Prospective Nested Case Control Study Research Articles

Risk factors of chronic endometritis in women who have undergone hysteroscopy: a prospective nested case–control study

There is limited research on risk factors for chronic endometritis regarding reproductive history and clinical symptoms. Thus, this nested case–control study identified risk factors for chronic endometritis in women who have undergone hysteroscopy. Endometrial tissue sections were obtained from 502 women with intrauterine disorders who underwent hysteroscopy. Chronic endometritis was diagnosed via CD138 immunostaining. The women were divided into two groups: 271 women without chronic endometritis and 231 women with chronic endometritis. The prevalence of chronic endometritis was 46%. Univariate logistic regression revealed that prolonged menstruation and intermenstrual bleeding were associated with chronic endometritis, and subsequent multivariate logistic regression analyses showed that these were further independently associated. With univariable logistic regression, the gravidity and abortion history were correlated with chronic endometritis; however, no significant correlation was found with the adjusted odds ratio (OR) of 0.74 (95% confidence interval [CI] 0.46–1.19) or 0.76 (95% CI 0.58–1.11), respectively. No significant correlation was found between caesarean section history and the rates of chronic endometritis. No significant difference was found in all other variables between the three groups with > 5, ≤ 5 plasma cells and in a unknown group. Prolonged menstruation and intermenstrual bleeding were risk factors associated with chronic endometritis. Chronic endometritis should be considered and CD138 immunohistochemical examination should be recommended in women with these symptoms.

Association of circulating long-chain free fatty acids and incident diabetes risk among normoglycemic Chinese adults: a prospective nested case–control study

BackgroundLong-chain free fatty acids (FFAs) are associated with risk of incident diabetes. However, a comprehensive assessment of the associations in normoglycemic populations is lacking. ObjectivesOur study aimed to comprehensively investigate the prospective associations and patterns of FFA profiles with diabetes risk among normoglycemic Chinese adults. MethodsThis is a prospective nested case–control study from the China Cardiometabolic Disease and Cancer Cohort (4C) study. We quantitatively measured 53 serum FFAs using a targeted metabolomics approach in 1707 incident diabetes subjects and 1707 propensity score–matched normoglycemic controls. Conditional logistic regression models were employed to estimate odds ratios (ORs) for associations. Least Absolute Shrinkage and Selection Operator (LASSO) penalty regression and quantile g-computation (qg-comp) analyses were implemented to estimate the association between multi-FFA exposures and incident diabetes. ResultsThe majority of odd-chain FFAs exhibited an inverse association with incident diabetes, wherein the ORs per SD increment of all 7 saturated fatty acids (SFAs), monounsaturated fatty acid (MUFA) 15:1, and polyunsaturated fatty acid (PUFA) 25:2 were ranging from 0.79 to 0.88 (95% CIs ranging between 0.71 and 0.97). Even-chain FFAs comprised 99.3% of total FFAs and displayed heterogeneity with incident diabetes. SFAs with 18–26 carbon atoms are inversely linked to incident diabetes, with ORs ranging from 0.81 to 0.86 (95% CIs ranging between 0.73 and 0.94). MUFAs 26:1 (OR: 0.85; 95% CI: 0.76, 0.94), PUFAs 20:4 (OR: 0.84; 95% CI: 0.75, 0.94), and 24:2 (OR: 0.87; 95% CI: 0.78, 0.97) demonstrated significant associations. In multi-FFA exposure model, 24 FFAs were significantly associated with incident diabetes, most of which were consistent with univariate results. The mixture OR was 0.78 (95% CI: 0.61, 0.99; P = 0.04159). Differential correlation network analysis revealed pre-existing perturbations in intraclass and interclass FFA coregulation before diabetes onset. ConclusionsThese findings underscore the variations in diabetes risk associated with FFAs across chain length and unsaturation degree, highlighting the importance of recognizing FFA subtypes in the pathogenesis of diabetes.

Associations of maternal exposure to multiple plasma metals with the risk of fetal congenital heart defects: a prospective nested case-control study

Abstract Background Congenital heart defects (CHDs) are the most common congenital anomalies with complex etiologies. There is knowledge gap with respect to the association between single and combined exposures to multiple heavy metals during pregnancy and the risk of CHDs in the fetus. Thus, we aimed to examine the association between maternal plasma heavy metal concentrations in mid-pregnancy and the risk of CHDs in the fetus. Methods A prospective nested case-control study was conducted in a cohort of 11,578 newborns. Exposure odds ratios (ORs) were compared between 164 CHD cases and 164 non-malformed controls delivered at the same hospital, individually matched by maternal age (±5 years) and parity. Concentrations of 21 metals were determined in maternal peripheral blood plasma via an ultra-performance liquid chromatography inductively coupled to mass spectrometry (ICP-MS). Single- and multiple-metal logistic regressions, the adaptive least absolute shrinkage and selection operator (LASSO) penalized regression analysis and restricted cubic spline (RCS) analysis were applied to explore the associations and dose-response relationships of plasma metals with CHD. We also applied Bayesian Kernel Machine Regression (BKMR) model to evaluate the cumulative effect of the exposure metals. Results Median (interquartile range, IQR) Vanadium (V) [0.3 (0.3-0.4) vs. 0.3 (0.3-0.4) μg/L, P = 0.027] and cadmium (Cd) [0.1 (0.0-0.1) vs. 0.1 (0.0-0.1) μg/L, P = 0.036] levels were different between the CHDs and control groups. Compared with the first quartile, the Directed acyclic graph(DAG) model-adjusted ORs (95% CI) were 3.12 (1.72-5.64) for kalium (K), 2.21 (1.23-3.94) for manganese (Mn), 0.55 (0.33-0.94) for cerium (Ce), 1.96 (1.06-3.64) for lead (Pb) in the second quartile, and ORs (95%CIs) were 1.88 (1.08-3.26) for V, 0.53 (0.30-0.93) for Cr, 1.92 (1.10-3.35) for copper (Cu), 2.09 (1.18-3.70) for Cd, 2.14 (1.24-3.70) for stannum (Sn) and 3.05 (1.69-5.49) for Pb in the third quartile. In the multi-metal model, compared to the lowest quartile, the ORs for Sn and Pb in the second quartile were 1.32 (95% CI: 0.69-2.55) and 1.94 (95% CI: 0.98-3.84), respectively, and the ORs for both metals in the third quartiles were 2.15 (95% CI: 1.16-3.98) and 3.32 (OR=0.66, 95% CI: 1.68-6.55), suggesting that Sn and Pb had relatively stable positive results with a linear dose progression. BKMR models with 2 cluster for 9 metals showed that the overall effect of metal mixture was not statistically significant at or below 35th percentile and at or above the 70th percentile, compared to their median levels. Pb was the major contributor to the combined effect. Conclusions Elevated level of plasma plumbum was associated with increased risk of CHDs. Further investigations in larger perspective cohorts are needed to confirm our findings.fig 1fig 2

Longitudinal changes of oxidative stress and PON1 lactonase activity and status in older pregnant women undergoing assisted reproductive technology: a prospective nested case-control study

BackgroundChildbearing in women with advanced maternal age (AMA) has increased the need for artificial reproductive technology (ART). ART and oxidative stress are associated with many pregnancy complications. Paraoxonase (PON) 1 is one of the key components responsible for antioxidative activity in high-density lipoprotein (HDL). This study aimed to investigate the longitudinal changes of oxidative stress and PON1 lactonase activity and status in older women undergoing ART.MethodsThis prospective nested case-control study included 129 control and 64 ART women. Blood samples were obtained respectively at different stages of pregnancy. PON1 level and lactonase activity were assessed using 7-O-diethylphosphoryl-3-cyano-4-methyl-7-hydroxycoumarin (DEPCyMC) and 5-thiobutyl butyrolactone (TBBL) as a substrate, respectively. A normalized lactonase activity (NLA) was estimated based on the ratio of TBBLase to DEPCyMCase activity. Serum total oxidant status (TOS), total antioxidant capacity (TAC), malondialdehyde (MDA), homocysteine (HCY), PON1 C-108T and Q192R genetic polymorphisms, and metabolic parameters were analyzed.ResultsLactonase activity and level of PON1 gradually decreased with pregnancy progression, while glycolipid metabolism parameters and TAC levels increased with pregnancy progression or significantly raised during the 2nd and 3rd trimesters, and NLA of PON1, TOS, OSI, MDA, and HCY significantly increased before delivery in the ART and control groups. Compared with the control women, the ART women had substantially higher or relatively high lactonase activity and NLA of PON1 and TAC during pregnancy; higher triglyceride (TG), total cholesterol, low-density lipoprotein cholesterol, atherogenic index, apolipoprotein (apo) B, and apoB/apoA1 ratio in the 1st trimester; and higher fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance, and TG levels before delivery. No significant differences were found in the frequencies of PON1 C-108T and Q192R genotypes and alleles between the ART and control groups.ConclusionsWomen with AMA undergoing ART had higher TAC, PON1 lactonase activity, and PON1 NLA than control women, suggesting increased compensatory antioxidant capacity in ART women, thus showing higher sensitivity to oxidative stress-related injury and diseases.

A combined clinical and specific genes’ model to predict live birth for in vitro fertilization and embryo transfer patients

BackgroundWe aimed to develop an accurate model to predict live birth for patients receiving in vitro fertilization and embryo transfer (IVF-ET) treatment.MethodsThis is a prospective nested case–control study. Women aged between 18 and 38 years, whose body mass index (BMI) were between the range of 18.5–24 kg/m2, who had an endometrium of ≥ 8 mm at the thickest were enrolled from 2018/9 to 2020/8. All patients received IVF-ET treatment and were followed up until Jan. 2022 when they had reproductive outcomes. Endometrial samples during the window of implantation (LH + 6 to 9 days) were subjected to analyze specific endometrial receptivity genes’ expression using real-time PCR (RT-PCR). Patients were divided into live birth group and non-live birth group based on IVF-ET outcomes. Clinical signatures relevant to live birth were collected, analyzed, and used to establish a predictive model for live birth by univariate analysis (clinical model). Specific endometrial receptivity genes’ expression was analyzed, selected, and used to construct a predictive model for live birth by The Least Absolute Shrinkage and Selection Operator (LASSO) analysis (gene model). Finally, significant clinical factors and genes were used to construct a combined model for predicting live birth using multivariate logistical regression (combined model). Different models’ Area Under Curve (AUC) were compared to identify the most predictive model.ResultsThirty-nine patients were enrolled in the study, twenty-four patients had live births, fifteen did not. In univariate analysis, the odds of live birth for women with ovulation dysfunction was 4 times higher than that for women with other IVF-ET indications (OR = 4.0, 95% CI: 1.125 − 8.910, P = 0.018). Age, body mass index, duration of infertility, primary infertility, repeated implantation failure, antral follicle counting, ovarian sensitivity index, anti-Mullerian hormone, controlled ovarian hyperstimulation protocol and duration, total dose of FSH/hMG, number of oocytes retrieved, regiment of endometrial preparation, endometrium thickness before embryo transfer, type of embryo transferred were not associated with live birth (P > 0.05). Only ovulation dysfunction was used to construct the clinical model and its AUC was 0.688. In lasso analysis, GAST, GPX3, THBS2 were found to promote the risk of live birth. AUCs for GAST, GPX3, THBS2 reached to 0.736, 0.672, and 0.678, respectively. The gene model was established based on these three genes and its AUC was 0.772. Ovulation dysfunction, GAST, GPX3, and THBS2 were finally used to construct the combined model, reaching the highest AUC (AUC = 0.842).ConclusionsCompared to the single model, the combined model of clinical (Ovulation dysfunction) and specific genes (GAST, GPX3, THBS2) was more accurate to predict live birth for IVF-ET patients.

Hypomethylation of ABCG1 in peripheral blood as a potential marker for the detection of coronary heart disease

BackgroundNovel molecular biomarkers for the risk assessment and early detection of coronary heart disease (CHD) are urgently needed for disease prevention. Altered methylation of ATP-binding cassette subfamily G member 1 (ABCG1) has been implicated in CHD but was mostly studied in Caucasians. Exploring the potential relationship between ABCG1 methylation in blood and CHD among the Chinese population would yield valuable insights.MethodsPeripheral blood samples were obtained from a case–control study (287 CHD patients vs. 277 controls) and a prospective nested case–control study (171 CHD patients and 197 matched controls). DNA extraction and bisulfite-specific PCR amplification techniques were employed for sample processing. Quantitative assessment of methylation levels was conducted using mass spectrometry. Statistical analyses involved the utilization of logistic regression and nonparametric tests.ResultsWe found hypomethylation of ABCG1 in whole blood was associated with the risk of CHD in both studies, which was enhanced in heart failure (HF) patients, female and younger subjects. When combined with baseline characteristics, altered ABCG1 methylation showed improved predictive effect for differentiating CHD cases, ischemic cardiomyopathy (ICM) cases, younger than 60 years CHD cases, and female CHD cases from healthy controls (area under the curve (AUC) = 0.68, 0.71, 0.74, and 0.73, respectively).ConclusionsWe demonstrated a robust link between ABCG1 hypomethylation in whole blood and CHD risk in the Chinese population and provided novel evidence indicating that aberrant ABCG1 methylation in peripheral blood can serve as an early detection biomarker for CHD patients.

Screening of placenta accreta spectrum disorder using maternal serum biomarkers and clinical indicators: a case–control study

BackgroundPlacenta accreta spectrum (PAS) disorder is a major cause of postpartum hemorrhage-associated maternal and fetal death, and novel methods for PAS screening are urgently needed for clinical application.MethodsThe purpose of this study was to develop new methods for PAS screening using serum biomarkers and clinical indicators. A total of 95 PAS cases and 137 controls were enrolled in a case–control study as cohort one, and 44 PAS cases and 35 controls in a prospective nested case–control study were enrolled as cohort two. All subjects were pregnant women of Chinese Han population. Biomarkers for PAS from maternal blood samples were screened based on high-throughput immunoassay and were further validated in three phases of cohort one. Screening models for PAS were generated using maternal serum biomarkers and clinical indicators, and were validated in two cohorts. The expression levels of biomarkers were analyzed using histopathological and immunohistochemical (IHC) techniques, and gene expression was examined by QPCR in the human placenta. Binary logistic regression models were built, and the area under the curve (AUC), sensitivity, specificity, and Youden index were calculated. Statistical analyses and model building were performed in SPSS and graphs were generated in GraphPad Prism. The independent-sample t test was used to compare numerical data between two groups. For nonparametric variables, a Mann–Whitney U test or a X2 test was used.ResultsThe results demonstrated that the serum levels of matrix metalloproteinase-1 (MMP-1), epidermal growth factor (EGF), and vascular endothelial growth factor-A (VEGF-A) were consistently higher, while the level of tissue-type plasminogen activator (tPA) was significantly lower in PAS patients compared with normal term controls and patients with pre-eclampsia (PE) and placenta previa (PP). IHC and QPCR analysis confirmed that the expression of the identified biomarkers significantly changed during the third trimester in human placenta. The generated screening model combining serum biomarkers and clinical indicators detected 87% of PAS cases with AUC of 0.94.ConclusionsSerum biomarkers can be used for PAS screening with low expense and high clinical performance; therefore, it may help to develop a practicable method for clinical prenatal PAS screening.

The relationship between neuron-specific enolase, high sensitivity C reactive protein, and diabetic peripheral neuropathy in Chinese patients with type 2 diabetes: A prospective nested case–control analysis

BackgroundDiabetic peripheral neuropathy (DPN) involves a very complex pathogenesis, and there is no neuro-specific marker for risk prediction. Neuron-specific enolase (NSE), a key enzyme in glycolysis, has a broad spectrum neurotrophic and neuroprotective effect on neurons, and also cause injury and inflammatory response of peripheral nerves. The relationship between neuron-specific enolase, highly sensitive c-reactive protein (hsCRP), and diabetic peripheral neuropathy remains unclear. We aimed to investigate whether elevated serum NSE and hsCRP levels increased the risk of DPN in patients with type 2 diabetes.Materials and methodsIn this prospective nested case–control study, a total of 1072 eligible subjects with type 2 diabetes constituted the follow-up cohort. Demographic data and parameters including serum NSE and hsCRP were collected at baseline. Two neuropathy screening scales (MNSI and MDNS) were used to assess DPN during follow-up period. Nerve conduction studies were performed at the end of follow-up. Conditional logistic regression was used to inspect the risk factors of the incidence of DPN.ResultsDuring an average follow-up period of 5.1 years, 176 subjects developed DPN. Serum NSE and hsCRP levels at baseline were significantly higher in DPN group than in matched non-DPN groups (p < 0.001). NSE was positively correlated with age and hsCRP (p < 0.001). The amplitude of sensory nerve action potential and compound muscle action potential of the lower extremity nerves were significantly decreased in the high tertile of NSE. After adjustment for matching and confusing factor, conditional logistic regression showed the risk of DPN in the high tertile of NSE level was still 3.176 times higher than that in the low tertile of NSE level (p < 0.001).ConclusionElevated serum NSE levels predicted the high incidence of DPN in Chinese patients with type 2 diabetes for an average of 5.1 years, which may be associated with increased neuroinflammatory response caused by high NSE levels, but further studies are needed.

Clinical and economic impact of adverse drug reactions in hospitalised patients: prospective matched nested case–control study in Ethiopia

ObjectivesThe purpose of this study was to assess the clinical and economic impact of adverse drug reactions (ADRs) among patients admitted to the University of Gondar Comprehensive Specialized Hospital (UoGCSH).Design...

Effectiveness of antenatal dexamethasone in reducing respiratory distress syndrome and mortality in preterm neonates: a nested case control study

BackgroundRespiratory distress syndrome (RDS) is a significant cause of preterm neonatal morbidity and mortality globally. Measures like the use of antenatal corticosteroids (ACS) and immediate resuscitation of the newborn after birth are taken to abate preterm related complications. Most studies that evidenced the benefit of ACS were done in high resource settings. Therefore, this study was conducted to assess the effectiveness of ACS in reducing RDS and neonatal mortality in preterm neonates in resource-limited settings.MethodsA three months prospective nested case–control study (1:2 unmatched) was conducted at Muhimbili National Hospital and Amana regional referral hospital in Dar es salaam, Tanzania. Neonates delivered at 28 to 34 gestational weeks were enrolled and followed up until discharge. Data analysis was done using the statistical package of social sciences version 23. Logistic regression analysis was used to determine the effect of ACS on the RDS and mortality in the cohort, controlling for important maternal and neonatal variables. All tests were considered statistically significant at p < 0.05.ResultsOut of 330 preterm neonates enrolled, 110 were cases and 220 were controls. The median gestational age at delivery was 30 weeks and 6 days (IQR 4.68) among cases and 33 weeks (IQR 3) among controls. One-minute APGAR score of < 7 (AOR: 3.11; 95% CI 1.54–6.30), and neonatal birth weight (AOR: 0.998; 95% CI 0.997–0.999) were significantly associated with RDS. No significant association was observed between ACS exposure and RDS occurrence (AOR: 1.65; 95% CI 0.86 – 3.15). The overall mortality rate was 9 per 1000 neonates. Neonatal mortality occurred only among cases whereby, a unit increase in gestational age was associated with a 30% reduction in neonatal mortality (Adjusted hazard ratio, AHR: 0.70, 95% CI: 0.5–0.92, p = 0.011).ConclusionDecrease in gestational age, one minute APGAR score of < 7 and decreasing birth weight were associated with RDS among preterm neonates. ACS was not associated with reduced RDS occurrence and neonatal mortality rates. Moreover, increase in gestation age was the only factor found to be protective against preterm neonatal mortality.

Development and validation of a prediction model for intrapartum cesarean delivery based on the artificial neural networks approach: a protocol for a prospective nested case–control study

IntroductionAlthough intrapartum caesarean delivery can resolve dystocia, it would still lead to several adverse outcomes for mothers and children. The obstetric care professionals need effective tools that can help them...

Serum microcystin-LR levels and risk of gestational diabetes mellitus: A Chinese nested case-control study.

Previous experimental studies have reported an association between microcystin-LR (MC-LR) and glucose homeostasis, but whether exposure to MC-LR is a risk factor for the pathogenesis of gestational diabetes mellitus (GDM) requires further epidemiological study. This study aims to explore the effects of MC-LR on GDM. A prospective nested case-control study was performed in the Hunan Provincial Maternal and Child Health Hospital (HPMCHH) in South China. A total of 119 patients with GDM and 238 controls were enrolled in the study. The two independent samples t-test, or chi-square test was used to compare the difference between the GDM group and the non-GDM group. Binary logistic regression was used to obtain odds ratios (ORs) by controlling for confounders. The cumulative incidence of GDM in our sample was 13.7%. The detection rate of MC-LR in the GDM group were significantly higher than those in the control group (44.2% vs. 29.4%; p=0.007). Our results show that an elevated serum MC-LR level in the first trimester of pregnancy was related to an increased risk of GDM (OR: 1.924; 95% CI: 1.092-3.391; p<0.05). When stratified by age, educational level, parity, and passive smoking, significantly relationships were observed among those aged >30 years, lower income, higher education, none passive smoking, and more likely to be multiparous. Our data reveals that serum MC-LR level in the first trimester is independently associated with GDM.

U-Net deep learning model for endoscopic diagnosis of chronic atrophic gastritis and operative link for gastritis assessment staging: a prospective nested case–control study

Background: The operative link for the gastritis assessment (OLGA) system can objectively reflect the stratification of gastric cancer risk in patients with chronic atrophic gastritis (CAG). Objectives: We developed a real-time video monitoring model for the endoscopic diagnosis of CAG and OLGA staging based on U-Net deep learning (DL). To further validate and improve its performance, we designed a study to evaluate the diagnostic evaluation indices. Design: A prospective nested case–control study Methods: Our cohort consisted of 1306 patients from 31 July 2021 to 31 January 2022. According to the pathological results, patients in the cohort were divided into the CAG group and the chronic non-atrophic gastritis group to evaluate the diagnostic evaluation indices. Each atrophy lesion was automatically labeled and the atrophy severity was assessed by the model. Propensity score matching was used to minimize selection bias. Results: The diagnostic evaluation indices and the consistency between OLGA staging and pathological diagnosis of the model were superior to those of endoscopists [sensitivity (89.31% versus 67.56%), specificity (90.46% versus 70.23%), positive predictive value (90.35% versus 69.41%), negative predictive value (89.43% versus 68.40%), accuracy rate (89.89% versus 68.89%), Youden index (79.77% versus 37.79%), odd product (79.23 versus 4.91), positive likelihood ratio (9.36 versus 2.27), negative likelihood ratio (0.12 versus 0.46)], areas under the curves (AUC) (95% CI) (0.919 (0.893–0.945) versus 0.749 (0.707–0.792), p &lt; 0.001) and kappa (0.816 versus 0.291)]. Conclusion: Our study demonstrated that the DL model can assist endoscopists in real-time diagnosis of CAG during gastroscopy and synchronous identification of high-risk OLGA stage (OLGA stages III and IV) patients. Trial registration: ChiCTR2100044458.

HTRA1 methylation in peripheral blood as a potential marker for the preclinical detection of stroke: a case–control study and a prospective nested case–control study

BackgroundStroke is the leading cause of mortality in China. DNA methylation has essential roles in multiple diseases, but its association with stroke was barely studied. We hereby explored the association between blood-based HTRA serine protease 1 (HTRA1) methylation and the risk of stroke.ResultsThe association was discovered in a hospital-based case–control study (cases/controls = 190:190) and further validated in a prospective nested case–control study including 139 cases who developed stroke within 2 years after recruitment and 144 matched stroke-free controls. We observed stroke-related altered HTRA1 methylation and expression in both case–control study and prospective study. This blood-based HTRA1 methylation was associated with stroke independently from the known risk factors and mostly affected the older population. The prospective results further showed that the altered HTRA1 methylation was detectable 2 years before the clinical determination of stroke and became more robust with increased discriminatory power for stroke along with time when combined with other known stroke-related variables [onset time ≤ 1 year: area under the curve (AUC) = 0.76].ConclusionsIn our study, altered HTRA1 methylation was associated with stroke at clinical and preclinical stages and thus may provide a potential biomarker in the blood for the risk evaluation and preclinical detection of stroke.

Leukotriene A4 Hydrolase and Hepatocyte Growth Factor Are Risk Factors of Sudden Cardiac Death Due to First-Ever Myocardial Infarction.

Patients at a high risk for sudden cardiac death (SCD) without previous history of cardiovascular disease remain a challenge to identify. Atherosclerosis and prothrombotic states involve inflammation and non-cardiac tissue damage that may play active roles in SCD development. Therefore, we hypothesized that circulating proteins implicated in inflammation and tissue damage are linked to the future risk of SCD. We conducted a prospective nested case–control study of SCD cases with verified myocardial infarction (N = 224) and matched controls without myocardial infarction (N = 224), aged 60 ± 10 years time and median time to event was 8 years. Protein concentrations (N = 122) were measured using a proximity extension immunoassay. The analyses revealed 14 proteins significantly associated with an increased risk of SCD, from which two remained significant after adjusting for smoking status, systolic blood pressure, BMI, cholesterol, and glucose levels. We identified leukotriene A4 hydrolase (LTA4H, odds ratio 1.80, corrected confidence interval (CIcorr) 1.02–3.17) and hepatocyte growth factor (HGF; odds ratio 1.81, CIcorr 1.06–3.11) as independent risk markers of SCD. Elevated LTA4H may reflect increased systemic and pulmonary neutrophilic inflammatory processes that can contribute to atherosclerotic plaque instability. Increased HGF levels are linked to obesity-related metabolic disturbances that are more prevalent in SCD cases than the controls.

Synergism between the metabolic syndrome components and cancer incidence: results from a prospective nested case–control study based on the China Health and Retirement Longitudinal Study (CHARLS)

ObjectivesSynergism between the metabolic syndrome (MetSyn) components and cancer incidence still remains inconclusive. We aimed to investigate the unique or joint role of MetSyn components in cancer onset.DesignWe conducted a...

Deep learning as a novel method for endoscopic diagnosis of chronic atrophic gastritis: a prospective nested case–control study

Background and aimsChronic atrophic gastritis (CAG) is a precancerous disease that often leads to the development of gastric cancer (GC) and is positively correlated with GC morbidity. However, the sensitivity of the endoscopic diagnosis of CAG is only 42%. Therefore, we developed a real-time video monitoring model for endoscopic diagnosis of CAG based on U-Net deep learning (DL) and conducted a prospective nested case–control study to evaluate the diagnostic evaluation indices of the model and its consistency with pathological diagnosis.MethodsOur cohort consisted of 1539 patients undergoing gastroscopy from December 1, 2020, to July 1, 2021. Based on pathological diagnosis, patients in the cohort were divided into the CAG group or the chronic nonatrophic gastritis (CNAG) group, and we assessed the diagnostic evaluation indices of this model and its consistency with pathological diagnosis after propensity score matching (PSM) to minimize selection bias in the study.ResultsAfter matching, the diagnostic evaluation indices and consistency evaluation of the model were better than those of endoscopists [sensitivity (84.02% vs. 62.72%), specificity (97.04% vs. 81.95%), positive predictive value (96.60% vs. 77.66%), negative predictive value (85.86% vs. 68.73%), accuracy rate (90.53% vs. 72.34%), Youden index (81.06% vs. 44.67%), odd product (172.5 vs. 7.64), positive likelihood ratio (28.39 vs. 3.47), negative likelihood ratio (0.16 vs. 0.45), AUC (95% CI) [0.909 (0.884–0.934) vs. 0.740 (0.702–0.778)] and Kappa (0.852 vs. 0.558)].ConclusionsOur prospective nested case–control study proved that the diagnostic evaluation indices and consistency evaluation of the real-time video monitoring model for endoscopic diagnosis of CAG based on U-Net DL were superior to those of endoscopists.Trial registrationChiCTR2100044458, 18/03/2020.

S231: GLUCOCORTICOID AND GLYCOLYSIS INHIBITORS COOPERATIVELY ABROGATE ACUTE GRAFT-VERSUS-HOST DISEASE

Background: Although glucocorticoids(GCs) are the standard first-line therapy for acute graft-versus-host disease(aGvHD), approximately 50% of aGvHD patients have no response to GCs. The role of T cell metabolism in murine aGvHD has been recently reported. Pharmacological inhibition of glycolysis by targeting 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(PFKFB3) ameliorates aGvHD. However, the question of whether glycolysis is required for the function of activated T cells and whether abnormal glycolysis is involved in the occurrence of human aGvHD need to be elucidated. Moreover, the issue as to whether GCs and metabolism regulators can cooperatively suppress T cell alloreactivity and ameliorate aGvHD remains to be elucidated. Aims: The study aimed to analyse the glucose metabolism profiles of activated T cells in aGvHD patients, and to evaluate the roles of PFKFB3-stimulated glycolysis in alloantigen-activated T cells and aGvHD induction. Furthermore, the study was performed to explore the issue of whether GCs could restore activated T cells by regulating glycolysis and the effect of GCs combined with glycolysis inhibitors on activated T cells. Methods: In this prospective nested case–control study, a total of 15 aGvHD patients at diagnosis and 15 matched non-aGvHD patients. The glucose consumption and lactate production rates were detected by glucose assay kit and lactate assay kit. Subsequently, to assess whether functional T cell activation is caused by the regulation of PFKFB3, we used lentivirus transduction for the genetic regulation of PFKFB3 in vitro and in a humanized xenogeneic aGvHD model. The effect of GCs and glycolysis inhibitors on activated T cells was further explored in vitro and in a humanized murine model of aGvHD and graft versus leukaemia (GVL). In addition, to evaluate the synergistic effect of GCs, 3PO or their combination, combination index (CI) studies were performed by using the Chou-Talalay method for drug interactions. Results: Increased glycolysis, which was characterized by elevated PFKFB3, as well as higher rates of glucose consumption and lactate production in aGvHD T cells. Importantly, in vitro treatment with glycolysis inhibitor 3PO improved the activity of T cells derived from aGvHD patients through down-regulating glycolytic activity of T cells. Genetic upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory T cells. In a humanized mouse model, PFKFB3-overexpressing T cells aggravated aGvHD, as characterized by high aGvHD clinical scores, pathological scores and rapid lethality. Importantly, our integrated data from patient samples in vitro showed that GCs combined with 3PO decreased proinflammatory T cells and T cell proliferation, reduced glucose consumption, lactate production and PFKFB3 expression compared with the single GCs group. Notably, the average CI values of GCs and 3PO were 0.364 for the synergistic inhibition of IFN-γ synthesis and 0.475 for the synergistic inhibition of proliferation, respectively. In a humanized murine model of aGvHD and GVL demonstrated that GCs and 3PO cooperatively reduced the alloreactivity of T cells and ameliorate aGvHD without a loss of GVL effects. Summary/Conclusion: Our data indicated that glycolysis is critical for T cell activation and the induction of human aGvHD. GCs combined with glycolysis inhibitors demonstrated synergistic effects on reducing T cell alloreactivity and ameliorating aGvHD by regulating T cell glycolysis in vitro and in vivo. Thus, GCs combined with glycolysis inhibitors promise to be a novel therapeutic strategy for aGvHD patients.

Predicting Mortality and Use of RISC Scoring System in Hospitalized Under-Five Children Due to WHO Defined Severe Community Acquired Pneumonia

Pneumonia acquired in the community is a leading cause of hospitalization and death in under-five children. Predicting mortality in children remains a challenge. There is a need of consolidated scoring system to predict mortality in under-five children in developing nations. This is a hospital-based prospective nested case-control study, conducted in a tertiary care teaching hospital of north India. Included were under-five hospitalized children due to WHO defined severe community acquired pneumonia (CAP). Those who did not survive were categorized as cases, while those who were discharged were categorized as controls. The mortality rate among the recruited 180 hospitalized children with severe CAP was 9.4%. The mortality in under-five children was higher among infants, children who resided in rural areas and were unimmunized or partially immunized for the present age. Mortality was also statistically significantly higher among under-five children with weight for age and weight for length/height below -2Z score; SpO2 < 90% at room air at admission, cyanosis, convulsion, high C-reactive protein (CRP), blood culture positive sepsis and end point consolidation. These predictors were found to be independent risk factors for the mortality after analyzing in multivariate model while presence of wheeze and exclusive breast feeding for first six months of life were found to be protective. The receiver operating characteristic (ROC) curve for respiratory index of severity in children (RISC) score has area under curve (AUC) 0.91 while AUC of RISC score with King George's Medical University (KGMU) modification has 0.88 for prediction of mortality. At the cut-off level of 3, the sensitivity of the RISC score in predicting mortality was 94.1% while the specificity was 73.6%. However, the sensitivity of the RISC score with KGMU modification in predicting mortality at cut-off level of 3 was 88.4% with a specificity of 74.8%. Various predictors for mortality under-five children are young age, malnutrition, cyanosis, high CRP, blood culture positive sepsis and end point consolidation. It is also possible to predict mortality using RISC score which comprises simple variables and can be easily used at centers of periphery. Similar accuracy had been also found through the use of an age independent modified score (RISC score with KGMU modification).Lay summaryPneumonia is a primary cause of hospitalization as well as death among the children under the age of five. A variety of severity or mortality predicting scores have been produced for adults, but such scores for children are scarce. Furthermore, their utility in developing nations has not been proven. This is a hospital-based prospective study. Included were children under five (2 to 59 months) hospitalized due to severe community acquired pneumonia (CAP) defined as per World Health Organization (WHO) and were not hospitalized in last 14 days elsewhere. Those who did not survive were classified as cases while those who were discharged were classified as controls. A total of 200 consecutively hospitalized children with severe CAP based on WHO were screened and 180 children were recruited. Among recruited children, the percentage of mortality was 9.4% while 90.6% were discharged. The mortality was higher among children younger than 12 months, those belonged to rural area and were unimmunized or partially immunized for the present age. Mortality was also higher among under-five children with severe malnutrition, anemia, SpO2 < 90% at room air at admission, cyanosis, convulsion, thrombocytopenia, high CRP, blood culture positive sepsis and end point consolidation. After assessing in a multivariate model, these predictors were determined to be independent risk factor for death, while wheezing and exclusive breast feeding throughout the first six months of life were found to be protective. The receiver operating characteristic (ROC) curve for respiratory index of severity in children (RISC) score has an area under curve (AUC) of 0.91 while AUC of RISC score with King George's Medical University (KGMU) modification was 0.88 for the prediction of death in under-five children hospitalized due to severe CAP.

IGFBP7 as a preoperative predictor of congestive acute kidney injury after cardiac surgery

ObjectiveCongestive acute kidney injury (c-AKI) refers to AKI in the presence of right ventricular failure (RVF) and is a highly morbid complication of cardiac surgery. However, treatment has traditionally been...