Assessing patients with chronic obstructive pulmonary disease (COPD) accounts for 30% of all pneumology outpatient evaluations. COPD is a heterogeneous disease and generates a massive public health problem. Overall morbidity, particularly cardiovascular disease, challenges patient management. This is an observational, multicentre study, performed at four hospitals in the Canary Islands (Spain), aimed at characterising patients with COPD referred to pneumology outpatient services. Demographic variables, lung function, and morbidity were assessed.Of the 877 included patients, 44.9% were active smokers with a mean (± SD) age of 68.2 ± 10.3 years. The median (IQR) score for the Charlson comorbidity index was 2 (2), and 70.6% of the patients were assigned high risk according to the Spanish Guidelines for COPD (GesEPOC) 2021. The degree of airflow obstruction defined by the GOLD 2021 stages 1, 2, 3, and 4 corresponded to 13.6%, 49%, 31%, and 6.3% of patients, respectively. The most frequently associated morbidities were arterial hypertension (59.5%), dyslipidaemia (54.3%), and type 2 diabetes mellitus (31.2%); 32% of the patients suffered heart disease. There is a high prevalence of active smoking, type 2 diabetes mellitus, and heart disease in patients referred for COPD to Canary Island pneumology outpatient services.The online version contains supplementary material available at 10.1186/s13104-022-05930-7. Chronic obstructive pulmonary disease (COPD) constitutes a public health problem with a huge impact on socio-economic costs –3. The dA range of studies has focused on the high morbidity in these patients, which worsens their prognosis and results in additional challenges in their management –9. The cAn observational, cross-sectional, multicentre study was performed involving four historical cohorts of outpatients with COPD from the University Hospital Nuestra Señora de Candelaria (Tenerife), the Hospital San Juan de Dios (Tenerife), the University Hospital Dr. Negrín (Gran Canaria), and La Palma General Hospital . The retrieved data covers a period from 2011 to 2020.1)/forced vital capacity (FVC) ratio < 70% upon administration of 400 μg of salbutamol. The presence of chronic respiratory diseases other than COPD, e.g., interstitial lung disease or pneumoconiosis, was considered an exclusion criterion, except historial of asthma.The study included 877 COPD patients where the following inclusion criteria were applied: (1) patient attending follow up in an outpatient pneumology service; (2) age > 40 years; (3) active or former smoker with a pack-year index (PYI) ≥ 10 or exposition to another known risk factor like smoke from home cooking and heating fuels, occupational dust or other chemicals; (4) a forced expiratory volume in 1 s . Data were de-identified for analysis. In this study, informed consent was waived for its retrospective, non-interventional design and the use of anonymous clinical data.2]), history of tobacco consumption assessed as PYI, peripheral oxygen saturation by means of pulse oximetry (SpO2)—performed with the patient at rest in a sitting position—dyspnoea assessment using the modified Medical Research Council scale , long-term home oxygen therapy and/or bi-level positive airway pressure (BiPAP) or continuous positive airway pressure ventilation (CPAP), the presence of chronic mucus hypersecretion, and the number of severe exacerbations requiring hospital stays during the year prior to the first visit as an outpatient. Chronic mucus hypersecretion was registered in all the corresponding databases. Previous admissions were confirmed reviewing hospital records. Data on the associated morbidities arterial hypertension (AHT), type 2 diabetes mellitus (T2DM), dyslipidaemia (DLP), obesity (defined as BMI ≥ 30 kg/m2), underweight (BMI < 18.5 kg/m2), atrial fibrillation (AF), ischaemic heart disease (IHD), chronic heart failure (CHF), cerebrovascular accidents (CVA), neoplasia , osteoporosis, and mood disorders (anxiety and depression) were obtained. Each associated morbidity was confirmed by a comprehensive review of the electronic, medical records, data from diagnostic procedures, and disease-specific therapies. The Charlson comorbidity index (CCI) not age-adjusted score [1%, FVC%, and the FEV1/FVC ratio. The patients' degree of airflow obstruction was classified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document 2021 [Variables included in the analyses were age, gender, body mass index , the median CCI was 2 (IQR = 2), and 70.6% were considered high risk patients according to GesEPOC 2021. The most frequently associated morbidities were AHT (59.5%), DLP (54.3%), and T2DM (31.2%).The baseline characteristics of the 877 patients-comprising study population are given in Table 1 < 50% had a higher smoking load  and higher percentage of patients that required hospital admission in the previous year . As to associated morbidities, no significant difference was detected . Table Patients with hospital stays for exacerbation prior to attending outpatient services were older  compared to individuals without hospital stays, had a higher percentage of patients with CCI score ≥ 3 , and a higher prevalence of cardiovascular morbidities and conditions related to mood disorders , had a higher smoking load  and a higher prevalence of cardiovascular diseases . Although these characteristics are in line with similar national studies , it is pNotwithstanding, different studies have revealed that patients with COPD are distinguishable from other smokers insofar as they have a higher degree of dependence and less motivation to quit smoking –23. In aThe patients with COPD on the Canary archipelago exhibit a high prevalence of T2DM and heart disease. T2DM was diagnosed in 30% of our patients. In patients with COPD, T2DM is a common morbidity –29, whicOf note, patients with COPD who had a history of severe exacerbations exhibited a high prevalence of active smoking, T2DM, and heart disease. A national study performed in 129 hospitals throughout the Spanish territory, with more than 5000 patients included, analysed the characteristics of patients admitted for COPD exacerbation and evidenced a prevalence of active smoking, T2DM, and heart disease of 30, 26, and 30%, respectively, clearly below the prevalence detected in our study  , 39. HowThis is the first multicentre study in the Canary archipelago that characterises patients with COPD who attend pneumology outpatient services. Its main strength lies in the large sample size and in the good characterization of the population. Although the study was carried out within a specialist-care setting, the high percentage of patients designated low risk according to GesEPOC 2021 may offer an initial view on individuals with relatively mild disease, a point to be confirmed in future studies.In conclusion, the patient population with COPD in the Canary archipelago is characterised by a high rate of active smokers, T2DM, and cardiovascular disease, which presumably adds complexity to disease management. The high prevalence of heart disease in our patients with COPD, particularly in those exhibiting more symptoms, corroborates the need to actively seek these patients.The main limitation of this study is a potential information bias due to the recorded variables from the patients' medical records. In addition, we must take into account the limitations of a cross sectional observational study. The temporal sequence of the variables studied could not be established, making it difficult to separate risk factors from prognostic factors. Furthermore, although five of the eight islands of the Canary archipelago are not represented in this study, the selected islands cover more than 80% of the Canary Island population, which adds to the validity of our results offering an overall vision of the patient with COPD in this region.Additional file 1: Table S1. Baseline characteristics of patients with chronic obstructive pulmonary disease according smoking status.Additional file 2: Fig. S1. Morbidity in patients with COPD according to the Spanish guidelines GesEPOC 2021 risk groups.


The prevalence of diabetes mellitus (DM) during pregnancy and childhood obesity is increasing worldwide. Factors affecting the growth of children with overweight whose mothers had DM are complicated and inconclusive. Few longitudinal studies have focused on the growth of infants with macrosomia born to mothers with DM and the factors influencing their overweight. This study explored risk factors for childhood overweight/obesity (OWOB) among children of mothers with DM. Perinatal, maternal socio-demographic, infant care, and maternal body weight characteristics as well as child growth until age 3 years were analyzed using a longitudinal design.In total, 24,200 pairs of mothers and their children from the Taiwan Birth Cohort Study were included. Combined Taiwan Children Growth Curve report classifications were analyzed for infant growth at birth and at 6, 12, 18, 24, and 36 months old (m/o). A multiple logistic regression analysis with different model settings was used to assess factors affecting the growth of high birth weight children of mothers with diabetic mellitus (HODM).Children in the HODM group had a higher average body weight than did those in the non-DM group at different age stages. Relative to the non-DM group, weight gain in the HODM group was slower before 18 m/o but faster from 18 to 36 m/o, particularly after 24 m/o. Maternal DM was a major risk factor for childhood OWOB (odds ratio [OR]: 3.25–3.95). After adjustment for related confounders, the OR was 2.19–3.17. Maternal overweight or obesity and higher gestational weight gain were greater risk factors for childhood OWOB at 3 years old after adjusted maternal DM and other selected confounders . Breastfeeding until 6 m/o was a protective factor against childhood OWOB (OR: 0.95). The HODM and non-DM groups did not differ significantly in perinatal, maternal socio-demographic, or infant care characteristics.Maternal DM is a major factor of childhood OWOB. Maternal body weight before and after pregnancy affects childhood OWOB, and this effect increases with the child’s age. The prevalence of diabetes mellitus (DM) is increasing rapidly worldwide and is the most common complication of pregnancy, affecting up to 10% of expectant mothers  to 3.5% Infants exposed to high glucose levels prenatally have an increased risk of long-term adverse outcomes, including childhood overweight and obesity (OWOB). Many risk factors contribute to childhood overweight. Maternal obesity is a known major risk factor for childhood obesity. Many studies have demonstrated that mothers with higher body mass index (BMI) are more likely to have overweight infants . AlthougTo our knowledge, no studies examining the association between maternal DM and childhood OWOB have considered all potential key confounders, including maternal obesity, gestational weight gain, maternal and infant lifestyle, and care factors. Women with preexisting DM have higher risks of preterm labor, congenital anomalies in their children, adverse perinatal complications, and slowed infant growth in the future. Studies that have not excluded infants with low birth weight born to mothers with DM, especially infants born to women with GDM and type 2 DM, have methodological limitations in their analyses of childhood obesity . A studyData used in this study were collected from the Taiwan Birth Cohort Study (TBCS). TBCS is a national population-based cohort study in Taiwan to investigate the health determinants of this 2005–2006 birth cohort at their newborn, infant, child, adolescent, and adult stages, from the life-course perspective. Formal first wave (6 m/o) survey was completed in 2005–2006, followed up in 2006–2007 (18 m/o), 2008 (3 y/o), 2010–2011 (5 y/o), 2013–2014 (8 y/o), and 2017–2018 12 y/o). The TBCS cohort was expected to follow up till 21 y/o (year 2026–2027). Of the 206,932 live births in the Taiwan birth registration database for 2005, 24,200 pairs of mothers and their children were sampled in the study from the TBCS through a multistage stratified systematic sampling method [ y/o. TheChildren were classified into four groups: children born to mothers without DM (non-DM), Offspring of mother with Diabetic Mellitus (ODM) with high birth weight , ODM with appropriate birth weight , and ODM with low birth weight . OWOB was defined as body weight above the 85th percentile at 6, 18, 24, or 36 m/o (separated by sex) according to Taiwan Children Growth Curve report classifications .2.Mothers were asked questions regarding awareness of diagnosed DM by doctors during pregnancy by trained interviewers (yes or no), maternal BMIs before pregnancy and 6 months after delivery , nationality, educational level, area of residence , family income, whether they breastfed or staple fed their children at 6 m/o, and main daytime caregiver (mother or others). Maternal age was defined as mother’s age at delivery (older or younger than 35 years). APGAR scores were classified as more or less than 7. Maternal body weight gain during pregnancy was divided into three categories: <10, 10–14, and >14 kg. Prepregnancy and postpartum BMI were divided into three categories: <18.5, 18.5–25, and >25 kg/mWe classified the variables of influential factors into four major categories, namely perinatal condition, maternal socio-demographic characteristics, infant care factors, and maternal body weight characteristics. Categorical variables were analyzed using the chi-square test among the non-DM, HODM, AODM, and LODM groups. Fisher’s exact test was conducted if necessary Table .Table 1P < 0.05 indicated statistical significance. Statistical analyses were performed using SAS 9.4. .Analysis of variance (ANOVA) in combination with the Tukey honestly significant difference post hoc test was conducted on normally distributed variables to compare children’s body weight at different time points  and perform a sensitive assessment of deviations in growth (Table P < 0.05). Differences in family income, main caregiver, and breastfeeding versus staple-food feeding at 6 m/o were non-significant. More adverse birth outcomes, such as preterm labor, lower APGAR scores 1 and 5 min after birth, and increased prevalence of birth defects, were present in infants in the ODM groups. Maternal BMIs before and after pregnancy were higher in the DM groups than in the non-DM group. In particular, mothers in the HODM group had obviously higher prevalence of high prepregnancy BMI (46.2% vs. 9.7%) and postpartum BMI (100.0% vs. 63.8%), (P < 0.001). Differences in maternal gestational weight gain among the four groups were nonsignificant (P = 0.157)  pairs of mothers and children were enrolled into our study. Among the pairs, 446 2.16%) children were born to mothers with diagnosed DM during pregnancy. Regardless of birth weight, all selected influential categories, including perinatal conditions, maternal socio-demographic characteristics, and maternal body weight characteristics, revealed significant differences between the non-DM group and ODM groups, except infant care factors. Compared with mothers without DM, mothers with DM were more likely to have advanced maternal age and live in urban areas. DM was less likely in immigrant women and those with higher education levels (6% childrP < 0.05). Figure Figure The disparities in infant body weight and body weight gain between the HODM and non-DM groups at birth, 6, 18, 24, and 36 m/o are shown in Table P > 0.05). Model C adjusted for the factors included in model A and maternal body weight factors to analyze the effects of maternal body weight on childhood OWOB. Compared with the non-DM group, mothers in the HODM group were more likely to have OWOB children when their gestational weight gain was >14 kg (OR: 1.12–1.25). Obesity (BMI > 25 kg/m2) before and after pregnancy also increased the risk of childhood OWOB . When we adjusted for all potential determinants in model D, maternal DM remained a major risk factor for childhood OWOB at different ages in the HODM group (OR: 2.19–3.17). Maternal body weight before and after pregnancy was a main factor affecting childhood OWOB, and the risk of childhood OWOB increased with the children’s age.Table GDM prevalence in Asia has been reported to range from 0.7 to 51.0% . A meta-p < 0.05). Their BMIs before pregnancy and postpartum at 6 months were higher than those of the non-DM group. In particular, mothers in the HODM group had higher prepregnancy BMIs. The disparity in maternal age may explain why mothers with DM had higher education levels; moreover, immigrant and indigenous mothers in Taiwan are relatively younger.Advanced maternal age, family history of DM, ethnicity, overweight or obesity, and smoking are well-documented risk factors for GDM . In addiBecause of the potential confounders including genetic factors, mother and infant lifestyle, and maternal obesity factors are difficult to control, the relationships between maternal DM and risk of childhood OWOB are complex. The Taiwan’s NHI has a high coverage rate and people face few barriers to medical assessments. We focused on the HODM group because mothers in the LODM group tended to have pregestational DM that increased the incidence of congenital anomalies and preterm labor. Our results indicate that maternal obesity before and after pregnancy increase the risk of childhood OWOB, and this risk increases as children age. These findings suggest that genetics may play a central role. A previous study identified many genetic polymorphisms in genome-wide association studies of adult BMI and the genetic susceptibility to childhood obesity; the association was partially explained by appetitive traits in infancy followed by an early childhood increase in BMI .Studies of the effects of gestational DM on childhood overweight and obesity have yielded inconclusive results. A meta-analysis reported inconsistent evidence of an association of GDM with childhood overweight and obesity because of methodological limitations in the included studies . HoweverBecause of mothers with overweight or obesity have a higher prevalence of DM, our study could not identify the prevalence of DM in ODM children. Mothers with obesity may have a genetic predisposition to have children who become overweight; in addition, maternal lifestyle, diet, and maternal cognition to infant body weight are factors of childhood overweight . In our The strength of our study is its focus on a particular infant population for comparison with children whose mothers did not have DM and its exclusion of infants with low birth weight and congenital anomalies to eliminate the effect of congenital or genetic factors that could confound the statistical results. We also used a stepwise logistic regression model to detect confounders and their interactions between DM and diabetes-related perinatal complications. In addition, we analyzed prepregnancy and postpartum BMI to compare the effects of maternal BMI and gestational body weight gain with childhood OWOB. Moreover, this cohort study can offer information on the determinants of childhood OWOB at different ages.Our research has some limitations. The design of the TBCS questionnaires did not differentiate between pregestational DM and GDM, neither lack of medical records about the severity of hyperglycemia and related medical intervention. This limitation makes genetic factors and the effects of DM control difficult to identify. Another limitation is the high rate of cesarean deliveries in Taiwan; some infants with macrosomia can be delivered earlier if their body weight is estimated to be overweight during prenatal examinations. This phenomenon may have reduced the number of infants in the HODM group. The maternal height and weight were self-reported instead of measurements might latent errors. This cohort study followed children to 36 m/o. Future studies may prolong the follow-up period to analyze the long-term relationships between mothers with DM and childhood obesity.2 prepregnancy and postpartum were the significant factors of childhood OWOB, and the maternal BMI effects increased as children aged. Prolonged breastfeeding to the age of 6 months and weight gain control during pregnancy are protection factors. DM control during pregnancy, restricted maternal gestational body weight gain, maternal BMI control, and prolonged breastfeeding are strategies for mothers with DM to prevent childhood overweight.In this population-based cohort study, maternal DM and BMI of mothers more than 25 kg/m


Thoracic multidetector computed tomography (MDCT) is essential for the detection of interstitial lung disease (ILD) in patients with systemic sclerosis (SSc). Thoracic MDCT assessment can reveal the presence of thoracic lymphadenopathies (LAP) whose signification remains uncertain. The purpose of the study was to describe the characteristics and to assess the significance of thoracic LAP in patients with diffuse SSc.We conducted a monocentric observational study on adult patients with diffuse SSc, and collected general patient and first thoracic MDCT characteristics, PET-CT and outcome data. Comparisons were made between patients with and without thoracic LAP.Forty-eight patients were included. There were 30 patients (62.5%) with an ILD and 23 (48%) with at least one thoracic LAP on the first MDCT assessment. Median number per patient of thoracic LAP was 3 [1–8], with a mean size of 11.7 ± 1.7 mm, mainly located in right para-tracheal area , right hilar area (20.3%), left hilar area (6.5%), and sub-carinal area (15.2%). PET-CT showed lymph node hypermetabolism in 11/15 patients (73.3%) with mean SUVmax at 4 ± 1.3. There were significantly more males (p = 0.002) and more patients exposed to silica (p = 0.001) in patients with thoracic LAP. ILD was significantly more extended according to Goh score (p = 0.03), and using semi-quantitative score for mixed ground-glass reticulation (p = 0.01) and global abnormalities (p = 0.03) in patients with thoracic LAP and ILD. Thirteen patients (27.1%) died during follow-up without significant difference according to the presence or not of thoracic LAP (p = 0.15). There was also no significant difference concerning immunosuppressive treatment initiation (p = 0.17).Thoracic LAP are common in diffuse SSc and are generally multiple, not bulky, moderately hypermetabolic, and located at the base of the mediastinum lymph node chains. Their presence correlates with the extent of ILD. In absence of ILD, thoracic LAP presence seems to be often explained by silica exposure.Trial Registration: NA. Systemic sclerosis (SSc) is a rare and chronic fibrosing auto-immune disease with a heterogenic phenotype and a variable prognosis . FibrogeThoracic multidetector computed tomography (MDCT) is essential to confirm and monitor ILD during SSc. It brings crucial information concerning the main pattern, but also extension, severity, and evolution of ILD. All patterns of ILD may be encountered, but non-specific interstitial pneumonia (NSIP) is the more frequent, concerning 70–80% of SSc associated ILD (SSc-ILD), followed by usual interstitial pneumonia (UIP) in 8–10% . ThoraciIn some cases of SSc, thoracic MDCT analysis identifies thoracic lymphadenopathies (LAP), which signification remains uncertain. Their presence, especially at the initial diagnosis of dSSc, may lead clinicians to prescribe complementary explorations such as nuclear imaging or biopsy, contributing to patient discomfort, iatrogenic risks, and increasing health expenditure.The literature is poor on the cause, the significance and the outcome of thoracic LAP in SSc. Previous studies suggested a link between SSc-ILD and thoracic LAP, but they did not bring much follow-up information –18. In tACR/EULAR 2013 criteria , neither in mean diameter  between the two groups according to the presence of thoracic LAP.PET-CT was performed in 9 patients (39.1%) with thoracic LAP and 6 patients (24.0%) without (p = 0.41). Lymph node hypermetabolism was significantly more frequent  and SUVmax was almost significantly higher  in patients with thoracic LAP.Four patients (8.3%) were lost to follow-up. Thirteen patients (27.1%) died during follow up with a mean duration of 6.5 ± 4.8 years: 9 among patients with thoracic LAP and 4 in the absence of thoracic LAP (p = 0.15). No diagnosis of neoplasia or systemic granulomatosis has been made during follow up. Thirty-seven patients (77.1%) had at least one immunosuppressant initiated during the follow up: corticosteroids for 29 (60.4%), mycophenolate mofetil for 25 (52.1%), cyclophosphamide for 18 (37.5%), methotrexate for 12 (25.0%), azathioprine for 2 (4.2%), and rituximab for 2 (4.1%). There was no significant difference concerning immunosuppressive treatment initiation between groups according to the presence of thoracic LAP (p = 0.17).Overall, 36 patients (75.0%) had at least two thoracic MDCT available in their follow-up, with a mean duration of 4.5 ± 3.6 years, allowing temporal comparison analysis.Evolution of thoracic LAP characteristics between first and last thoracic MDCT available are shown in Fig. Evolution of ILD global extension score between first and last thoracic MDCT available according to the semi-quantitative score among patients with thoracic LAP is shown in Fig. Our study is the second that provides precise information about thoracic LAP seen on MDCT in patients with dSSc. Almost 50% of our patients had at least one thoracic LAP with a median number of 3 and a moderate mean size of 11.7 ± 1.7 mm. The more frequent thoracic topographies were right para-tracheal (22.8%), right hilar area (20.3%), left hilar area (16.5%), and sub-carinary area (15.2%). Their presence was significantly more frequent in men and in patients exposed to silica, but no significant differences concerning other characteristics have been found between groups, except for joint involvement (arthritis and/or synovitis and/or contracture of fingers and/or hand and/or wrists), more frequently noted in patients without thoracic LAP, whose meaning remains unclear. The number of lymph nodes remained stable or decreased mainly in patients over time. The occurrence of ILD was similar between groups according to the presence of thoracic LAP, and the main pattern was NSIP, as expected. However, ILD was more extended in the presence of thoracic LAP. When PET-CT was available, there was frequently a mediastinal lymph node hypermetabolism (73%) with mean SUVmax measured at 4 ± 1.3 and a trend to be more important in the thoracic LAP group. When available, mediastinal lymph node histological analysis did not show granuloma nor neoplasia. Analysis over time did not show significant evolution of thoracic LAP and differences between groups according to the presence of thoracic LAP concerning ILD.The prevalence of thoracic LAP in our study was similar to that found in the only study on homogenous population of dSSc patients (58%) . It is aIn the context of ILD, the literature suggests a mechanism of lymph node hypertrophy reactive to inflammatory activity of the lung, which is supported by pathophysiological postulates and by several correlations established between ILD and thoracic LAP , 27. OurSurvival was not significantly different in patients with thoracic LAP during follow-up. Moreover, the use of immunosuppressive treatment was similar in groups according to the presence of thoracic LAP. The information on immunosuppressive treatment was important to collect because these treatments may influence ILD, thoracic LAP, and broncho-alveolar cytology. Several studies evaluating broncho-alveolar lavage analysis in SSc patients have shown a tendency to decrease the total number of cells and/or the proportion of granulocytes in patients under immunosuppression –34 and iOne of our study’s strengths is the homogenous characteristic of our population composed only by patients with dSSc, whether or not associated with ILD. However, this is a retrospective monocentric study on a rare disease, explaining the low number of patients. Furthermore, inaccuracies in the analysis of the extent of ILD may have occurred. The semi-quantitative assessment is by definition an approximation at the discretion of the reader. The boundary between ground-glass and normal parenchyma or the detection of cross-linkages can be subtle and intra/inter-observer agreement has not been studied. Another limitation of the ILD quantification methodology can also be raised: the asymmetry in the number of lung lobes on the right and left is the cause of an overweighting of the right lung score. Some publications have taken this problem into account by, for example, adding a correction factor for each lobe . It shouThoracic LAP are common in dSSc and are generally multiple, not bulky, not extensive nor compressive, moderately hypermetabolic, and located at the base of the mediastinum lymph node chains. Their number are mainly stable in time. Their presence correlates with the extent of ILD. No diagnosis of neoplasia or granulomatosis have been made in the follow-up. In the absence of ILD, thoracic LAP presence seems to be explained by epidemiological factors, such as exposure to silica, frequently involved in secondary dSSc, especially in men.


Lithium administration can reportedly cause toxicity, including lithium-associated thrombosis; however, not all reported cases of this adverse effect have been attributable to lithium overdoses. We report here two cases of deep vein thrombosis that occurred in association with lithium toxicity. Lithium overdose was deemed to be the cause in only one of these cases; a patient in whom deep vein thrombosis occurred 11 days after identification of lithium toxicity. In the other patient, the deep vein thrombosis occurred 15 days after diagnosis of lithium toxicity; this patient was not considered to have been overdosed. Both patients had other risk factors in addition to receiving lithium. We recommend monitoring D-dimer concentrations to facilitate early detection of deep vein thrombosis in patients with lithium toxicity. Despite sometimes causing toxicity, lithium is a widely used first-line maintenance treatment for bipolar disorder –3. SymptDeep vein thrombosis (DVT) is defined as the formation or presence of a thrombus in the deep veins. The causes of venous thromboembolism, including DVTs, can be divided into two groups: inherited and acquired. Many patients have multiple causes . HereditSome cases of thrombosis associated with lithium use have been reported. Wasay et al.  reportedRecently, we investigated lithium toxicity by comparing patients being treated with lithium who did and did not take lithium ODs . We hereA 31-year-old woman who had been treated at another institution for bipolar disorder was rushed to our hospital because of a drug OD. Her level of consciousness was E3V3M5 on the Glasgow Coma Scale. She had been treated with a combination of lithium (600 mg/d), risperidone (1 mg/d), quetiapine (50 mg/d), valproic acid (600 mg/d), lorazepam (1.5 mg/d), brotizolam (0.25 mg/d), zopiclone (7.5 mg/d), and biperiden (2 mg/d) and had overdosed on all of these drugs . On admission, her lithium concentration was 3.95 mEq/L. She had been maintained on lithium for 9 years, her usual lithium concentration being approximately 1 mEq/L. She had no history of thrombosis.Hemodialysis was performed on the day of hospitalization, followed by continuous hemodiafiltration until Day 4. She was only exposed to a high lithium concentration (≥1.5 mEq/L) for 1 day, after which her lithium concentration rapidly decreased to within the recommended range . IntermiA 66-year-old woman had undergone total knee arthroplasty 1 month previously at our hospital. She had no history of thrombosis. She had previously been treated with a combination of lithium (1000 mg/d), quetiapine (50 mg/d), and flurazepam (15 mg/d) for bipolar disorder and simvastatin (5 mg/d) for hyperlipidemia. She has been maintained on lithium for at least 2 years. At the time of the knee surgery, her lithium concentration was unknown; however, her creatinine clearance (Cockcroft & Gault equation) was 63 mL/min. Postoperatively, graduated compression stockings were used, edoxaban (15 mg/d) was prescribed for 2 weeks to prevent venous thromboembolism, and she was transferred to another hospital for rehabilitation. She was subsequently readmitted to our hospital because of disordered consciousness and lithium toxicity  . Her levFollowing readmission, her lithium concentration decreased on fluid replacement therapy alone, without hemodialysis or continuous hemodiafiltration. She was exposed to high lithium concentrations (≥1.5 mEq/L) for 8 days before readmission but was able to eat normal meals. Although her D-dimer concentration was high on Day 2, no thrombi were detected by lower extremity venous ultrasonography. Rehabilitation was resumed on the same day, despite the fact that she was dehydrated and had hypernatremia. Because the delirium that had been apparent at the time of readmission had worsened, asenapine was started on Day 3. On Day 7 (15th day after identification of lithium toxicity), her D-dimer concentration remained high, and lower extremity venous ultrasonography revealed DVTs at the level of both knees. There was no swelling or color changes. The placement of an inferior vena cava filter was considered unnecessary, and apixaban (10 mg/d) was started. Resolution of the thrombi was identified on Day 13. She was discharged on ongoing apixaban on Day 17 for outpatient follow-up.Lithium toxicity contributed to the development of DVTs in these two patients (11 and 15 days after identification of lithium toxicity). Only the former patient had taken a lithium OD. No hereditary risk factors for DVT were identified in either patient; however, both had some acquired risk factors. Case 1 had undergone insertion of a central intravenous catheter, engaged in prolonged bed rest while being sedated, and been administered antipsychotic agents. She had also developed an infection. Case 2 had undergone total knee arthroplasty and was 66 years old, dehydrated, and taking antipsychotic agents. The presence of multiple acquired risk factors is consistent with previous reports [Although we identified DVTs after lithium toxicity, thrombosis has also been reported in patients with normal lithium concentrations. Kamijo et al.  reportedAfter recognizing lithium toxicity, we measured D-dimer concentrations frequently in both of our cases, possibly resulting in early diagnosis of their DVTs. However, D-dimer is a nonspecific marker, high concentrations being found in many conditions . Conversely, high D-dimer concentrations are found in nearly all patients with acute DVTs . Thus, rAlthough lithium has been used as a maintenance treatment for bipolar disorder for many years, recent data , 19 haveWe here report two cases of DVT associated with lithium toxicity. DVTs may develop even in patients taking lithium as prescribed. Regular monitoring of lithium concentrations and renal function is essential during lithium use. We also recommend taking care to maintain adequate hydration and monitoring D-dimer concentrations for early detection of DVTs.


Cortisol is a steroid hormone acting as a stress hormone, which is crucial in regulating homeostasis. Previous studies have linked cortisol concentration to body mass and body composition.The investigations were carried out in 2016–2017. A total of 176 children aged 6–13 years in primary schools in central Poland were investigated. Three types of measurements were performed: anthropometric , body composition (fat mass FM (%), muscle mass – MM (%), body cellular mass - BCM (%), total body water - TBW (%)), and cortisol concentration using saliva of the investigated individuals. Information about standard of living, type of feeding after birth, parental education and maternal trauma during pregnancy was obtained with questionnaires.p = 0.026), explaining 2.32 % of the fat mass variability and positively associated with MM (%)  explaining 3.09 % of the muscle mass variability.The results of regression models after removing the environmental factors  indicate a statistically significant association between the cortisol concentration and fat mass and muscle mass. The cortisol concentration was negatively associated with FM (%) .The online version contains supplementary material available at 10.1186/s12887-021-02837-3. ID2, C3, and OASI [Cortisol is a steroid hormone produced by the adrenal cortex, widely known as a stress hormone, crucial in the regulation of homeostasis. Cortisol acts as a neuroendocrine mediator of stress responses in organs and effector tissues such as the brain, cardiovascular system, immune system, fat, and muscle tissue . The actNumerous studies of the association between body mass/proportion and stress level have been performed using questionnaires and measurements of cortisol concentration e.g. . RegardlElevated stress levels were found to be associated with decreased body mass among children aged 7–18 years during the political transformation in Poland in the early 1990s .Most studies of associations between body composition and cortisol concentration have focused on fat and muscle tissue. Cortisol has a catabolic impact on fat tissue, and chronically persistent high concentrations of cortisol affects lipolysis leading to the release of glycerol and free fatty acids. This effect can be a direct action of the hormone or a result of reduced glucose uptake of adipose tissues . High coThis study aimed to assess if the cortisol concentration is associated with the composition and proportion of Polish children stratified according to parental education, the standard of living, type of feeding after birth, and maternal trauma during pregnancy.The investigations were carried out between December 2016 and December 2017. A total of 176 children in primary schools in central Poland  were included in the study. However, due to the lack of questionnaires concerning four children and unsuccessful results of the saliva sample of one child, only results of investigations of 171 children  were included.2 (m2) and waist to hip ratio (WHR = waist circumference (cm)/hip circumference (cm)) were calculated. The body composition was assessed by the staff of the Biobank Laboratory of the University of Lodz including percent of fat mass - FM (%), the percent of muscle mass – MM (%), percent of body cellular mass - BCM (%), and percent of total body water - TBW (%) using the bioelectrical impedance vector analysis . Information about the standard of living, type of feeding after birth, parental education, and maternal trauma during pregnancy was obtained with questionnaires.The anthropometric measurements of body weight and height, waist and hip circumferences were performed according to Martin’s method  by the s The parents of the children provided signed approval for the investigations and filled in questionnaires. The standard of living was divided into three categories, as were also applied in the previous studies –17: (1) Children that were breastfed (independently of duration) were included in the breastfed group.The parental educational background was categorized as: (1) basic , (2) secondary education (4–5 years at secondary school or bachelor degree) and (3) higher education (full university degree).The information about breastfeeding was categorised as yes (breastfeeding for at least one month) or no.The children’s mothers reported if they had experienced traumatic events during the pregnancy such as violence in the family, natural disasters, pedestrian injuries and death of family members, and this variable was treated as categories, i.e. yes or no.Saliva samples were collected in sterile Falcon tubes (Nest Biotechnology). The children did not eat, drink, chew chewing gum, or brush teeth for the last 30 min before sampling. Cortisol has the highest physiological concentrations in the morning around 8 am and then slightly decreases during the day and evening . The corThe normalised cortisol concentrations were divided into three groups: (1) low (below Q1 (lower quartile)), (2) medium (between Q1 and Q3), and (3) high (above Q3 (upper quartile)).The saliva was collected between 8 am and 2 pm. Immediately after the collection, the samples were stored at 2–8 °C and, on the same day, frozen and stored at − 20 °C until the investigation, no longer than three months after collection [The cortisol concentration of the saliva samples was measured using an enzyme-linked immunosorbent assay (ELISA) kit , USA).https://www.aatbio.com/tools/four-parameter-logistic-4pl-curve-regression-online-calculator/). The concentration range of the investigated samples was in agreement with information supplied by the kit producer. Intra-assay CVs were less than 10 %. Correlation between saliva and serum cortisol level is noticed but the concentration values are not equal, thus it should be considered during drawing the conclusions [Each sample was measured in duplicates. The assay included seven standard concentrations. A micro plate reader  was used to measure the absorbance at 450 nm. The 4PL method was used to plot the standard curves using an open-source software (clusions . Howeverclusions  indicatehttps://www.fantaproject.org/sites/default/files/resources/FANTA-BMI-charts-Jan2013-ENG_0.pdf). The Chi-squared Pearson test was used to evaluate the sex differences between underweight, normal-weight, overweight, and obese children.The children were divided into groups according to the calendar age. The FM (%), MM (%), BCM (%), TBW (%), WHR, and BMI values were standardised according to age and sex. Z-score equivalents were used for the calculations. Additionally, WHO norm BMI for age (2007) was used to arrange the adequate range for underweight, normal weight, overweight and obesity (p < 0.05).The following variables were normally distributed: FM (%), MM (%), BCM (%), TBW (%), WHR and BMI values, while the cortisol concentration was not normally distributed , MM (%), BCM (%), TBW (%), WHR. The ANOVA or nonparametric Kruskal-Wallis tests were applied to assess possible differences between the cortisol concentration  and the composition and proportion of the body. The post hoc Tukey’s HSD test was used to perform multiple comparisons of all pairs of means. Additionally, the Spearman test was applied to calculate the correlation between cortisol concentration and the composition and proportion of the body.Stepwise forward multiple regression models were used to identify variables that were statistically significantly correlated with FM (%), MM (%), BCM (%), TBW (%), WHR, and BMI. The residues for each body component, BMI, and WHR were used to assess the correlation with the cortisol concentration.https://www.danielsoper.com/statcalc/calculator.aspx?id=48). Cohen’s d was applied for the Mann-Whitney U test and ANOVA in the case of multiple regression Cohen’s f2 was done.The effect size for each test was performed using online calculator: . Written informed consent was obtained from all the subjects’ parents.Among all children, 77.19 % had normal BMI (including 43.86 % of girls and 33.33 % of boys), 0.58 % were underweight, the rest of the children with excess BMI 16.37 % were overweight (including 9.94 % of girls and 6.43 % of boys) and 5.85 % were obese (including 0.58 % of girls and 5.26 % of boys)  (Table The cortisol concentration was higher among children from families with a high standard of living (mean=-0.200) than among children with a medium standard of living mean=-0.354), H = 6.532; 54, H = 6We did not find any statistically significant difference in cortisol concentration between children with BMI in norm and excessive BMI in neither of the sexes Table .p = 0.043). The post hoc Tukey’s HSD test showed that the children with a medium concentration of cortisol had higher muscle mass (mean=-0.060) than those with a high concentration of cortisol (mean=-0.191) (p < 0.05)  p < 0.0 (Table 55) Table .Table 5p = 0.027; R=-0.230, p = 0.002, respectively) and positively correlated with MM (%) (R = 0.224 p = 0.003).The cortisol concentration was negatively correlated with FM (%) and WHR z-score  FM (%), BCM (%), MM (%), TBW (%), BMI, and WHR and (2) breastfeeding, maternal trauma during pregnancy, the standard of living, and parental education to evaluate their association with dependent variables and calculate residues for each of dependent variable.p = 0.033) with the control of standard of living medium (vs. low), higher paternal education (vs. basic), and breastfeeding (vs. no) explaining 3.95 % of the variability of FM (%). MM (%) was positively correlated with higher paternal education (vs. basic)  with the control of secondary paternal education (vs. basic), secondary maternal education (vs. basic), and breastfeeding (vs. no) explaining 6.07 % of the variability. No statistically significant correlation was found between BCM (%) and the investigated parameters. TBW (%) was negatively correlated with a high standard of living (vs. low)  with the control of medium standard of living (vs. low), higher and secondary paternal education (vs. basic), secondary maternal education (vs. basic), and maternal trauma during pregnancy explaining 7.02 % of the variability. BMI was positively correlated with a high standard of living (vs. low)  and medium standard of living (vs. low)  with the control of higher and secondary maternal education (vs. basic) explaining 5.95 % of the variability. The model for WHR was not statistically significantly associated with any parameter. Table p = 0.026), explaining 2.32 % of the fat mass variability, and positively correlated with MM (%) , explaining 3.09 % of the muscle mass variability (Table The obtained residues for each dependent variable in the linear regression models were used to evaluate the correlations between body components and BMI and between WHR and cortisol concentration . The corty Table . HoweverThe obesity of children is a global problem . Our resWe found that the cortisol concentration was increased among children with a high standard of living. These findings might indicate that children from well-off families are under higher pressure, possibly due to increased expectations and increased sports activities . Thus, tThe parental education level was associated with body composition. Higher and secondary education among fathers was associated with increased muscle mass among the children. Similar results were previously obtained for mothers . Post etThe study has some limitations. Firstly, the sample collection was only conducted once, and it is indicated by some authors that the level of the cortisol collected at the different time points may be different and preferable is the mean value of the a few daily measurements. Additionally, the body composition measurements using the BIA method may give inconsistent results , 34. ThuWe conclude that cortisol concentration is positively associated with muscle mass and negatively associated with fat mass, even when the cortisol concentration was adjusted according to environmental factors. We did not find any statistically significant differences in the cortisol concentration between children with normal BMI and excessive BMI in none of the sexes. The cortisol concentration was increased among children from well-of families.Additional file 1


CVD is the main cause of morbidity and mortality in individuals with diabetes. It is currently unclear whether daily glucose variability contributes to CVD. Therefore, we investigated whether glucose variability is associated with arterial measures that are considered important in CVD pathogenesis.n = 853; age: 59.9 ± 8.6 years; 49% women, 23% type 2 diabetes). We studied the cross-sectional associations of two glucose variability indices (CGM-assessed SD [SDCGM] and CGM-assessed CV [CVCGM]) and time in range (TIRCGM) with carotid–femoral pulse wave velocity (cf-PWV), carotid distensibility coefficient, carotid intima–media thickness, ankle–brachial index and circumferential wall stress via multiple linear regression.We included participants of The Maastricht Study, an observational population-based cohort, who underwent at least 48 h of continuous glucose monitoring (CGM) . In the model additionally adjusted for CGM-assessed mean sensor glucose (MSGCGM), SDCGM and MSGCGM contributed similarly to cf-PWV . In the fully adjusted models, both higher CVCGM  and lower TIRCGM  were statistically significantly associated with higher cf-PWV. Such consistent associations were not observed for the other arterial measures.Higher SDCGM are associated with greater aortic stiffness (cf-PWV) but not with other arterial measures. If corroborated in prospective studies, these results support the development of therapeutic agents that target both daily glucose variability and TIRCGM to prevent CVD.Our findings show that greater daily glucose variability and lower TIRThe online version contains supplementary material available at 10.1007/s00125-021-05474-8. CVD is the main cause of morbidity and mortality in individuals with type 2 diabetes . Additio1c) that have been periodically measured over weeks, months, or years /cIMT and CWSpuls = [braPP×(LD/2)]/cIMT [We calculated carotid lumen diameter (LD) according to the following formula : LD = IA2)]/cIMT .Last, the Omron VP2000  was used to automatically determine the ankle–brachial index (ABI) based on simultaneous BP measurements at both ankles and upper arms. The left and right ABI were calculated by dividing the systolic BP measured at the ankle by the highest systolic BP measured at either upper arm. We used the lowest ABI in our analyses and excluded individuals with an ABI above 1.4 .1c and lipid profile in fasting venous blood samples; measured albumin excretion in two 24 h urine collections; and calculated the eGFR based on serum creatinine only, as cystatin C values were not presently available in this subpopulation.As described previously , we caten (%). We used multiple linear regression with a complete-case approach to study the associations of daily GV with arterial measures. The crude analyses only included SDCGM as a determinant. Model 1 was adjusted for demographics: age, sex and education level. Model 2 was additionally adjusted for cardiovascular risk and lifestyle factors: MAP , office systolic BP (in case of cIMT and ABI), braPP (in case of CWSmean), mean heart rate (in case of cf-PWV and ABI only), BMI, total-to-HDL-cholesterol levels, smoking status, alcohol use and antihypertensive and lipid-modifying drug use. To study its contribution relative to SDCGM, the associations were further adjusted for MSGCGM in an additional model . The main regression results are presented as regression coefficients (B) with corresponding 95% CI and p values.Normally distributed data are presented as mean and SD, non-normally distributed data as median and IQR, and categorical data as CGM results to be negatively impacted by multicollinearity because of the strong correlation between SDCGM and MSGCGM (rho = 0.69) [CGM back to the VIF of model 2 . The ridge regression results are presented as standardised regression coefficients (st.β) with 95% CIs and p values. The median st.βs (95% CIs) were estimated with use of resampling (1000 bootstrap).We presumed the reliability of our model 2 + MSG = 0.69) . Hence,  = 0.69) . Ridge rCGM with CVCGM and TIRCGM. For clarity, the regression coefficients of both indices are presented per 10% difference instead of per 1%. To further explore the clinical applicability of our results in the context of the International Consensus on TIRCGM [CGM ≥ 70% (yes/no) as the main determinant. In addition, we investigated whether the associations were modified by sex [CGM × sex) to model 2.In secondary analyses, we replaced the main determinant SDn TIRCGM , we reped by sex , age [25CGM with GMS, HbA1c or fasting plasma glucose; (2) adding physical activity and diet as a separate model because many missing values were observed for these confounders  replacing MSG replacinp value of <0.05 statistically significant. Statistical analyses were performed with use of the Statistical Package for Social Sciences  and the R programming language  with package glmnet (version 4.0.2).We considered a n = 643–816). Table CGM. With higher GV, participants were older, more often male, and were generally characterised by a more unfavourable cardiometabolic profile . GMS did not fully correspond with daily GV. Namely, 31 (17%) of the 185 individuals with type 2 diabetes were not in the highest tertile of SDCGM, participants with prediabetes were evenly distributed between the tertiles, and 58 (13%) of the 454 individuals with NGM were not in the lowest or middle tertiles. ESM Table CGM values.The total CGM study population comprised 853 individuals . Because outcome and covariate data could not be obtained in all individuals ESM Fig. , the numCGM with cf-PWV and carDC estimated by use of multiple linear regression. Higher SDCGM was statistically significantly associated with higher cf-PWV after adjustment for demographics, cardiovascular risk factors and lifestyle factors . Although numerically, the regression estimate was attenuated by a third after additional adjustment for MSGCGM , the coefficients were not statistically significantly different.Figure CGM and MSGCGM, as estimated with ridge regression, to allow better comparison of the strength of association of both indices with cf-PWV. The coefficients were comparable and both not statistically significant .Table CGM as the determinant, the association with cf-PWV was statistically significant after full adjustment . CVCGM and TIRCGM ≥ 70% were also not associated with carDC . While CVCGM and TIRCGM were not independently associated with cIMT . Adjustment for MSGCGM numerically altered the regression coefficient but did not affect statistical significance . Although CVCGM and TIRCGM were not independently associated with ABI . The association between SDCGM and cIMT was stronger in women . This approach is justified by the substantial overlap in CGM-derived indices between GMS groups, which can be appreciated from ESM Table mean, but not with carDC, cIMT and CWSpuls [n = 1849–1978) and current study populations (n = 643–816). Although Lu et al. previously reported on the relation between TIRCGM and cIMT [CGM with cf-PWV.Few studies have investigated the association of CGM-measured GV with arterial measures –22 in co CWSpuls . NotablyCGM-adjusted associations with SDCGM, and – as secondary analyses – associations with the intrinsically MSGCGM-adjusted index CV and with TIRCGM, which inversely reflects both mean blood glucose levels and GV [CGM) and mean glucose  [CGM and MSGCGM (rho = 0.69), the substantial increase (121–139%) in VIF from model 2 to model 2 + MSGCGM  all indicate multicollinearity [CGM and MSGCGM  . The strase 121–19% in VIFinearity . Previouinearity , 51, butThe biological mechanisms that mediate the relationship between GV and aortic stiffness require further elucidation. Several studies observed that greater GV augments inflammation and oxidative stress , 53. ThiCGM unit (mmol/l) increase in the final regression models , which corresponds with 3–4 years of vascular ageing [CGM difference between the first and third SDCGM tertile  can improve CVD risk or incidence [Aortic stiffness, assessed via cf-PWV, is an independent determinant of CVD, cardiovascular mortality and all-cause mortality –28. We fr ageing . Hence, le Table  can be tr ageing . After ffference . This stable CGM . Prospecncidence , 62.CGM and MSGCGM; and (5) the robustness of the results, i.e., the overall consistency of several sensitivity analyses, in particular for cf-PWV.This study has strengths and limitations. Strengths include: (1) the use of the gold-standard methods for daily GV quantification ; (2) theCGM and lower TIRCGM spectrum may have biased the regression estimates towards null [n = 249; 29.2%) [CGM, CVCGM and TIRCGM are conceptually and statistically related [Our study has specific limitations. First, a relatively large number of individuals were excluded because of missing outcome data ESM Fig. . Althougrds null . Third, ; 29.2%) , as for ; 29.2%) . While t; 29.2%) , it coul; 29.2%) . However; 29.2%) , 66, esp; 29.2%) . Further related , 29. SixCGM are determinants of worse aortic stiffness, but do not support this for other arterial measures. Interestingly, the fully adjusted associations of SDCGM and MSGCGM with cf-PWV were comparable. Taken together, this study further underscores the pathophysiological relevance of daily GV, irrespective of mean glycaemia, in the context of macrovascular complications. Future studies should explore this association prospectively and assess whether interventions that specifically target CGM-measured GV or TIRCGM can prevent CVD.Our findings support the concept that greater daily GV and lower TIRESM(PDF 1101 kb)


Simple objective modalities are required for evaluating suspected autoimmune gastritis (AIG). This cross-sectional study aimed to examine whether pepsinogen, gastrin, and endoscopic findings can predict AIG. The diagnostic performance of endoscopic findings and serology in distinguishing AIG was evaluated. AIG was diagnosed in patients (N = 31) with anti-parietal cell antibody and/or intrinsic factor antibody positivity and histological findings consistent with AIG. Non-AIG patients (N = 301) were seronegative for anti-parietal cell antibodies. Receiver operating characteristic curve analysis of the entire cohort (N = 332) identified an endoscopic atrophic grade cutoff point of O3 on the Kimura–Takemoto classification (area under the curve [AUC]: 0.909), while those of pepsinogen-I, I/II ratio, and gastrin were 20.1 ng/mL (AUC: 0.932), 1.8 (AUC: 0.913), and 355 pg/mL (AUC: 0.912), respectively. In severe atrophy cases , the cutoff values of pepsinogen-I, I/II ratio, and gastrin were 9.8 ng/mL (AUC: 0.895), 1.8 (AUC: 0.86), and 355 pg/mL (AUC: 0.897), respectively. In conclusion, endoscopic atrophy is a predictor of AIG. High serum gastrin and low pepsinogen-I and I/II ratio are predictors even in the case of severe atrophy, suggesting their usefulness when the diagnosis of AIG is difficult or as serological screening tests. AIG develops by the following two mechanisms: (1) a decrease in parietal cells resulting in hypochlorhydria or achlorhydria, and a lack of intrinsic factor; and (2) corpus-restricted inflammation progressing to severe oxyntic gland atrophy3. Hypergastrinemia, neuroendocrine tumor, and iron deficiency anemia induced by hypochlorhydria; macrocytic-megaloblastic anemia induced by intrinsic factor-dependent vitamin B-12 deficiency; and low serum pepsinogen (PG) I secondary to advanced oxyntic gastric atrophy are the major clinical findings. Although it is clinically important to detect AIG considering the high coincidence rates of gastric cancer, neuroendocrine tumors, macrocytic-megaloblastic anemia, and other autoimmune disorders4, diagnosis is usually difficult, and most cases are overlooked because of their nonspecific and subtle clinical manifestations6.Autoimmune gastritis (AIG) is an uncommon chronic gastritis characterized by immune-mediated destruction of parietal cells3; however, AIG cannot be diagnosed merely based on these autoantibodies, and they are not recommended for screening owing to lack of cost-effectiveness, the high false positive rate of APCA, and low sensitivity of AIFA8. Histological examination is another established diagnostic tool for AIG3; however, despite its high sensitivity, negative results cannot always rule out AIG because of the inherent limitations of biopsy in only a limited area of the gastric mucosa. Since distinct diagnostic criteria for AIG have not yet been established, the method of diagnosis differs considerably among investigators and includes histology alone10; histology and autoantibodies13; histology, autoantibodies, endoscopy, and gastrin14; histology and serology15; autoantibodies and endoscopy16; autoantibodies or pernicious anemia; and endoscopy and serology without any histological information17. However, the most reliable and objective finding would be a combination of autoantibodies and histology, which is considered the gold standard by several investigators18. Thus, we aimed to examine other potential predictors of AIG, focusing on endoscopic findings, PG, and gastrin.The two diagnostic autoantibodies of this disease are the anti-parietal cell antibody (APCA) and anti-intrinsic factor antibody (AIFA)19 and Gastropanel® (PG and gastrin)20. Using these tests, clinicians can effectively evaluate the presence of suspected AIG without any histological evidence.PG and gastrin are useful in establishing a diagnosis of AIG when autoantibody and histological findings are inconclusive, for example, when false positive or false negative results are observed in strongly suspected cases. Furthermore, these markers are included in the serological screening tests such as the ABC method (PG)21, several investigators suggested that gastrointestinal symptoms are another important clue. Carabotti et al. reported that 56.7% of AIG cases are associated with gastrointestinal symptoms, 69.8% of which are dyspepsia22. Soykan et al. reported that an unexpectedly high rate of 50.4% of patients with AIG complained of abdominal symptoms23. Miceli et al. reported that 34% of AIG cases were diagnosed according to histological findings of gastritis after endoscopy12, and a multicenter study in Japan demonstrated that the most common modality for diagnosing AIG was endoscopy17. These studies suggest the importance of endoscopy as an initial detection tool in some patients with AIG who have abdominal symptoms or those who are negative for anemia or other autoimmune diseases.Macroscopic endoscopic findings are also clinically significant as the potential first diagnostic clues of AIG. Although the most common initial findings of AIG are hematological disordersIn this cross-sectional study, we assessed the performance of endoscopic findings and serology (PG and gastrin) in diagnosing AIG in (1) patients with AIG strictly defined based on autoantibody positivity and characteristic histological findings, and (2) non-AIG patients seronegative for autoantibodies.As shown in Fig. Helicobacter pylori (H. pylori) serology, and autoantibodies were evaluated for all patients, as shown in Table Age, sex, serum biomarker levels (PG and gastrin), P < 0.001; normal value, < 70 ng/mL) and PG I/II ratios  were significantly lower, and gastrin levels  were significantly higher in patients with AIG than in those without. Severe endoscopic atrophy (atrophic border of O3 and O4)  and the disappearance of the gastric fold  were significantly more common in patients with AIG than in those without. Age, sex, PG II level, and the prevalence of gastric cancer were similar between the two groups. The detailed clinical findings of AIG are shown in Table H. pylori serology (≥ 10 U/mL) were positive in 8/20 (40%) and 4/31 (12.9%) patients, respectively. Two-thirds of patients with AIG  showed a moderate to high titer (≥ 20) of APCA. Anemia, pernicious anemia, and Hashimoto’s thyroiditis were diagnosed in 8/31 (25.8%), 6/23 (26.1%), and 11/27 patients (40.7%), respectively. One case each of primary biliary cholangitis and Hunter’s glossitis was diagnosed before AIG diagnosis.The clinical characteristics of patients with AIG and non-AIG gastritis were compared Table . The med.5 3.6–7., P < 0.0(P < 0.01); however, those between the endoscopic atrophic border and gastrin, PG I, and I/II ratio were not significant, according to the Delong test. Figure The diagnostic ability of endoscopic findings, gastrin, and PG for predicting AIG was evaluated by ROC analysis of the entire study cohort  , PG I/II ratio , and prevalence of H. pylori seropositive cases  were significantly lower and the median gastrin level  was significantly higher in patients with AIG than in those without. The prevalence of severe endoscopic atrophy extending to the entire corpus (O4) was significantly higher in patients with AIG than in those without . ROC analysis revealed that the optimal cutoff value of gastrin was 355 pg/mL , with a sensitivity of 96.3%, specificity of 74.2%, and overall accuracy of 84.5%, while that of PG I was 9.8 ng/mL , with a sensitivity of 81.5%, specificity of 90.3%, and overall accuracy of 86.2%. The optimal cutoff value of the PG I/II ratio was 1.8 , with a sensitivity of 96.3%, specificity of 67.7%, and overall accuracy of 81.0%. The AUROCs of PG I and I/II ratio were not significantly different from that of serum gastrin according to the Delong test  was extracted  indicated that the diagnostic performance of advanced endoscopic atrophy (≥ O3 in the Kimura–Takemoto classification) and serology, including PG  and gastrin (≥ 355 pg/mL), was high; therefore, they have sufficient diagnostic performance for use in daily clinical practice.In this study, we evaluated the relevance of several clinical findings in AIG diagnosis among (1) patients diagnosed by autoantibody positivity and characteristic histology and (2) non-AIG patients diagnosed based on autoantibody negativity whose As our results showed that advanced endoscopic atrophy itself may be a marker of AIG, it may be useful if highly suspected cases of AIG among patients with advanced atrophy can be further evaluated by serology . Based on this idea, an ROC curve analysis of patients with severe gastric atrophy only  was performed. Our results indicated that the diagnostic performance of PG  and gastrin (≥ 355 pg/mL) was also high  and that they may be valid predictors. These findings are especially useful when severe atrophy is found during endoscopy, which may be the commonest way of identifying AIG in clinical practice.In our study, gastrin (355 pg/mL) and PG I/II ratio (1.8) exhibited the same cutoff values for the prediction of AIG in both the overall study cohort and the subset of patients with advanced atrophy. These results highlight how they may be especially useful as serum markers in clinical practice. Considering the high AUROC of these serological markers, we advocate that PG and gastrin should be additionally checked in cases where the diagnosis is challenging, for example, when pathological examination of biopsy specimens does not show findings typical of AIG despite a positive APCA result. Re-biopsy and histological evaluation may be recommended if PG or gastrin levels are strongly suggestive of AIG. Moreover, in serological screening tests, these cutoff values are useful in detecting AIG; in this study; endoscopy was indicated in approximately half (45.2%) of the AIG cases based on a positive serology test using the ABC method.25, and this atrophy grade was imposed for all upper gastrointestinal endoscopic cases in the Japan Endoscopy Database Project26. Although O4 is useful in detecting AIG of high prevalence compared with non-AIG (64.5% vs. 3.0%), new endoscopic criteria are not necessary for AIG diagnosis as it is included as part of grade O3 in the Kimura–Takemoto classification. In AIG diagnosis, endoscopy is often performed merely to take biopsies for histopathological diagnosis with low specificity and objectivity27. However, herein, we demonstrated that the “endoscopic atrophic border” had a Kappa value of 0.654. This is consistent with the report by Terao et al.17, wherein high interobserver variability (0.705) was shown in the “degree of atrophy;” however, in the case of “sticky mucosa,” our Kappa value seems to be lower than their value (0.352 vs. 0.604). Although corpus-predominant advanced atrophy compared with the antral region, which we referred to as the “corpus-predominant atrophic pattern,” has been used as a diagnostic criterion16, it did not have a reliable Kappa value in our study. Regarding the disappearance of the gastric fold in the gastric corpus, it cannot be used as a diagnostic modality because it has a low AUROC value (0.773), even though its Kappa value was > 0.6. Hence, other objective endoscopic findings should be evaluated.The endoscopic atrophic grade (Kimura–Takemoto classification) is considered highly objective by several investigators28. The cutoff value of gastrin for diagnosing AIG with severe atrophy was reported as 395 pg/mL11, and Terao et al.17 set hypergastrinemia > 350 pg/mL as one of the criteria for AIG in a multicenter study, which is similar to the 355 pg/mL cutoff value for gastrin in this study. In Checchi et al.’s study, the cutoff value of gastrin (43 pg/mL) was close to normal (< 39.3 pg/mL), suggesting the possible diagnosis of individuals without AIG as having AIG28. Simple comparisons with other reports are difficult because of differences in the gastrin unit of measurement (pg/mL and pmol/L)29.In this study, the cutoff values of gastrin for the diagnosis of AIG obtained from the ROC analysis (355 pg/mL) were higher than those previously reported by Checchi et al.30. The cutoff values for PG I (20.1 ng/mL) and PG I/II ratio (1.8) in our study were similar to those reported by Koc et al.30, but significantly lower than those in the studies by Venerito et al.10  and Checchi et al. 28. However, considering that the definition of AIG employed by Venerito et al. was confined to the histology of enterochromaffin-like hyperplasia and the almost normal cutoff value of gastrin reported by Checchi et al., their cutoff values may be set higher than the actual physiological values. The evaluations of the cutoff value of PGs to predict AIG in other studies were inherently limited by various issues. A report evaluated the ROC curve of PGs in appropriately defined patients with AIG, but did not calculate the cutoff value31. Three more studies did not analyze the cutoff value in a strictly defined AIG cohort, including participants with multifocal atrophy32, pangastritis29, or severe atrophy of Operative Link on Gastric Intestinal Metaplasia Assessment > stage 2 and autoantibody positivity15. Because Koc et al. only analyzed a limited number of patients (N = 16) with AIG, this is the first report to demonstrate the practical cutoff value of PG in the diagnosis of AIG using a sufficient cohort of strictly defined patients with AIG.Regarding PGs, various cutoff values have been reported by several investigators; however, few reports involved an ROC analysis using a histology-based definition of AIG34, can be a major problem in serological screening for AIG. However, it is unclear whether eradication influences gastrin in patients with AIG because severe hypochlorhydria is induced by AIG in many cases, and eradication may not affect it. As for PG and gastrin, these would theoretically normalize after eradication; however, because of the extremely low PG level and extremely high gastrin level in AIG, eradication treatment does not seem to affect the results of serological screening.In this study, individuals on acid inhibitors were strictly excluded; however, in clinical practice, the possible effects of acid inhibitory drugs should be considered when using these cutoff values. Hypergastrinemia characterized by gastrin levels over 500 pg/mL, which is induced by PPIs or potassium competitive acid blockers (PCABs)35. However, 45.2% of patients with AIG in our study had H. pylori infection , an incidence higher than those in previous reports of seropositivity rates . In our study, 29/31 patients with AIG (94%) were accurately evaluated by more than two modalities to establish H. pylori infection, and eradication was diagnosed by normalization of the urea breath test, which may explain the high infection rate in our study.In our study, the median value (IQR) of gastrin was 1,310  pg/mL, and the PG I level and PG I/II ratio were 6.4 (3.8–15.9) ng/mL and 1.0 (0.6–1.5), respectively, suggesting that the clinical characteristics of AIG in our study were generally comparable to those in previous studies16. Eighteen patients with AIG, who were included in the analysis, were already being followed-up at our hospital with regular endoscopy. Thus, the prevalence of first-visit cases was 13/536 (2.4%), which is still higher than the national prevalence rate. However, we believe that this is reasonable given how rare cases tend to cluster at major referral hospitals, such as ours.The prevalence of AIG  in this study is higher than the reported overall prevalence in Japan (0.49%)This study has some limitations. First, the identification of patients with AIG was based only on autoantibodies and histological findings. In this study, 2/31 histologically defined AIG cases (6.4%) had normal gastrin levels, suggesting that false positive cases were inevitably included , and that additional criteria using serological markers, such as gastrin and/or PG, may be required to increase the accuracy of the diagnosis of AIG, as described earlier. Second, other endoscopic findings, including remnant oxyntic mucosa, scattered minute whitish protrusions, and intestinal metaplasia were not evaluated. They may be potential predictive factors of AIG and should, therefore, be evaluated. Furthermore, the small sample size of patients from a single institution may limit the generalizability of the obtained results.In conclusion, in this study, we demonstrated that endoscopic findings of severe atrophy (≥ O3 in the Kimura–Takemoto classification) are useful predictors of AIG. High serum gastrin levels and low PG I and I/II ratio are also predictors of AIG. The cutoff values of serum gastrin levels (≥ 355 pg/mL) and low PG I/II ratio (≤ 1.8) can be used in both the general population and those with endoscopic atrophy (≥ O3). Thus, patients with advanced atrophy with a strong suspicion of AIG can be further evaluated using these cutoff values. Clinicians should also note that AIG can be suspected by serology, especially when false negative or positive results are suspected or during serological screening for gastritis involving PG and/or gastrin.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study design was approved by the Ethics Committee of Tokyo Dental College Ichikawa General Hospital . Written informed consent was obtained from all participants.36. Most of the excluded individuals were excluded by interview before enrollment.In this cross-sectional study, 536 consecutive patients who underwent upper gastrointestinal endoscopy at Tokyo Dental College Ichikawa General Hospital between January 2017 and March 2020 were enrolled after obtaining written informed consent. The exclusion criteria for this study were as follows: (1) use of histamine-2 receptor antagonists, PPIs, or PCABs within the preceding 2 months; (2) presence of viral diseases; (3) pregnancy or lactation; (4) presence of renal and/or liver dysfunction; or (5) a past history of gastric cancer or any type of esophageal or gastric surgery8. Non-AIG controls were defined as individuals who tested negative for APCA, and 57 were excluded due to inadequate APCA or gastrin data, 13 due to PPI treatment, and 3 due to history of gastric cancer.A flowchart of the target group selection is shown in Fig. H. pylori infection status in the control participants was defined as follows: Patients who were seronegative for APCA and with a clear history of successful eradication, confirmed by a negative result on either a urea breath or stool antigen test, were defined as “H. pylori-eradicated patients.” In contrast, those with a result < 2.5% in the urea breath test were classified as negative according to the manufacturer’s recommended cutoff value. Patients negative for APCA and with a history of eradication were further classified into two subgroups: patients positive (≥ 10 U/mL) and negative (< 10 U/ml) for H. pylori antibody titer. The former was defined as “present H. pylori infection cases.” The latter individuals with an atrophy grade from C0 to C1, which is regarded as an atrophy score of 0 (negative) in the Kyoto classification37, were defined as “H. pylori-uninfected cases.” The patient group negative for H. pylori antibody (< 10 U/mL) and endoscopic atrophy (≥ C-2) may include those who are H. pylori-infected and those with previous infection-induced atrophic gastritis39. Among these patients, those with at least one positive urea breath, stool antigen, or culture test were classified as “present H. pylori infection cases,” whereas previous infection-induced atrophic gastritis cases were defined when negative results were obtained in urea breath or stool antigen tests, as we reported previously40. If a urea breath or stool antigen test was not performed, individuals with an eradication history and those with endoscopic atrophy (≥ C2) and seronegative results of H. pylori were excluded.H. pylori infection status was defined differently in patients with AIG because of the extreme case bias. Those with at least one positive urea breath, stool antigen, H. pylori antibody titer, or culture test were classified as “present H. pylori infection cases”. The cutoff value for a positive diagnosis in the urea breath test was set at 5% instead of 2.5%41 because false-positive results tend to be obtained in AIG. Patients with an apparent history of successful eradication, confirmed by a negative result in either a urea breath or stool antigen test, were defined as “H. pylori-eradicated patients.” The cutoff value for a negative result in these urea breath tests was strictly 2.5%. It is difficult to differentiate between H. pylori-uninfected individuals and those with a previous infection among patients with AIG; thus, for simplicity, patients other than those with a present infection or history of eradication were defined as H. pylori-uninfected.To evaluate the diagnostic validity and determine the threshold values of the serological tests and endoscopic findings for predicting AIG, an ROC curve analysis was performed.H. pylori antibody titers, and APCA were examined in the enrolled patients. Briefly, serum PG I and PG II levels were measured using a commercial chemiluminescence enzyme immunoassay kit ; H. pylori IgG antibodies were measured using an enzyme immunoassay kit ; and gastrin level was determined with radioimmunoassay , as previously reported36. In patients clinically suspected of having AIG , thyroglobulin antibodies, thyroid microsomal antibodies, serum vitamin B12, and AIFA were additionally measured. APCA and AIFA measurements were outsourced to SRL Co. Ltd. , and thyroglobulin and thyroid microsomal antibody measurements were performed by LSI Medience Co., Ltd. . Anemia was defined as hemoglobin < 13 g/dL (men) or 11.4 g/dL (women); vitamin B12 level < 233 pg/mL was considered low; and pernicious anemia was defined as vitamin B12 < 233 pg/mL, mean corpuscular volume (MCV) > 80 fL, and hemoglobin < 13 g/dL (men) or 11.4 g/dL (women)17. Hashimoto’s disease was defined as positivity for thyroglobulin antibodies or thyroid microsomal antibodies. APCA and AIFA were analyzed using a fluorescent antibody test and chemiluminescence enzyme immunoassay, respectively. APCA was considered positive when fluorescence was produced at a dilution of tenfold or more according to the manufacturer’s instruction. Although there is limited information on the sensitivity of APCA, a study reported that 33.59% of APCA-positive cases were diagnosed as AIG7.Fasting serum samples (after an overnight fast) were collected before endoscopy. PG, gastrin, 14: (1) oxyntic mucosal atrophy, (2) pseudo-pyloric and intestinal metaplasia, (3) diffuse lymphocytic cell infiltration, (4) proportion of gastric pits/duct in the gastric mucosa (> 1.0 or none), and (5) enterochromaffin-like cell hyperplasia. Typical histological findings are shown in Fig. Patients positive for either APCA or AIFA with available gastric corpus biopsies were histologically evaluated by an experienced pathologist (AS) who was blinded to the patients’ endoscopic and serological information and medical charts. Biopsy specimens were fixed with buffered formalin and stained using hematoxylin and eosin. The following five findings were evaluated to diagnose AIG based on previous reportsaplasia,  diffuse 17, the following five endoscopic findings considered specific for AIG were evaluated individually: (1) endoscopic atrophic grade, (2) characteristic corpus-predominant atrophic pattern , (3) disappearance of the fold in the greater curvature of the gastric body in the sufflation state, (4) presence of sticky adherent dense mucous, and (5) hyperplastic polyps. Sticky adherent dense mucous has a denser, creamy white-yellowish color and firmly adheres to the mucosa, as defined by Terao et al.17. The endoscopic atrophic grade was defined according to the Kimura–Takemoto classification42, which categorized gastric mucosal atrophy into closed (C1–3) and open types (O1–3). We added “O4” for severe endoscopic atrophic corpus gastritis, which was defined as marked vascular visibility observed not only on the lesser curvature but also on the whole greater curvature of the corpus. This is included in the O3 category of the Kimura–Takemoto classification and is similar to the definition provided by Terao et al.17; however, it was not associated with the disappearance of the fold according to our definition. Figures Upper gastrointestinal endoscopy was performed using an Olympus Elite system and Olympus electronic panendoscopes, including the GIF-HQ290 or GIF-HQ290Z . Based on previous reportsn state,  presencen state,  presencen state,  presencen state,  presencen state,  presencen state,  presencen state,  presencen state,  presencen state,  presencen state,  presencen state,  presencen state,  presencen state,  presenceThree experienced endoscopists , blinded to the clinical, serological, and histological status of the patients, independently evaluated the five endoscopic images and determined the final endoscopic findings by consensus.U test was used to determine the significance of the differences between patients with and without AIG. The χ2 test or Fisher’s exact test was performed to analyze categorical variables. Interobserver agreement between the diagnosis of endoscopic findings was analyzed using Kappa values. The strength of agreement was determined based on the guidelines by Landis and Koch43, and ≥ 0.6 was considered suitable. AUROC values were used to identify the optimal cutoff value. Comparison of AUROC values was performed using the Delong test. Sensitivities, specificities, positive predictive values, negative predictive values and overall accuracy were also calculated. All statistical analyses were performed using SPSS  and EZR 44, and a two-sided P < 0.05 was considered statistically significant.Serum gastrin and PG values are presented as medians (IQR), and statistical analyses were performed using nonparametric tests. The Mann–Whitney Supplementary Tables.


The significance of renal arteriosclerosis in the prediction of the renal outcomes of diabetic kidney disease (DKD) remains undetermined.We enrolled 174 patients with DKD from three centres from January 2010 to July 2017. The severity and extent of arteriosclerosis were analysed on sections based on dual immunohistochemical staining of CD31 and α-smooth muscle actin. An X-tile plot was used to determine the optimal cut-off value. The primary endpoint was renal survival (RS), defined as the duration from renal biopsy to end-stage renal disease or death.2, and the average 24-h urine protein was 4.52 (2.45 ~ 7.66) g/24 h. The number of glomeruli in the biopsy specimens was 21.07 ± 9.7. The proportion of severe arteriosclerosis in the kidney positively correlated with the Renal Pathology Society glomerular classification , interstitial fibrosis and tubular atrophy (IFTA) , urine protein , systolic BP , and age  and significantly negatively correlated with baseline eGFR . In the multivariable model, the primary outcomes were significantly correlated with glomerular class , IFTA  and the modified arteriosclerosis score . After risk adjustment, RS was independently associated with the baseline eGFR , urine proteinuria  and the modified arteriosclerosis score , and the nomogram exhibited good calibration and acceptable discrimination .The baseline estimated glomerular filtration rate (eGFR) of 135 qualified patients was 45 (29 ~ 70) ml/min per 1.73 mThe severity and proportion of arteriosclerosis may be helpful prognostic indicators for DKD.The online version contains supplementary material available at 10.1186/s12882-021-02492-x. Diabetic kidney disease (DKD) is the most common complication in patients exposed to long-term hyperglycaemia . In ChinIn 2010, the Research Committee of the Renal Pathology Society (RPS) developed a pathologic classification system of diabetic nephropathy . HoweverDKD is a common vascular complication of diabetes. Renal ischaemia and endothelial injury play important roles in the pathological processes that promote renal fibrosis and CKD –19. AlthIn the current study, we hypothesized that the proportion of damaged arteries to all arteries in the tissue may contribute to the prognosis of DKD. To validate the significance of renal artery damage in the prediction of renal outcomes of DKD, we employed dual immunoperoxidase staining to better identify arteries with or without lesions and developed a modified arteriosclerosis score for the severity and proportion of all counted arteries. Nomograms were then used to predict the risks of DKD with all clinical characteristics as well as the pathological score –22.This was a multi-centre, retrospective study of patients with DKD diagnosed by renal pathology. Patients were enrolled between January 2010 and July 2017 from three hospitals . Of the 174 patient-included cohorts, 135 patients were eventually enrolled. The exclusion criteria included patients with DKD coincident with other patterns of kidney injury and inadequate renal tissue samples  .All demographic and clinical data were carefully documented from electronic medical clinical records of three hospitals. Demographics included age at the time of biopsy and sex. Clinical parameters collected included body mass index (BMI), blood pressure, hypertension, diabetic retinopathy (DR), diabetes duration, smoking, glycosylated haemoglobin (HbA1c) level, total cholesterol (Chol) level, serum albumin (ALB) level, urine protein (UPRO) level, eGFR, follow-up time, and follow-up serum creatinine (sCr) level. Hypertension was considered in patients with systolic blood pressure greater than 140 mmHg, diastolic blood pressure greater than 90 mmHg or antihypertensive drug administration. DR was defined as the presence of any characteristic lesion as described by the International Clinical Diabetic Retinopathy Disease Severity Scale, which is a grading standard designed according to the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). Hyperuricaemia was defined as serum uric acid ≥420 μmol/L in males or ≥ 360 μmol/L in females. Urinary protein was expressed in g per 24 h. The eGFR was estimated using the creatinine-based Chronic Kidney Disease Epidemiology Collaboration equation .The clinical outcomes were considered to evaluate the predictive value of renal pathology variables, ESRD , or all-cause death. The follow-up time was defined as the duration from renal biopsy to ESRD or all-cause death , 25, theAll renal biopsies were performed and processed by standard techniques , 25. TheGlomerular lesions and interstitial lesions were scored according to the DKD pathologic classification issued by RPS , 25. ForTo assess the proportion of all involved arteries distributed in the tissues, severe arteriosclerosis, which was defined as arteries with thickening exceeding the intima thickness, to all arteries in sections was calculated. Since the proportion of severe arteriosclerosis was a continuous variable, X-tile software was used to find the best cut-off value and convert it to hierarchical data , 28. EveWithout knowledge of the clinical outcomes, two experienced nephropathologists (Qifeng Jiang and Yifan Zhang) were assigned to independently evaluate and score light microscopy slides. Pathological scoring disagreements were resolved by consensus.Student’s t-test between groups, one-way analysis of variance (ANOVA) in multiple groups, or Pearson’s test for correlation analysis. Nonparametric variables are presented as the medians and interquartile ranges (IQR) and were analysed with the Mann–Whitney test between groups, Kruskal–Wallis test in multiple groups, or Spearman rank correlation test. Categorical variables were expressed as percentages and compared using the Pearson χ2 test.Variables with a normal distribution are presented as the means and standard deviations and were subjected to unpaired Kaplan-Meier (KM) survival curves with log-rank tests and the Cox proportional hazards model to identify the potential association between clinical and pathologic variables and outcomes. Variables with a significance of P < 0.1 in the univariate models were included in the multivariable models [P < 0.1 in the univariate models. The second multivariable model  included only those pathological variables significant to P < 0.1 in the univariate models. The “Fully Risk-Adjustment Model” incorporated clinical variables significant at P < 0.05 in the clinical model, as well as pathological variables significant at P < 0.05 in the pathological model. Then, the AUCs of different risk variables and two models in predicting RS were estimated using time-dependent receiver operating curves (ROCs).The modified arteriosclerosis score cut-off value was analysed using the X-tile plot . Survivae models . Three mTo estimate median and individual postdiagnosis renal survival probabilities at 1, 3, and 5 years, a nomogram was constructed based on the “Fully Risk-Adjustment Model” . ValidatP-value < 0.05 considered statistically significant. All statistical analyses were performed using X-tile software version 3.6.1 (http://tissuearray.org), GraphPad Prism 7 software (GraphPad Software) or R version 3.6.3 .All tests used were two-sided, with a Of 174 patients with biopsy-proven DKD, 37 patients were excluded due to coincidence with other kidney diseases, and 2 patients were excluded due to inadequate tissue samples. Finally, 135 patients were enrolled in this study. The mean number of glomeruli for each biopsy specimen was 21.07 ± 9.7. During the 21-month follow-up  , 10 pati2. The median duration of diabetes was 7 (3–11) years, with HbA1c of 7.72 ± 3.88%, SBP of 157.12 ± 25.92 mmHg, and total cholesterol of 5.89 (4.9–6.81) mmol/L. The median urine protein at enrolment was 4.52 (2.45–7.66) g/24 h, with a median baseline eGFR of 45 (29–70) ml/min per 1.73 m2.The baseline clinical data of 135 DKD patients are listed in Table The pathological characteristics of the patients are tabulated in Table r = 0.28, P<0.012) and IFTA   but significantly positively correlated with urine protein , SBP , and age . Univariable and multivariable Cox regression analyses were used to explore the association between clinical characteristics and renal survival (ESRD or death). Only clinical variables that showed significance in the univariate analysis (P < 0.1) were included in the multivariable clinical model. The only clinical variables to remain significant in the multivariable clinical model were baseline eGFR, urine proteinuria and albumin , IFTA , arteriosclerosis score  and modified arteriosclerosis score  were correlated with shorter RS time in DKD patients.As shown in Table P < 0.05 in univariate analysis were also used to construct two multivariable models. In the pathological model, only RPS glomerular class and IFTA were statistically significant if RPS glomerular class , IFTA  or arteriosclerosis scores  were included. However, if the modified arteriosclerosis score  was used instead of the arteriosclerosis score in the model, all three variables were statistically significant. In the second multivariable model, clinical features  and RPS glomerular class, IFTA or modified arteriosclerosis score were included. The full risk-adjustment model showed that only baseline eGFR , urine proteinuria  and modified arteriosclerosis score  were independently associated with RS. The forest plot in Fig. Pathological variables with Figures A prognostic nomogram for 1-, 3-, and 5-year RS was established Fig. a. BaseliIn terms of discrimination, the C-index for renal survival was 0.82 (95% CI: 0.75–0.87). The calibration curve for the probability of survival at 1, 3 or 5 years after biopsy showed optimal agreement between the prediction by the nomogram and the actual observation  and provided a prognostic nomogram and score . As a toOur study has multiple strengths. The main strength of our study is that we illustrated the modified arteriosclerosis score vascular lesion as an independent marker of time to diabetic ESRD with a modified definition. Our method could identify DKD patients with a worse prognosis. Furthermore, the new immunohistochemical method we performed showed more comprehensive characteristics of vascular lesions than conventional staining, which may be used as a reference for the pathological score of DKD in the future. Third, our study was constructed in the framework of a multicentre cohort study with a broad spectrum of parameters available at diagnosis. Multicentre studies can better represent real-world heterogeneity and are more generalizable than single-centre studies. Moreover, we created a nomogram for DKD patients to help nephrologists make clinical decisions. Nomograms have the ability to generate an individual probability of a clinical event by integrating diverse prognostic and determinant variables, which meets our desire for biologically and clinically integrated models and fulfils our drive towards personalized medicine. Finally, the blinded evaluation of renal biopsy is another strength of this study.Despite these strengths, some limitations must be considered when interpreting our findings. First, it was a retrospective study. However, all end points were based on objectively measured laboratory values that reduced the chance for bias. Second, it was a small sample size. Therefore, our findings are hypothetical and need to be reexamined with a larger data set. Third, we did not evaluate the therapeutic interventions during follow-up, which may have had miscellaneous impacts on renal prognosis. Finally, histologic changes were assessed based on a simple classification, but diabetic glomerulopathy is far more complicated.In conclusion, we present here a novel renal survival prediction model based on three key independent prognostic factors. Other studies are required to determine whether the modified arteriosclerosis score can be applied as a novel, independent marker of time to ESRD for DKD patients. The prognostic nomogram and the score proposed may help offer the opportunity to define risk-adapted strategies for DKD management in the future.Additional file 1: Figure S1. Time-dependent ROC of different risk factors for RS at 24 months of follow-up. Abbreviations: AUC, area under curve; CI, confidence interval; eGFR, estimated glomerular filtration rate; IFTA, interstitial fibrosis and tubular atrophy; MAS, modified arteriosclerosis score; UPRO, urine protein.Additional file 2: Figure S2. Time-dependent ROC of different models for RS at 24 months of follow-up.