Antimicrobial resistance (AMR) is a public health concern. We wanted to determine if various environmental and socioeconomic variables as well as markers of antimicrobial use impacted on the level of AMR in countries of different income levels.Escherichia coli (QREC) in blood culture as the dependent variable. Access to safe water and sanitation, other socioeconomic variables, and human and animal antimicrobial consumption were analysed.We performed cross-national univariate and multivariable analyses using the national proportion of quinolone-resistant In middle-income countries, unsafely managed sanitation, corruption and healthcare access and quality were significantly associated with the national proportion of blood culture QREC (%) in univariate analyses, whereas no variables remained significant in the multivariable models. For the multivariable high-income country model, corruption and healthcare access and quality were significantly associated with blood culture QREC (%) levels. For the model including all countries, human fluoroquinolone use, corruption level, livestock and crop production index were significantly associated with blood culture QREC (%) levels in the univariate analyses.Corruption is a strong predictor of AMR, likely reflecting a multitude of socioeconomic factors. Sanitation quality contributed to increased blood culture QREC (%) levels in middle-income countries, although was not an independent factor, highlighting the need to also focus on infrastructure such as sanitation services in the context of AMR.The online version contains supplementary material available at 10.1186/s12889-022-12776-y. Antimicrobial Resistance (AMR), the ability of a disease-causing microbe to survive antimicrobial agents, is a growing global public health concern. The reduced options to treat infectious diseases can lead to longer duration of illness, increased hospital time and increased mortality rates across all areas of healthcare. AMR is currently estimated to account for 700,000 deaths annually worldwide, increasing to approximately 10 million deaths and US$ 100 trillion annually by 2050 [The development and spread of AMR is a complex issue, partly due to the fact that environmental bacteria, predating the antibiotic era, carried genes that encode for resistance to antibiotics . Indeed,Antimicrobial agents are used in many societal sectors. Apart from their role in human and veterinary medicine, they are used extensively in agriculture, aquaculture and the farming industry. There is much emphasis on the impact of inappropriate antibiotic  use in human medicine on the development of AMR, resulting in the development of the World Health Organization (WHO) guideline on antibiotic stewardship , as wellThe role of the environment and quality of sanitation and water infrastructure as drivers for the development and spread of AMR, in addition to rate of disease spread, has become a recent focus of research . When enet. al. showed that a country’s income predicts their levels of AMR, with an 11·3% decrease in the prevalence of E. coli resistant to broad-spectrum cephalosporins for each log increase in Gross National Income (GNI) per capita [. This study did not consider any potential confounders. The authors’ proposed explanation was that countries with a lower income have a higher population density, suboptimal sewage systems, poor sanitation and lack of access to clean water as well as inadequate antimicrobial stewardship programmes, low vaccination rates and lower education levels [et.al. looked at the contribution of poor governance and corruption in European countries on AMR levels and demonstrated that higher levels of corruption are strongly associated with an increase in AMR [et.al., published a paper that emphasised the need to move away from solely focusing on antibiotic use and AMR, and to consider anthropogenic and environmental drivers of AMR [The correlation between socioeconomic factors and AMR has also become a focus of research. Alvarez-Uria r capita . This stn levels . Colligne in AMR . They pre in AMR . These sSome of the most robust data on water and sanitation is produced by the World Health Organization (WHO) and United Nations Children’s Fund (UNICEF) Joint Monitoring Programme (JMP) for Water Supply, Sanitation and Hygiene (WASH) . The JMPIn order to further evaluate the impact of water and sanitation on AMR, along with various socioeconomic, environmental and agricultural factors, we performed a cross-national multivariable analysis. Furthermore, we wanted to assess whether the determinants of AMR remain consistent across high-income, middle-income and low-income countries. For example, while poor infrastructure may drive AMR in low-income countries, other factors may be at play in high-income countries where the standard of infrastructure remains consistently high. An answer to this could promote a more stratified response to the issue of AMR according to the drivers of AMR specific to each country.Escherichia coli (QREC %) in blood culture samples as our model pathogen and dependent variable. This was chosen as an indicator for national levels of AMR as E. coli is the prototypical faecal indicator bacterium [E. coli is the target bacterial species of the WHO Tricycle AMR Surveillance Project, which focuses on the proportion of extended-spectrum beta-lactamase (ESBL) producing E. coli across the human, animal/food safety and environment compartments [We chose to use the proportion of quinolone-resistant acterium . Furtherartments . Fluoroqartments . They arartments .E. coli, we retrieved data on potential explanatory variables (Table Data on blood culture QREC (%) is available across multiple countries. We obtained this data from the Resistance Map Repository, produced by the Centre for Disease Dynamics, Economics and Policy (CDDEP). This database has aggregated data from 1999 to 2017 on antibiotic resistance from several sources including national and regional AMR surveillance databases . CDDEP hCountries included in the study were categorized into high-income, middle-income and low-income groups according to the updated World Bank classification . There wE. coli isolates tested). Regression coefficients and p-values for the independent variables analysed using univariate regression can be found in the Additional file 2) to describe the direction and strength of associations between the dependent variable and potential explanatory variables.Descriptive statistics were obtained for all variables using medians with interquartile ranges (IQR’s). Given all variables were numerical and fairly normally distributed we used univariate linear regression analysis to determine the association between individual independent variables and the outcome variable (proportion of QREC (%) among blood culture p-value < 0·05) in the univariate analyses were included in a multivariable linear regression model. We performed analyses for and reported on separate multivariable models for all countries, high-income countries and middle-income countries. We also attempted to further stratify countries by income by testing models looking at upper-middle and lower-middle income countries, but we found that there was too little data in these sets and were concerned about low statistical power. We considered removing Malawi from the data-set as it was the only lower-income country, however, removing it made no impact on the significance of the results and we decided to analyse it in the middle-income country group for completeness of the data set. A p-value of less than 0·05 was considered significant in the multivariable regression models. The fit of each model was described using the coefficient of determination, R2.We performed multivariable linear regression to determine the effect of each variable when controlling for the others. All variables that were significantly associated with the outcome variable  was used to test for multicollinearity, with a VIF of > 6 considered as potentially serious multicollinearity. We used the Missing Completely at Random (MCAR) for multivariate data test to detect any bias in the dataset.E. coli by country.STATA version 14.0  was used for statistical analysis. Microsoft Excel 2019 was used to illustrate the proportion of QREC (%) among blood culture Seventy-one countries had data on blood culture QREC (%), of which 42 represented high-income countries, 28 were middle-income countries, and one country  was a low-income country Fig. . The medp < 0·05, namely, unsafely managed sanitation, unsafely managed water, human fluoroquinolone consumption, average annual temperature, livestock production index (quantity of production of meat and milk relative to base period 2004–2006) and crop production index . An increase in GNI per capita, corruption perceptions index (a higher score in the index is indicative of lower corruption levels), education level and healthcare access and quality were negatively correlated with the level of blood culture QREC (%).As visualised in Fig. p < 0·05. GNI per capita, corruption perception index, education level, healthcare access and quality were negatively associated with an increase in blood culture QREC (%) at p < 0·05.For the univariate linear regression models including only high-income countries human fluoroquinolone consumption, animal antimicrobial consumption, population density, and average annual temperature were positively associated with an increase in blood culture QREC (%) at For the univariate linear regression models including only middle-income countries and one low-income country, an increase in unsafely managed sanitation was significantly associated with an increase in blood culture QREC (%), while an increase in corruption perception index and healthcare access and quality were significantly associated with a decrease in blood culture QREC (%).n = 53, Table 3, All Countries column), the model explained 73% of the total variation in blood culture QREC (%). Human fluroquinolone consumption and corruption perception index remained significant at p < 0·01. A one-unit improvement in the corruption perception index score resulted in a decrease of blood culture QREC (%) isolates by 0·45% if all other variables remain unchanged, while a one-unit increase in human fluroquinolone consumption resulted in a 0·01% increase in blood culture QREC (%) isolates. Livestock production index and crop production index also remained significant in this model with an increase in production relative to the baseline period being positively associated with blood culture QREC (%).In the multivariable linear regression model with all countries that had complete data , corruption perception index and healthcare access and quality remained negatively and positively associated with blood culture QREC (%) at p < 0·05 respectively, with this model also explaining 73% of the total variation in blood culture QREC (%). In the model with only middle-income countries Table Middle-Income Countries column), there were only 26 observations and no variables remained significantly associated with blood culture QREC (%).In the multivariable linear regression model with only high-income countries  was p = 0.10 indicating that we cannot reject that the data was normally distributed. The mean Variance Inflation Factor was 4·10 which is less than 6·00, the indicator for multicollinearity. Finally, the p value of the Breusch-Pagan Test for heteroscedasticity for all the models was p < 0·01  indicating that we can reject the hypothesis that the data is homoscedastic and assume that the variability of the variables is unequal. Heteroscedasticity was adjusted for by using robust standard errors.The The potential health impact from AMR has prompted researchers to determine the main drivers for the development and spread of AMR. Several studies have assessed the effect of socioeconomic factors, including income level, corruption and infrastructure, on promoting AMR –10. Our An increase in unsafely managed drinking water was significantly associated with an increase in blood culture QREC (%) when analysed with univariate regression in the combined model and the middle-income model, although it lost its significance in the multivariable models. We suggest that there was too little variance in the data to draw the conclusion that unsafely managed drinking water contributed independently to blood culture QREC (%) levels.et. al. which found a positive correlation between infrastructure (i.e. access to sanitation), and AMR levels [In the univariate analysis, we found that as the proportion of unsafely managed sanitation increased, so too did the levels of blood culture QREC (%). Poorer quality sanitation results in an environmental breeding ground for antibiotic resistance and thus explains the positive relationship with blood culture QREC (%) . IncreasR levels . In the et. al. on the other hand did include these additional factors and found that antibiotic use was not significant in any of the multivariable models [Human fluoroquinolone consumption had a positive association with blood culture QREC (%) level in the multivariable model including all countries, and when analysed in high-income countries only, but not for middle-income countries. A vast body of research shows that high consumption of antimicrobials is a main driver of AMR. Most of these studies, however, are performed in high-income settings, and have not included possible socioeconomic and environmental factors. Collignon e models . Their fet. al. who explained it by the fact that wealthier countries use more antibiotics [et. al. where they found that income was inversely related to AMR, although no other variables were considered in this study [An increase in GNI per capita was significantly associated with an increase in blood culture QREC (%) in the univariate analyses in both the combined and high-income countries only analyses, however, it lost its significance in the multivariable models. This positive association is consistent with the findings of Collignon ibiotics . The resis study .p value < 0·05) in all three univariate analyses. It also remained significant in the multivariable models that analysed all countries and in the high-income countries only, although it lost its significance in the middle-income multivariable model, likely due to too few observations. It is probable that countries with more corruption will have fewer antibiotic stewardship programmes and less stringent policies on the disposal of pharmaceuticals, as well as worse infrastructure and water and sanitation services.The corruption perceptions index  remained strongly negatively associated with blood culture QREC (%) across all models, being the only significant variable  in univariate and multivariable analyses of all countries combined but showed no significance when analysed in the high and middle-income models only. Often policy makers focus only on the misuse of antimicrobials amongst the human population, but antimicrobials are also used extensively in the agricultural, farming and aquaculture industry. As demonstrated above, as the quantity of livestock and agricultural production increases in a country, there is an associated increase in blood culture QREC (%). This could be as a result of increased use of antimicrobials in these industries and subsequent run-off into the environment.The major downfall of our study was the quantity of data available and the non-randomness of some of the missing data. The data we used was also cross-sectional which prevented us from capturing relationships which take place with a time lag. Data collection is a costly process and one that requires a stable economy and political state. Consequently, developed countries are over-represented, and indeed, there was only one low-income country with data on blood culture QREC (%). While we can draw relatively certain conclusions on high-income countries, it is possible that there are different drivers in low-income countries for which we have little data, and even within the middle-income group for which we probably had insufficient data. The collection of national data on AMR via the WHO GLASS project is a relatively new endeavour and one that requires large input from governments and health departments. Several countries have enrolled in GLASS, but it will take many years before it becomes routine data collection internationally.Our study only looked at blood culture QREC (%) as a marker of AMR. It has been shown that pathogens have different responses to antimicrobial use and it is possible that by focusing on a single drug-pathogen combination that the results may have limited generalisability . It has In addition, while we included diverse variables, it is possible that some statistical errors of endogeneity exist. There is potential for reverse causality where factors associated with AMR also influence prescribing practices or where the level of AMR influences the independent variables. It is also possible that some factors that are drivers for AMR were omitted or unobserved or that some of the included variables exhibit simultaneity. For example, it is possible that countries with higher income have both less corruption, greater access to antimicrobials and improved sanitation and water infrastructure. Indeed, it is unlikely that corruption itself causes higher levels of AMR, this association likely reflects a range of socioeconomic factors which are correlated with perceived corruption. We tried to account for potential multi-collinearity by calculating the Variance Inflation Factor (< 6) which demonstrated the likelihood of the analysed variables being correlated with each other. When performing multivariate analysis, there is always a balance between potentially omitting relevant drivers or including too many, resulting in simultaneity or reversed causality, and we acknowledge this as a limitation.This aside, our study analysed a large number of socioeconomic and environmental factors associated with AMR. Our study is the first we know to perform multivariable analyses where we stratified drivers of AMR by different levels of income. Although there is uncertainty about details in our results, they did indicate there might be different main drivers of AMR in different economic settings, pointing to the need for differentiated policies to fight AMR. There has been a call for environmental regulation and monitoring to be included in AMR action plans, although a lack of understanding of the drivers and pathways of AMR and the differences between these drivers in different settings has resulted in an inability to include many of them in policy until now . As otheWe have identified gaps in the research, namely, in the amount of data available on AMR in low-income countries. We recommend steps to improve AMR surveillance in low-income countries. If such data becomes available, we suggest running further multivariable analyses of AMR drivers in low-income countries in order to guide political prioritization of action against AMR.AMR is a global health concern. Using blood culture QREC (%) as a marker of AMR in a country, we found that corruption and antibiotic use were strong predictive factors for both high- and middle-income countries, with sanitation services also playing a role in middle-income countries. The association between corruption and AMR likely reflects a range of socioeconomic factors which are correlated with the variables and the mechanism behind these associations needs to be explored in more detail. Especially for low-income countries, it is imperative to improve AMR surveillance, in order to guide political prioritization of action against AMR.Additional file 1.


P-value = 0.002) and opportunistic infection . IVIg exerted a protective effect for bacterial infection . The recovery of renal function was complete at 3 months after AMR treatment in 67% of episodes. One-year death-censored graft survival was 90.9%. Four patients (6.2%) died during the first year (two due to severe infection). In this nationwide cohort we found significant heterogeneity in therapeutic approaches for acute AMR. Infectious complications were common, particularly among KT recipients receiving plasmapheresis.Acute antibody-mediated rejection (AMR) remains a challenge after kidney transplantation (KT). As there is no clear-cut treatment recommendation, accurate information on current therapeutic strategies in real-life practice is needed. KT recipients from the multicenter Swiss Transplant Cohort Study treated for acute AMR during the first post-transplant year were included retrospectively. We aimed at describing the anti-rejection protocols used routinely, as well as patient and graft outcomes, with focus on infectious complications. Overall, 65/1669 (3.9%) KT recipients were treated for 75 episodes of acute AMR. In addition to corticosteroid boluses, most common therapies included plasmapheresis (56.0%), intravenous immunoglobulins (IVIg) (38.7%), rituximab (25.3%), and antithymocyte globulin (22.7%). At least one infectious complication occurred within 6 months from AMR treatment in 63.6% of patients. Plasmapheresis increased the risk of overall (hazard ratio [HR]: 2.89;  Acute antibody-mediated rejection (AMR) is a potential cause of kidney allograft loss –3. DespiHistorically alloantibody removal by plasmapheresis was the first strategy used, associated or not with the immunomodulating effect of IVIg therapy –13. ThisIn view of the lack of high level evidence to guide the optimal choice of acute AMR treatment after kidney transplantation (KT) and the risks associated with the subsequent increase in immunosuppression, we analyzed in a real-life nationwide transplant cohort the current therapeutic practices and the resulting outcomes in terms of efficacy and safety, in particular regarding infectious complications.www.stcs.ch, ClinicalTrials.gov: NCT01204944), that was approved by the Ethics Committees of all participating centers (Swissethics BASEC project 2018–022394). Written informed consent was given by all participants, enabling the use of patient- and graft-specific data  or ATG-Fresenius® [MTD: 28 mg/Kg]), eculizumab , or bortezomib (MTD: 50 mg/m2 body surface area). Of note, the substitutive doses of IVIg (0.4 g/Kg) given after plasmapheresis were not considered as anti-rejection therapy.Two different extracorporeal techniques, plasmapheresis or immunoadsorption, were used depending on availability at each center. Immunosuppressive drugs used as anti-rejection therapy included IV methylprednisolone boluses , high-dose IVIg (MTD: 2 g/Kg), rituximab (MTD: 375 mg/mP. jirovecii and parasites (e.g. toxoplasmosis). Only episodes of symptomatic CMV disease were taken into account in the risk factors analysis ) with at least one treated episode of acute AMR within the first post-transplant year. Seven patients experienced >1 episode , and one patient received two kidney transplants during the study period . Two recipients with combined transplantations were included (kidney-liver and kidney-pancreas). Demographics and clinical characteristics of the study population are summarized in Fig 1). The median interval from transplantation to the first episode was 14.0 days (IQR: 7.0–93.0). Primary graft non-function was reported in one patient with pre-existing DSA. Of note, of the 75 episodes of acute AMR, 21 biopsies (28%) showed also some signs of T-cell mediated rejection (TCMR). However, all patients had the clinical  and histological features of acute active AMR .Most (54.7% [41/75]) acute AMR episodes occurred within the first 4 weeks post-transplantation and 68.0% (51/75) within the first 3 months . Eculizumab and bortezomib were rarely used. Overall, there were up to 20 different combination regimens. The most common double therapy consisted of plasmapheresis (or immunoadsorption) with methylprednisolone boluses, and the most common triple therapy included plasmapheresis (or immunoadsorption), methylprednisolone and IVIg. One patient with pre-existing DSA underwent splenectomy after multiple sessions of immunoadsorption and plasmapheresis, one dose of rituximab and four doses of bortezomib.The combination of two different anti-rejection therapies was used in most episodes (44.0% [33/75]), followed by three therapies in 21.3% (16/75), four in 12.0% (9/75) and 5 in 5.3% (4/75). Monotherapy with methylprednisolone boluses was used in 17.3% of cases [13/75]. In addition to methylprednisolone boluses, the most common treatment modalities were plasmapheresis/immunoadsorption  having had 5 sessions, 3/19 patients with 4 sessions, 3/19 only 2 sessions; 6–10 sessions: 38%; >10 sessions: 17%) and IVIg, alone or in combination, followed by rituximab and ATG . Eighteen episodes of opportunistic infections occurred in 18.2% (12/66) of patients and included BK polyomavirus-associated nephropathy (33.3% [6/18]), CMV disease (27.8% [5/18]), invasive pulmonary aspergillosis (11.1% [2/18]); and Pneumocystis jirovecii pneumonia (PCP), Candida esophagitis, VZV encephalitis, herpes zoster and mucocutaneous HSV infection . Regarding CMV infection, 16.7% [3/18] of episodes occurred in D+/R- recipients . The patient who developed VZV encephalitis was treated for severe AMR within the previous month with multiple immunoadsorption and plasmapheresis sessions, methylprednisolone boluses , one dose of rituximab and four doses of bortezomib.Overall, 63.6% (42/66) of recipients developed 96 episodes of infection within the first 6 months following the diagnosis of acute AMR (incidence rate: 0.77 episodes/100 patient-days). The distribution of clinical syndromes and causative agents is detailed in Table 4 shows the results of the multivariate analysis for predicting the occurrence of overall infections in the “per-patient” analysis, in which BMI at the time of rejection  and plasmapheresis  were risk factors. Accordingly, patients receiving plasmapheresis (either as single therapy or in combination regimens) had higher cumulative incidence of overall infection . These results remain essentially unchanged in the “per-episode” analysis (S1 Table in S1 File). When bacterial infection was specifically analyzed, induction with rituximab  and BMI at the time of rejection  were risk factors, whereas there was a protective effect with IVIg anti-rejection therapy  (Table 5). The cumulative incidence of bacterial infection was significantly lower in patients treated with IVIg-containing regimens . Rituximab induction and plasmapheresis remained as risk factors for bacterial infection in the multivariate model based on the “per-episode” analysis. Regarding opportunistic infection, plasmapheresis was the only risk factor found in the “per-patient” analysis (S2 Table in S1 File). When the model was constructed on a “per-episode” basis, plasmapheresis  also was identified as independent risk factor, and the administration of CMV antiviral prophylaxis  was protective (Table 6).At month 3 after AMR, full recovery of renal graft function was achieved in 66.7% (50/75) of episodes, intermediate recovery occurred in 18.7% (14/75), whereas no recovery was observed in 14.7% (11/75).Fig 4A). Two patients died due to severe infectious complications. The first patient received corticosteroids, multiple plasmapheresis sessions, IVIg and one dose of rituximab following the diagnosis of AMR at day 7 post-transplantation. He successively experienced CMV disease (at day 17) and norovirus infection . The patient died at month 3 due to multiple organ failure in the context of PCP (despite trimethoprim-sulfamethoxazole prophylaxis). The second patient experienced three different episodes of AMR . Anti-rejection therapies included methylprednisolone boluses, multiple plasmapheresis sessions, ATG, IVIg and two doses of rituximab. After developing different complications , he died due to invasive pulmonary aspergillosis 6 months after transplantation. The causes of death for the other 2 patients were acute coronary syndrome (at month 5 post-transplantation), and gastric cancer .At one year after acute AMR, patient survival was 93.8%  at one year after the treatment of acute AMR. The causes of graft loss were chronic AMR (4 cases), primary graft non-function, acute tubular necrosis in the setting of norovirus infection, and hemorrhagic shock due to gastrointestinal bleeding secondary to duodenal ulcers.Death-censored graft survival was 89.4% (Table 3). We found a differential impact of the anti-rejection strategies used on the associated risk of infection, giving support for the individualization of prophylaxis and monitoring regimens in this challenging KT population with acute AMR.In this large nationwide cohort of KT recipients, 3.9% of patients experienced an acute AMR episode that was managed using a large variety of therapeutic approaches within the first year post-transplantation. As the pathogenesis and diagnostic criteria of acute AMR have been refined over the past fifteen years, we did not expect such heterogeneity in the therapeutic practices in this prospective contemporary cohort. Our observation however reflects the lack of validated recommendations regarding the treatment of AMR after kidney transplantation. Despite satisfactory overall patient and allograft outcomes, infectious complications (including episodes of severe and life-threatening opportunistic infections) were however common, particularly bacterial infections  and 217/1964 (11%) of all episodes of infection, respectively, mainly responsible for urinary tract infections. Among viral pathogens, HSV and CMV accounted for 130/1964 (6.6%) and 125/1964 (6.4%) of all episodes of infection, respectively. Infection due to Candida albicans was the most common fungal infectious complication in all KT recipients . In comparison, while the majority of infections were also due to bacterial pathogens  in our patients that were treated for acute AMR, we observed more episodes of opportunistic infections (18.2%), in particular CMV infection, BK polyomavirus-associated nephropathy and invasive pulmonary aspergillosis.In this cohort, almost two thirds of the patients developed infectious complications within 6 months following acute AMR. We could compare these data to a recent study by Van Delden et al. that investigated the epidemiology of infectious events within the first year after transplantation in the whole STCS database during the same study period between 2008 to 2014 . RegardiCMV infection represented 18.8% of all episodes, including 5.2% of CMV disease. Of note, a recent case-control study showed that AMR and/or therapy for AMR appears to be a risk factor for CMV infection , so thatDespite the large variability in therapeutic modalities used, the data granularity provided by the STCS offered the opportunity to explore some effects of anti-rejection regimens on the susceptibility to infection. We found that the use of plasmapheresis (whatever other therapy it was combined with) significantly increased the risk of overall infection, both in the “per-patient” and “per-episode” analyses. Chung et al. also reported that KT recipients who underwent pre-transplant plasmapheresis associated with rituximab induction had higher cumulative incidence of infection than those without plasmapheresis . It can In addition to the detailed data on AMR treatment-associated infectious complications, the present study extends previous observations regarding the relatively good prognosis of early acute AMR if diagnosed and treated appropriately and rapidly , 39. TheOur study has several limitations, the most significant being the absence of a control group. Such an ideal control group should have had similar demographics and immunological baseline characteristics, and have developed only acute T-cell mediated rejection (TCMR) without AMR or no acute rejection. Nevertheless, this adjustment was not feasible, since sensitized recipients with DSA pre-transplant tend precisely to develop acute AMR rather than TCMR. This is the reason why we opted to provide some information on the recent study by Van Delden et al., which analyzed the entire KT population within the STCS prospective cohort . On the In conclusion, the data obtained from the ongoing nationwide cohort showed a wide heterogeneity in the immunosuppressive therapies used to treat acute AMR after KT. Response to therapy at three months was overall good, with one-year graft and patient survival rates exceeding 90%. However, infectious complications were common after acute AMR treatment. Our findings suggest that such risk varied according to the therapeutic modality, with an increased risk for plasmapheresis while a trend for a protective effect was observed for IVIg on bacterial infection. Finally, our experience emphasizes the need for well-designed prospective controlled studies in AMR among KT recipients in order to define optimal therapeutic regimens in terms of patient and graft outcomes, infectious complications and cost-effectiveness .S1 File(DOCX)Click here for additional data file.


BackgroundUnderrepresented-minorities (URM) remain few in number amongst practicing cardiologists and across cardiology fellowship training programs in the U.S. Increased diversity is needed across the entire field and is particularly necessary within graduate medical education cardiology fellowship training programs.ObjectivesThis cross-sectional study was performed to identify which strategies were supported and implemented by cardiology fellowship program directors (PDs) to increase URM representation, to determine which entities hold the responsibility to increase diversity according to program directors, and to quantify URM representation in cardiology fellowship programs.MethodsA 15-item survey was submitted to all American College of Graduate Medical Education (ACGME) accredited cardiology fellowship programs via electronic mail.ResultsOf 250 cardiology fellowship programs, 71 responses were received (28.4%). The number of URM faculty varied from 0-1 to more than six, and URM faculty held leadership roles in most programs (62.0%). A total of 16 respondents (22.5%) were URM program directors. Most respondents agreed that diversity was important to their training program (85.9%). The majority endorsed direct recruitment of URM applicants (60.6%), opportunities for applicants to connect with (54.9%) or be recruited by URM fellows (54.9%), holistic application review (67.6%), promoting mentorship by URM faculty (69.0%), URM faculty involvement in applicant interviewing (54.9%), and increased recruitment of URM faculty members (73.2%). Program directors allocated major responsibility to increase diversity to fellowship programs (71.8%), residency programs (63.3%), and medical schools (53.5%).ConclusionsThis study found that most cardiology programs have URM faculty in leadership roles, and nearly a quarter of the surveyed program directors were URMs. Cardiology program directors endorsed and employed numerous strategies to increase diversity and URM representation in fellowship programs. Additionally, program directors held fellowship training programs most responsible for increasing URM representation in the field of cardiology. Underrepresented-minority (URM) physicians, specifically African American, Native American, Hispanic, and/or Pacific Islander, constitute only about 10% of practicing cardiologists . DiversiA review of data from the past decade has shown progress in increasing the number of cardiology trainees who would be considered URMs. However, URM cardiologists remain a considerable minority in the cardiologist workforce nationally. In fact, the percentage of URM cardiologists increased only modestly from 11.1% to 12.4% from 2006 to 2016, respectively . In addiGiven that fellowships constitute the entryway into the field of cardiology, the role of the fellowship program director (PD) in increasing diversity in the cardiologist workforce cannot be overstated. A 2016 survey by Crowley et al. reported that 63% of fellowship program directors believed that diversity in their program was adequate and did not require further intervention; this study also reported that 69% of the same respondents agreed with the statement, “diversity is a driver of excellence in healthcare delivery” . AnotherThis survey of cardiology fellowship program directors builds upon previous research in several unique ways. This study was structured to quantify URM applicants, fellows, and faculty members in ACGME-accredited cardiology fellowship programs and identify which strategies are supported and currently implemented by program directors. Moreover, this study seeks to determine which entities are viewed by fellowship directors to have a role in increasing diversity in cardiology training programs.Fellowship program database constructionThe University of Southern California Biomedical Institutional Review Board (BioIRB) determined this study to be exempt (#HS-20-00319). After receiving this IRB approval, we conducted an anonymous cross-sectional study of 250 ACGME-accredited cardiology fellowship program directors in the United States. The following data were collected: program name and location, director full name, program director email address, and program coordinator email address. Data were abstracted from the Fellowship & Residency Electronic Interactive Database (FREIDA) and cross-referenced with the ACGME website. If the program director's contact information was unavailable, we attempted to obtain this information through internet searches of faculty directories, corresponding author contact information , and scientific databases .Survey development and disseminationSurvey questions were created through an iterative process by members of the research team & diversity content experts and by referencing previous surveys created to assess diversity in medical fellowship programs . The surStatistical analysisDescriptive statistics were applied to the dataset. Fisher’s exact tests were used to compare the number of respondents that supported each strategy to increase diversity to respondents that actively implemented those measures. Predictors of strategies implemented by PDs to increase diversity were identified a priori: URM status and agreement with the statement “diversity is important to my residency program.” We then dichotomized agreement regarding the importance of diversity into two variables prior to comparison: PDs that “strongly agreed” versus PDs that “somewhat agreed,” “neither agree nor disagreed,” “somewhat disagreed,” and “strongly disagreed” with the above statement. The latter group was hereby referred to as “not strongly agreed” in ensuing data comparisons. Fisher’s exact tests were used to (1) compare strategies that were implemented by respondents who identified themselves as a URM to respondents who identified themselves as non-URM members, and (2) compare strategies that were implemented by PDs that “strongly agreed” versus those who did “not strongly agree.” P-values less than 0.05 were considered statistically significant.A total of 71 responses were obtained from 250 ACGME-accredited cardiology fellowship training programs, constituting a 28.4% response rate. The total number of fellowship training positions available ranged from 3 to 35, with an average of 15.3 positions per program (standard deviation (SD) = 6.8). Cardiology fellowship training program characteristics are described in Table URM representation in cardiology fellowship programsThe number of URM fellows ranged from 0 to 20, with an average of 4.5 URM fellows per program (SD = 3.8). Of interviewed applicants, the number of URM matriculants ranged from 0 to 4, with an average of 1.3 (SD = 1.1). The reported number of URM faculty per program included 0-1 , 2-3 , 4-5 , and 6 or more . URM faculty members reportedly held leadership roles in the majority of fellowship programs , although respondents from two programs were unsure if URM faculty held leadership roles (2.8%). Of 71 program directors, 22.5% (n = 16) considered themselves URM. A detailed analysis of URM representation in cardiology fellowship programs is described in Table Outreach strategies to URM residentsRespondents’ support of strategies to increase fellowship diversity and current, active implementation of outreach to URM residents is described in Table Modifications of URM application reviewStrategies to address diversity through changes to the application process that are supported by and implemented by cardiology fellowship directors are indicated in Table The use of diversity-related programmingThe numbers and percentages of fellowship directors that support and implement various diversity-related programming are described in Table Support systems for URM fellows & diversity initiativesStrategies of active promotion of diversity within cardiology fellowship training programs according to program directors are described in Table Comparing responses of URM program directors vs. non-URM program directorsOf 71 program director respondents, 22.5% (n = 16) identified themselves as URM members, while 77.5% (n=55) identified themselves as non-URM members. A statistically significant difference was found regarding the involvement of current program fellows in informal recruitment of URM applicants (p =0.0007) as 70.9% (n=39) of non-URM program directors implemented this strategy compared to only 31.3% (n=5) of URM program directors. No other statistically significant differences were found in the implementation of any other strategies between URM PDs compared to non-URM PDs (p > 0.05).Implementation strategies of program directors that “strongly agree” vs. “not strongly agree” that diversity is important to their fellowship programComparative responses of diversity strategies that are currently being implemented by respondents who responded as “strongly agreed” (n=49) to the statement, “diversity is important to my residency program,” were contrasted against program directors who responded with any other response (n=22) (“not strongly agree”). Despite similarities between the groups, a statistically significant difference was found between the groups when implementing a holistic review of URM fellowship applicants (p = 0.028) as program directors that “strongly agree” with the importance of diversity implemented this strategy at a rate of 77.6% (n=38), while only 50.0% (n=11) of program directors that placed lesser importance on diversity implemented this strategy. No other statistically significant differences were found in the implementation of any other strategies between “strongly agree” PDs compared to “not strongly agree” PDs (p > 0.05).Whose responsibility is it to increase diversity in cardiology fellowships?Responsibility for increasing diversity according to fellowship program directors is described in Figure This cross-sectional study was performed to assess the strategies endorsed and implemented by cardiology fellowship training program directors and the representation of URM applicants and faculty in ACGME-accredited programs. This study found that the vast majority of PDs expressed agreement with the view that diversity is important in fellowship training programs (85.9%). However, PDs remain unsure how to implement the desire for diversity in the process of selecting candidates and creating a rank list . In factFurthermore, this study showed that PDs tended to support several different methods to increase URM representation and implemented these strategies to increase diversity in their program. These findings suggest that program directors believe that they have the means to employ methods that meaningfully increase diversity within their programs. As in previous studies, most fellowship directors claimed to support diversity, although a previous study found that less than half of directors reported having a formalized plan to achieve this goal -12. AchiIn order to achieve a higher degree of diversity and inclusion, cardiology fellowship directors largely expressed support for increasing the number of URM faculty members (73.2%). It has previously been shown that the presence of URM faculty, mentorship of URM faculty with URM fellows, and communication between URM faculty and fellows with URM applicants on interview day is critical to recruiting competitive, diverse cardiology fellows . In our Implementation of diversity strategies by URM program directors was similar compared to that of non-URM directors, with the exception of involving current program fellows in the informal recruitment of URMs. Non-URM members overwhelmingly implemented this strategy at a rate of 70.9% (n=39) compared to only 31.3% (n=5) URM program directors. As previously described by Auseon et al., having URM leadership in cardiology fellowship programs is often a “rate-limiting step” to attracting URM fellows to a program . As suchProgram directors that “strongly agreed” that diversity is important to their program implemented diversity strategies at similar rates compared to program directors who did “not strongly agree” with the statement. One notable exception was noted with the implementation of conducting a holistic review of all applicants. More than three-fourths of “strongly agree” respondent program directors implemented this method compared to only half of “not strongly agree” respondents. A previous study conducted within an internal medicine residency program found that a holistic review of applicants increased the percentage of URM applications reviewed by 6.3%, increased URM interviews conducted by 8.5%, and resulted in an overall 19.2% increase in URM candidates matriculated . These fFellowship directors held fellowship programs most responsible for increasing diversity, followed by residency programs and medical schools. These responses suggest that directors of cardiology fellowship programs believe that increasing representation in cardiology requires the cooperation of administrators in undergraduate medical education as well as post-graduate training. Crowley et al. takes this argument a step further and encourages program directors to diversify the field through the development of a “deep pipeline” recruitment model through a partnership with local universities, high schools, and even elementary schools to recruit URMs to cardiology through early exposure to the field as a potential future career option . FurtherThis study adds to the literature in two ways: (1) It informs cardiology fellowship program directors of what many of their colleagues believe increases diversity in their programs as well as which strategies they implemented. These strategies may offer options for program directors seeking to increase diverse applicants. (2) These results may inform future research to identify which strategies statistically significantly increase the number of applicants and residents that are underrepresented minorities. In particular, prospective studies are needed with clearly defined metrics to track the success of initiatives to increase the number of URM applicants and eventual residents.LimitationsOur study is not without limitations. Despite not using a previously validated survey instrument, we employed a robust developmental process that included review by content experts, presentations of the survey tool at local conferences to invite methodological critiques, and appraisal by associate cardiology program directors. Although our response rate was 28.4%, we used several strategies to drive responses, such as sending reminder emails and offering an optional lottery incentive. Notably, although we received responses from programs from different community settings and geographic locations, we were unable to compensate for non-response bias in this study, in which participants who responded to the disseminated survey may have disproportionately been interested in achieving increased racial and ethnic diversity within their programs compared to non-respondents. Also, this study was not designed to investigate female representation in cardiology fellowships, although women remain underrepresented in cardiology sub-specialty training . TherefoThis cross-sectional study of cardiology fellowship program directors found that program directors (1) overwhelmingly supported increasing diversity in cardiology fellowship programs, (2) endorsed multiple strategies to increase diversity within their programs, and (3) believed that fellowship programs were most responsible for increasing diversity in the subspecialty of cardiology. Additionally, this study was able to quantify the amount of URM representation in ACGME accredited cardiology programs and identified that a majority of cardiology programs have URM faculty in leadership roles, and nearly a quarter of the surveyed program directors were URMs themselves. Interestingly, program directors held fellowship training programs most responsible for increasing URM representation in the field of cardiology. It is our hope that the results of this study may inform current cardiology fellowship program directors of which interventions are being used in other programs, which strategies are most supported by their peers, and which initiatives may yet need to be implemented. These findings may also be of value to medical students and resident physicians interested in applying to cardiology fellowships. Future research is needed to determine which strategies are most effective to increase URMs in cardiology fellowship programs in the United States.


In Ethiopia, bovine tuberculosis (BTB) is a neglected disease that affects the economy and livelihoods of farmers. However, the available data is limited due to insufficient disease surveillance in the country. Therefore; this study aimed to assess the prevalence and distribution of lesions of BTB in cattle slaughtered at Gondar, Northwest Ethiopia.Postmortem examinations were used to detect tuberculous lesions, while smear microscopy and histopathology were performed for the identification of acid-fast bacilli (AFB).Of 497 inspected slaughtered cattle, 45  were diagnosed with BTB suggestive tuberculous lesions. A higher proportion of gross lesions was recorded in lymph nodes of lungs; at the mediastinal  and bronchial  lymph nodes, and followed by mesenteric lymph nodes . Of 45 tuberculous lesions; only 2 (4.4%) were identified as AFB positive by smear microscopy and histopathology. In the overall statistical analysis, body conditions of slaughtered cattle were found to be significantly associated with BTB tuberculous lesions (p < 0.05).This finding provides the prevalence of BTB and distribution of tuberculous lesions in cattle slaughtered at the abattoir and highlights the need for a practicable control strategy of the disease in the region. Mycobacterium bovis (M. bovis), is a chronic infectious bacterial disease affecting domestic animals [Bovine tuberculosis (BTB), caused by  animals ,2 and wi animals ,4, with  animals . Althoug animals . The dis animals .M. bovis infection in humans [M. bovis accounts for 37.7% of human tuberculosis (TB) in Africa [M. bovis has been isolated from lymph node aspirates of TB patients [In many developing countries with limited resources, including Ethiopia, BTB is one of the most important public health problems and is reported as re-emerging zoonosis ,10,11, bn humans  and suggn humans ,16,17, an humans ,6,12,18.patients ,20. Besipatients .M. bovis [In Ethiopia, various studies in different areas have reported the prevalence of BTB; it ranges from 3.5% to 5.2% in slaughterhouses and 3.5–50.0% in dairy farms . The disM. bovis .Despite the significant economic impacts and zoonotic risks associated with BTB ,33, the The study was conducted at ELFORA abattoir, in Gondar town, which is located 740 km far from the capital city, Addis Ababa, in the Northwest of Ethiopia at 12° 36ʹ 10.8648” N and 37° 27ʹ 7.6752” E, . The curA cross-sectional study with a systematic random sampling method was conducted between October 2017 and June 2018. The selection of cattle to be included in the study was made arbitrarily among cattle slaughtered each day. For this study, among cattle slaughtered each day; on average 7 heads of cattle, were considered for post-mortem examination with a proper undertaking of detail necropsy inspection. Slaughter cattle examination was performed 5 days per week except for Christian fasting events, including Wednesday and Friday when animals were not slaughtered due to fasting days.All cattle that were presented for slaughter were local zebu breed, and the sex of examined animals was male, while female animals were not slaughtered in an abattoir during this study. Besides, animal identification and animal-related variables such as age and body condition score (BCS) of the individual animal were recorded. The age of cattle was determined based on dental eruption as described previously , and catThe sample size was calculated assuming the expected prevalence of BTB lesions to be 11.6% , using aexp = expected prevalence; d2 = desired absolute precision Where n = required sample size; PSubsequently, a total of 497 slaughtered cattle were examined for tuberculous lesions suspected of BTB, for proportionate sampling.Clinical examination of cattle was conducted physically following the antemortem examination protocol  before tet al. [Postmortem examinations for BTB were carried out according to the procedure described by the meat inspection manual for developing countries . Additioet al. ,43. Lympet al. ,43. InspSuspected macroscopic tuberculous lesions from slaughtered cattle were collected under aseptic conditions in a screw-capped universal bottle containing 5 ml of sterile 0.85% saline water, and then transported by maintaining a cold chain to Pathology laboratory, University of Gondar Comprehensive Specialized Hospital, and kept at −20°C until the acid-fast stain and histopathology analysis.Preliminary identification of tubercle bacilli was done primarily by observation of acid-fast bacilli (AFB) using Ziehl–Neelsen (ZN) smear microscopy following the World Health Organization (WHO) protocol . BrieflyCollected tissue and organ samples were fixed with 10% formalin and then processed by the paraffin embedding technique . SamplesThe collected data from the abattoir and laboratory were entered in a Microsoft Excel spreadsheet and analyzed using SPSS version 20 . Descriptive statistics were used to analyze the overall proportion of tuberculous lesions and lesion frequency in different anatomical sites. Pearson’s chi-square test (χ2) was performed to determine the association of age and body conditions of cattle with the occurrence of BTB suggestive lesions and prevalence of BTB. A p-value of <0.05 was considered statistically significant.A total of 497 slaughtered cattle were examined in this study; of which 425 were from adults and 72 from the old age category. All slaughtered cattle were male and local zebu breed, with the majority of the cattle (85.5%) categorized in the adult age category (≤ 7 years old). The BCS of slaughtered cattle displayed 141 (28.4%) good, 176 (35.4%) medium, and 180 (36.2%) poor body condition, .Table 1.Among the total 497 inspected slaughtered heads of cattle, 45  were found with BTB suggestive tuberculous lesions. The high frequency of tuberculous lesions was observed in the age category of adult (<7 years old) , and poor body conditioned slaughtered cattle , . In the Of the total 45 BTB suggestive lesions detected during the postmortem examination; a higher proportion was identified in the lymph nodes of the lungs; specifically at the mediastinal  and bronchial  lymph nodes, and followed by the mesenteric lymph nodes  and lymph nodes of the head  and retropharyngeal  lymph nodes). The least distribution of BTB suggestive tuberculous lesions was observed from lungs tissue , and hepatic lymph node , . Only a Macroscopically, the most common change seen in BTB suspected tuberculous lesioned tissues and organs was the presence of circumscribed yellowish-white lesions of various sizes. The lesioned tissues were dry and gritty with coalescing areas of caseous and calcified necrosis .Figure 2In this study, out of 45 BTB suspected tuberculous lesions, only 2 (4.4%) were identified as acid-fast bacilli (AFB) by smear microscopy (Ziehl–Neelsen) and morphological characteristics, , while tHistopathologically, granulomatous changes were observed with tissue cells and central caseous necrosis only from the two AFB smear-positive tuberculous lesions, . Focal net al. [et al. [M. bovis can infect [M. bovis have gross tuberculous lesions that are visible in the tissues examined at slaughter [Given the future possible intensification of cattle production and the subsequent increase in the likelihood of zoonotic transmission of BTB in Ethiopia , such a et al.  in Wolay [et al.  in Addis [et al. ,51. Thesn infect . Severallaughter . The lowlaughter ,54–56, iA study in Ethiopia indicated that BTB is one of the major causes of carcass condemnation due to TB and TB-like lesions , as alsoIn our findings, we observed only 4.4% of AFB positive samples among the total tuberculous lesion using bacteriological (ZN staining) and histopathological methods. As shown by the previous report  ZN can dIn the present study, BTB suggestive lesions were found distributed across lymph nodes of the lungs, in which the majority were found on mediastinal followed by bronchial lymph nodes. This finding was in line with previous studies ,38,63 whThe findings from this study have documented the prevalence of BTB in cattle in North Gondar, Ethiopia using data from postmortem inspections at the abattoir. A higher proportion of tuberculous lesions were identified in the lymph nodes of the lungs; the mediastinal and bronchial lymph nodes and followed by the mesenteric lymph nodes and lymph nodes of the head. Thus, the findings highlight the importance of continuous abattoir investigations of BTB in animal populations and need feasible and practical control strategy of the disease in the region.


Mycobacterium tuberculosis. As the location of much of the bacteria in the infected host, the granuloma is a central point of interaction between the host and the infecting bacterium. This review describes the signals and cellular reprogramming that drive granuloma formation. Further, as a central point of host-bacterial interactions, the granuloma shapes disease outcome by altering host immune responses and bacterial susceptibility to antibiotic treatment, as discussed herein. This new understanding of granuloma biology and the signaling behind it highlights the potential for host-directed therapies targeting the granuloma to enhance antibiotic access and tuberculosis-specific immune responses.The defining pathology of tuberculosis is the granuloma, an organized structure derived from host immune cells that surrounds infecting  Mycobacterium tuberculosis, the etiologic agent of tuberculosis, from host immune cells . While this circular depiction of granulomas is true to what is commonly observed in histological sections and is also representative of many smaller lesions, classical work as well as recent PET-CT and micro-CT analysis of granulomas in human patients has found that larger granulomas form substantially more complex structures –32. Thes airways . This coMtb model are inbred mouse models such as C57BL/6 and BALB/c mice, which possess an expansive suite of immunological tools  and extensively drug-resistant (XDR) strains, which in turn have substantially longer and more complicated treatment regimens and greatly increased mortality   . FinallyMtb, targeting of granuloma structure is a distinct approach to enhance the treatment of Mtb and is complementary to ongoing efforts to improve existing therapies and the development of new therapeutics. With the recent advances made in understanding granuloma formation and the molecular changes that underlie it, potential new points of intervention for therapies altering granuloma formation have been identified. Targeting these pathways may enable the rational development of new granuloma-targeted interventions.While it remains to be seen whether there will be detrimental effects to therapies targeting granuloma structure, it may be possible to manage any potential drawbacks by timing the dissociation of granulomas. For instance, reduction of bacterial numbers through an initial period of antibiotic treatment may ultimately enable the safe disassembly of granulomas to improve subsequent therapies. Regardless, the ongoing difficulties in treating tuberculosis suggest that novel approaches to treating tuberculosis are worth pursuing. Adjunctively targeting the granuloma may enhance the effectiveness of existing treatments and shorten the duration of therapy required for these complex therapies. Granuloma dissociation could also enhance antimycobacterial immune responses, potentially boosting existing therapeutic approaches for both drug-sensitive and drug-resistant tuberculosis which could be further combined with immunomodulatory and antibiotic therapies. Lastly, targeting granuloma integrity may allow for the development of a wider palette of chemotherapeutics including drugs that fail to penetrate complex millieu of the organized granuloma. With the continued burden of tuberculosis worldwide and the increasing threat of drug-resistant The author confirms being the sole contributor of this work and has approved it for publication.This work was supported by the Max Planck Society.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


We aimed to investigate the clinical characteristics and islet β-cell function in patients with Klinefelter syndrome (KS) and hyperglycemia.This is a retrospective study. In total, 22 patients diagnosed with KS were identified from the electronic medical record system, including 9 patients with hyperglycemia  and 5 hyperglycemic KS patients with oral glucose tolerance test (OGTT) results (HG-KS group). An additional 5 subjects with hyperglycemia and 5 normal glucose tolerance (NGT) subjects matched based on body mass index were included as the HG group and NGT group, respectively. Data from clinical and laboratory examinations were collected. We further performed a literature review of KS and hyperglycemia.p = 0.047) were significantly, indicating higher insulin secretion levels in the HG-KS group.We found that KS patients developed abnormal glucose metabolism earlier in life than those without KS, and the median age was 17 years, ranging from 10 years to 19 years. Six of 17 (35.3%) patients were diagnosed with diabetes mellitus and 3 of 17 (17.6%) patients were diagnosed with prediabetes. Among 10 patients with both fasting blood glucose and insulin results recorded, there were 8 out of 17 (47.1%) KS patients had insulin resistance. The prevalence of hypertension and dyslipidemia was higher in patients with hyperglycemia and KS than in patients with NGT KS. Compared with the HG group, insulin sensitivity levels were lower in HG-KS group, whereas homeostasis model assessment of β-cell function levels (KS patients develop hyperglycemia earlier in life than those without KS and show lower insulin sensitivity and higher insulin secretion. These patients also have a higher prevalence of other metabolic diseases and may have different frequencies of developing KS-related symptoms.The online version contains supplementary material available at 10.1186/s12902-021-00893-5. Klinefelter syndrome (KS) is the most frequent sex chromosome disorder of the male population , and thePrevious studies have observed that KS is associated with the development of diabetes mellitus (DM), insulin resistance, hyperinsulinemia, hyperlipidemia, obesity and other metabolic diseases . The preIn this study, we retrospectively summarized the characteristics of patients with hyperglycemia and KS from a single Chinese hospital database, compared clinical features, insulin sensitivity and islet β-cell secretion function between hyperglycemic subjects with and without KS, and further performed a literature review. We aimed to describe the clinical features and characteristics of islet β-cell function in patients with KS and hyperglycemia and to help select the appropriate hypoglycemic therapy for DM patients with KS.n = 8), and 9 KS patients had hyperglycemia . Among these 9 patients, 4 patients diagnosed with DM but without records of OGTT were excluded, and the remaining 5 patients, including 2 DM patients and 3 prediabetes patients, were enrolled in the KS and hyperglycemia group . All patients did not start testosterone treatment at the time of collecting the clinical data. An additional 10 subjects, including 5 subjects with hyperglycemia but without KS  and 5 NGT subjects , were matched with patients in the HG-KS group based on BMI.This was a retrospective study. The electronic medical record system of Peking Union Medical College Hospital (PUMCH) was used to identify patients with a final diagnosis of KS from January 2000 to December 2019 by searching the clinical notes. KS was diagnosed according to the definite diagnosis of KS in other hospitals or karyotyping records, and 22 KS patients were identified. After excluding 5 patients without electronic records of laboratory tests, 8 KS patients had normal glucose tolerance  and the Helsinki Declaration of 1964, as revised in 2013. All participants provided written consent for the inclusion of materials pertaining to themselves and acknowledged that they could not be identified via the paper. The participants were fully anonymized.2). Blood pressure was measured thrice after 5 min of rest and was recorded as the mean value of three measurements.Clinical history, physical examination and laboratory examination results were collected from the medical database during the period of admission. BMI was calculated as weight (kg) divided by the square of the height in meters (mGlu/AUCIns) [Ins) were calculated to reflect islet β-cell secretion function.Blood samples were collected at baseline (0 min), as well as 30 min, 60 min, 120 min and 180 min after 75-g anhydrous glucose load by oral administration after fasting for 8 to 12 h. Blood samples were used for serum glucose, insulin and C-peptide assays. The quantitative insulin sensitivity check index (QUICKI) , insulin/AUCIns)  were cal/AUCIns)  and areaWe searched PubMed for manuscripts with full texts in English published prior to February 2020 using key words “Klinefelter syndrome” OR “Klinefelter’s syndrome” AND “diabetes mellitus” OR “DM” OR “insulin resistance” OR “hyperglycemia” OR “impaired glucose tolerance” OR “impaired fasting glucose” OR “prediabetes” OR “metabolic syndrome”. Two coauthors extracted the medical information of the enrolled patients and the literature using standardized forms independently. If any difference was noted, another coauthor assisted in checking differences between the two coauthors. Twelve studies , 20–29 at test was used to compare differences between continuous variables of each group, and the continuous variables that failed the normality test were logarithmically transformed before analysis or tested by the nonparametric test. A p-value less than 0.05 was considered significant. All statistical analyses were performed using the statistical program SPSS .Continuous variables are expressed as the mean ± standard deviation. Student’s Among the 17 KS patients recruited in this study, 35.3% (6 out 17) of patients were diagnosed with DM, 17.6% (3 out 17) of patients diagnosed with prediabetes, and 47.1% (8 out 17) of patients presented insulin resistance with HOMA-IR ≥ 2.5. The clinical data of KS patients in the PUMCH center are summarized in Table p<0.01)  values were significantly increased in the HG-KS group compared with those with hyperglycemia only. In addition, AUCIns were also increased in the HG-KS group, but no significant differences were noted.KS patients developed abnormal glucose metabolism earlier in life compared with those without KS (1) Table . The avep = 0.032) was significantly increased in the HG-KS group, and ISImatsuda (p = 0.009), QUICKI (p = 0.028) and IAI (p = 0.028) were significantly decreased. HOMA-β (p = 0.047) levels were higher in the HG-KS group. Figure In the comparison between the HG-KS group and NGT group, HOMA-IR p = 0.03 was signIn the literature review, previous studies showed that the prevalence of DM in KS patients ranged from 6.8 to 39%, and the prevalence of insulin resistance in KS patients ranged from 24.0 to 38.5% (Table The specific clinical data of patients with hyperglycemia in both the PUMCH center and previous literature are summarized in Supplementary Table In this study, we summarized the clinical features of KS patients in a single Chinese hospital center and evaluated the characteristics of islet β-cell function in KS and hyperglycemia patients compared with hyperglycemia patients without KS and NGT subjects. The prevalence of DM in KS patients in the PUMCH center was 35.3%. This value was much higher than the prevalence of DM in the general population, which was 10.4% in China according to the guidelines of the Chinese Diabetes Society published in 2017 and 14.3% in the United States . KS is cWe found that hyperglycemia developed earlier in life in KS patients compared with those without KS, which was consistent with previous observations that found that the course of DM in KS patients was approximately 30 years old . InsulinBest practices for hypoglycemic therapy in hyperglycemic KS patients have still not been established. The effects of TRT on the improvement of glucose control remain controversial. Some clinical trials observed improvement in HbA1c levels after TRT , 49, wheBased on the results of clinical features associated with KS, those patients with hyperglycemia were more likely to present gynecomastia, which was consistent with the findings of lower testosterone levels compared with those with NGT. The prevalence of cryptorchidism was lower in hyperglycemia patients, whereas the prevalence of behavioral and intelligence problems was increased. We also found an increased frequency of development of other metabolic diseases in hyperglycemia and KS patients, including hypertension and dyslipidemia. These results confirmed that other metabolic factors, including blood pressure and serum lipid levels, may have effects on glucose metabolism in KS patients.This study has some limitations. First, KS is a rare disease, and this is a retrospective study in a single Chinese center. Thus, the sample size was small. Second, the clinical information was limited, and data on some clinical features were missing. Third, the age of patients in the HG-KS group did not match that in the HG group because adolescents with type 2 diabetes mellitus were mostly obese, thus the BMI values of these patients could not be matched with those of KS patients.In conclusion, we found that KS patients develop hyperglycemia earlier in life.compared with those without KS. Patients with KS and hyperglycemia were more likely to have other metabolic diseases and may have different frequencies of developing KS-related symptoms than NGT KS patients. The prevalence of gynecomastia and behavioral and intelligence problems was higher, whereas the prevalence of cryptorchidism was lower. KS patients with hyperglycemia tended to have decreased insulin sensitivity and hyperinsulinemia and increased insulin secretion compared with hyperglycemia patients without KS. Based on the characteristics of glucose metabolism in KS patients, we recommend evaluating islet β-cell function before hypoglycemic treatment, given that oral hypoglycemic drugs may be the first choice for those still with islet β-cell secretion function rather than insulin preparations, because decreased insulin sensitivity may have a poor hypoglycemic effect.Additional file 1. Supplementary Table 1. Characteristics of patients in our center and previous case reports