caregivers were not considered although their burden is expected to decrease with the reduction of disease complications. Further, the expected reduction in the utilisation of resources during hospitalisation (e.g. with the reduction of septic shock) was not valued because in-hospital episodes are financed through all-inclusive tariffs . The direct costs considered in this study included treatment costs, administration costs, disease management costs, disease complication costs and treatment-related adverse event costs.The CEA compared Vaborem with BAT as the main standard of care comparator in line with the TANGO II study and confirmed by an Italian medical expert. BAT includes : carbapenem, aminoglycoside, polymyxin B, colistin, tigecycline or ceftazidime-avibactam (monotherapy only) . A majorSince QoL data were not collected during the TANGO II study , health The costs considered in the CEA were associated with: (i) pharmacological treatment (drug acquisition), (ii) management of the infections during hospitalisation, and (iii) complications associated with the infections such as: therapeutic failure, chronic RRT, and LTC. The costs associated with drug administration, nephrotoxicity, and the use of RRT during the first hospitalisation were not considered in the analysis as they were already included in the all-inclusive DRG tariff for hospitalisation.At the beginning of the model, all patients received one course of either Vaborem, or BAT based on their treatment group. The acquisition costs for the BAT were estimated based on the ex-factory price without value-added tax after applying lawful discounts . All othThe disease management costs are associated with the hospitalisation stay. The in-hospital costs were estimated at € 4533.27 based on the National DRG tariffs , which aThe model assumes that upon treatment failure patients received a second course of antibiotic. The estimated cost for the second course of therapy, independently of the treatment arm, was considered to be equal to BAT in terms of both drug acquisition costs and hospitalisation costs . The annual cost for chronic RRT  was extracted from a retrospective study in an Italian cohort and was estimated to be €38,819.40 . The cosDeterministic and probabilistic sensitivity analyses were performed to explore the level of uncertainty in the model results. In order to assess the robustness of the baseline scenario results, deterministic sensitivity analyses were carried out in which the most uncertain parameters were varied. The uncertain parameters included the demographics characteristics of Italian multicentre study conducted on patients with CRE-KPC infections  , shorterIn the probabilistic sensitivity analysis 1000 random extractions (Monte Carlo simulations) of the model’s inputs were simulated. The gamma distribution was considered for the continuous and positive variables  and the beta distribution for the variables that assumed values between 0 and 1 . For the efficacy variables coming from TANGO II, the relative standard errors were considered and for the other parameters a standard error of 20% of the average value was considered. Mean incremental results were recorded and illustrated through an incremental cost-effectiveness plane and a cost-effectiveness acceptability curve (CEAC) was also plotted.Over a 5-year time horizon, the cohort receiving Vaborem accrued 1.786 QALYs at a cost of €29,750.85, while patients receiving BAT accrued 1.403 QALYs at a cost of €26,202.28. Hence, the increase in costs associated with Vaborem versus BAT treatment for a representative patient with CRE-KPC infection was €3548.57. This increase in cost is mainly attributable to the costs of the treatment drug and LTC associated with higher survivability  were not valued in the analysis since costs were estimated based on omni-comprehensive DRG tariffs. Indeed, in TANGO II the only treatment-emergent adverse events with higher incidence for patients treated with Vaborem than BAT was hypokalaemia . Third, N = 47) [The study also presents some limitations. A major limitation of the study is that model inputs were mainly estimated based on the TANGO II study, in which the sample size of microbiologic-CRE-modified intent-to-treat (mCRE-MITT) was small (N = 47) . Still, N = 47)  performeAdditionally, in the TANGO II study the follow-up period was relatively short (28 days) leading to the need to integrate its data from information retrieved from published literature and medical experts’ opinion in order to simulate data for a longer time horizon (5-years). The uncertainty associated to longer time horizon of the model (5-year) compared to the clinical trial follow-up (28 days) was assessed in a scenario analysis resulting in better results.Furthermore, during the sensitivity analysis the possibility of carrying out an indirect comparison analysis to compare the effectiveness of Vaborem  versus cThe inclusion of Vaborem into the treatment armamentarium for serious CRE-KPC infections is expected to lead to a significant improvement in the clinical cure rates, while lowering nephrotoxicity rates and mortality. From this study it emerges that, in the Italian setting, the introduction of Vaborem will lead to a substantial increase in the quality of life together with a minimal cost impact. Hence, Vaborem is expected to be a cost-effective treatment strategy compared to BAT for the treatment of CRE-KPC infections.Additional file 1.


Klebsiella pneumoniae (CP-Kp) infection represents a serious threat to solid organ transplant (SOT). All patients admitted between 1 May 2011 and 31 August 2014 undergoing SOT were included in the retrospective study. The primary outcomes included a description of the association of enteric colonization and invasive infections by CP-Kp with one-year mortality. Secondary outcomes were the study of risk factors for colonization and invasive infections by CP-Kp. Results: A total of 5.4% (45/828) of SOT recipients had at least one positive rectal swab for CP-Kp, with most (88.9%) occurring after transplantation. 4.5% (35/828) of patients developed a CP-Kp-related invasive infection, with 68.6% (24/35) being previously colonized. The 1-year mortality was 31.1% in patients with enteric colonization with CP-Kp and, it was 51.4% among patients with CP-Kp-related invasive infections. At univariate analysis, colonization, invasive infections, sepsis, severe sepsis, and septic shock were significantly associated with 1-year mortality. At multivariate analysis, only invasive infections and the combination of sepsis, severe sepsis, or septic shock were significantly associated with 1-year mortality, whereas gastrointestinal colonization was significantly associated with survival. In this population, the 1-year mortality was significantly associated with invasive infections; otherwise, gastrointestinal colonization was not associated with increased 1-year mortality.Carbapenemase-KPC producing  Klebsiella pneumoniae (CP-Kp), with high morbidity and mortality [Kp that is colonized in patients undergoing transplantation have not been systematically evaluated .In recent years, the growing spread of multi-drug-resistant (MDR) organisms has threatened the efficacy of certain advanced care options, such as solid organ transplant (SOT), for a number of end-stage organ diseases by undermining the control of such procedures’ infective complications . Recent ortality ,3,4. Theortality . FurtherKp infection along with pneumonia and renal failure [These trends strongly highlight the need for sound, effective diagnostic tools for detection and treatment strategies for management of MDR pathogens in SOT recipients to minimize infectious complications and graft failure as well as reduce infection control failures of hospital programs ,4. SOT r failure Kp in a cohort of SOT recipients in a large tertiary care hospital in Turin, Italy. We focused our analysis on the impact of CP-Kp colonization and invasive infections on mortality one year after transplant.In this retrospective observational study, we aimed to describe the prevalence of gastroenteric colonization and invasive infections that are caused by CP-All patients admitted to the Città della Salute e della Scienza di Torino–Presidio Molinette Hospital between 1 May 2011 and 31 August 2014 undergoing SOT were included in the study. The SOTs included heart, lung, liver, kidney, pancreas, and combined organ transplants that were performed at our institution.cytomegalovirus (CMV) serology, hospital admission >48 h within 6 months prior to the SOT, previous isolation of extended-spectrum beta-lactamases (ESBL) or CP bacteria from any clinical specimen within 3 months prior to the SOT. Other data included date of admission and SOT, indication for SOT, date of last post-transplant follow-up visit or death, date of graft loss (where applicable), pre-SOT ICU admission duration, corticosteroid treatment before SOT , complications after SOT, which were defined as hemodynamic instability, acute kidney injury (AKI), sepsis, severe sepsis or septic shock [A retrospective review of medical charts was performed to collect demographics and clinical data. These included comorbidities, such as cardiovascular diseases, chronic obstructive pulmonary disease (COPD), chronic kidney failure, chronic liver failure, previous solid and hematological malignancy, splenectomy, previous SOT, Kp was defined as a patient having at least one rectal swab (RS) positive for CP-Kp during their hospital stay before and/or after transplantation; CP-Kp invasive infection was defined by clinical and laboratory evidence of any invasive infection plus at least one culture positive for CP-Kp from a biological sample other than RS; bloodstream infection (BSI) was defined as a patient having at least one positive blood culture (BC) for CP-Kp.Enteric colonization with CP-Appropriate empiric treatment was defined as any antimicrobial treatment initiated empirically within 24 h from the microbiological sample collection with at least 1 active agent. Appropriate targeted treatment was defined as any antimicrobial treatment containing at least one active antimicrobial agent and initiated any time after receiving the final susceptibility test, which was performed on a bacterial isolate.® system  followed by biochemical identification of isolated colonies and an antimicrobial sensitivity test with the MicroScan system . Surveillance RSs for MDR bacteria were performed at admission and weekly on all high-risk patients (defined as patients admitted to the ICU and immunocompromised patients) according to the local Infection Control Policy (Regione Piemonte n° 30335/DB.2001). As clinically indicated, peripheral and central BCs and other samples were taken from urine, surgical wounds, drainage, tracheal bronchoaspiration (BA), alveolar bronchoalveolar lavage (BAL), bile, stools, and organ preservation solution. Bacterial growth in blood was detected by the BacT/ALERT system (bioMérieux) after 37 °C incubation with CO2 colorimetric detection, followed by Gram staining and bacterioscopy. Antimicrobial susceptibility was tested with the MicroScan system and defined according to the EUCAST breakpoint definitions [Kp isolates. Furthermore, detection of carbapenem resistance genes was carried out using an Xpert Carba-R assay The microbiological testing included the following: RS, that was performed by inoculation on MacConkey II Agar , with the automated WASPinitions . The HodKp.The primary outcomes included a description of the association of enteric colonization and invasive infections by CP-Kp with one-year mortality. Secondary outcomes were the study of risk factors for colonization and invasive infections by CP-Kp BSI and one-year mortality, significant values in the univariate analysis were evaluated with a multivariate model: a logistic regression model for CP-Kp BSI and a proportional risk model (Cox’s model) for one-year mortality. A p-value of <0.05 was considered significant. The statistical analysis was conducted using SAS system 9.3 .The continuous variables’ values are described as either mean and standard deviation (SD) or with a median and inter-quartile range (IQR). The categorical variables’ values are expressed as frequency measure and percentage. To compare the continuous variables, we used the t-test for normal distribution and the Wilcoxon–Mann–Whitney test for non-normal distribution. To compare discrete variables, we used the chi-square test or Fisher’s test accordingly. Considering the outcome of CP-Ethical committee approval was waived due to the retrospective nature of the study, which was approved by the medical director of the hospital (protocol number 0116265).During the study period, 920 SOTs were performed. In total, 92 were excluded from the analysis, with 16 emergency re-transplants during the same hospitalization considered a single episode, 20 pediatric recipients transferred to a different hospital for follow-up after the intervention, and 56 episodes excluded because the clinical documentation was not fully available for review. Combined transplants were considered a single episode for each organ. The final analysis included 828 episodes. The demographic features of the study population, comorbidities, hospitalization details, and ICU-associated procedures are summarized in Enteric colonization with CP-Kp was found in 45 patients (5.4%), with most cases occurring (88.9%) after SOT . There were 35 invasive infections (4.2%) with a mortality of 51.4%. These include18 (51.4%) were associated with a BSI and mortality of 66.7%. Kp BSI there were CP-Kp enteric colonization and multi-site CP-Kp colonization. The duration of hospital and ICU stays were also associated with the development of a CP-Kp BSI as well as previous hospital admission and corticosteroid use in the six months preceding the SOT. A lung or heart transplant procedure was significantly associated with the development of a CP-Kp BSI . Among the comorbidities, COPD was correlated with the development of a CP-Kp BSI.Among the risk factors for the development of a CP-Kp BSI, 29,4% received appropriate empiric treatment within 24 h from the BC collection, and 88.2% received appropriate targeted treatment. While two patients with a CP-Kp BSI (11.1%) died of septic shock within 24 h of diagnosis, two other patients developed a CP-Kp BSI and were successfully treated with an appropriate empiric gentamycin monotherapy within 24 h. In addition, 13 patients (86.7%) received a combination therapy: 2 with 2 active agents, and the remaining 11 received 3 active agents. The CP-Kp strains that were isolated were colistin-resistant in 27% of the cases, resistant or intermediate to tigecycline in 11% and 33%, respectively, and intermediate to gentamycin in 22%, without any isolate resistance to the latter.Among patients with a CP-The results of the univariate and multivariate analyses for one-year mortality are given in In the univariate analysis, colonization, invasive infections as well as sepsis, severe sepsis, and septic shock were significantly associated with one-year mortality. In the multivariate analysis, only invasive infections and the combination of sepsis, severe sepsis, and septic shock were significantly associated with one-year mortality, whereas gastrointestinal colonization was significantly associated with survival.Kp BSI was significantly reduced compared to those without a CP-Kp BSI  circulation remains high according to the local epidemiology and other factors [The aim of this study was to assess the impact of CP- factors .Clostridioides difficile during the 30 days prior to an SOT and an intensive care unit stay >2 weeks were associated with the acquisition of CPE, suggesting a central role played by disrupted gastrointestinal flora in the susceptibility to CPE [Kp BSIs were caused by pathogens that were potentially of enteric origin, highlighting the importance of the gut as a bacterial reservoir in these patients [In a recent retrospective study, the stool sample positivity for vancomycin-resistant Enterococci and/or y to CPE . In our patients . Interespatients .Kp invasive infection (4.2%) and CP-Kp BSI mortality rates (66.7%) were similar to previously published studies.In our study, there was a lower colonization rate compared to a previously reported multicentre Italian study where the enteric colonization rate was 18.4% . The oveKp invasive infections and in 11.1% of the CP-Kp BSI cases in our cohort, the enteric colonization with MDR pathogen status was unknown, resulting in delayed administration of the appropriate antibiotic therapy and an increased risk of nosocomial spread of CP-Kp.Notably, 16.8% of the studied patients did not undergo an RS during their stay, despite the regional Infection Control Policy protocol, which had already been operative in the hospital during the study period. Consequently, in 5.7% of the CP-Kp invasive infection during the year after LT was the strongest predictor of one-year mortality; patients with a CP-Kp BSI had lower survival compared to those without a BSI, whereas a BSI that was caused by bacteria other than CP-Kp had no impact on one-year mortality. The high rate of septic shock among the deceased patients points to the difficulty of controlling these infections, which is partially due to the limited therapeutic tools available against this pathogen [The results may appear somehow conflicting, although they should be analyzed in the context of the local epidemiology of drug resistance, immunosuppression, and the SOT population. In our study, CP-pathogen .Kp invasive infection in the multivariate analysis, it was not associated with one-year mortality. There may be a multitude of explanations for this, including possible early appropriate empiric antibiotic treatment or that, in our patient population, the main drivers of invasive infections were different and possibly multiple in determining the rate of invasive infections .Even though enteric colonization was a significant risk factor for the development of CP-Kp was also studied in a large Italian multicentre study, which was not limited to SOT recipients, where Tumbarello et al. highlighted how 67% of all documented CP-Kp infections were associated with a BSI and had a 14-day mortality of 34% [Kp was found. All the patients had enteric colonization and received appropriate empiric antimicrobial treatment within 24 h of their clinical diagnosis [The issue of mortality in patients with infections by CP-y of 34% . In a smiagnosis .Kp infection. A Greek study from Mouloudi et al. reported significantly higher mortality in liver transplant recipients in the ICU with a CP-Kp BSI compared to a control group without a CP-Kp BSI  [Kp outbreak in a German hospital [Kp infections, which were associated with a BSI in 38.7% of the cases, including a significantly reduced survival rate and an association with a higher SOFA score at the time of diagnosis [Several studies have described the impact of these bacteria in different cohorts of SOT patients, highlighting an increased susceptibility to CP-ctively) . Similarhospital . In a laiagnosis .Kp urinary tract infections had a lower 2-year survival rate compared with those without CP-Kp infections (76% vs. 90%). Additionally, CP-Kp bacteriuria after kidney transplant was associated with mortality and antimicrobial failure after treatment [According to a Brazilian retrospective study, kidney transplant recipients with CP-reatment .In accordance with updated Italian recommendations, CPE colonization should not be viewed as an absolute contraindication for organ donation unless the colonization is in the organ to be transplanted, given the low risk of CPE transmission from donor to recipient .By contrast, the role of immunosuppressive therapy is unclear in this context. Our results do not allow any deduction about the role of immunosuppressive treatment in terms of the risk of MDR pathogen infections, which has not been confirmed by previous studies ,27.Similarly, we cannot confirm any protective role of these drugs due to their impact on the systemic inflammatory response, as previously proposed ,17.Recently, novel beta-lactams/beta-lactams inhibitors combinations such as ceftazidime/avibactam (C/A), meropenem/vaborbactam (M/V) and imipenem/relebactam (I/R) significantly reduced mortality patients with carbapenem-resistant Enterobacteriaceae infections ,28,29. NKp infections on the SOT recipient subgroup, a comparison with the epidemiology of this pathogen in the entire hospital is needed. Such measurement is currently unavailable due to the lack of surveillance data about CP-Kp prevalence in the hospital wards that are not defined as high risk for MDR pathogens.This study has several limitations, including its retrospective nature. To ensure a better understanding of the true impact of CP-Kp. Finally, the limited number of CP-Kp BSI cases did not allow any statistically significant conclusion on the use of antimicrobial agents in our cohort of patients.Furthermore, the data presented pertain only to the hospital admission that is related to the transplantation for each patient. A longer clinical and microbiological follow-up would be helpful for understanding the long-term impact of CP-In summary, post-transplant BSIs occurred at a high rate during the year after SOT, particularly within the first four weeks following surgery. Patients with a BSI had a significantly lower survival rate than those without a BSI. New antibiotics have recently been approved for CRE infections.Our results suggest that identification of enteric colonization is crucial to preventing the nosocomial spread of these pathogens and protecting more vulnerable patients by safeguarding the outcome of complex and costly life-saving treatments.


Adverse local tissue reactions secondary to mechanically assisted crevice corrosion (MACC) at the trunnion is a complication of total hip arthroplasty known to cause local soft-tissue damage. However, what is not as well appreciated is that MACC in metal-on-polyethylene (MOP) articulations can lead to cobalt ion serum elevations with associated neurological dysfunction just as in metal-on-metal articulations. We report a compelling case for the association of neurologic dysfunction tied to metal ion elevations secondary to MACC at two distinct MOP tapers in a 58-year-old intensive care unit nurse with two hips implanted 3 years apart. This report further raises awareness about the potential of MACC-generated elevated ion levels to produce neurological symptoms that might otherwise be overlooked in patients with MOP articulations. Mechanically assisted crevice corrosion (MACC) at the trunnion refers to confirmed wear and corrosion of the femoral head-neck taper in total hip arthroplasty (THA) implants and is sometimes referred to as trunnionosis, taperosis, or pseudotumor . The conMACC can manifest clinically as adverse local tissue reactions such as implant failure, soft-tissue damage, and, less frequently, end-organ damage ,4. SysteToxicity from cobalt ions released into the circulation from total hip replacement implants has been implicated as a mechanism for systemic symptoms . It is pIn this case report, we describe the case of a 58-year-old female who underwent staged bilateral THA procedures 3 years apart with the same implants. She subsequently presented with neurologic symptoms associated with elevations in cobalt ion levels caused by MACC at the trunnion 7-8 years after each index surgery.Informed patient consent was taken from the patient. Institutional review board approval was not required as all data are deidentified.A 58-year-old woman who works as a pediatric intensive care unit nurse at a large academic medical center presented in 2009 with bilateral hip pain and pelvic radiographs consistent with advanced degenerative arthritis of both hips. Her past medical history was notable for longstanding hypothyroidism managed with levothyroxine. A corticosteroid injection was given with temporary relief in each hip. One year later, the hip pain worsened and was significantly impacting her quality of life. Pelvic radiographs demonstrated progression of her degenerative arthritis .Figure 1She subsequently underwent a left total hip arthroplasty (L-THA) in April 2010 at the age of 59 years. An anterolateral approach was used along with an intraoperative repair of the gluteus medius. The following implants were placed: Zimmer Trilogy Cluster-Holed Shell  acetabular cup, Zimmer Longevity Crosslinked Polyethylene acetabular liner , Zimmer Versys Cobalt-chromium femoral head , and Zimmer ML Taper Standard Offset, size 12.5 mm, Tivanium Alloy femoral stem . The only complication was a unicortical calcar fracture above the level of the lesser trochanter that was immediately identified and addressed by passing a single cerclage wire around the proximal femur to prevent subsidence.The patient was asked to use crutches for weight-bearing for 6 weeks and had an unremarkable postoperative recovery with excellent osseous integration of the stem and no evidence of subsidence. At the 2-year follow-up, she expressed feeling very pleased with the result of her L-THA and had returned to an active lifestyle. While she reported no significant left-sided hip pain, her right hip pain had grown progressively more painful in association with radiographic evidence of osteoarthritis progression .Figure 2In May 2013, the now 62-year-old patient underwent an uncomplicated right total hip arthroplasty (R-THA) using an anterolateral approach and gluteus medius repair with the following implants: Zimmer Trilogy Cluster-Holed Shell  acetabular cup, Zimmer Longevity Crosslinked Polyethylene acetabular liner , Zimmer Versys Cobalt-chromium femoral head , and Zimmer ML Taper Standard Offset, stem size 12.5 mm, Tivanium Alloy femoral stem . There were no intraoperative fractures, and the patient was allowed to weight-bear fully.Her postoperative course was uncomplicated, and she was able to walk 2 miles and swim daily by 6 weeks after surgery. Pelvic films at follow-up demonstrated well-fixed and well-aligned cementless bilateral total hip replacements . She retShe remained in her usual state of health until May 2015, 5 years after L-THA and 2 years after R-THA. At that point, she reported anterior left hip and groin discomfort. Inflammatory labs showed a normal erythrocyte sedimentation rate (ESR) of 16 mm/h and mildly elevated C-reactive protein (CRP) of 12.7 mg/L. She was referred to physical therapy for hip strengthening. Metal ion levels were not obtained by the treating surgeon.In September 2016, the patient presented with intermittent left-sided posterior gluteal pain associated with strenuous physical activity. Given the infrequency of the pain and onset only with high levels of activity, no further workup was performed, and the plan was to continue monitoring. However, the left-sided intermittent hip pain did not subside. Furthermore, by May 2017, the patient also reported 3 months of new-onset vertigo, headache, generalized fatigue, vision blurriness, and memory issues as well as anxiety and mood disturbance. In particular, the patient described her mood symptoms as a “constant feeling of unrest” and feeling “sad, uneasy, and withdrawn.” Her neurological complaints were alarming and superseded in importance her buttock and groin pain. Now 7 years after L-THA and 4 years after R-THA surgery, metal ion labs were ordered. The results were notable for an elevated plasma chromium level of 4.0 mcg/L and elevated blood cobalt level of 10.6 mcg/L. ESR and CRP were normal. Plain radiographs taken in March 2017 were suggestive of left-sided cup loosening , and a sGiven her clinical symptoms and high suspicion for systemic cobalt toxicity from possible MACC, likely gluteus medius deficiency, and possible aseptic loosening of the acetabulum, a L-THA revision surgery was performed in June 2017. Surgical exploration of the L-THA was notable for a loose cup with fibrous ingrowth, black debris inside the 32-mm head and on the femoral neck taper consistent with MACC, and a less than 25% partial detachment of the gluteus medius most likely from a failed repair of the gluteus medius following the anterolateral approach. The extent of metal ion deposition inside the head and on the trunnion was not noted in the record. The cable was removed simply because it served no function and was in no way in contact with the stem. The cup, liner, and femoral head were exchanged with a new cup, polyethylene liner, and ceramic head with a titanium sleeve. The stem was retained, the trunnion manually cleared of gross debris with a wet sponge and no abrasive surfaces, and the gluteus medius tendon tear repaired with a suture anchor using our previously published technique . The patAt her 4-week follow-up from the L-THA revision, the patient reported resolution of her neurologic and mood symptoms. At 6 months after L-THA revision, her plasma chromium and blood cobalt levels were within normal limits .The patient remained in good health and returned to an active lifestyle for the next 2 years until January 2021, when she presented with 2 months of headaches, vertigo, fatigue, vision blurriness, and memory issues accompanied by anxiety and mood disturbance. The patient reported that these symptoms were similar in nature to those that appeared before her L-THA revision surgery. She had no significant mechanical symptoms or pain in the right hip. Now 8 years after R-THA and 3 years after L-THA revision surgery, labs showed an elevated plasma chromium of 8.1 mcg/L and elevated blood cobalt of 9.4 mcg/L. ESR and CRP labs were within normal limits at 6 mm/h and 1.2 mg/L, respectively.Metallosis at the trunnion of the original R-THA was suspected, and revision R-THA was recommended. A multiacquisition variable-resonance image combination protocol MRI showed no evidence of a pseudotumor or of a possible gluteus medius failed repair. Notably, the onset of symptoms for the left and right hips both occurred approximately 7 years after THA.As with the left hip, during the revision R-THA surgery to replace the metal head in February 2021, the trunnion was found to be corroded with deposition of black material inside the head and over approximately 50% of the trunnion. The cobalt-chromium head was replaced with a ceramic head with a titanium sleeve. The cup was well fixed, but a 50% detachment of the gluteus medius tendon from the greater trochanter not seen in the preoperative MRI was seen intraoperatively and surgically repaired . The patThis case illustrates a presentation of cobalt toxicity manifesting as neurologic symptoms in the context of MACC at the trunnion after THA. Although fatigue, headache, vertigo, memory decline, and mood changes are relatively nonspecific, the elevated serum cobalt levels on laboratory testing in the absence of other contributory comorbidities or lab abnormalities point to MACC as the most likely cause. In particular, the patient presented twice with similar symptoms, and subsequent workup revealed elevated metal ion levels on a nearly identical timeline after each THA surgery. Resolution of symptoms and ion level abnormalities after revision further supports an association between the patient’s symptoms and MACC. The delayed diagnosis after the initial presentation underlines the poorly understood relationship between the neurologic presentation of cobaltism and THA.With few case reports in the literature, the existence of systemic cobaltism from MACC at the trunnion, much less its long-term effects, remains poorly established ,21. ThisAlthough systemic cobaltism from MACC is exceedingly rare, cobalt toxicity from metal-on-metal contact at the acetabular femoral head interface, occupational exposure, and following treatment of anemia is better described ,21,24. FMACC should be considered in patients with cobalt-containing prosthetic joints presenting with new-onset neurologic changes. The expected onset of symptoms has been reported as being on the order of 1-9 years from implantation with a mean of 3.7 to 4.3 years,  as MACC The recognition of MACC with cobalt implants led to device recalls and a shift in surgical practice to favor ceramic femoral heads, which appear to be less susceptible to corrosion than cobalt-chromium alloy heads ,12,21. HIt should be noted that the Zimmer Versys cobalt chromium head implant used in this patient has been implicated in multiple cases of MACC when paired with the Zimmer M/L Taper trunnion ,6,12. ThThis case report has several limitations, the most apparent being the lack of generalizability with this research design. The patient’s neurologic symptoms  are nonspecific and could be due to alternative causes other than cobalt ion level elevation. As described previously, however, the dual nearly identical presentations, time course, laboratory and surgical finding of MACC during revision surgery, as well as symptom resolution after revision offer an unusually compelling narrative for MACC at the head-neck taper as opposed to other causes. Given the patient’s age, some of these symptoms such as memory loss might be attributed to normal cognitive changes, but age-related dementia would not be expected to reverse with surgical intervention.In summary, we presented the case of a single patient who received bilateral, staged, identical THAs and who later developed neurologic symptoms associated with serum metal ion elevations on two separate occasions separated by the same time delay from the index surgeries. We feel this case report makes a compelling argument for a causal link between MACC and systemic cobalt ion toxicity manifesting as neurologic symptoms. This case report alerts clinicians to consider screening for MACC when new-onset neurologic symptoms follow total hip replacement surgery, particularly in patients in whom this type of metal-on-polyethylene device has been implanted.


Indications changed significantly over time, with a higher proportion of patients being transplanted for malignancies and metabolic disease and indications of PFIC and α1AT-deficiency declining. The era of transplantation  and indication of acute liver failure  impairs patient/graft survival significantly in the multivariate analysis. Furthermore, patient survival is worsened by re-transplantation  and prolonged waiting times in high-urgency status , whereas the indication of biliary atresia improved outcome . Graft survival was additionally impaired by pre-existing portal vein thrombosis . (4) Conclusions: Despite more complex indications, patient and graft survival after pLTx continue to improve.. Acute liver failure remains the indication with poorest outcome, and listing for high urgency liver transplantation should be considered carefully and early to keep waiting time on HU list short. Furthermore, pre-transplant portal vein thrombosis should be prevented whenever possible to improve graft survival.(1) Background and Aim: Despite excellent long-term results in pediatric liver transplantation (pLTx), mortality and graft loss still are to be diminished. We aim to describe time-dependent changes and long-term outcome of a large single-center pLTx cohort and to identify independent recipient-related risk factors impairing patient and graft survival. (2) Methods: This is a retrospective single-center study analyzing all pediatric liver transplants from 1983–2020. Risk factors for mortality and graft loss were identified by univariable and multi-linear regression analysis. (3) Results: We analyzed 858 liver transplantations in 705 pediatric patients. Five-year patient/graft survival increased from 60.9%/48.0% (1983–1992) to 97.5%/86.5% (OR = 12.5;  T.E. Starzl, who performed the first orthotopic liver transplantation in 1963 , both inRisk factors for impaired patient survival after pediatric liver transplantation have been analyzed in several studies, but, at least partially, with controversial conclusions. Consistently, transplantation in earlier years/eras was found to be a risk factor ,7,8, as Risk factors for impaired graft survival have been described as the era of transplantation . Some reMost of the previously discovered risk factors are given and not to be modified; our aim was to identify ideally modifiable recipient-specific risk factors for impaired graft and patient survival in order to create the optimal, baseline conditions for patient and graft survival. Furthermore, this is the first study to describe the long-term outcome of our pediatric liver transplant cohort and the largest European single-center pediatric liver transplant cohort described so far. The first liver transplantation was performed at Hannover Medical School in 1972, the first pediatric liver transplant in 1979 and a regular pediatric liver transplant program was set up in 1983. With more than 850 pediatric liver transplants in total and an actual annual rate of around 30 pLTX, Hannover Medical School is one of the largest pLTX programs in Europe. We aimed to detect changes over time, regarding indications and outcome of pLTx recipients.This is a single center (EUROTRANSPLANT region) retrospective cohort study analyzing the data of all consecutive liver transplants in pediatric patients (<18 years at date of pLTx) from 1983 to 2020. All transplantations took place at our center and were performed by the department of visceral and transplant surgery and medically attended by the department of pediatric hepatology and the pediatric intensive care unit.For the main analysis, all pediatric liver transplantations were included; no pediatric liver transplant recipients were excluded. Three patients in our cohort who had already reached adulthood at the time of transplantation while the transplantation was still performed under pediatric care were excluded. Sub-analyses were performed within the group of primary transplantations. For sub-analyses, patients were divided into pediatric age groups  and eras of transplantation . The main outcome parameters were patient survival (endpoint: death after pediatric liver transplantation), graft survival (endpoint: loss of graft due to re-transplantation or death of the patient).n = 141) or the date of last known follow-up (n = 564). Follow-up was performed by screening the documentation of visits in pediatric and adult hepatology clinics and, in case of patients being lost to follow-up data were gained from population registries. Median follow-up period after transplantation was 10.16 years ; adding up to 8547 years at risk after pLTx.All patients were followed up from the date of transplant until either death  table. Statistics were calculated in JMP (Version 14 pro). All parents/caregivers of patients analyzed in this study provided informed consent that their children’s data were allowed to be used for scientific purposes. Patient data were anonymized prior to analysis. Ethics counselling was not necessary because of the retrospective design of the study, according to the guidelines of our Ethics’ Committee.n) and percentages (%) within analyzed groups of patients. The Wilcoxon test was used to compare continuous data between groups and the two-sided Pearson’s Chi-squared test was used to compare the proportions of binary variables between groups. Continuous data are represented in this study as median, interquartile range, and minimum and maximum, whereas binary variables are represented as positive frequencies  were considered for inclusion into multivariable regression modeling. Final multivariable regression models were achieved by gradual reverse probability elimination of insignificant variables until only significant variables (p < 0.05) remained in the final logistic regression models.Risk factors for patient and graft survival and their significance were calculated by univariable regression analysis . Factors with For continuous variables, hazard ratios were calculated by Cox regression analysis and displayed per change of unit in regression.Changes in the percentage of specific indications over time were analyzed by nominal logistic regression analysis, odds ratios are displayed for comparison of Era 1 to Era 5.Odds ratios (OR) and hazard ratios (HR) and their respective 95-confidence intervals (95%-CI) are provided for uni- and multivariate logistic and Cox regression analysis results, respectively. Survival rates of different transplant eras were compared by nominal logistic regression analysis.From 1 January 1983 to 31 December 2020, 858 orthotopic liver transplantations were performed in 705 pediatric patients . The main indications for primary liver transplantation were biliary atresia (more than one third of the patients), acute liver failure (12%), PFIC and Alagille syndrome, metabolic and malignant diseases, alpha-1-AT-deficiency, Wilson’s disease, PSC and autoimmune liver disease . The KasMain indications for re-transplantation were vascular complications, chronic graft failure, primary non-function of the graft, biliary complications, and chronic rejection.p = 0.0486) and α1AT-deficiency  significantly decreased. The percentage of patients being transplanted for acute liver failure (17.7% in Era 1 to 9.7% in Era 5) and Alagille syndrome (5% to 2%) receded, too, but did not reach a level of significance. Over time, analysis of the indications for primary liver transplantation related to the eras, shows a significant change of indications in our center. Whereas the percentage of patients being transplanted for biliary atresia  did not show a clear tendency, transplantation for PFIC  and malignant diseases . The percentage of patients with cystic fibrosis also increased (0% to 7.6%), but due to the small patient numbers could not be statistically analyzed , while mean age was 6.03 years, showing the non-Gaussian distribution of the age at transplant. Nearly 40% of the children were transplanted within the first two years of age. Gender distribution was nearly even with 413 girls (48.1%). Mean overall time on waiting list, irrespective of status, was 158.9 days, with 199.5 days in non-high-urgency status and 6.2 days in high urgency status. Pre-transplant portal vein thrombosis was present in 21 (3.6%) of the children. All baseline characteristics can be found in p < 0.001); 10 year survival rose from 58.0% in Era 1 to 89.2% in Era 4 , whereas 20-year survival improved from 54.6% in Era 1 to 72.6% in Era 2 . Of all patients who died after transplantation (141/20.6%), more than two-thirds (103/14.4%) were transplanted in the two early eras and only 3 (1.14%) were transplanted in the most recent era, while group sizes in all eras were similar. As the oldest patient was born in 1967, no natural death would be expected, so far.Overall, for the whole group, 1-year patient survival was 84.6%, 5-year-survival 79.2%, 10-year survival 72.8%, 20-year survival 62.5%. As shown in the Kaplan–Meier-curve , patientn = 141, 20.0%) after pLTx were infection (43.9%), cerebral events (14.4%), graft dysfunction (12.2%) and malignancies (de novo/recurrence) (9.4%), as shown in The main reasons for recipient mortality  were observed. The main reasons for graft loss were death of the recipient (mostly caused by infection) (21.4%), vascular complications (17.5%), initial non-function of the graft (15.6%), chronic rejection (9.8%), and chronic graft failure (5.6%).p < 0.0001); 20-year-graft-survival also improved significantly from 39.4% in Era 1 to 58.3% in Era 2 .Overall, 5-year-graft-survival was 68.1%, with a significant increase from 48.0% in Era 1 to 86.5% in Era 5 , in keeping with this, adolescent age at time of transplantation (age group > 12–18 years) was another risk factor for impaired survival  and infants were at lowest risk .Univariable proportional hazard analysis for patient survival revealed risk factors associated with premature death after liver transplantation . A highep < 0.001), whereas transplantation for biliary atresia , PFIC  had a significantly better outcome. Other indications did not have a significant impact on survival in our cohort. Re-transplantation was significantly associated with impaired patient survival . Children transplanted for acute liver failure had a significantly higher risk of mortality after pLTx , as with an elevated INR . Recipient’s total bilirubin at the time of pLTx correlated negatively with survival  and era 2  had a significantly higher risk of premature death, whereas children transplanted in era 4 and 5 had a significantly better chance of survival . The factor of being on a high-urgency waiting list for liver transplantation was significantly associated with impaired patient survival . Longer waiting times on the transplant list, independent of the waiting list status, was positively correlated with survival , whereas a waiting time in T status did not have a significant influence and a prolonged waiting time on the high-urgency list led to a higher risk of premature death after pLTx . The Lab-MELD-Score was not significantly associated with post-Tx survival, whereas an increased pediatric MELD-score was associated with better survival after transplantation.The era of transplantation had a significant impact on patient survival, as children transplanted in era 1 .Biliary anastomosis during liver transplantation via biliodigestive anastomosis was associated with better survival , whereas a prolonged non-ICU in-patient stay was correlated with improved survival .A longer duration of the post-pLTx ICU stay had a significant, negative influence on patient survival .The need for re-transplantation was highly correlated to impaired survival , length of waiting time on the high-urgency list , diagnosis of acute liver failure , and subsequent re-transplantation  were independent and highly significant risk factors for impaired patient survival (p = 0.0315).Multivariate analysis showed that era of transplantation  were significantly less often affected by graft loss .Increased recipient INR was a risk factor for graft loss , regardless of the reason for graft loss, whereas a diagnosis of cystic fibrosis was significantly associated with better graft survival . Diagnosis of acute liver failure was a risk factor for impaired graft survival , while pLTx in era 4  and era 5  led to better graft survival.The era of transplantation significantly affected graft survival, irrespective of definition of graft loss, with transplantation in era 1 being a risk factor for graft loss , whereas a longer non-ICU inpatient stay improved graft survival.Prolonged post-transplant ICU stay impaired graft survival , underlying diagnosis of acute liver failure , and pre-existing portal vein thrombosis   .This is the first study to describe the complete pediatric liver transplant cohort at our center and the largest European single center pLTx cohort. Overall, patient survival is comparable to pediatric liver transplantation cohorts in other experienced centers, the one- and 5-year patient survival of 97.5% in the most recent era is slightly higher when compared to the recently published reports of the North American SPLIT registry , documenAnalysis of the indications for primary liver transplantation related to the eras, shows a significant shift of the percentual share of transplant indications in our center from some of the “classic” indications for pediatric liver transplantation, such as PFIC and a1AT-deficiency, to more complicated, often multisystemic indications such as metabolic diseases and malignancy.The change of indications over time has also been documented by other authors, McKiernan et al., documented a decrease in patients being transplanted for a1-AT-deficiency and Wilson’s disease, while the percentage of patients being transplanted for metabolic disease, without structural liver damage, was rising in the north American registry, which supports our findings . Other sThe indication for liver transplantation had a significant impact on patient survival in our study—patients with acute liver failure being at higher risk of mortality after pLTx, which is consistent with most studies ,14,23,24Regarding the age at transplantation, our study showed higher age to be a risk factor for mortality, patients transplanted in infancy had a significantly better outcome, whereas transplantation in adolescence was a risk factor for premature death. This stands in contrast to most studies, which—if at all—have found early infancy to be a risk factor for impaired survival ,11,25,26A higher INR and bilirubin level at the time of transplantation was also associated with an inferior outcome, in keeping with other studies  and clinThe waiting list status and waiting time had an influence on patient survival, with patients being listed in high urgency status at higher risk of mortality, especially with a prolonged waiting time with the latter being reproducible as an independent risk factor in multivariate analysis. The association of status-independent prolonged waiting time with improved patient survival was biased by the fact that the waiting time for patients in HU status was generally shorter and these patients had a higher risk of mortality.The era of transplantation was highly and significantly associated with patient survival; remarkably, this improvement continues up to the most recent era, even when compared to the era around 2010 (but not on significant level). As we have included patients transplanted until the end of 2020 in the recent era, only 56 of 162 patients (34.6%) have completed the 5-year-surveillance. Advancements in surgical techniques, pediatric intensive care and pre- and post-transplant pediatric hepatology attendance, immunosuppressive therapy, and screening for known complications, improve survival after pLTx. The era of transplantation was also the most significant and highest correlated factor in multivariate analysis, which supports the findings of many colleagues .Re-transplantation was a highly significant risk factor for impaired patient survival in uni- and multivariate analysis, being another critical procedure in potentially instable patients, as seen in many other studies ,11,12,29The length of post-transplant ICU-stay, indicating a more complicated course, also led to a higher mortality risk.The analysis of factors influencing graft survival revealed a lower risk for graft loss in the group of patients between 6 and 12 years of age. As age groups have been defined differently, a direct comparison is difficult, but some other studies have seen this age group rather as a risk factor for an unfavorable outcome ,28 and lRegarding indications, a diagnosis of acute liver failure was not only associated with impaired patient survival, but also an independent risk factor for impaired graft survival, as seen by other researchers ,24 in unInterestingly, we found cystic fibrosis and hepatoblastoma to be indications with improved graft survival, but these indications lost their significance in multivariate modeling, probably due to confounders—we have not found comparative data in other studies, except for another study reporting a small cohort of liver-transplanted CF patients without graft loss . CF patiAs in most previous studies, the era of transplantation had a highly significant impact on graft survival in univariate and multivariate analysis, underlining the impact of the advances in surgical and medical care, enabling long-term graft survival ,25.Pre-existing portal vein thrombosis before liver transplantation was an independent and significant risk factor for graft loss in the multivariate analysis in our study. Obviously, with a pre-existing thrombosis one might suspect a worse portal vein flow, with possible post-transplant PV thrombosis. To our knowledge, there is only one study in a pediatric cohort that found pre-Tx-PV-thrombosis to be a risk factor for mortality , and a study in adult patients that found it to be a risk factor for graft loss, but interestingly by hepatic artery thrombosis post-transplant . In our Due to the retrospective design of this study, we had to deal with some missing data which could not be retrieved retrospectively, especially regarding pre-transplant laboratory variables of the recipients, which limits the explanatory power of our data.Data regarding graft loss or re-transplantation may be incomplete, as some patients are no longer under the care of our center and, in most cases, we do not have access to the patients’ data who had a possible re-transplantation in another center. In the follow-up, we could retrieve data regarding survival of patients no longer under our care from population registries, but in cases of mortality we have no information regarding the cause of death.Due to the single-center design of the study, some observed developments, especially regarding changes in indications over time, may be center-specific effects that would need to be validated in bigger, multi-center cohort studies.However, with more than 850 pediatric liver transplantations in more than 700 patients this is one of the largest pediatric single-center studies and to our knowledge the largest European single-center cohort described so far. We have gathered pre-, peri-, and post-transplant data comprising nearly four decades of pediatric liver transplantation in which major developments and new treatment options have been established and identified changes and influencing factors in this large cohort.Our analysis of independent recipient-specific risk factors for patient and graft survival after pediatric liver transplantation has supported the results of previous analyses, but also led to new findings. Patient and graft survival improved continuously over the years and has reached an excellent level in the recent era. We see a significant change in indications from “classic” pediatric indications  to more complex diagnoses of malignant and metabolic diseases.In multivariate analysis, early era of transplantation and the diagnosis of acute liver failure impair patient and graft survival independently and significantly. Further, patient survival was better in patients with biliary atresia. Prolonged waiting time in high urgency status for HU patients was a risk factor for mortality. For graft survival, we found pre-existing portal vein thrombosis to be an additional, independent risk factor. Many of the risk factors can hardly be modified, but as clinicians working in the field of pediatric liver transplantation, we should lay our focus on the factors that can, at least partially, be influenced: careful and early choice of patients needing high urgency transplantation and prevention of portal vein thrombosis, often a careful balancing act between diuretics and fluid intake, especially in end-stage liver disease patients with ascites. Further multicenter studies validating the impact of the risk factors identified in our study would be desirable.